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6,401 | bound to several proteins and has at least two functions: cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre RNA. Defects in RMRP cause CHH by disrupting a function of RMRP RNA that affects multiple organ sys tems. In vitro studies show decreased numbers of T cells and defec tive T cell proliferation because of an intrinsic defect related to the G1 phase, resulting in a longer cell cycle for individual cells. NK cells are increased in number and function. Clinical Manifestations Clinical features include short, pudgy hands; redundant skin; hyperex tensible joints of hands and feet but an inability to extend the elbows completely; and fine, sparse, light hair and eyebrows. Infections range from mild to severe (Fig. 165.5). Associated conditions include defi cient erythrogenesis, Hirschsprung disease, and an increased risk of malignancies. The bones radiographically show scalloping and scle rotic or cystic changes in the metaphysis and flaring of the costochon dral junctions of the ribs. Diagnosis The diagnosis of CHH is suspected by the clinical constellation of skel etal dysplasia and immune deficiency and supporting laboratory find ings. Homozygous or compound heterozygous pathogenic variants in the RMRP gene confirms the diagnosis. Treatment Treatment of CHH is supportive. Some patients have been treated with HSCT, which will correct the T cell immunodeficiency and erythro genesis but will not affect other organ systems. ANHIDROTIC ECTODERMAL DYSPLASIA WITH IMMUNODEFICIENCY Anhidrotic ectodermal dysplasia with immunodeficiency (EDA ID) is a CID characterized by susceptibility to infection, thin sparse hair, abnormal dentition (conical teeth), and absence of salivary gland (Chapter 690). Genetics and Pathogenesis X linked EDA ID results from hypomorphic gene variants in the IKK gene that encodes the NF B essential modulator (NEMO). Complete loss of function (LOF) variants are deleterious early in embryogen esis. Carriers of LOF variants have features of incontinentia pigmenti. NEMO is a member of the IKK complex that phosphorylates the inhibitor of NF B (IB), which then allows NF B to translocate to the nucleus and turn on gene expression. In lymphocytes, NF B is involved in signaling via the antigen receptors, the tumor necrosis fac tor (TNF) receptor family, and toll like receptors as well as the inter leukin (IL) 1 receptor. Defects in NEMO affect both the innate and adaptive immune systems and can be severe. Autosomal dominant gain of function variants in IB also result in a similar phenotype that affects both females and males as well as gain of function variants in IKBKB. The latter is also associated with recurrent bacterial, viral, and fungal infections, but the ectodermal defects are variable. Clinical Manifestations Patients with EDA ID suffer from recurrent and severe infections from gram positive and gram negative bacteria, mycobacteria, viruses, and fungi. Patients have thin sparse hair and conical teeth and may have coli tis. More severe variants may be associated with osteopetrosis and lymph edema; their disease is termed OL EDA ID (osteopetrosis, lymphedema, EDA ID). Diagnosis The diagnosis can be suspected from the clinical features |
6,402 | of anhidro sis, ectodermal dysplasia, and recurrent infections. Patients frequently present with hypogammaglobulinemia as in the hyper IgM syndrome because CD40 signaling involves NF B, with elevated IgM in some patients. Most if not all patients have poor NK cell function. The diag nosis can be confirmed by identification of hypomorphic variants in the IKK gene or gain of function variants in the IB gene. Treatment Patients are usually treated with immunoglobulin replacement and close monitoring. The outcome is dependent on the severity of the phenotype. HSCT has been successful in some patients, but it may not correct the colitis or other features of the disease. Calcium Channel Defects Calcium signaling plays an important role in T cell activation, where ini tially calcium is released from the endoplasmic reticulum into the cyto plasm, which is sensed by STIM1 that in turn activates calcium release activated channels (CRACs), which are made up of the pore forming sub unit ORAI 1, to bring in additional calcium from outside the cell. Intracel lular calcium activates calcium dependent enzymes including calcineurin, which activates the nuclear factor of activated T cells (NFAT), which Fig. 165.5 Metaphyseal dysplasia, McKusick type. Note the fine, sparse hair and short limbs. (From Jones KL, Jones MC, Del Campo M. Smiths Recognizable Patterns of Human Malformation. 8th ed. Phila delphia: Elsevier; 2022. Fig.1, p. 529.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 165 u TCell and Combined Deficiencies 1275 translocates to the nucleus and activates gene transcription including IL 2 and the CD40 ligand. Pathogenic variants in ORAI 1 or STIM1 result in a CID associated with hypotonia because calcium is also important for muscle function. Clinical Manifestations Patients with calcium channel defects have recurrent and severe infections with bacteria, viruses, and fungi. They typically have pneumonia but may present with a variety of infections including BCG lymphadenitis, chronic rotavirus diarrhea, and mucocutaneous candidiasis. They may also present with failure to thrive, ectodermal dysplasia defective dental enamel, and mydriasis. Patients also have a nonprogressive hypotonia. Diagnosis Patients have normal numbers of T cells, but the T cells have decreased or have absent proliferation to mitogens, antigens, or anti CD3. Although serum immunoglobulins are normal or increased, specific antibody levels are diminished and NK cell function may also be decreased as B cells and NK cells also depend on calcium signaling for their activation. The clinical features and laboratory test results are similar for both ORA 1 and STIM1 deficiency. Therefore genetic test ing is required to identify the specific pathogenic variants, which will aid in genetic counseling and prenatal diagnosis. Treatment HSCT is the optimal treatment for the immunodeficiency; however, it does not correct the hypotonia, which may contribute to recurrent pneumonia. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 165.3 Thymic Disorders Ramsay L. Fuleihan The thymus is the organ where T |
6,403 | cell development occurs and cen tral T cell tolerance to self proteins develops by negative selection of self reactive thymocytes or development of regulatory T cells. Defects in thymic development affect T cell development causing a variable degree of T cell immunodeficiency and are associated with higher risk for the development of autoimmunity. DIGEORGEVELOCARDIOFACIAL SYNDROME CHROMOSOME 22Q11.2 DELETION SYNDROME (22Q11.2DS) Chromosome 22q11.2 deletion syndrome is the most common of the T cell disorders, occurring in about 1 in 3,000 births in the United States. Chromosome 22q11.2 deletions disrupt development of the third and fourth pharyngeal pouches during early embryogen esis, leading to hypoplasia or aplasia of the thymus and parathyroid glands. Other structures forming at the same age are also frequently affected, resulting in anomalies of the great vessels (right sided aor tic arch), esophageal atresia, bifid uvula, congenital heart disease (conotruncal, atrial, and ventricular septal defects), a short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and posteriorly rotated ears (see Chapter 99) (Fig. 165.6). With advanced fetal ultrasound and fetal echocardiog raphy, the diagnosis is often identified prenatally. Other patients may be identified by low TREC counts on newborn screening for SCID or sometimes by the development of hypocalcemic seizures during the neonatal period. Genetics and Pathogenesis Chromosome 22q11.2 deletions occur with high frequency because complex repeat sequences that flank the region represent a challenge for DNA polymerase. This condition is inherited in an autosomal dom inant fashion and occurs with comparable frequency in all populations. Within the deleted region, haplosufficiency for the TBX1 transcription factor appears to underlie the majority of the phenotype. The pheno type is highly variable; a subset of patients has a phenotype that has also been called DiGeorge syndrome, velocardiofacial syndrome, or conotruncal anomaly face syndrome. Variable hypoplasia of the thymus occurs in 75 of the patients with the deletion, which is more frequent than total aplasia; aplasia is present in 1 of patients with 22q11.2 deletion syndrome. Slightly less than half of patients with complete thymic aplasia are hemizygous at chromosome 22q11.2. Approximately 15 are born to diabetic mothers. Another 15 of infants have no identified risk factors. Approximately 30 of infants with complete DiGeorge syndrome have CHARGE association (coloboma, heart defect, choanal atresia, growth or developmental retardation, geni tal hypoplasia, and ear anomalies including deafness). Pathogenic variants in the chromodomain helicase DNA binding protein 7 (CHD7) gene on chromosome 8q12.2 are found in approximately 6065 of individuals with CHARGE syndrome; some have pathogenic variants in SEMA3E. Clinical Manifestations Children with partial thymic hypoplasia may have little trouble with infec tions and grow normally. Patients with thymic aplasia (complete DiGeorge syndrome) resemble patients with SCID in their susceptibility to infections with low grade or opportunistic pathogens, including fungi, viruses, and P. jiroveci, and to GVHD from nonirradiated blood transfusions. Patients with thymic aplasia can develop an atypical phenotype in which oligo clonal T cell populations appear in the blood associated with rash and lymphadenopathy. These atypical |
6,404 | patients appear phenotypically similar to patients with Omenn syndrome or maternal T lymphocyte engraftment. It is critical to ascertain in a timely manner whether an infant has thy mic aplasia, because this disease is fatal without treatment. A T cell count should be obtained on all infants born with primary hypoparathyroidism, CHARGE syndrome, and conotruncal cardiac anomalies with syndromic features. Some but not all infants are identified by newborn screening for SCID and when 22q11.2 deletion is suspected, a calcium level should be obtained at the time of T cell evaluation. The three manifestations with the highest morbidity in early infancy are profound immunodeficiency, severe cardiac anomaly, and seizures from hypocalcemia. Thus an early focus on these concerns is warranted even before the diagnosis is confirmed. Affected patients may also develop autoimmune cytopenias, juvenile idio pathic arthritis, atopy, and malignancies (lymphomas). Fig. 165.6 Typical facial appearance of a child with DiGeorge syn drome. Notice the microstomia, hypertelorism, upturned nose, and pos teriorly rotated and small, low set ears. (From Chinn IK, Chinen J, Shearer WT. Primary immunodeficiency diseases. In: Cherry JD, Harrison GJ, Ka plan SL, et al., eds. Feigin and Cherrys Textbook of Pediatric Infectious Diseases. 8th ed. Philadelphia: Elsevier; 2019. Fig. 67.1, p. 641.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1276 Part XII u Immunology Diagnosis The clinical features of DiGeorgeCHARGE22Q11.2DS will help in establishing the diagnosis, but there is a wide variety of clinical phe notypes. In most patients, absolute lymphocyte counts are usually only moderately low for age. The CD3 T cell counts are variably decreased in number, corresponding to the degree of thymic hypoplasia. Lympho cyte responses to mitogen stimulation are absent, reduced, or normal, depending on the degree of thymic deficiency. Immunoglobulin levels are often normal, but there is an increased frequency of IgA deficiency, low IgM levels, and some patients develop progressive hypogamma globulinemia. FISH for 22Q11.2 may identify patients with 22Q11.2DS as well as the more sensitive DNA microarray. Pathogenic variants in TBX1 may be found in DiGeorge syndrome, and pathogenic variants in CHD7 or SEMA3E in CHARGE syndrome. Treatment The immunodeficiency in thymic aplasia is correctable by cultured allogenic (donor derived) thymic tissue transplants. Following thymic tissue transplantation, a cytokine release syndrome may develop. Some infants with thymic aplasia have been given nonirradiated unfraction ated bone marrow or peripheral blood transplants from a human leu kocyte antigenidentical sibling, with subsequent improved immune function because of adoptively transferred T cells. Infants and children with low T cell counts but not low enough to consider transplantation should be monitored for evolution of immunoglobulin defects as well as autoimmunity. Infections in these patients are multifactorial. Their anatomy may not favor drainage of secretions; they have a higher rate of atopy, which may complicate infections; and their host defense may allow persistence of infections. Interventions range from |
6,405 | hand hygiene, probiotics, prophylactic antibiotics, and risk management to immu noglobulin replacement for those who have demonstrated defective humoral immunity. Live viral vaccines should be avoided until ade quate CD4 and CD8 T cell counts are confirmed and normal response to antigens is documented with T cell proliferation to antigens or a protective antibody response to a protein vaccine such as tetanus. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 165.4 Inborn Errors of Immunity with a Strong Atopic Diathesis Ramsay L. Fuleihan AUTOSOMAL DOMINANT HYPER IgE SYNDROME STAT3 DEFICIENCY (JOB SYNDROME) This syndrome is associated with early onset atopy and recurrent skin and lung infections. Genetics and Pathogenesis The autosomal dominant hyper IgE syndrome is caused by heterozy gous pathogenic variants in the gene encoding signal transducer and activator of transcription 3 (STAT3). These pathogenic variants result in a dominant negative effect. The many clinical features are caused by compromised signaling downstream of the IL 6, type I interferon, IL 22, IL 10, and epidermal growth factor (EGF) receptors. Clinical Manifestations The characteristic clinical features are staphylococcal abscesses, pneuma toceles, osteopenia, and unusual facial features. There is a history from infancy of recurrent staphylococcal abscesses involving the skin, lungs, joints, viscera, and other sites. Persistent pneumatoceles develop as a result of recurrent pneumonia. Patients often have a history of sinusitis and mas toiditis. C. albicans is the second most common pathogen. Allergic respi ratory symptoms are usually absent. The pruritic dermatitis that occurs is not typical of atopic eczema and does not always persist. There can be a prominent forehead, deep set wide spaced eyes, a broad nasal bridge, a wide fleshy nasal tip, mild prognathism, facial asymmetry, and hemihyper trophy, although these are most evident in adulthood. In older children, delay in shedding primary teeth, recurrent fractures, and scoliosis occur. These patients demonstrate an exceptionally high serum IgE concentra tion; usually normal concentrations of IgG, IgA, and IgM; pronounced blood and sputum eosinophilia; and poor antibody and cell mediated responses to neoantigens. Although IgE levels 2,000 IUmL are charac teristic, IgE levels may fluctuate and even decrease in adulthood. In neo nates and infants with the pruritic pustular dermatosis, IgE levels will be elevated for age and are usually in the 100s. In vitro studies show normal percentages of blood T, B, and NK lymphocytes, except for a decreased percentage of T cells with the memory (CD45RO) phenotype and an absence or deficiency of T helper type 17 (Th17) cells. Most patients have normal T lymphocyte proliferative responses to mitogens but very low or absent responses to antigens or allogeneic cells from family members. Blood, sputum, and histologic sections of lymph nodes, spleen, and lung cysts show striking eosinophilia. Hassalls corpuscles and thymic architec ture are normal. Treatment Therapy is generally directed at prevention of infection using antimi crobials including antibiotics and antifungals as well as immunoglobu lin replacement. DOCK8 DEFICIENCY Deficiency of DOCK8 (dedicator of cytokinesis 8) is an autosomal recessive severe immunodeficiency that most often presents with |
6,406 | impressively severe eczema in infancy and toddlerhood, food allergy, and eosinophilic esophagitis. Patients commonly have cutaneous viral infections with herpes simplex virus (HSV), varicella, or molluscum contagiosum; susceptibility to infection by CMV and EBV; recurrent pneumonia leading to bronchiectasis; and opportunistic infections with PJP. In some patients, cryptosporidia causes sclerosing cholangitis (Fig. 165.7). The infectious susceptibility tends to worsen over time, as do the laboratory features of immune dysfunction, most often low T cell counts and poor proliferative function. Serum IgE levels tend to be elevated with eosinophilia, whereas other immunoglobulin levels may be decreased, especially IgM. Specific antibody levels are variably decreased. Patients are also susceptible to autoimmune disease as well as cancer. Although these patients can survive to adulthood without transplantation, they suffer many complications and their quality of life is often poor. For this reason, most patients are now transplanted early in life to avoid the later complications. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 165.7 Mucocutaneous inflammation and infections in DOCK8 HIES. Severe eczema, molluscum contagiosum and fungal skin infec tions, and benign tumorous mucosa proliferations progressing from the inner eyelid and from oral mucosa are clinical signs of DOCK8 HIES. (From Hagl B, Heinz V, Schlesinger A, et al. Key findings to expedite the diagnosis of hyper IgE syndromes in infants and young children. Pediatr Allergy Immunol. 2016;272:177 184. Fig. 1) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 166 u BCell and Antibody Deficiencies 1277 Of the primary immunodeficiency diseases (PIDDs), those affecting antibody production are the most prevalent. Selective absence of IgA is the most common defect, with rates ranging from 1 in 333 to 1 in 18,000 persons among different races and ethnicities. Patients with antibody deficiency are usually recognized because they have recurrent infections with encapsulated bacteria, predominantly in the upper and lower respiratory tracts. Some individuals with selective IgA deficiency or infants with transient hypogammaglobulinemia may have few or no infections. These conditions have a complex and likely polygenic inheritance, as do the common variable immunodeficiency (CVID) syndromes. The gene defects for many primary antibody deficiency disorders have been identified (Table 166.1). Sometimes the defect is not in the B cell itself but in T cells, which are required for complete B cell function. Some disorders are caused by unknown factors or are secondary to an underlying disease or its treatment. 166.1 Agammaglobulinemia Vivian P. Hernandez Trujillo and Camile Ortega X LINKED AGAMMAGLOBULINEMIA Patients with X linked agammaglobulinemia (XLA), or Bruton agam maglobulinemia, have a profound defect in B lymphocyte devel opment resulting in severe hypogammaglobulinemia, an absence of circulating B cells, small to absent tonsils, and no palpable lymph nodes. These patients present with an increased susceptibility to infec tion (Fig. 166.1) and have increased risk of neutropenia and autoim munity, particularly presenting as colitis. Genetics and Pathogenesis The variant gene |
6,407 | in XLA maps to q22 on the long arm of the X chromo some and encodes the B cell protein tyrosine kinase Btk (Bruton tyro sine kinase). Btk is a member of the Tec family of cytoplasmic protein tyrosine kinases and is expressed at high levels in all B lineage cells, including pre B cells. Some pre B cells are found in the bone marrow, but the percentage of peripheral blood B lymphocytes is 1. The per centage of T cells is increased, ratios of T cell subsets are normal, and T cell function is intact. The thymus is normal. Several autosomal recessive defects have also been shown to result in agammaglobulinemia with an absence of circulating B cells (see Table 166.1; Table 166.2), including pathogenic variants in the genes encoding the (1) heavy chain gene; (2) Ig and (3) Ig signaling molecules; (4) B cell linker adaptor protein (BLNK); (5) surrogate light chain, 514.1; (6) leucine rich repeat containing 8 (LRRC8); (7) p85 subunit of phos phatidylinositol 3 kinase; (8) p110 subunit of phosphatidylinositol 3 kinase; (9) TCF3; (10) SLC39A7; and (11) TOP2B. These are rare but are clinically indistinguishable from the X linked form (see Fig. 166.1). Clinical ManifestationsComplications Most males afflicted with XLA remain well during the first 6 9 months of life by virtue of maternally transmitted IgG antibodies. Thereafter they acquire infections with extracellular pyogenic organisms, such as Streptococcus pneumoniae and Haemophilus influenzae, unless they are given prophylactic antibiotics or immunoglobulin therapy. Infections include sinusitis, otitis media, pneumonia, or, less often, sepsis or men ingitis (Fig. 166.2). Infections with Mycoplasma are also particularly problematic, specifically as they can affect the joints. Chronic fungal infections are seen; Pneumocystis jirovecii pneumonia rarely occurs. Viral infections are usually handled normally, with the exceptions of hepatitis viruses and enteroviruses. There are examples of paraly sis when live polio vaccine was administered to these patients, and chronic, eventually fatal, central nervous system (CNS) infections with various echoviruses and coxsackieviruses have occurred in a significant number of patients. An enterovirus associated myositis resembling dermatomyositis has also been observed. Enteroviral encephalitis can also be life threatening in patients with XLA. Neutropenia, typically seen at diagnosis when infected, can be associated with Pseudomonas or staphylococcal infections. In addition, Pseudomonas can lead to severe and life threatening invasive infections. Giardia can also lead to diarrhea and weight loss. A sudden decrease in serum IgG level should prompt an evaluation for Giardia. Long term complications include bronchiectasis and colitis, pre senting like an inflammatory bowel disease. Gastrointestinal (GI) dis ease has been increasingly reported in patients with XLA. Although immune globulin replacement decreased severe infectious complica tions, the chronic lung disease persisted in a recent cohort study. In addition, in a separate cohort, infections were highest before initiation of antibody replacement; however, patients continued to have infec tions despite adequate IgG levels. Diagnosis The diagnosis of XLA should be suspected if lymphoid hypoplasia is found on physical examination (minimal or no tonsillar tissue and no |
6,408 | palpable lymph nodes), and serum concentrations of IgG, IgA, IgM, and IgE are far below the 95 confidence limits for appropriate age and race matched controls; total immunoglobulins are usually 100 mgdL. Levels of natural antibodies to type A and B red blood cell polysaccharide antigens (isohemagglutinins) and antibodies to anti gens given during routine immunizations are abnormally low in XLA, whereas they are typically normal in transient hypogammaglobu linemia of infancy. In infants below the age of 6 months, care should be taken when interpreting normal IgG, which can represent maternal IgG passed in utero. In this case, flow cytometry is essential in making the diagnosis of XLA. Flow cytometry is an important test to demon strate the absence of circulating B cells, which will distinguish XLA from most types of CVID, the hyper IgM syndrome, and transient hypogammaglobulinemia of infancy (Fig. 166.3). Genetic testing is also available to detect absence of Btk. AUTOSOMAL RECESSIVE AGAMMAGLOBULINEMIA Autosomal recessive agammaglobulinemia (ARA) is a clinically indistin guishable disorder from XLA presenting in males and females. The success ful assembly and subsequent signaling capacity of the pre B cell receptor complex (pre BCR) in the bone marrow is central to the production of B cells and antibody secreting plasma cells. A pathogenic variant in any of the components of the pre BCR, or in the downstream signaling cascade, results in these rare forms of agammaglobulinemia (see Fig. 166.1). Genetics and Pathogenesis Hematopoietic stem cells develop into B cells in the bone marrow. The maturation into antibody secreting plasma cells occurs in periph eral lymphoid tissues. B cell development relies on a tightly regulated sequence of events from the pro B cell stage to the formation of the pre BCR and onward (see Fig. 166.1). The pre BCR is composed of the membrane form of the heavy chain, the surrogate light chain composed of VpreB and 514.1 and the immunoglobulin associated signal transducing chains, Ig and Ig. An autosomal pattern of inheritance occurs in approximately 10 of agammaglobulinemic syndromes, and, in some affected fami lies, there is known consanguinity. Approximately half of these patho genic variants are in heavy (IGHM) and have a clinical picture that Chapter 166 BCell and Antibody Deficiencies Vivian P. Hernandez Trujillo and Camile Ortega Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1278 Part XII u Immunology Table 166.1 Genetic Basis of the Most Common Primary Antibody Deficiency Disorders GENE PHENOTYPE DISORDER BAFFR CVID Hypogammaglobulinemia CD19 CVID Hypogammaglobulinemia CD20 CVID Hypogammaglobulinemia CD21 CVID Hypogammaglobulinemia CD81 CVID Hypogammaglobulinemia CTLA4 CVID Hypogammaglobulinemia, pronounced lymphoproliferation and autoimmunity ICOS CVID Hypogammaglobulinemia, autoimmunity, neoplasia LRBA CVID Hypogammaglobulinemia, pronounced lymphoproliferation and autoimmunity NFKB2 CVID Hypogammaglobulinemia, autoimmunity NFKB1 CVID Hypogammaglobulinemia, autoimmunity PIK3CD (AD) CVID Hypogammaglobulinemia, adenopathy PI3KR1 (AD) CVID Hypogammaglobulinemia TNFRSF13B CVID Hypogammaglobulinemia, low penetrance of disease Unknown CVID Hypogammaglobulinemia, autoimmunity Majority of patients with CVID have no known |
6,409 | gene variant Unknown IgG subclass deficiency Variable association with infection Unknown Specific antibody deficiency Normal immunoglobulin levels with poor vaccine responses Unknown Transient hypogammaglobulinemia of infancy Vaccine responses are usually preserved, and most children outgrow this by age 3 yr Unknown Selective IgA deficiency Low or absent IgA; low concentrations of all immunoglobulins and of switched memory B cells in CVID BLNK Agammaglobulinemia Absence of antibody production, lack of B cells BTK Agammaglobulinemia Absence of antibody production, lack of B cells, X linked agammaglobulinemia CD79A Agammaglobulinemia Loss of the Ig required for signal transduction, absence of antibody production, lack of B cells CD79B Agammaglobulinemia Loss of the Ig required for signal transduction, absence of antibody production, lack of B cells IGHM Agammaglobulinemia Loss of the Ig heavy chain, absence of antibody production, lack of B cells IGLL1 Agammaglobulinemia Loss of the surrogate light chain, absence of antibody production, lack of B cells PI3KR1 (AR) Agammaglobulinemia Loss of signal transduction through the B cell receptor, absence of antibody production, lack of B cells PIK3CD (AR) Agammaglobulinemia Severely impaired signal transduction through B cell receptor, absence of antibody production, lack of B cells SLC39A7 Agammaglobulinemia Impaired signal transduction through the B cell receptor, absence of antibody production, lack of B cells TCF3 Agammaglobulinemia Loss of a key transcription factor for B cell development, absence of antibody production, lack of B cells AID Class switch defect Failure to produce IgG, IgA, and IgE antibodies CD40 Class switch defect Failure to produce IgG, IgA, and IgE antibodies, Pneumocystis and Cryptosporidium susceptibility CD154 Class switch defect Failure to produce IgG, IgA, and IgE antibodies, Pneumocystis and Cryptosporidium susceptibility INO80 Class switch defect Failure to produce IgG, IgA, and IgE antibodies MSH6 Class switch defect Failure to produce IgG, IgA, and IgE antibodies, malignancy UNG Class switch defect Failure to produce IgG, IgA, and IgE antibodies CD27 EBV lymphoproliferation Memory B cell deficiency Hypogammaglobulinemia NEMO Anhidrotic ectodermal dysplasia with immunodeficiency Phenotype highly variable but includes specific antibody deficiency and CVID AD, autosomal dominant; AR, autosomal recessive; CVID, common variable immunodeficiency; EBV, Epstein Barr virus. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 166 u BCell and Antibody Deficiencies 1279 is similar to XLA. Variants in the genes encoding for Ig (CD79a), Ig (CD79b), 5 (IGLL1), BLNK, and p85 (PI3KR1) have been identified as other, more rare, causes for ARA in humans (see Fig. 166.1). Autoso mal dominant forms of agammaglobulinemia have also been identified in patients with an unusual phenotype characterized by an increased expression of CD19, but with the absence of the BCR. Genetic stud ies demonstrated a de novo variant in the broadly expressed tran scription factor E47, which functions as a quality control mechanism of enforcing a block to prevent cells that lack a pre BCR from further development. Clinical Manifestations Absent peripheral B cells and |
6,410 | severe hypogammaglobulinemia due to a developmental arrest at the pro B stage to pre B stage is characteristic of ARA. Although these patients generally have clinical findings that are indistinguishable from Btk mutations, patients with the pathogenic variants in any of the components of the BCR leading to ARA tend to have a more severe phenotype. ARA is diagnosed at a mean age of 11 months, rather than 35 months in patients with XLA. There is also a higher incidence of enteroviral infections and Pseudomonas sepsis with neutropenia. These differences suggest there is protective value in ADA deficiency AK2 deficiency Pro B cell Pre B cell Immature B cell B cell T cell NK cell Monocyte GATA2 deficiency GMP ETP MPPHSC MLP MEP CMP Granulocyte Erythrocyte Megakaryocyte Platelets Dendritic cell CD19 RAG (RAG1 and RAG2) deficiency NHEJ (Artemis) deficiency CD19 B cell and NK cell progenitor Self renewal HoyeraalHreidarsson (shelterin deficiency) BTK deficiency BLNK deficiency PI3K (p85) deficiency 5 deficiency C deficiency lg or lg deficiencies GATA2 deficiency Fig. 166.1 B cell development defects in primary antibody deficiencies (PADs) result from developmental defects that are either B cell specific or affect several hematopoietic cell lineages. B cell development occurs in the bone marrow, where hematopoietic stem cells (HSCs) undergo B cell lineage specification. Some autosomal recessive forms of severe combined immunodeficiency (SCID) are associated with an early defect in both B and T cells and are diagnosed in the first few months or years of life. For example, adenosine deaminase (ADA) deficiency leads to an accumula tion of adenosines and thus the death of the lymphocytes. Moreover, adenylate kinase 2 (AK2) deficiency (also known as reticular dysgenesis) is a metabolic defect that mostly affects T cells, natural killer (NK) cells, neutrophils, and (in some cases) B cells. It is associated with very early onset hypogammaglobulinaemia or even agammaglobulinaemia. Dyskeratosis congenita is caused by mutations in genes encoding components of the telomerase or shelterin complexes; it is a rare inherited bone marrow failure syndrome that leads to progressive B and T cell lymphopenia and hypogammaglobulinaemia. Finally, mutations in GATA2 (which encodes a transcription factor required for early differentiation of hematopoietic cells in the bone marrow) also lead to B cell, dendritic cell, monocyte, and NK cell deficiencies. Successive B cell differentiation stages are character ized by ordered gene expression and stochastic immunoglobulin gene rearrangements. The V(D)J recombination of the immunoglobulin locus is achieved by the lymphocyte specific RAG molecules and the nonlymphocyte specific nonhomologous end joining (NHEJ) complex and leads to the expression of the pre B cell receptor (BCR). Defects in V(D)J recombination (as observed in RAG deficiency and NHEJ deficiency) typically result in the absence of mature B and T cells. The pre BCR is affected in these cases, leading to PADs as V(D)J recombination is required for heavy chain expression. The dashed lines indicate a block of differentiation. BLNK, B cell linker; Btk, Bruton tyrosine kinase; CMP, common myeloid progenitor; ETP, early T cell precursor; GMP, granulocytemacrophage progenitor; |
6,411 | MEP, megakaryocyteerythrocyte progenitor; MLP, multi lymphoid progeni tor; MPP, multipotent progenitor; PI3K, phosphoinositide 3 kinase. (From Durandy A, Kracker S, Fischer A. Primary antibody deficiencies. Nat Rev Immunol. 2013;13:519 533. Box 1, p. 520.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1280 Part XII u Immunology the small amount of immunoglobulins produced by patients with XLA. Treatment using immunoglobulin and aggressive use of antibiotics is identical to that for patients with XLA. Diagnosis Due to the early B cell developmental arrest, ARA variants have been associated with the complete absence of CD19 B cells in the periph eral circulation and profound hypogammaglobulinemia. Identifying a genetic cause of ARA is challenging, and there is a need for a better understanding of susceptibility genes and modifying genetic factors. The goal of further areas of investigation should include the identifica tion of variant genes in patients who do not appear to have defects in the genes already associated with immunodeficiency. Whole genome sequencing will greatly facilitate the molecular diag nosis of abnormalities in additional genes that can cause ARA. Inheritance Patterns XLA affects males, as it is an X linked disorder. The inheritance pat terns include all female offspring as carriers, and none of the male offspring will be affected. Autosomal recessive forms of agammaglobu linemia result in both males and females affected, as each parent passes on the affected gene. Patients with agammaglobulinemia tend to have more severe disease, often presenting earlier in life compared with patients with hypogammaglobulinemia, specific antibody deficiency (SAD), or CVID. Treatment with antibody replacement and prophylactic antibiotics for patients with any form of agammaglobulinemia is essential in pre venting infections and will be further reviewed later. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 166.2 Hypogammaglobulinemia, Transient Hypogammaglobulinemia of Infancy, Specific Antibody Deficiency, and Common Variable Immunodeficiency Vivian P. Hernandez Trujillo and Camile Ortega Patients with low IgG may present at different ages. Hypogammaglobu linemia results from low, but not absent, levels of serum immunoglobu lins. If a patient is diagnosed with a specific pathologic genetic variant, this aids in making a specific diagnosis. Otherwise, in patients with a low IgG, the diagnosis may be arbitrary when considering the differential of hypogammaglobulinemia, SAD, and CVID (Tables 166.3 and 166.4). Table 166.2 Patterns of Inheritance for Different Forms of Agammaglobulinemia DISEASE GENEPROTEIN AFFECTED PATTERN OF INHERITANCE XLA Btk X linked IGHM heavy chain Autosomal recessive Ig CD79a Autosomal recessive Ig CD79b Autosomal recessive 5 IGLL1 Autosomal recessive BLNK BLNK scaffolding protein Autosomal recessive PIK3R1 PIK3 regulatory subunit Autosomal recessive PIK3CD PIK3 regulatory subunit Autosomal recessive SLC39A7 Zinc transporter protein ZIP7 Autosomal recessive TCF3 Transcription factors E12 and E47 Autosomal recessive or autosomal dominant LRRC8 LRRC8 deficiency Autosomal dominant Hoffman syndrome TOP2B Autosomal dominant XLA, X linked agammaglobulinemia. Fig. 166.2 Types of Infections in a cohort of X linked agammaglobulinemia (XLA) patients. USIDNET |
6,412 | Reg istry. Infections affect many body systems in XLA pa tients. CNS, Central nervous system: ENT, ear, nose, and throat; GU, genitourinary. (Data from Groth D, Wright H, Marsh R, et al. X linked agammaglobulinemia: Infection frequencies in 226 patients from the USIDNET Registry. J Allergy Clin Immunol. 2020;1452 Supplement:AB80.) 0 10 ENT Res pir at or y Pne um on ia Em py em a Sinu sit is Otiti s m ed ia Skin Upp er re sp ira to ry Con jun cti vit is Gas tro int es tin al CNS Sep sis Sep tic a rth rit is GU Oste om ye liti s Ora l c an did ias is Ly m ph ad en itis L ym ph an git is 20 30 40 50 60 70 80 90 Types of infections in XLA patients patients Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 166 u BCell and Antibody Deficiencies 1281 HYPOGAMMAGLOBULINEMIA The most common types of PIDD are antibody deficiencies charac terized by hypogammaglobulinemia and recurrent infections and are usually present in childhood. Primary hypogammaglobulinemia repre sents a spectrum of disease, with more severe phenotypes characterized by profound hypogammaglobulinemia or agammaglobulinemic states, as was described in the previous section. SAD and CVID are presented in the following sections, and onset may occur later in childhood and adolescence. This is in contrast to transient hypogammaglobulinemia of infancy, which presents in the first few months of life. The secondary forms are more common in adults and are a result of decreased production or increased loss. Decreased production can be drug induced (rituximab, glucocorticoids, and antiepileptics), from malignancy or premalignant disorders (chronic lymphocytic leukemia, lymphoma, multiple myeloma, or Waldenstrm macroglobulinemia), and from Good syndrome (thymoma with hypogammaglobulinemia). Increased loss can result from protein losing enteropathies, intestinal lymphangiectasia, nephrotic syndrome, burns, and trauma. Specific Antibody Deficiency SAD is defined as patients, 2 years old and older, with recurrent infections and normal immunoglobulin isotypes who lack antibody response to purified S. pneumoniae capsular polysaccharide antigens, while responding normally to protein antigens. Genetics and Pathogenesis Infants demonstrate robust antibody responses to protein antigens through T celldependent activation. Response to purified polysaccha ride vaccines (PPVs) does not involve T cell activation, and is only con sidered to be fully developed by 2 years of age. The response to protein antigens, including those contained in the protein conjugated vaccines (PCVs), typically remains intact in patients with SAD. In SAD, some patients lack of response to PPV may represent physiologic immatu rity of the immune system, and may resolve over time. In SAD patients with recurrent infections requiring antibiotics, there is likely an under lying immunologic abnormality. The cause for this delay in maturation remains unknown. Abnormalities in a specific pathogen associated molecular pathway may be responsible for the variability in which indi viduals respond |
6,413 | to specific protein or polysaccharide antigens despite normal total immunoglobulin levels. A number of cellular pathways produce antibodies against purified or conjugate polysaccharides and are likely to be altered by different defects. The response seen to PPV, which can occur in patients who lack a response to PCV, demonstrates how conjugate and purified polysaccharides induce antibodies through different activation pathways. The variation in phenotypes of SAD also supports the likelihood of different pathogenic mechanisms resulting in polysaccharide antibody deficiencies. The use of large scale DNA studies, along with IgM memory and class switched memory B cells as immunologic markers, is expected to provide useful information for the evaluation and management of patients with SAD in the future. Clinical Manifestations Patients with SAD present in a manner consistent with those with defects of humoral immunity. Frequent, severe, or prolonged sinopul monary infections are most common. Rapid recurrence of infection on discontinuation of antibiotics, following initial improvement, is also common. Invasive and life threatening infections are not frequent. Approximately half of children show resolution of SAD in 3 years and treatment may be temporary. A new diagnosis of SAD during adoles cence or adulthood could indicate a previously missed diagnosis or progression of a mild phenotype. Pathogen susceptibility is not spe cific and not limited to S. pneumoniae. Other encapsulated bacteria, (H. influenzae and Moraxella catarrhalis), Staphylococcus aureus and respiratory viruses cause significant disease in SAD. SAD patients with allergic disease are among the most challenging to identify due to increased risk of sinopulmonary infections result ing from persistent inflammation and anatomic dysfunction associated with asthma and rhinitis. It is important to consider underlying SAD in this population, as IgE mediated sensitization is only present in some of these patients. Mucociliary or anatomic defects should also be con sidered in those who have developed high titers in response to natural infection, but maintain an abnormal pattern of infections. Although lack of antibody response to polysaccharide antigens is found frequently in patients without any associated immune defi ciency, selective antibody deficiencies are also common in patients with known PIDDs with normal total immunoglobulin levels such as ataxia telangiectasia, asplenia, hyper IgE syndrome, selective IgA defi ciency, IgG subclass deficiencies, Wiskott Aldrich syndrome, and par tial DiGeorge syndrome. A subset of adolescents and adults with SAD may progress to more severe forms of PIDD, including other forms of hypogammaglobulinemia and CVID. Diagnosis The gold standard for the diagnosis of SAD involves evaluating the response to the 23 valent pneumococcal polysaccharide vac cine (PPV23). In patients immunized with protein conjugated 1 Suspected primary antibody deficiency in patient 4 years of age 2 Measure serum immunoglobulins, IgG subclasses, antibodies to vaccination, and lymphocyte subsets 3 Is IgG profoundly reduced? Yes No Yes No Yes No Yes No Yes No Yes No 6 Pursue combined immune deficiency 7 Are B cells profoundly reduced? 10 Consider AGAM and CVID 11 Consider CVID or HIGMS 12 Consider IgG subclass deficiency 13 Is IgA reduced? 14 Consider IgA deficiency 15 |
6,414 | Consider alternative diagnosis 8 Consider SAD 9 Are IgG subclasses reduced? 4 Are T cells profoundly reduced? 5 Are levels to antibodies to vaccination reduced? Fig. 166.3 Algorithm for evaluation of a patient with suspected pri mary antibody deficiency. AGAM, Congenital agammaglobulinemia; CVID, common variable immunodeficiency; HIGMS, hyperIgM syn drome; SAD, specific antibody deficiency. (From Maglione PJ. Primary antibody deficiency. In: Leung DYM, Akdis CA, Bacharier LB, et al., eds. Pediatric Allergy Principles and Practice. 4th ed. Philadelphia: Elsevier, 2021. Fig. 5.1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1282 Part XII u Immunology pneumococcal vaccines (PCV 7, PCV 13, PCV 10, PCV15, PCV20), the evaluation must be based on the serotypes not present in conjugate vaccines. In unimmunized patients, a complete absence of protective titers to all serotypes is unusual, as most individuals would be expected to have developed some in response to natural infection by 2 years of age. The standard and reproducible method used for analysis is the third generation World Health Organization enzyme linked immu nosorbent assay (ELISA) and the antigens are individual serotype specific capsular polysaccharides of pneumococci. Antibody titers are expressed as mgmL and although titers as low as 0.35 mgmL have been considered protective against invasive infections, a titer of 1.3 mgmL is used as the threshold of response to PPV23 and generally considered protective against mucosal infections. Four different phe notypes of SAD have been described based on the response to the available pneumococcal vaccines: mild, moderate, severe, and mem ory. Although all phenotypes presume an abnormal pattern of infec tion, severity or susceptibility to infection may or may not correlate clinically. The severe phenotype is defined as nearly absent protective titers to 2 serotypes following PPV23. The moderate phenotype is based on age: for those less than 6 years old, less than 50 protective serotypes and those age 6 years old and greater, less than 70 pro tective serotypes. Many patients fall in the mild phenotype, which is less well defined as a failure of response to multiple phenotypes. The memory phenotype, also dependent on age, is defined as an adequate initial response and subsequent loss of protective titers within 6 months. The evaluation of specific antibodies against S. pneumoniae polysaccharides provides guidance in determining the need for addi tional immunization, antibiotic therapy, or IgG replacement therapy in SAD patients. Children and adults who have not been immunized and have not developed protective titers in response to natural infec tion should be immunized with PCV followed by PPV23, as they have been shown to respond both clinically and serologically. Patients who fail to respond to the initial challenge with PPV23 may respond to the conjugated vaccine, when given 1 year after PPV23. Most patients have an excellent prognosis with appropriate treatment. COMMON VARIABLE IMMUNODEFICIENCY CVID is a syndrome characterized by hypogammaglobulinemia after an initial |
6,415 | period of apparent normal immune function. Serum IgG must be 2 standard deviations below the age adjusted norms, with low IgA andor IgM levels. CVID patients may appear similar clinically to those with XLA in the types of infections experienced and bacterial etiologic agents involved, except that enterovirus meningoencephalitis is rare in patients with CVID. In contrast to XLA, the sex distribution in CVID is almost equal, the age at onset is later, and infections may be less severe. CVID is the most common of the antibody defects. Table 166.3 Main Phenotypes of Primary Antibody Deficiencies PHENOTYPE MAIN CLINICAL FEATURES MAIN B CELL FEATURES Agammaglobulinemia Bacterial infections (in respiratory tract) and enterovirus infections Absence of CD19 B cells Common variable immunodeficiency Bacterial infections (in respiratory tract and gut), autoimmunity, cancer, and increased risk of granuloma Highly variable; may see decreased memory B cells Class switch defects Bacterial and opportunistic infections Decreased frequency of memory B cells Selective IgA deficiency Most often asymptomatic Normal IgG subclass deficiency Frequent bacterial infections; diagnosis after age 2 yr B cell subsets normal Selective polysaccharide antibody deficiency Bacterial infections (after age 2 yr) Normal IgG (including IgG2 and IgG4) levels, normal B cell subsets Table 166.4 Antibody Deficiency Disorders with Laboratory Evaluation LABORATORY VALUES XLAAR AGAMMA SELECTIVE IgA SPECIFIC ANTIBODY DEFICIENCY COMMON VARIABLE IMMUNO DEFICIENCY TRANSIENT HYPOGAMMA GLOBULINEMIA IgG Decreased Normal Normal Decreased to normal Decreased IgA Decreased Decreased Normal Decreased to normal Normal IgM Decreased Normal Normal Varies Normal LYMPHOCYTES B CD19 Decreased to absent Normal Normal Decreased to normal memory B cells Normal T CD4CD3 Normal to increased Normal Normal Normal Normal CD8CD3 Normal to increased Normal Normal Normal Normal NK 1656 Normal to increased Normal Normal Normal Normal SPECIFIC ANTIBODY TITERS Protein Decreased Normal Normal Decreased to normal Normal Polysaccharide Decreased Normal Decreased Decreased to normal Normal AR, Autosomal recessive; NK, natural killer; XLA, X linked agammaglobulinemia. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 166 u BCell and Antibody Deficiencies 1283 Genetics and Pathogenesis CVID is a phenotypic diagnosis with a polygenic inheritance in most cases. Genes known to produce the CVID phenotype when pathogenic variants occur include ICOS (inducible co stimulator) deficiency, SH2DIA (responsible for X linked lymphoproliferative disease XLP), CD19, CD20, CD21, CD81, BAFF R (B cellactivating factor of the tumor necrosis factor family of receptors), NFKB1 and NFKB2, IKZF1, ATP6AP1, MOGS, TACI, and TRNT1 (Fig. 166.4). With rare excep tions, management of CVID does not depend on a genetic diagnosis. In the setting of atypical infections or autoimmunity, pursuing a genetic diagnosis can be useful because some genetic etiologies can have a poor prognosis and transplantation should be considered. Targeted treatment options may also be available to treat some forms of CVID related to LRBA or CTLA4 pathogenic variants. Despite normal numbers of circulating B cells in many patients and the |
6,416 | presence of lymphoid cortical follicles, blood B cells from CVID patients do not differentiate normally into immunoglobulin producing cells. They may have a deficiency of switched memory B cells. Clinical Manifestations The serum immunoglobulin and antibody deficiencies in CVID are associated with recurrent sinopulmonary infections (sinusitis, otitis, pneumonia). Most patients present before age 20. Close monitoring for the development of chronic lung disease is needed. Repeated pulmo nary infections may produce bronchiectasis; interstitial lung disease is common (Fig. 166.5). Sepsis and meningitis with encapsulated bacteria occur more frequently than in the general population. Patients with recurrent infections as their only manifestation typically have a normal life expectancy and do well with immunoglobulin replacement. The presence of autoimmune disease or lymphoproliferation confers a poor prognosis, as antibody replacement does not improve these conditions. Patients with CVID often have autoantibody formation and normal sized or enlarged tonsils and lymph nodes; about 25 of patients have splenomegaly. CVID has also been associated with a spruelike enter opathy with or without nodular lymphoid hyperplasia of the intestine. Other autoimmune diseases include alopecia areata, hemolytic ane mia, thrombocytopenia, gastric atrophy, achlorhydria, and pernicious anemia. Lymphoid interstitial pneumonia, intestinal lung disease, pseudolymphoma, B cell lymphomas, amyloidosis, and noncaseating sarcoid like granulomas of the lungs (granulomatous and lympho cytic interstitial lung disease GLILD), spleen, skin, and liver also occur. Patients should be monitored closely over time for symptoms involving multiple tissues. 166.3 Class Switch Defects Vivian P. Hernandez Trujillo and Camile Ortega The hyper IgM syndrome is genetically heterogeneous and character ized by normal or elevated serum IgM levels associated with low or absent IgG, IgA, and IgE serum levels, indicating a defect in the class switch recombination (CSR) process. Causative pathogenic variants have been identified in the CD40 ligand gene on the X chromosome and three genes on autosomal chromosomes: the activation induced cytidine deaminase (AID) gene, the uracil DNA glycosylase gene (UNG), and the CD40 gene on chromosome 20. Distinctive clinical features permit presumptive recognition of the type of pathogenic vari ants in these patients, thereby aiding proper choice of therapy. All such patients should undergo molecular analysis to ascertain the affected gene for purposes of genetic counseling, carrier detection, and deci sions regarding definitive therapy. X LINKED HYPER IgM CAUSED BY MUTATIONS IN CD40 LIGAND GENE X linked hyper IgM is caused by pathogenic variants in the gene that encodes the CD40 ligand (CD154, CD40L), which is expressed on activated T helper (Th) cells. Males with this syndrome have very low serum concentrations of IgG and IgA, with a usually normal or some times elevated concentration of polyclonal IgM; may or may not have small tonsils; usually have no palpable lymph nodes; and often have profound neutropenia. This disease, unlike the autosomal recessive forms of hyper IgM, affects both B and T cells. Genetics and Pathogenesis The B cells are normal in this condition; the defect is in the T cells. CD40L is the ligand for CD40, which is present on B cells and |
6,417 | mono cytes. CD40L is upregulated on activated T cells. Mutations result in an inability to signal B cells to undergo isotype switching, and thus the B cells produce only IgM. The failure of T cells to interact with B cells through this receptor ligand pair also causes a failure of upregulation of the B cell and monocyte surface molecules CD80 and CD86 that Monogenic cause (estimated 210) Unknown genetic cause modifier genes (prevalence unknown): TNFRSF13B (TACI), TNFRSF13C (BAFFR), MSH5, MSH2, MLH1, RAD50, FCGR2A, HLADQDR, ORC4L, CLEC16A, etc. PRKCD, 2.14 PLCG2, 2.14 NFKB2, 5.35 NFKB1, 1.60 PIK3R1, 4.81 VAV1, 0.53 RAC2, 0.53 BLK, 0.53 IKZF1 (IKAROS), 3.21 IRF2BP2, 0.53 ICOS, 3.74 TNFSF12 (TWEAK), 0.53 CD19, 3.74 CD81, 0.53 CR2 (CD21), 1.07 MS4A1 (CD20), 0.53 TNFRSF7 (CD27), 4.81 IL21, 0.53 IL21R, 3.21 PIK3CD, 26.74 CTLA4, 6.42 LRBA, 26.74 Fig. 166.4 Known genetic etiology of common variable immunodeficiency (CVID). The majority of cases of CVID do not have a defined genetic cause. Many of these are likely to be multifactorial, and the genomic duplication and deletion burden in CVID suggests this to be the case; 115 of the mutations have been identified. The colored pie chart represents their breakdown and relative frequency. (From Bogaert DJ, Dullaers M, Lambrecht BN, et al. Genes associated with common variable immunodeficiency: One diagnosis to rule them all? J Med Genet. 2016;539:575 590. Fig 1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1284 Part XII u Immunology interact with CD28CTLA4 on T cells, resulting in failure of crosstalk between immune system cells. Clinical Manifestations Males with the CD40 ligand defect become symptomatic during the first or second year of life with recurrent pyogenic infections, including otitis media, sinusitis, pneumonia, and tonsillitis. They have marked susceptibility to P. jirovecii pneumonia and can be neutropenic. Lymph node histology shows only abortive germinal center formation with severe depletion and phenotypic abnormalities of follicular dendritic cells. These patients have normal numbers of circulating B lympho cytes, but a decreased frequency of CD27 memory B cells. Circulat ing T cells are also present in normal numbers and in vitro responses to mitogens are normal, but there is decreased antigen specific T cell function. In addition to opportunistic infections such as P. jirovecii pneumonia, there is an increased incidence of extensive verruca vul garis lesions, Cryptosporidium enteritis, subsequent liver disease, and an increased risk of malignancy. Treatment Because of the poor prognosis, the treatment of choice is an HLA identical hematopoietic stem cell transplant at an early age. Alternative treatment for this condition is lifelong infusions of immune globulin. In patients with severe neutropenia, the use of granulocyte colony stimulating factor has been beneficial. AUTOSOMAL RECESSIVE HYPER IgM Genetics and Pathogenesis In contrast to patients with the CD40L defect, B cells from these patients are not able to switch from IgM secreting to IgG , IgA , |
6,418 | or IgE secreting cells, even when co cultured with normal T cells. The defects are all B cell intrinsic. The most common autosomal recessive defect is in a gene that encodes AID. AID deaminates cytosine into uracil in targeted DNA, which is followed by uracil removal by UNG. Severely impaired CSR was found in three hyper IgM patients reported to have UNG deficiency. Their clinical characteristics were similar to those with AID deficiency, with increased susceptibility to bacterial infections and lymphoid hyperplasia. Histologic examination of the enlarged lymph nodes reveals the presence of giant germinal centers (5 10 times normal) filled with highly proliferating B cells. Autoso mal recessive hyper IgM can be caused by defects in CD40. Clinical manifestations included recurrent sinopulmonary infections, P. jirovecii pneumonia, and Cryptosporidium parvum infections, very similar to the manifestations seen in X linked hyper IgM syndrome. Patients with INO80 deficiency may present with severe bacterial infections; whereas in MSH6 deficiency patients may have increased IgM, family or personal history of cancer, and low switch memory B cells. Clinical Manifestations Concentrations of serum IgG, IgA, and IgE are very low in AID, UNG, and CD40 deficiencies. In contrast to the CD40 ligand defect, however, the serum IgM concentration in patients with AID deficiency is usually markedly elevated and polyclonal. Patients with AID and UNG muta tions have lymphoid hyperplasia, are generally older at age at onset, do not have susceptibility to P. jirovecii pneumonia, often do have iso hemagglutinins, and are much less likely to have neutropenia unless it occurs on an autoimmune basis. The lymphoid hyperplasia distin guishes these patients from many others with antibody deficiency, par ticularly agammaglobulinemia, which leads to a paucity of lymphoid tissue. They have a tendency, however, to develop autoimmune and inflammatory disorders, including diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn disease, and chronic uveitis. Treatment and Prognosis With early diagnosis and antibody replacement, as well as good man agement of infections with antibiotics, patients with AID and UNG mutations generally have a more benign course than do those with the CD40L or CD40 defects. CD40 deficiency is rare but appears to mimic the manifestations of CD40L quite closely. Treatment of Antibody Deficiency Except for the CD40 ligand defect, for which stem cell transplanta tion is recommended, judicious use of antibiotics to treat documented infections and regular administration of immunoglobulin are the only effective treatments for primary B cell disorders. The most common forms of replacement therapy are either intravenous or subcutaneous immune globulin (IVIG or SCIg). Broad antibody deficiency should be carefully documented before such therapy is initiated. The rationale for the use of IVIG or SCIg is to provide missing antibodies, not to raise the serum IgG or IgG subclass level. The development of safe and effective immunoglobulin preparations is a major advancement in the treatment of patients with severe antibody deficiencies, although it is expensive and there have been national shortages. Almost all commercial preparations are isolated from normal plasma by the |
6,419 | Cohn alcohol fractionation method or a modification of it. Cohn fraction II is then further treated to remove aggregated IgG. Additional stabilizing agents such as sugars, glycine, and albumin are added to prevent reaggregation and protect the IgG molecule during lyophiliza tion. The ethanol used in preparation of immunoglobulin inactivates Fig. 166.5 Chronic lung disease in common variable immunodefi ciency. A, Lung disease types by radiographs andor pathology reports (n 124). B, Interstitial lung disease pathologies (n 46). Thirteen of 65 subjects with ILD had concurrent bronchiectasis. BOOP, bronchiolitis obliterans organizing pneumonia; ILD, inter stitial lung disease; LIP, lymphoid interstitial pneumonia. (From Ho HE, Cunningham Rundles C. Non infectious complications of common variable immunodefi ciency: Updated clinical spec trum, sequelae, and insights to pathogenesis. Front Immunol. 2020;11:149. Fig. 1) 0 Gra nu lom as LI P Ly m ph oid h yp er pla sia (N OS) BOOP Pulm on ar y f ibr os is pr ed om ina te s Foll icu lar b ro nc hio liti s 20 P er ce nt ag e ( ) 40 60 B Bronchiectasis only, 32.3 ILD pulmonary nodules, 62.9 Lymphoma, 4.8 A Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 166 u BCell and Antibody Deficiencies 1285 HIV, and an organic solventdetergent step inactivates hepatitis B and C viruses. Some preparations are also nanofiltered to remove infectious agents. Most commercial lots are produced from plasma pooled from 10,000 to 60,000 donors and therefore contain a broad spectrum of antibodies. Each pool must contain adequate levels of antibody to anti gens in various vaccines, such as tetanus and measles. However, there is no standardization based on titers of antibodies to more clinically relevant organisms, such as S. pneumoniae and H. influenzae type b. The IVIG and SCIg preparations available in the United States have similar efficacy and safety. Rare transmission of hepatitis C virus has occurred in the past, but this has been resolved by the additional treat ment step. There has been no documented transmission of HIV by any of these preparations. IVIG or SCIg at a dose of 400600 mgkg per month achieves trough IgG levels close to the normal range. Higher doses are indicated in patients with chronic or severe respiratory infections. Systemic reactions may occur, but rarely are these true anaphylactic reactions. Neutropenia associated with B cell defects has responded to granulocyte colony stimulating factor. Treatment of inflammatory bowel disease is essential in maintaining adequate IgG levels. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 166.4 Isotype Defects Vivian P. Hernandez Trujillo and Camile Ortega SELECTIVE IgA DEFICIENCY An isolated absence or near absence (5 mgdL) of serum and secre tory IgA is the most common well defined immunodeficiency disor der, with a disease frequency as high as 0.33 in some populations. Patients may be asymptomatic or may develop sinopulmonary |
6,420 | or gas trointestinal (GI) infections (especially Giardia). IgA deficiency is also associated with celiac disease and other autoimmune disorders. The diagnosis cannot be made until about 4 years of age, when IgA levels should be matured to adult levels. The basic defect resulting in IgA deficiency is unknown. Pheno typically normal blood B cells are present. In these patients, normal levels of other isotypes and normal specific antibody levels are seen. This defect also often occurs in pedigrees containing individuals with CVID. Indeed, IgA deficiency may evolve into CVID over time. IgA deficiency is noted in patients treated with the same drugs associated with producing CVID (phenytoin, d penicillamine, gold, and sul fasalazine), suggesting that environmental factors may trigger this dis ease in a genetically susceptible person. Clinical Manifestations Infections occur predominantly in the respiratory, GI, and urogenital tracts. Bacterial agents responsible are the same as in other antibody deficiency syndromes. Intestinal giardiasis is common. Serum concen trations of other immunoglobulins are usually normal in patients with selective IgA deficiency, although IgG2 (and other) subclass deficiency has been reported. Serum antibodies to IgA are reported in as many as 44 of patients with selective IgA deficiency. These antibodies can cause nonhemolytic transfusion reactions. Washed erythrocytes (frozen blood would have this done routinely) or blood products from other IgA deficient indi viduals should be administered to patients with IgA deficiency. Many immune globulin preparations contain sufficient IgA to cause reac tions. It is important to note that administration of immune globu lin, which is 99 IgG, is not indicated because most IgA deficient patients make IgG antibodies normally. IgG Subclass Deficiencies Some patients have deficiencies of one or more of the four subclasses of IgG despite normal or elevated total IgG serum concentration. Most patients may be asymptomatic. Some patients with absent or very low concentrations of IgG2 also have IgA deficiency. They may present with bacterial infections. Other patients with IgG subclass deficiency have gone on to develop CVID, suggesting that the presence of IgG subclass deficiency may be a marker for more generalized immune dysfunction. The biologic significance of the numerous moderate deficiencies of IgG subclasses that have been reported is difficult to assess. IgG subclass measurement is not cost effective in evaluating immune function in the child with recurrent infections. The more rel evant issue is a patients capacity to make specific antibodies to pro tein and polysaccharide antigens, because profound deficiencies of antipolysaccharide antibodies have been noted even in the presence of normal concentrations of IgG2. For this reason, immune globulin should not be administered to patients with IgG subclass deficiency unless they are shown to have a deficiency of antibodies to a broad array of antigens. Immunoglobulin Heavy and Light Chain Deletions Some completely asymptomatic individuals have been documented to have a total absence of IgG1, IgG2, IgG4, andor IgA1 as a result of gene deletions. These patients illustrate the importance of assessing specific antibody formation before deciding to initiate immune globu lin therapy in IgG |
6,421 | subclassdeficient patients. Low or undetectable lev els of IgG subclasses alone is, therefore, not an indication for antibody replacement. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 166.5 Transient Hypogammaglobulinemia of Infancy Vivian P. Hernandez Trujillo and Camile Ortega A common laboratory finding in infants, transient hypogammaglobu linemia represents developmental delay in the production of immu noglobulin. It is thought to occur in as many as 1:1,000 children. Most infants begin to produce IgG in the first 3 months of life, and the quan tity produced increases throughout infancy. For reasons incompletely understood, a small number of infants either begin late or do not increase their production as expected. This condition will resolve with no intervention, but represents a source of diagnostic confusion. A key distinction is that responses to vaccines are usually preserved in this condition, whereas in the others, including SAD, antibody responses will be low to absent. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1286 Part XII u Immunology Natural killer (NK) cells are lymphocytes that have a critical role in the innate immune response to pathogenic challenge and cel lular stress. NK cells are capable of rapid target cell killing and can quickly secrete large amounts of preformed granzymes and perfo rins in response to viral infections, especially those of the herpesvi rus family. They are also crucial in tumor surveillance. NK cells are found in the circulating blood as approximately 315 of lympho cytes and are also found in both primary and secondary lymphoid tissues where they are in a constant state of surveillance for cellular abnormalities. NK cells use a detection system composed of a wide range of germline encoded cell surface receptors that contribute to simultaneous NK activating and inhibitory signals. NK cells are constantly receiving both activating and inhibitory signals with the balance of signals tilted toward inactivation until NK cell recogni tion of a target cell occurs. With target cell recognition, the balance between inhibitory and activating signals leans in favor of activa tion and NK cell killing is initiated. NK cells are defined as innate immune lymphocytes because unlike B and T lymphocytes, they do utilize recombination activating gene (RAG) proteins required for DNA rearrangement and assemblage of diverse antigen specific receptors in response to antigen expo sure. However, they can develop long lived and highly antigen specific immunologic memory responses to different antigens through RAG independent adaptive immunity, which provides life long immune memory responses. This means that despite a lack of receptor diversity accrued via DNA rearrangement like B cells and T cells, NK cells do have characteristics associated with the adap tive immune system; distinguishing healthy from diseased cells, producing robust antiviral responses, and maintaining a collection of long lived cells that expand during cellular stress responses. NK CELL MARKERS, SUBSETS, AND MATURATION Mature |
6,422 | NK cells are traditionally defined as non T, non B lympho cytes that can rapidly produce interferon gamma (IFN ) and can mediate cellular cytotoxicity. Like all lymphocytes, they express clus ter of differentiation (CD) markers that identify their cell type and stage of development that are also upregulated or downregulated for cell homing purposes. However, there are no surface markers that are unique and specific for NK cells. NK cells have been tradition ally identified by using flow cytometry to exclude the cellular surface presence of leukocyte expressing markers specific to other leukocytes, such as CD3 and CD5 (T cells), CD19 and CD20 (B cells), and CD13 and CD14 (myelomonocytic cells). Further identification of NK cells follows via their expression of CD56 (neural cell adhesion molecule 1) andor CD16, their low affinity Fc gamma receptor that mediates antibody dependent cellular cytotoxicity (ADCC). Neither CD56 nor CD16 is specific or unique to the NK cell lineage; however, these CD markers are functionally important and thus used to characterize major subsets of NK cells. NK cells develop from CD34 hematopoietic stem cells (HSCs) in the bone marrow and then undergo maturation in secondary lym phoid tissues. NK cell development occurs through a series of six functionally distinct developmental stages distinguishable by cel lular expression of cell surface markers including CD34, CD117, CD94NKG2A (surface inhibitory receptor), NKp80 (surface activating receptor), CD16, and CD57. Once mature, NK cells then circulate through the peripheral blood (PB) or are found in organ tissues such as the secondary lymphoid tissues, liver, lungs, uterus, kidneys, or gut. For example, stage 1 cells found in the bone marrow are marked by the presence of only CD34, and subsequent stages occur through the upregulation and downregulation of previously mentioned cell surface markers; whereas, stage 6 mature NK cells in the PB express Nkp80, CD16, and CD57 (Fig. 167.1). NK cells express CD56 at different levels of development. CD56bright NK cells that express high levels of CD56, without expressing much CD16, are considered stage 4b and are approximately 310 of cir culating PB NK cells. Most PB NK cells express CD16 and low levels of CD56 and are referred to as CD56dim NK cells. Distinguishing cells as CD56bright and CD56dim refers to the increased fluorescent inten sity for CD56 cells seen in comparison to cells negative for CD56. CD56bright and CD56dim cells are functionally different. CD56bright NK cells are considered to be developmentally immature and produce higher levels of cytokines such as IFN with less cytotoxic capacity. They can rapidly produce large amounts of cytokines and chemokines; however, they contain low levels of perforin and granzymes and have low or absent CD16, making them poor mediators of direct cytotoxic ity and ADCC. In contrast, CD56dim cells are developmentally more mature, contain high levels of perforin, are cytotoxic, and recognize antibody coated cells through CD16. CD56dim cells are able to produce large amounts of cytokines but not to the degree of CD56bright cells. The cell surface marker expression for NK cells |
6,423 | in the PB and tissues are phenotypically distinct due to the influence of each tissues unique microenvironment. Similarly, the ratio of CD56bright and CD56dim NK subsets in the tissues is not the same as the ratios found in the PB. In the bone marrow, lung, spleen, subcutaneous adipose tissue, and breast tissue, CD56dim NK cells predominate, whereas CD56bright NK cells predominate in the mucosa associated lymphoid tissues (MALTs; e.g., gastric and intestinal mucosa), liver, uterus, visceral adipose tissue, adrenal gland, and kidney. NK Cell Functions NK cells have a critical role in the control of tumor growth and metastasis and are vital for the innate immune response against infections, particularly certain viruses. Additionally, there is increas ing recognition of the importance of NK cells in immunoregulation, coordination of immunity, and modulation of autoreactivity. NK cell activity is a balance between inhibitory and activating signals. NK cell surfaces contain a wide range of receptors that affect NK cell expression. Healthy host cells express high amounts of major histocompatibility complex class I (MHC I) molecules that ligate NK cell inhibitory receptors and prevent unwanted killing of healthy cells. Infected or malignant host cells downregulate their MHC I expression and express ligands for NK cell activating recep tors, which triggers NK cell killing of the diseased cell. The balance of signals for NK cell inhibition by MHC I expression in healthy cells and NK cell activation by MHC I downregulation during cel lular stress allows NK cells to defend against viruses and tumors and have protective roles in fungal, extracellular bacterial, intracel lular bacterial, and parasitic infections. Many viruses have evolved to specifically downregulate MHC I in cells they infect to prevent the host cell from presenting antigenic peptides to virus specific cytotoxic T lymphocytes (CTLs). Although this strategy does allow virus infected cell evasion from CTLs, it makes the infected cell more susceptible to recognition by NK cells. The three main functions of NK cells include cytokinechemokine production, contact dependent co stimulation, and cytotoxicity. Addi tionally, NK cells are capable of interfacing with the adaptive immune system through their IgG Fc receptor, CD16, which allows them to engage in antibody dependent killing. CytokineChemokine Production Activated NK cells secrete a wide variety of cytokines and che mokines in response to stimulation by interleukin (IL) 12, IL 15, and IL 18. IFN is one of the most potent cytokines released by Chapter 167 Natural Killer Cells Jessica M. Palmieri, Vibha A. Szafron, and Lisa Forbes Satter These authors contributed equally to this work. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 167 u Natural Killer Cells 1287 NK cells. It is crucial for the antiviral, antibacterial, and antitumor activity of NK cells through modulating death ligand expression of caspase, FasL, and TRAIL. NK cells are thus able to target cells for death through expression of these death |
6,424 | ligands. Death ligand killing is not as rapid as lytic granule killing. Additional NK cell released cytokines include TNF , IL 10, IL 5, and IL 13. NK cells also produce chemokines (chemotactic agents) such as MIP 1, MIP 1, IL 8, and RANTES. It is important to note that cytokines and chemokines in NK cells are compartmentalized separately from the lytic granules allowing them to be accessed separately from their cytotoxicity function. Contact Dependent Co Stimulation NK cells can promote and regulate immunity through direct receptor ligand interactions with other cells, or contact dependent co stimulation. NK cells express or can be induced to express a variety of co stimulatory and inhibitory ligands including the CD40 ligand, CD28, and PD 1, which can then interact with other types of immune cells to alter immune responses. NK CELL SPONTANEOUS CYTOTOXICITY Similar to cytotoxic T cells, NK cells secrete specialized lysosome related organelles known as lytic granules. However, unlike CTLs, the lytic granules inside NK cells are preformed and abundant while the cell is at rest, which allows for their rapid killing response on rec ognition of cellular distressdisease. Lytic granule contents include perforin (pore forming molecule) and pro apoptotic enzymes such as granzymes. Once an NK cell recognizes an activation signal from a distressed cell, the NK cell will polarize its lytic granules toward the portion of the NK cell membrane in contact with the target cell where the lytic granules will then dock. This is followed by fusion of the secretory lysosome with the plasma membrane of the target cells. The site of NK cell connection with the target cell is called the lytic immunologic synapse. Once a stable connection is formed at the lytic immunologic syn apse, cellular killing by the lytic granules will be completed in less than 2 hours. Perforin will insert into the target cell membrane, which will allow for pro apoptotic granzymes to travel to the target cell and initi ate cellular killing. NK CELL ANTIBODY DEPENDENT KILLING NK cells are also able to kill target cells via ADCC. NK cells have an IgG Fc receptor, CD16, expressed on their cell surfaces that allows them to recognize IgG opsonized targets to promote killing without priming via lysing of the target cell. ADCC also causes NK cell secretion of cytokines like INF for recruitment of adaptive immune cells. Etiologies of NK Cell Deficiency NK cells are lymphocytes that are critical for the immune response to viral infections. Patients with recurrent severe and refractory cutane ous viral and herpes viral infections should be evaluated for NK cell deficiency (NKD) with both enumeration and functional studies. However, ultimate evaluation should be completed with immunoge netic analysis as patients with diagnosed NKD may benefit from anti viral prophylaxis and eventual HSC transplant. NKD accounts for a small subset of primary immunodeficiencies (PIDs) that often present as clinical and diagnostic challenges. In general, NKD is suspected in patients who appear to have increased susceptibility to herpesvirus infections as well |
6,425 | as select other viral pathogens such a human papillomavirus (HPV). NK cells can be decreased in number or function for many rea sons. More commonly, severe illness and emotional stress can cause decreases of these cells. In addition, immunosuppressive medica tions such as corticosteroids, mycophenolate, cyclosporine, aza thioprine, and 6 mercaptopurine can depress NK cells. Given many factors are known to affect the stability of NK cells, repetition of the test is required to document true deficiency. If a patient is found to have abnormal NK cell studies 3 times, drawn at least 1 month Stage 4aStage 4bStage 5Stage 6 Stage 1 Stage 2 HSC CD34 CD45RA CD34 CD117 CD117 CD94NKG2A NKp80 CD16 CD57 Perforin CD117 CD94NKG2A NKp80 CD16 Perforin CD117 CD94NKG2A NKp80 CD117 CD94NKG2A CD34 CD117 Stage 3 CD34 Early CD56dim CD56brightLate CD56dim Peripheral blood Secondary Lymphoid Tissue Bone Marrow Fig. 167.1 Stages of NK cell development. HSC, Hematopoietic stem cell. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1288 Part XII u Immunology apart, inborn errors in immunity should be also considered, as described next. More than 50 PIDs include abnormalities in NK cells as part of their immunophenotypes. This occurs secondary to disruption in matura tion, proliferation, or survival of NK cells. Forms of severe combined immune deficiency (SCID) including IL2RG, JAK3, and AK2 defi ciency are known to present with low or absent NK cell numbers. In addition, given the importance of lytic granule secretion to NK cyto toxicity, conditions with abnormal granule secretion, such as primary hemophagocytic lymphohistiocytosis, or abnormal cytoskeletal function, such as Wiskott Aldrich syndrome, also can lead to NK cell aberrations. NKDs are classified as classical or functional. In classical NKD, there is a significantly decreased or absent number of CD3 CD56 cells, making up less than 1 of the total peripheral lymphocytes. Alterna tively, although the number of NK cells can be normal in functional NKD, these cells are functionally impaired. Classical NK Cell Deficiency Classical NKDs include pathogenic variants in MCM4, MCM10, GINS1, GATA2, RTEL1, and IRF8. MCM4 and MCM10 MCM (mini chromosome maintenance complex member) 4 and 10 are a part of the MCM replisome progression complex important for DNA replication. MCM4 is part of the Cdc45 MCM2 7 GINS1 (CMG) helicase complex and MCM10 is a replication factor asso ciated with this complex. In times of cellular stress, variant com plexes have resulted in abnormal DNA breakage (Fig. 167.2). These patients have a decreased number of NK cells, specifically CD56dim NK cells. CD56dim NK cells are mature NK cells that express CD16 (Fc receptor) and are important for ADCC. It is possible that CD56dim NK cells are particularly reliant on the MCM complex for survival. Alternatively, the pathogenic variant may cause an interruption along development before mature NK cell expansion. Patients with biallelic pathogenic variants in MCM4 have Epstein Barr virus (EBV) |
6,426 | driven lymphoproliferation and viral pneumo nitis. As MCM4 is widely expressed in many cells, these patients can also have adrenal insufficiency, short stature, and development delay. MCM10 deficient patients have a similar immunologic pheno type related to their NK cell abnormalities and the patients reported were found to have severe cytomegalovirus (CMV) infection. GINS1 Go Ichi Ni San complex subunit 1 (GINS1) is a protein involved in the CMG helicase complex that is important for DNA replica tion. Biallelic pathogenic variants in GINS have been seen to cause growth retardation, neutropenia, and NKD. It is important to note that both CD56dim and CD56bright cells are affected in this disorder. MCM4, MCM10, and GINS1 defects causing classical NKD suggests that chromosomal maintenance is critical to NK cell development and function. GATA2 Pathogenic variants in GATA2 (GATA binding protein 2), inherited in an autosomal dominant manner, can cause immune aberrations affecting many different cell lines. The pathogenic variant prevents appropriate NK cell development with specific deficiency of immature CD56bright NK cells causing an absence of the CD56bright population, leaving a functionally impaired CD56dim population. These patients are known to have refractory HPV infections, among other cutaneous viral infections, myelodysplasias, cytopenias, and a risk of acute and chronic myeloid leukemias. RTEL1 Biallelic pathogenic variants in regulator of telomerase elongation (RTEL1), a DNA helicase, cause a form of dyskeratosis congenita, bone marrow failure, and immunodeficiency known as Hoyeraal Hreidarsson syndrome. One patient reported with a history of dis seminated varicella infection was found to have abnormal NK cells in number and function. IRF8 Interferon regulatory factor 8 (IRF8) is a transcription factor involved in B cell, dendritic cell, granulocyte, monocyte, and NK cell production. IRF8 is vital for the NK cell response to viral infec tions and patients have been found to have severe EBV infections. Terminal NK cell maturation is disrupted and CD56dim cells are decreased in patients with biallelic IRF8 pathogenic variants. FUNCTIONAL NK CELL DEFICIENCY (FNKCD) CD16 Deficiency Patients with CD16 deficiency have severe infections with herpes viral pathogens such as varicella zoster virus (VZV), herpes simplex virus (HSV) and EBV. One patient was reported to have EBV driven Castleman disease. The deficiency is caused by a homozygous patho genic variant in the FCGR3A gene, which encodes CD16. CD16 is the Fc receptor on NK cells required for ADCC. As CD16 deficiency is an FNKCD, patients have normal levels of NK cells, but abnormal function. Although CD16s main function is to facilitate ADCC, patients with CD16 deficiency have been found to have abnormal spontaneous cytotoxicity with normal antibody dependent cyto toxicity (Fig. 167.3). Further analysis helped uncover a new func tion of the CD16 protein related to spontaneous cytotoxicity, which clarifies this unexpected finding. The variant sequence in CD16 deficiency encodes for the distal B73.1 domain of the CD16 mol ecule. Studies from patients with this pathogenic variant revealed that this region is needed for co activation of the NK cell CD2 stim ulatory receptor, which is required for spontaneous cytotoxicity. |
6,427 | Alternatively, immunoglobulin binding, which is integral to ADCC, occurs at the proximal 3G8 domain of CD16, which is not affected by the variant. For diagnostic purposes, two anti CD16 monoclonal antibodies are utilized against the distal B73.1 and proximal 3G8 domains. Therefore patients with CD16 deficiency will have absent B73.1 expression and normal 3G8 expression. These diagnostic tests can help identify patients with CD16 deficiency in addition to genetic analysis of FCGR3A. ELF4 E74like ETS transcription factor 4 (ELF4) is a protein involved in transactivation of gene promoters through DNA binding. Perforin expression, an important component of NK cell activity, has been shown to be dependent on ELF4regulated promoters. Pathogenic variants in ELF4 can result in poor terminal NK cell maturation MCM Cdc45 GINS1 6 4 P 7 3 5 MCM10 2 Fig. 167.2 Cell division cycle complex pathogenic variants associated with NK cell deficiency: MCM4, MCM10, and GINS1. Schematic illus tration of the cell division cycle complex including the CMG (Cdc45, mini chromosome maintenance MCM 2 7, GINS1) helicase complex and MCM10. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 167 u Natural Killer Cells 1289 from CD56bright to CD56dim (cytotoxic) NK cells. A rare, hemi zygous variant in ELF4, located on the X chromosome, has been described as a novel cause of NK cell deficiency. Patients with this variant can present with recurrent sinopulmonary and varicella zos ter infections, as well as lymphoproliferative and malignant disease. Laboratory analysis has shown decreased number and function of NK cells, specifically with an abnormal immature NK cell CD56bright to mature CD56dim NK cell ratio. Because these patients also can present with decreased B cells and hypogammaglobinemia, further work is needed to elucidate the role of ELF4 in B cell development and function. NK Cell Diagnostic Tests When evaluating for possible NK cell defects, it is important to exam ine the total NK cell count and percentage, the distribution of NK cell subsets, and NK cell function. NK Cell Count and Percentage The absolute NK cell count and NK cell percentage of total lympho cytes is often calculated using a lymphocyte subset analysis or enu meration assay. This test is performed using flow cytometry and will identify the CD16 and CD56 markers of NK cells. The majority of lymphocyte enumeration assays use a combined CD5616 antibody and cannot distinguish between CD56bright and CD56dim NK cells. Fur ther delineation of NK cell subsets (CD56dim, CD56bright, etc.) can be obtained with further flow cytometry for additional NK cell markers. Evaluation of NK cell phenotypes and ratios such as the CD56 bright to dim ratio becomes important in evaluating for NK cell defects such as GATA2 deficiency. FUNCTIONAL ASSAYS AVAILABLE FOR CLINICAL EVALUATION NK Cell Cytotoxicity Assay NK cytotoxic killing ability can be evaluated using a flow cytome trybased assay to quantify NK cell cytotoxic activity or a |
6,428 | chromium release (51CR) cytotoxicity assay. The 51CR is technician dependent and requires the use of radioactive material. Many laboratories are doing the flow cytometry based assay. Individual clinical laboratories have normal ranges that are particular to their specific assay; however, the values for this assay are dependent on the percentage of NK cells present in the sample. A peripheral blood mononuclear cell (PBMC) sample with lower numbers of NK cells may not identify as much NK cell cytotoxicity as a sample with higher levels of NK cells, thus it is essential to take the percentage of NK cells into account when interpreting these assays. CD107a Degranulation Lysosomal associated membrane protein 1 (LAMP 1) or CD107a is contained in NK cell lytic granules. CD107a is significantly upregulated on the surface of NK cells following lytic granule fusion with the NK cell membrane after activation by MHC I downregulated target cells. CD107a is thus often used as a way to evaluate activation induced NK cell degranulation. In this test, NK cells are stimulated and the upregu lation of CD107a is measured using flow cytometry. CD107a degranulation has advantages and disadvantages when compared to the NK cell cytotoxicity assay. The main advantage is that CD107a degranulation can be measured in individual cells and is therefore independent of the NK cells percentage. The disadvantage is that it does not directly measure NK cell killing ability. NK cell killing can be impaired despite appropriate degranulation for reasons such as abnormal lytic effector molecules. Ten to 30 of resting NK cells can be induced to degranulate when measured by flow cytometry, and in normal individuals CD107a degranulation reasonably correlates with killing ability. NK CELL DEFICIENCY TREATMENT Primarily, treatment of NKD targets the infectious complications that occur in these patients. Specifically, HSV infections should be treated with antiviral therapy such as acyclovir. Longterm pro phylaxis should be considered after completion of treatment. HPV infections can be significant and recurrent, and patients should be referred to dermatology for medical and surgical management. Additional therapies such as immunoglobulin replacement and anti mycobacterial prophylaxis can be utilized depending on the genetic cause of NKD. The only curative therapy for classical NKDs at this time is HSC transplantation. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 167.3 Functional natural killer (NK) cell deficiency secondary to CD16 pathologic variants. Schematic of the CD16 (Fc) NK cell receptor. The proximal domain of the CD16 receptor, 3G8, binds the Fc portion of immu noglobulin, which is important for antibody depending cytotoxicity. The distal domain of the CD16 receptor, B73.1, co localizes with the CD2 stimulatory receptor facilitating spon taneous cytotoxicity. In CD16 deficiency, the B73.1 domain of the CD16 receptor is not ad equately expressed causing impaired sponta neous cytotoxicity. NK Cell CD2 CD16 B73 .1 3G8 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1290 Part XII |
6,429 | u Immunology Section 3 The Phagocytic System THE PHAGOCYTIC INFLAMMATORY RESPONSE The phagocyte system includes both granulocytes (neutrophils, eosinophils, and basophils) and mononuclear phagocytes (mono cytes and tissue macrophages). Neutrophils and mononuclear phagocytes share primary functions, including the defining prop erties of large particle ingestion and microbial killing. Phagocytes participate primarily in the innate immune response but also help initiate acquired immunity. Neutrophils provide the rapid effector arm of the innate immune system. They circulate in the bloodstream for only about 6 hours (Table 168.1), but on encountering specific chemotactic signals, they adhere to the vascular endothelium and transmigrate into tissues. There they ingest and kill microbes and release chemotactic signals to recruit more neutrophils and to attract dendritic cells and other initiators of the acquired immune response. HEMATOPOIESIS The hematopoietic progenitor system can be viewed as a continuum of functional compartments, with the most primitive compartment composed of very rare pluripotential stem cells, which have high self renewal capacity and give rise to more mature stem cells, including cells that are committed to either lymphoid or myeloid development (Fig. 168.1). Common lymphoid progenitor cells give rise to T and B cell precursors and their mature progeny. Common myeloid progen itor cells eventually give rise to committed single lineage progenitors of the recognizable precursors through a random process of lineage restriction in a stepwise process (see Chapter 495). The capacity of lineage specific committed progenitors to proliferate and differenti ate in response to demand provides the hematopoietic system with a remarkable range of response to changing requirements for mature blood cell production. The proliferation, differentiation, and survival of immature hemato poietic progenitor cells are governed by hematopoietic growth factors, a family of glycoproteins (see Chapter 495). Along with regulating pro liferation and differentiation of progenitors, these factors influence the survival and function of mature blood cells. During granulopoiesis and monopoiesis, multiple cytokines regulate the cells at each stage of dif ferentiation from pluripotent stem cells to nondividing, terminally dif ferentiated cells (monocytes, neutrophils, eosinophils, and basophils). As cells mature, they lose receptors for most cytokines, especially those that influence early cell development; however, they retain receptors for cytokines that affect their mobilization and function, such as granu locyte and macrophage colony stimulating factors. Mature phagocytes also express receptors for chemokines, which help direct the cells to sites of inflammation. Chemokine receptors such as CXCR4 and its ligand SDF 1 play a key role in retention of developing myeloid cells within bone marrow. NEUTROPHIL MATURATION AND KINETICS The process of intramedullary granulocyte maturation involves changes in nuclear configuration and accumulation of specific intra cytoplasmic granules. The bone marrow microenvironment supports the normal steady state renewal of peripheral blood neutrophils through the generation of growth and differentiation factors by stro mal cells. Growth factors such as granulocyte colony stimulating factor (G CSF) and granulocyte macrophage colony stimulating fac tor (GM CSF) not only stimulate cell division, but also induce the expression of transcription factors that regulate the biosynthesis of functional components of |
6,430 | the neutrophil, such as granule proteins. The transcription factor PU.1 is essential for myelopoiesis, both as a positive regulatory element and as a suppressor of GATA1, a tran scription factor that directs nonmyeloid differentiation. Other tran scription factors, such as Runx1 (AML1), c myb, CDP, CEBP, C EBP, and MEF, are expressed in the myeloblast and promyelocyte, and some of these are required for azurophil granule protein expres sion. As cells enter the myelocyte stage, Runx1 and myb are downreg ulated, whereas PU.1 and CEBP expression rise to initiate terminal differentiation. Granulocytes survive for only 6 12 hours in the circulation; there fore daily production of 2 104 granulocytesL of blood is required to maintain a level of circulating granulocytes of 5 103L (see Table 168.1). The relatively small peripheral blood pool includes the rapidly interchanging circulating and marginating pools; the latter provides entrance into the tissue phase, where neutrophils may sur vive for hours or days. The circulating pool is fed and buffered by a much larger marrow population of mature neutrophils and myeloid precursors, representing the marrow reserve and proliferating pools, respectively. Proliferation of myeloid cells, encompassing approxi mately five mitotic divisions, takes place only during the first three stages of neutrophil development, in myeloblasts, promyelocytes, and myelocytes. After the myelocyte stage, the cells terminally dif ferentiate into nondividing, maturing metamyelocytes, bands, and neutrophils. Neutrophil maturation is associated with nuclear condensation and lobulation and the sequential production of characteristic granule pop ulations. A myeloblast is a relatively undifferentiated cell with a large oval nucleus, a sizable nucleolus, and a deficiency of granules. Promy elocytes acquire peroxidase positive azurophilic (primary) granules, and then myelocytes and metamyelocytes acquire specific (second ary) granules; tertiary granules and secretory vesicles develop in the final stage of neutrophil maturation. Chapter 168 Neutrophils Thomas D. Coates Table 168.1 Neutrophil and Monocyte Kinetics NEUTROPHILS Average time in mitosis (myeloblast to myelocyte) 7 9 days Average time in postmitosis and storage (metamyelocyte to neutrophil) 3 7 days Average half life in the circulation 6 hr Average total body pool 6.5 108 cellskg Average circulating pool 3.2 108 cellskg Average marginating pool 3.3 108 cellskg Average daily turnover rate 1.8 108 cellskg MONONUCLEAR PHAGOCYTES Average time in mitosis 30 48 hr Average half life in the circulation 36 104 hr Average circulating pool (monocytes) 1.8 107 cellskg Average daily turnover rate 1.8 109 cellskg Average survival in tissues (macrophages) Months From Boxer LA. Function of neutrophils and mononuclear phagocytes. In: Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia: Saunders; 1996. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 168 u Neutrophils 1291 NEUTROPHIL FUNCTION Neutrophil responses are initiated as circulating neutrophils flow ing through the postcapillary venules detect low levels of chemo kines and other chemotactic substances released from a site of infection. The sequence of events |
6,431 | as the neutrophil moves from cir culating in the blood to the encounter and destruction of bacteria is carefully orchestrated by a series of biochemical events, defects of which are associated with genetic disorders of neutrophil func tion (Fig. 168.2). In fact, these disorders of neutrophil function lead to our understanding of the cell biology of phagocyte function. A subset of circulating neutrophils loosely adheres to the endothelium through low affinity receptors called selectins and rolls along the endothelium, forming the marginated pool. Soluble effectors of inflammation trigger subtle changes in surface adhesion molecules ? MCSF IL5GCSF IL3 IL5 GMCSF IL6 IL11 SCF GCSF MCSF GMCSF polymorphonuclear Lineage Specific Hematopoietic Growth Factors BFUE GMP CFU G CFU M Eo CFU MEG CFU CFU b IL6 IL11 IL1 Earlyacting Hematopoietic Growth Factors erythrocyte monocyte eosinophilplatelet leukocyte Pre B Cell Pre T Cell B Cell T Cellbasophil CFUE macrophage GMCSF IL3 SCF IL1 TNF endothelial cell and fibroblast CMP Flt3 Ligand Tpo Epo Pre NK NK Cell CLP LTR HSC Epo MEP Tpo Wnt Jagged Angiopoietinlike 23 BMP Osteopontin Stem Cell Growth Factors Runx1 SclTal1 Lmo2 Mll Gfi1 Tel Bmi1 GATA2 Stem Cell Transcription Factors CEBP? CEBP? Gfi1 GATA1 GATA1 GATA2 FOG1 GATA1 FOG1 Gfi1b EKLF GATA1 Gfi1b CEBP? CEBP? GATA1 PU.1 PU.1 Ikaros E2A EBF Pax5 Bcl11a MPP MLP Notch1 TCF1 GATA3 Fig. 168.1 Major cytokine sources and actions and transcription factor requirements for hematopoietic cells. Cells of the bone marrow microen vironment, such as macrophages, endothelial cells, and reticular fibroblastoid cells, produce macrophage, granulocyte macrophage, and granu locyte colony stimulating factors (M CSF, GM CSF, G CSF), interleukin 6 (IL 6), and probably stem cell factor (SCF) (cellular sources not precisely determined) after induction with endotoxin (macrophage) or IL 1tumor necrosis factor (TNF) (endothelial cells and fibroblasts). T cells produce IL 3, GM CSF, and IL 5 in response to antigenic and IL 1 stimulation. These cytokines have overlapping actions during hematopoietic differentiation, as indicated, and for all lineages, optimal development requires a combination of early acting and late acting factors. Transcription factors important for survival or self renewal of stem cells are shown in red at the top, whereas stages of hematopoiesis blocked after the depletion of indicated transcription factors are shown in red for multipotent and committed progenitors. (From Sieff CA, Daley GQ, Zon LI. Anatomy and physiology of hematopoiesis. In: Orkin SH, Fisher DE, Ginsburg D, et al., eds. Nathan and Oskis Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia: Elsevier; 2015. Fig 1.7.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1292 Part XII u Immunology on endothelial cells at the site of infection. The rolling of neutro phils allows more intense exposure of neutrophils to activating fac tors such as tumor necrosis factor or interleukin 1 (see Fig. 168.2). Exposure of neutrophils to these same activating factors |
6,432 | induces qualitative and quantitative changes in the family of 2 integrin adhesion receptors (the CD11CD18 group of surface molecules), leading to tight adhesion between neutrophils and endothelial cells at the site of inflammation and ultimately to transmigration of the neutrophil into the tissue. Once through the endothelium, the neutrophil senses the gradi ent of chemokines or other chemoattractants and migrates to sites of infection. Neutrophil migration is a complex process involving rounds of receptor engagement, signal transduction, and remodeling of the actin microfilaments composing in part the cytoskeleton. Actin polymerization depolymerization occurs in approximately 8 second cycles and drives cyclic extension and retraction of the actin rich lamella at the front of the neutrophil. Receptors at the leading edge of the lamella detect the gradient of attractant and follow microorganisms, then ingest and destroy them. When the neutrophil reaches the site of infection, it recognizes pathogens by means of Fc immunoglobulin and complement receptors, toll like receptors, fibronectin receptors, and other adhesion molecules. The neutrophil ingests microbes that are coated by opsonins, serum proteins such as immunoglobulin and complement component C3. The pathogens are engulfed into a closed vacuole, the phagosome (Fig. 168.3), where two cellular responses essential for optimal micro bicidal activity occur concomitantly: degranulation and activation of nicotinamide adenine dinucleotide phosphate (NADPH)dependent oxidase. Fusion of neutrophil granule membranes with the phagosome membrane delivers potent antimicrobial proteins and small peptides into the phagosome. Assembly and activation of NADPH oxidase occur at the phago some membrane as well (see Fig. 168.3), generating large amounts of superoxide (O2 ) from molecular oxygen, which in turn decomposes to produce hydrogen peroxide (H2O2) and singlet oxygen. Myeloper oxidase, a major azurophil granule component, catalyzes the reaction Leukocyte adhesion defect I ChediakHigashi syndrome HyperIgE (Job) syndrome Actin polymerization defect Neonatal neutrophils Localized juvenile periodontitis Sialyl Lewis carbohydrates Integrin receptor Selectins ICAM1, 2 PECAM1 Chemotactic receptor Chemotactic agent Leukocyte adhesion defect I Actin polymerization defect ChediakHigashi syndrome Chronic granulomatous disease ChediakHigashi syndrome Specific granule deficiency Neutrophil G6PD deficiency Bacterial killing defects Bacteria Complement Fc receptor Antibody Chemotactic defect Phagocytic defect Impaired Eselectin adhesion (absent sialyl Lewis) Leukocyte adhesion defect II Endothelium Specific granules NADPH oxidase Impaired integrin adhesion Leukocyte adhesion defect I Fig. 168.2 The neutrophil mediated inflammatory response and associated neutrophil dysfunction syndromes. Circulating neutrophils loosely at tach to endothelium via selectins and roll along the vessel wall until they arrive at the site of infection. Inflammatory monokines, interleukin 1 (IL 1), and tumor necrosis factor (TNF) activate endothelial cells to express E and P selectins. E and P selectins serve as counter receptors for neutrophils sialyl Lewis X and Lewis X to cause low avidity neutrophil rolling. Activated endothelial cells express intracellular adhesion molecule (ICAM) 1, which serves as a counter receptor for neutrophil 2 integrin molecules, leading to high avidity leukocyte spreading and the start of transendothelial migration at the infection site. Neutrophils invade through the vascular basement membrane with the release of proteases and reactive oxidative intermediates, causing local destruction of |
6,433 | surrounding tissue at sites of high concentrations of chemotactic factors, and migrate to the site of infec tion, where they ingest and kill the bacteria. NADPH, Nicotinamide adenine dinucleotide phosphate; PECAM, platelet endothelial cell adhesion molecule. (Modified from Kyono W, Coates TD. A practical approach to neutrophil disorders. Pediatr Clin North Am. 2002;49:929.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 169 u Eosinophils 1293 Plasma membrane Cytoplasm Phagosome Fungus Bacteria HOCl MPO Rac 2 p40phox p67phox p47phox p67phox p40phox p47phox gp91phox p22phox RAC 2 P P P P P NADPH NADP? CAT SOD H2O2 H2O ? O2 ClOH Fe3? Fe2? O2 O2 ? Fig. 168.3 Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components and activation. On activation of phagocytic cells, the 3 cytosolic components (red) of the NADPH oxidase (p67phox, p47phox, and p40phox), plus the small guanosine triphosphatase (GTPase) pro tein Rac2, are translocated to the membrane of the phagocytic vacuole. The p47phox subunit binds to the flavocytochromeb558 membrane com ponent (blue green) of the NADPH oxidase (gp91phox plus p22phox). The NADPH oxidase catalyzes the formation of superoxide by transferring an electron from NADPH to molecular oxygen (O2), thereby forming the superoxide free radical. The unstable superoxide anion is converted to hydrogen peroxide, either spontaneously or by superoxide dismutase (SOD). H2O2 can follow different metabolic pathways into more potent reactive oxidants, such as OH or HOCl) or degradation to H2O O2. (Adapted from Stiehm ER, Ochs HD, Winkelstein JA. Immunologic Dis orders in Infants and Children, 5th ed. Philadelphia: Saunders; 2004, p. 622.) of H2O2 with ubiquitously present chloride ions to create hypochlorous acid (HOCl) in the phagosome. H2O2 and HOCl are potent microbici dal agents that break down and clear pathogens from sites of infection. In addition, neutrophils secrete a wide variety of cytokines and che mokines that recruit more neutrophils to fight the infection, attract monocytes and macrophages that possess both microbicidal and scav enger functions, and promote antigen presentation to help initiate the adaptive immune response. Also, the reactive oxidants can inactivate chemotactic factors and may serve to terminate the process of neu trophil influx, thereby attenuating the inflammatory process. Finally, the release of reactive oxygen species, granule proteins, and cytokines can also damage local tissues, leading to the classic signs of inflamma tion or to more permanent impairment of tissue integrity and func tion. In addition to the role of neutrophils in tissue damage, they are now known to play a significant role in regulation of inflammation and promoting tissue repair. Turning off inflammation and removing tissue debris is an important role and, like seeking and destroying bacteria, this process is highly regulated as well. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Eosinophils are nondividing, fully differentiated cells with a diam eter of approximately 8 m and a bilobed nucleus that are distin guished from other leukocytes by their |
6,434 | morphology, constituent products, and association with specific diseases. Their characteris tic membrane bound specific granules stain bright pink with eosin and are cytotoxic for the larval stages of helminthic parasites and are also thought to contribute to much of the inflammation asso ciated with chronic allergic diseases such as asthma (see Chapter 185). Eosinophil granule proteins including major basic protein, eosinophil cationic protein, eosinophil derived neurotoxin, and eosinophil peroxidase are thought to inflict epithelial cell damage, although recent studies indicate their role may be more nuanced and not purely destructive. Eosinophil granule contents activate other proinflammatory cells, including mast cells, basophils, neutrophils, and platelets and have the capacity to generate large amounts of the lipid mediators, which can cause vasoconstriction, smooth muscle contraction, and mucus hypersecretion (Fig. 169.1). Eosinophils are a source of several proinflammatory cytokines and have also been shown to influence T cell recruitment and immune polarization in inflammatory settings. Thus eosinophils have considerable poten tial to initiate and sustain the inflammatory response of the innate and acquired immune systems. Eosinophil migration from the vasculature into the extracellular tis sue is mediated by the binding of leukocyte adhesion receptors (e.g., VLA 4) to their ligands or counterstructures (VCAM 1) on the post capillary endothelium. Eosinophils are recruited to tissues in inflam matory states by a group of chemokines known as eotaxins (eotaxin 1, 2, and 3). These unique pathways account for selective accumula tion of eosinophils in allergic and inflammatory disorders. Eosinophils normally dwell primarily in tissues, especially tissues with an epithelial interface with the environment, including the respiratory, gastrointes tinal (GI), and lower genitourinary tracts. The life span of eosinophils may extend for weeks within tissues. Interleukin (IL) 5 selectively enhances eosinophil production, adhesion to endothelial cells, and function. Considerable evidence shows that IL 5 has a pivotal role in promoting eosinophilopoiesis. It is the predominant cytokine in allergen induced pulmonary late phase reaction, and antibodies against IL 5 (mepolizumab, reslizumab, ben ralizumab) decrease sputum eosinophils and reduce exacerbations in a subset of patients with asthma. Eosinophils also bear unique receptors for several chemokines, including RANTES (regulated on activation, normal T cell expressed and secreted), eotaxin, and monocyte chemo tactic proteins 3 and 4. These chemokines appear to be key mediators in the induction of tissue eosinophilia. DISEASES ASSOCIATED WITH EOSINOPHILIA The absolute eosinophil count (AEC) is used to quantify peripheral blood eosinophilia. Calculated as the white blood cell (WBC) countL percentage of eosinophils, it is usually 450 cellsL and varies diur nally, with eosinophil numbers higher in the early morning and dimin ishing as endogenous glucocorticoid levels rise. Many diseases with allergic, infectious, hematologic, autoimmune, or idiopathic origins are associated with moderate (AEC 1,500 5,000 cellsL) or severe (AEC 5,000 cellsL) eosinophilia in peripheral blood (Table 169.1). These disorders may range from mild and tran sient to chronic and life threatening. Importantly, blood eosinophil numbers do not always reflect the extent of eosinophil involvement in tissues and degranulation products may more accurately reflect disease activity. Because |
6,435 | prolonged eosinophilia is associated with end organ Chapter 169 Eosinophils Benjamin L. Wright and Brian P. Vickery Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1294 Part XII u Immunology Fig. 169.1 Schematic diagram of an eosinophil and its diverse properties. Eosinophils are bilobed granulocytes that respond to diverse stimuli, in cluding allergens, helminths, viral infections, al lografts, and nonspecific tissue injury. Eosinophils express the receptor for interleukin (IL) 5, a critical eosinophil growth and differentiation factor, as well as the receptor for eotaxin and related chemokines (CCR3). The secondary granules contain four pri mary cationic proteins designated eosinophil per oxidase (EPX), major basic protein (MBP), eosino phil cationic protein (ECP), and eosinophil derived neurotoxin (EDN). All four proteins are cytotoxic molecules; also, ECP and EDN are ribonucleases. In addition to releasing their preformed cationic proteins, eosinophils can release a variety of cy tokines, chemokines, and neuromediators and generate large amounts of leukotriene C4 (LTC4). Last, eosinophils can be induced to express ma jor histocompatibility complex (MHC) class II and co stimulatory molecules and may be involved in propagating immune responses by presenting an tigen to T cells. PAF, platelet activating factor; VIP, vasoactive intestinal peptide. (From Leung YM, Szefler SJ, Bomilla FA, Akdis CA, Sampson HA. Pediatric Allergy: Principles and practice. 3rd ed. Philadelphia: Elsevier; 2016. p. 42.) MHC II B7.2 MBP EDN CCR3 Dendritic cell activation Th2 polarization Triggers Allergens Helminths Tissue injury Viral infection Mast cell activation Antigen presentation Mitochondrial DNA defense Secreted Cytokines IL2, IL3, IL4, IL5, IL6, IL8 IL12, IFN , GMCSF, TNF?, TGF?? Chemokines Eotaxin RANTES MIP1? Cytotoxic proteins ECP, EDN, EPX, MBP Lipid mediators Leukotrienes PAF Neuromediators Substance P VIP Eotaxin3 IL5 IL5R damage, especially involving the heart, patients with persistently ele vated AECs should undergo a thorough evaluation to search for an underlying cause. Allergic Diseases Allergy is the most common cause of eosinophilia in children in the United States. Patients with allergic asthma typically have eosinophils in the blood, sputum, andor lung tissue. Hypersensitivity drug reactions can elicit eosinophilia, and when associated with organ dysfunction (e.g., DRESS drug rash with eosinophilia and systemic symptoms), these reactions can be serious (see Chapter 193). If a drug is suspected of trig gering eosinophilia, biochemical evidence of organ dysfunction should be sought, and if found, the drug should be discontinued. Various skin diseases have also been associated with eosinophilia, including atopic dermatitiseczema, pemphigus, urticaria, and toxic epidermal necrolysis. Eosinophilic gastrointestinal diseases (EGIDs) are important emerging allergic causes of eosinophilia in tissue and, in some cases, peripheral blood (see Chapter 383). In these conditions, eosinophils are recruited to the esophagus, stomach, andor intestine, where they may cause tissue inflammation and clinical symptoms such as dyspha gia, food aversion, abdominal pain, vomiting, or diarrhea. Eosinophilic esophagitis is the most common EGID. Treatment options include pro ton pump inhibitors, allergen elimination |
6,436 | diets, topical corticosteroids, and biologics (e.g. dupilumab). Patients with nonesophageal EGIDs often require treatment with systemic steroids. Infectious Diseases Eosinophilia is often associated with invasive infection with multicel lular helminthic parasites, which are the most common cause in devel oping countries. Table 169.1 includes examples of specific organisms. The level of eosinophilia tends to parallel the magnitude and extent of tissue invasion, especially by larvae such as visceral larva migrans (see Chapter 344). Eosinophilia often does not occur in established parasitic infections that are well contained within tissues or are solely intralumi nal in the GI tract, such as Giardia lamblia and Enterobius vermicularis infection. In evaluating patients with unexplained eosinophilia, the dietary history and geographic or travel history may indicate potential expo sures to helminthic parasites. It is frequently necessary to examine the stool for ova and larvae at least three times. Additionally, the diag nostic parasite stages of many of the helminthic parasites that cause eosinophilia never appear in feces. Thus normal results of stool exami nations do not absolutely preclude a helminthic cause of eosinophilia; diagnostic blood tests or tissue biopsy may be needed. Toxocara causes visceral larva migrans usually in toddlers with pica (see Chapter 344). Most young children are asymptomatic, but some develop fever, pneu monitis, hepatomegaly, and hypergammaglobulinemia accompanied by severe eosinophilia. Isohemagglutinins are frequently elevated, and serology can establish the diagnosis. Two fungal diseases may be associated with eosinophilia: aspergil losis in the form of allergic bronchopulmonary aspergillosis (see Chapter 283) and coccidioidomycosis (see Chapter 286) following primary infection, especially in conjunction with erythema nodosum. HIV infection can also be associated with peripheral eosinophilia. Hypereosinophilic Syndrome The idiopathic hypereosinophilic syndrome is a heterogeneous group of disorders characterized by sustained overproduction of eosinophils. The three diagnostic criteria for this disorder are (1) AEC 1,500 cellsL persisting for 6 months or longer or at least on two occasions or with evidence of tissue eosinophilia; (2) absence of another diagno sis to explain the eosinophilia; and (3) signs and symptoms of organ involvement. The clinical signs and symptoms of hypereosinophilic syndrome can be heterogeneous because of the diversity of potential organ (pulmonary, cutaneous, neurologic, serosal, GI) involvement. Organ specific signs and symptoms direct the diagnostic evaluation, but common initial tests used to evaluate hypereosinophilia and poten tial end organ complications include a comprehensive metabolic panel, inflammatory markers, troponin level, urinalysis, antineutrophil cyto plasmic antibodies, immunoglobulin levels, vitamin B12 level, trypt ase level, stool examination for ova and parasites, parasite serologies, HIV testing, and a chest x ray. Eosinophilic endomyocardial disease, one of the most serious and life threatening complications, can cause heart failure from endomyocardial thrombosis and fibrosis. Screen ing for cardiac involvement should also include an electrocardiogram, an echocardiogram, and in some cases a cardiac MRI. Evaluation of the hypereosinophilic syndrome requires morphologic review of the blood and marrow, cytogenetics, fluorescence in situ hybridization, immunophenotyping by flow cytometry, and T cell clonality assess ment to detect histopathologic or clonal evidence for hematolymphoid neoplasm. Eosinophilic leukemia, |
6,437 | a clonal myeloproliferative variant, may be distinguished from idiopathic hypereosinophilic syndrome Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 169 u Eosinophils 1295 Table 169.1 Causes of Eosinophilia ALLERGIC DISORDERS Allergic rhinitis Asthma Acute and chronic urticaria Atopic dermatitis Angioedema Hypersensitivity drug reactions (drug rash with eosinophilia and systemic symptoms DRESS) Eosinophilic gastrointestinal disorders Interstitial nephritis Mastocytosis INFECTIOUS DISEASES Tissue Invasive Helminth Infections and Other Infections Trichinosis Toxocariasis Strongyloidiasis Ascariasis Filariasis Schistosomiasis Echinococcosis Amebiasis Malaria Scabies Toxoplasmosis Pneumocystis jirovecii Scarlet fever Allergic bronchopulmonary aspergillosis (ABPA) Coccidioidomycosis Human immunodeficiency virus (HIV) MALIGNANT DISORDERS Hodgkin disease and T cell lymphoma Acute myelogenous leukemia Myeloproliferative disorders Eosinophilic leukemia Brain tumors GASTROINTESTINAL DISORDERS Inflammatory bowel disease Peritoneal dialysis Chronic active hepatitis Eosinophilic Gastrointestinal Disorders Eosinophilic esophagitis Eosinophilic gastritis Eosinophilic enteritis Eosinophilic colitis RHEUMATOLOGIC DISEASE Rheumatoid arthritis Eosinophilic fasciitis Scleroderma Dermatomyositis Systemic lupus erythematosus IgG4 related disease Eosinophilic granulomatosis with polyangiitis (Churg Strauss vasculitis) IMMUNODEFICIENCYIMMUNE DYSREGULATION DISEASE Hyperimmunoglobulin E syndromes Wiskott Aldrich syndrome Graft versus host disease Omenn syndrome Severe congenital neutropenia Autoimmune lymphoproliferative syndromes (ALPS) Immune dysregulation, polyendocrinopathy, X linked (IPEX) and IPEX like syndrome Transplant rejection (solid organ) MISCELLANEOUS Thrombocytopenia with absent radii Hypersensitivity pneumonitis Adrenal insufficiency Postirradiation of abdomen Histiocytosis with cutaneous involvement Hypereosinophilic syndromes Cytokine infusion Pemphigoid by demonstrating a clonal interstitial deletion on chromosome 4q12 that fuses the platelet derived growth factor receptor (PDGFRA) and FIP1 like 1 (FIP1L1) genes; this disorder is treated with imatinib mesylate, a tyrosine kinase inhibitor, which helps target the fusion oncoprotein (Fig. 169.2). Therapy is aimed at suppressing eosinophilia and is initiated with corticosteroids. Patients with possible exposure to Strongyloides should receive concomitant empiric treatment with ivermectin to prevent corticosteroid associated hyperinfection syndrome. Imatinib mesylate may be effective in FIP1L1 PDGFRAnegative patients. Hydroxyurea or interferon alfa may be beneficial in patients unresponsive to corti costeroids. Specific antiIL 5 monoclonal antibodies (mepolizumab) target this cytokine, which has a central role in eosinophil differen tiation, mobilization, and activity. With therapy, the eosinophil count declines and corticosteroid doses may be reduced. For patients with prominent organ involvement who fail to respond to therapy, the mor tality is about 75 after 3 years. Miscellaneous Diseases Eosinophilia is observed in many patients with primary immunode ficiency syndromes, especially hyper IgE syndrome, Wiskott Aldrich syndrome, and Omenn syndrome (see Chapter 165). Eosinophilia is also frequently present in the syndrome of thrombocytopenia with absent radii and in familial reticuloendotheliosis with eosinophilia. Eosinophilia can be found in patients with Hodgkin disease, as well as in acute lymphoid and myeloid leukemia. Other considerations include GI disorders such as ulcerative colitis, Crohn disease during symptomatic phases, chronic hepatitis, eosinophilic granulomatosis with polyangiitis (Churg Strauss vasculitis), mastocytosis, and adrenal insufficiency. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use |
6,438 | only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1296 Part XII u Immunology Hypereosinophilic syndromes (HESs) Lymphocytic forms Myeloproliferative forms Populations of T cells secreting eosinophil hematopoietins Overlap Undefined Organ restricted eosinophilic disorders Associated Eosinophilia in association with a defined diagnosis, such as IBD or CSS Familial Family history of documented persistent eosinophilia of unknown cause Myeloproliferative HES Features of myeloproliferative disease without proof of clonality CEL Clonal eosinophilia including FIP1L1 PDGFRA positive CEL Clonal T cells T cells often exhibit an abnormal immuno phenotype No T cell clone Aberrant immuno phenotype or evidence of marked T cell activation Benign Asymptomatic with no evidence of organ involvement Episodic Cyclic angioedema and eosinophilia Other Symptomatic without features of myeloproliferative or lymphocytic forms Fig. 169.2 Revised classification of hypereosinophilic syndromes. Changes from the previous classification are indicated in red. Dashed arrows identify hypereosinophilic syndrome (HES) forms for which at least some patients have T celldriven disease. Classification of myeloproliferative forms has been simplified, and patients with HES and eosinophil hematopoietinproducing T cells in the absence of a T cell clone are included in the lymphocytic forms of HES. CEL, Chronic eosinophilic leukemia; CSS, Churg Strauss syndrome; IBD, inflammatory bowel disease. (From Simon HU, Rothenberg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126:45 49.) Neutrophils are the first line of defense against microbial invasion. They arrive at the site of inflammation during the critical 2 4 hours after microbial invasion to contain the infection and prevent hema togenous dissemination. Much of our knowledge about neutrophil function derives from studies done in patients with genetic errors in neutrophil function. These critical functions and their associated dis orders are depicted in Figure 168.2. Children with phagocytic dysfunc tion present at a young age with recurrent infections that often involve unusual organisms and are poorly responsive to treatment. Primary defects of phagocytic function comprise 20 of immuno deficiencies, and there is significant overlap in the presenting signs and symptoms between phagocytic disorders and lymphocyte and humeral disorders. Children with phagocytic defects present with deep tissue infection, pneumonia, adenitis, cutaneous lesions, or osteomyelitis rather than bloodstream infections (Tables 170.1 and 170.2; Fig. 170.1). In the past, diagnosis of these disorders relied on very specialized biologic assays. Because the genes for most of these disorders have been identified, the first step in diagnosis for all of these disorders is to obtain DNA analysis through commercially available genetic panels for immunodeficiency. Chemotaxis, the direct migration of cells into sites of infection, involves a complex series of events (see Chapter 168). Disorders of adhesion or granule abnormalities can have intermediate or profound motility defects, and the propensity to infections is related to a combi nation of these functional deficits. One family with recessively inherited neutrophil actin dysfunction demonstrated that a pure severe chemo tactic defect can result in fatal recurrent infection. Defective in vitro chemotaxis of neutrophils can be detected in children with various clinical conditions. However, |
6,439 | unless chemotaxis is essentially absent, it is difficult to establish whether frequent infections arise from a primary chemotactic abnormality or occur as secondary medical complications of the underlying disorder. Dental infection with Capnocytophaga is associated with a clear neutrophil motility defect that resolves when the infection is eliminated. Motility defects present with significant skin and mucosal infections. Tender cutaneous nodular lesions may also be present and characteris tically do not contain neutrophils. In fact, the presence of a true abscess makes the diagnosis of a significant chemotactic defect less likely. Laboratory tests of chemotaxis are biologic assays and have high variability except in the most experienced hands. The assays must be done on freshly obtained blood and are affected by many factors related to the blood sampling. It is best to assay other features of the suspected disorder, such as surface marker expression, to establish a specific diagnosis. Chapter 170 Disorders of Phagocyte Function Thomas D. Coates Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 170 u Disorders of Phagocyte Function 1297 Table 170.2 Clinical Disorders of Neutrophil Function DISORDER ETIOLOGY IMPAIRED FUNCTION CLINICAL CONSEQUENCE DEGRANULATION ABNORMALITIES Chdiak Higashi syndrome (CHS) Autosomal recessive; disordered coalescence of lysosomal granules; responsible gene is CHSILYST, which encodes a protein hypothesized to regulate granule fusion Decreased neutrophil chemotaxis, degranulation, and bactericidal activity; platelet storage pool defect; impaired NK function, failure to disperse melanosomes Neutropenia; recurrent pyogenic infections; propensity to develop marked hepatosplenomegaly as a manifestation of hemophagocytic syndrome Specific granule deficiency Autosomal recessive; functional loss of myeloid transcription factor arising from a pathogenic variant or arising from reduced expression of Gfi 1 or CEBP, which regulates specific granule formation Impaired chemotaxis and bactericidal activity; bilobed nuclei in neutrophils; defensins, gelatinase, collagenase, vitamin B12binding protein, and lactoferrin Recurrent deep seated abscesses ADHESION ABNORMALITIES Leukocyte adhesion deficiency 1 (LAD 1) Autosomal recessive; absence of CD11CD18 surface adhesive glycoproteins (2 integrins) on leukocyte membranes most commonly arising from failure to express CD18 messenger RNA Decreased binding of iC3b to neutrophils and impaired adhesion to ICAM 1 and ICAM 2 Neutrophilia; recurrent bacterial infection associated with a lack of pus formation Leukocyte adhesion deficiency 2 (LAD 2) Autosomal recessive; loss of fucosylation of ligands for selectins and other glycol conjugates arising from pathogenic variants of GDP fucose transporter Decreased adhesion to activated endothelium expressing ELAM Neutrophilia; recurrent bacterial infection without pus Leukocyte adhesion deficiency 3 (LAD 1 variant syndrome) Autosomal recessive; impaired integrin function arising from pathogenic variants of FERMT3, which encodes kindlin 3 in hematopoietic cells; kindlin 3 binds to integrin and thereby transmits integrin activation Impaired neutrophil adhesion and platelet activation Neutrophilia, recurrent infections, bleeding tendency Continued Table 170.1 Infections and White Blood Cell Defects: Features That Can Be Seen in Phagocyte Disorders SEVERE INFECTIONS RECURRENT INFECTIONS SPECIFIC INFECTIONS UNUSUALLY LOCATED INFECTIONS TYPE OF INFECTION DIAGNOSIS TO CONSIDER SITE |
6,440 | OF INFECTION DIAGNOSIS TO CONSIDER MICRO ORGANISM DIAGNOSIS TO CONSIDER SITE OF INFECTION DIAGNOSIS TO CONSIDER Cellulitis Neutropenia, LAD, CGD, HIES Cutaneous Neutropenia, CGD, LAD, HIES Staphylococcus epidermidis Neutropenia, LAD Umbilical cord LAD Colitis Neutropenia, CGD Gums LAD, neutrophil motility disorders Serratia marcescens, Nocardia, Burkholderia cepacia CGD Liver abscess CGD Osteomyelitis CGD, MSMD pathway defects Upper and lower respiratory tract Neutropenia, HIES, functional neutrophil disorders Aspergillus Neutropenia, CGD, HIES Gums LAD, neutrophil motility disorders Gastrointestinal tract CGD, MSMD pathway defects (salmonella) Nontuberculous mycobacteria, BCG MSMD pathway defects, SCID, CGD Lymph nodes CGD, MSMD pathway defects (mycobacteria) Candida Neutropenia, CGD, MPO Osteomyelitis CGD, MSMD BCG, Bacille Calmette Gurin; CGD, chronic granulomatous disease; HIES, hyper IgE syndrome; LAD, leukocyte adhesion deficiency; MPO, myeloperoxidase; MSMD, mendelian susceptibility to mycobacterial disease; SCID, severe combined immunodeficiency. From Leung DYM. Pediatric Allergy: Principles and Practice. 2nd ed. Philadelphia: Saunders; 2010. p. 134. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1298 Part XII u Immunology DISORDER ETIOLOGY IMPAIRED FUNCTION CLINICAL CONSEQUENCE DISORDERS OF CELL MOTILITY Enhanced motile responses; FMF Autosomal recessive gene responsible for FMF on chromosome 16, which encodes for a protein called pyrin; pyrin regulates caspase 1 and thereby IL 1 secretion; mutated pyrin may lead to heightened sensitivity to endotoxin, excessive IL 1 production, and impaired monocyte apoptosis Excessive accumulation of neutrophils at inflamed sites, possibly the result of excessive IL 1 production Recurrent fever, peritonitis, pleuritis, arthritis, amyloidosis DEPRESSED MOTILE RESPONSES Defects in the generation of chemotactic signals IgG deficiencies; C3 and properdin deficiency can arise from genetic or acquired abnormalities; mannose binding protein deficiency predominantly in neonates Deficiency of serum chemotaxis and opsonic activities Recurrent pyogenic infections Intrinsic defects of the neutrophil, e.g., LAD, CHS, specific granule deficiency, neutrophil actin dysfunction, neonatal neutrophils In the neonatal neutrophil there is diminished ability to express 2 integrins, and there is a qualitative impairment in 2 integrin function Diminished chemotaxis Propensity to develop pyogenic infections Direct inhibition of neutrophil mobility, e.g., drugs Ethanol, glucocorticoids, cyclic AMP Impaired locomotion and ingestion; impaired adherence Possible cause for frequent infections; neutrophilia seen with epinephrine arises from cyclic AMP release from endothelium Immune complexes Bind to Fc receptors on neutrophils in patients with rheumatoid arthritis, systemic lupus erythematosus, and other inflammatory states Impaired chemotaxis Recurrent pyogenic infections Hyper IgE syndrome Autosomal dominant; responsible gene is STAT3 Impaired chemotaxis at times; impaired regulation of cytokine production Recurrent skin and sinopulmonary infections, eczema, mucocutaneous candidiasis, eosinophilia, retained primary teeth, minimal trauma fractures, scoliosis, and characteristic facies Hyper IgE syndromeAR Autosomal recessive; more than one gene likely contributes to its etiology High IgE levels, impaired lymphocyte activation to staphylococcal antigens Recurrent pneumonia without pneumatoceles sepsis, enzyme, boils, mucocutaneous candidiasis, neurologic symptoms, eosinophilia MICROBICIDAL ACTIVITY Chronic granulomatous disease (CGD) X linked and AR; failure to express functional gp91phox in the phagocyte membrane in p22phox (AR) Other |
6,441 | AR forms of CGD arise from failure to express protein p47phox or p67phox Failure to activate neutrophil respiratory burst, leading to failure to kill catalase positive microbes Recurrent pyogenic infections with catalase positive microorganisms G6PD deficiency 5 of normal activity of G6PD Failure to activate NADPH dependent oxidase; hemolytic anemia Infections with catalase positive microorganisms Myeloperoxidase deficiency Autosomal recessive; failure to process modified precursor protein arising from missense variant H2O2 dependent antimicrobial activity not potentiated by myeloperoxidase None Rac2 deficiency Autosomal dominant; dominant negative inhibition by variant protein of Rac2 mediated functions Failure of membrane receptor mediated O2 generation and chemotaxis Neutrophilia, recurrent bacterial infections Deficiencies of glutathione reductase and glutathione synthetase AR; failure to detoxify H2O2 Excessive formation of H2O2 Minimal problems with recurrent pyogenic infections AMP, Adenosine monophosphate; AR, autosomal recessive; C, complement; CD, cluster of differentiation; ELAM, endothelial leukocyte adhesion molecule; FMF, familial Mediter ranean fever; G6PD, glucose 6 phosphate dehydrogenase; GDP, guanosine diphosphate; ICAM, intracellular adhesion molecule; IL 1, interleukin 1; NADPH, nicotinamide adenine dinucleotide phosphate; NK, natural killer. Adapted from Curnutte JT, Boxer LA. Clinically significant phagocytic cell defects. In: Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Disease. 6th ed. New York: McGraw Hill; 1985. p. 144. Table 170.2 Clinical Disorders of Neutrophil Functioncontd Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 170 u Disorders of Phagocyte Function 1299 LEUKOCYTE ADHESION DEFICIENCY Leukocyte adhesion deficiency types 1 (LAD 1), 2 (LAD 2), and 3 (LAD 3) are rare autosomal recessive disorders of leukocyte function. LAD 1 affects about 1 per 10 million individuals and is characterized by recurrent bacterial and fungal infections and depressed inflamma tory responses despite striking blood neutrophilia (Table 170.3). Genetics and Pathogenesis LAD 1 results from pathogenic variants of the gene on chromo some 21q22.3 encoding CD18, the 95 kDa 2 leukocyte trans membrane integrin subunit. Normal neutrophils express four heterodimeric adhesion molecules: LFA 1 (CD11aCD18), Mac 1 (CD11bCD18, also known as CR3 or iC3b receptor), p150,95 (CD11cCD18), and 12 (CD11dCD18). These four transmem brane adhesion molecules are composed of unique extracellular 1 encoded on chromosome 16, and they share a common 2 subunit (CD18) that links them to the membrane and connects them to intracellular signal transduction machinery. This group of leuko cyte integrins is responsible for the tight adhesion of neutrophils to the endothelial cell surface, egress from the circulation, and adhe sion to iC3b coated microorganisms, which promotes phagocytosis and particulate activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Some pathogenic vari ants of CD11CD18 allow a low level of assembly and activity of integrin molecules, resulting in retention of some neutrophil integ rin adhesion function and a moderate phenotype. Because of their inability to adhere firmly to intercellular adhe sion molecules 1 (ICAM 1) and 2 (ICAM 2) expressed on inflamed endothelial cells (see Chapter |
6,442 | 168), neutrophils cannot transmigrate through the vessel wall and move to the site infection. Furthermore, neutrophils that do arrive at inflammatory sites fail to recognize micro organisms opsonized with complement fragment iC3b, an important stable opsonin formed by the cleavage of C3b. Therefore other neu trophil functions such as degranulation and oxidative metabolism normally triggered by iC3b binding are also greatly compromised in LAD 1 neutrophils, resulting in impaired phagocytic function and high risk for serious and recurrent bacterial infections. Monocyte function is also impaired, with poor fibrinogen binding function, an activity that is promoted by the CD11CD18 complex. Con sequently, such cells are unable to participate effectively in wound healing. Children with LAD 2 share the clinical features of LAD 1 but have normal CD11CD18 integrins. Features unique to LAD 2 include neu rologic defects, cranial facial dysmorphism, and absence of the eryth rocyte ABO blood group antigen (Bombay phenotype). LAD 2 (also known as congenital disorder of glycosylation IIc (CDG IIc) derives from pathogenic variants in the gene encoding a specific guanosine diphosphate (GDP) l fucose transporter of the Golgi apparatus. This abnormality prevents the incorporation of fucose into various cell sur face glycoproteins, including the carbohydrate structure sialyl Lewis X that is critical for low affinity rolling adhesion of neutrophils to vas cular endothelium. This is an important initial step necessary for sub sequent integrin mediated activation, spreading, and transendothelial migration. Infections in LAD 2 are milder than that in LAD 1. LAD 3 is characterized by a Glanzmann thrombasthenialike bleeding disorder, delayed separation of the umbilical cord, and seri ous skin and soft tissue infections similar to those seen in LAD 1, and failure of leukocytes to undergo 2 and 1 integrinmediated adhe sion and migration. Pathogenic variants in KINDLIN3 affect integrin activation. Clinical Manifestations Patients with the severe clinical form of LAD 1 express 0.3 of the normal amount of the 2 integrin molecules, whereas patients with the moderate phenotype may express 27 of the normal amount. Children with severe forms of LAD present in infancy with recurrent, indolent bacterial infections of the skin, mouth, respiratory tract, lower intestinal tract, and genital mucosa. Significant neutrophilic leukocyto sis, often 25,0000mm3, is a prominent feature. They may have a his tory of delayed separation of the umbilical cord, usually with associated infection of the cord stump. The presence of significant omphalitis is an important feature that distinguishes these rare patients from the 10 of healthy infants who can have cord separation at age 3 weeks or later. Skin infection may progress to large chronic ulcers with polymicrobial infection, including anaerobic organisms (Fig. 170.2). The ulcers heal slowly, need months of antibiotic treatment, and often require plastic surgery grafting. Severe gingivitis can lead to early loss of primary and secondary teeth (Fig. 170.3). Infected areas characteristically have very little neutrophilic infiltration (absent pus). The pathogens infecting patients with LAD 1 are similar to those affecting patients with severe neutropenia (see Chapter 171) and Fig. 170.1 Algorithm for clinical |
6,443 | evaluation of patients with recurrent infections. Shown are the evaluations that can be done in a routine clinical laboratory. The complete blood count (CBC) can detect marked leukocytosis in leukocyte adhesion deficiency (LAD) and giant granules of Chdiak Higashi syndrome may be seen on the smear. Chemotaxis and all other neutrophil function assays require highly specialized research laboratories. CD, Cluster of differentiation; CRP, C reactive protein; DHR, dihydrorhodamine; ESR, erythrocyte sedimentation rate; FACS, fluorescence activated cell sorter; HIV, human immunodeficiency virus; IgE, immunoglobulin E; NBT, nitroblue tetrazolium; PHA, phytohemagglutinin. (Adapted from Dinauer, MC, Coates TD: Disorders of neutrophil function. In: Hoffman R, Benz EJ, Silberstein LE, et al., eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia: Saunders; 2012.) Recurrent deep tissue infection (e.g., lymphadenitis, pneumonia, osteomyelitis, liver abscess) Unusual or resistant infection (S. aureus, Pseudomonas, Klebsiella, Serratia, Candida, Aspergillus, Nocardia) Periodontal disease or tooth loss Omphalitis Family history of recurrent infection Gingivitis Chronic diarrhea Infections with absence of neutrophilic infiltration CRPESR Splenomegaly or hepatomegaly Moderate lymphadenopathy Inflammatory anemia In fe ct io ns H is to ry a nd p hy si ca l U n u su al f re q u en cy o r ty p e o f in fe ct io n Initial evaluation CBC, ESR, ro lymphopenia Quantitative immunoglobulins lgE Immunoglobulin subsets TB cell quantitation and subsets PHA stimulation Response to tetanus immunization HIV Neutrophil evaluation CBC NBT slide test or DHR by FACS CD18CD11b by FACS CD15a by FACS Bombay blood group (Chemotaxis) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1300 Part XII u Immunology include Staphylococcus aureus and enteric gram negative organisms such as Escherichia coli. These patients are also susceptible to oppor tunistic infection by fungi such as Candida and Aspergillus. Typical signs of inflammation, such as swelling, erythema, and warmth, may be absent. Pus does not form, and few neutrophils are identified micro scopically in biopsy specimens of infected tissues. Despite the paucity of neutrophils within the affected tissue, the circulating neutrophil count during infection typically exceeds 30,000L and can surpass 100,000L. During intervals between infections, the peripheral blood neutrophil count may chronically exceed 12,000L. LAD 1 genotypes with only moderate, rather than absent, amounts of functional integ rins at the surface of the neutrophil have significantly reduced severity and frequency of infections compared with children with the severe form, although gingival disease is still a prominent feature. Laboratory Findings The diagnosis of LAD 1 is established most readily by flow cytometric measurements of surface CD11bCD18 in stimulated and unstimu lated neutrophils. Neutrophil and monocyte adherence, aggregation, chemotaxis, and iC3b mediated phagocytosis demonstrate strik ing abnormalities. However, these assays are not clinically available. Delayed type hypersensitivity reactions are normal, and most individ uals have normal specific antibody synthesis, although some patients have impaired T lymphocytedependent antibody responses. The diag nosis of LAD |
6,444 | 2 is established by flow cytometric measurement of sialyl Lewis X (CD15) on neutrophils. It is important to note that the flow cytometric assays are not done the same as the more common lympho cyte subset analysis and require specialized approaches to detect levels of surface expression, especially to detect milder phenotypes. Treatment Treatment of LAD 1 depends on the phenotype, as determined by the level of expression of functional CD11CD18 integrins. Early allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for severe LAD 1 (and LAD 3). One patient was successfully treated with ustekinumab, an inhibitor of interleukins 12 and 23. Other treat ment is largely supportive. Patients can be maintained on prophylactic trimethoprimsulfamethoxazole (TMPSMX) and should have close sur veillance for early identification of infections and initiation of empirical treatment with broad spectrum antibiotics. Specific determination of the etiologic agent by culture or biopsy is important because of the prolonged antibiotic treatment required in the absence of neutrophil function. Some LAD 2 patients have responded to fucose supplementation, which induced a rapid reduction in the circulating leukocyte count and appearance of the sialyl Lewis X molecules, accompanied by marked improvement in leukocyte adhesion. Fig. 170.3 Oral pathology in a patient with leukocyte adhesion defi ciency type 1 (LAD 1). Gingivitis and severe periodontitis are hallmarks of LAD 1. (From Rich RR. Clinical Immunology: Principles and Practice. 4th ed. Philadelphia: Saunders; 2013, p. 273.) Fig. 170.2 Skin infection of a patient with leukocyte adhesion defi ciency type 1. Failure to form pus, inability to demarcate the fibrotic skin debris, and limited inflammation. Enterococcus gallinarium was cultured from the wound. (From Rich RR. Clinical Immunology: Princi ples and Practice. 4th ed. Philadelphia: Saunders; 2013, p. 273.) Table 170.3 Leukocyte Adhesion Deficiency Syndromes LEUKOCYTE ADHESION DEFICIENCY (LAD) TYPE 1 (LAD 1) TYPE 2 (LAD 2 OR CDG IIc) TYPE 3 (LAD 3) E SELECTIN DEFICIENCY Rac2 DEFICIENCY OMIM 116920 266265 612840 131210 602049 Inheritance pattern Autosomal recessive Autosomal recessive Autosomal recessive Unknown Autosomal dominant Affected protein(s) 2 Integrin common chain (CD18) Fucosylated proteins (e.g., sialyl Lewis X, CD15s) Kindlin 3 Endothelial E selectin expression Rac2 Neutrophil function affected Chemotaxis, tight adherence Rolling, tethering Chemotaxis, adhesion, superoxide production Rolling, tethering Chemotaxis, super oxide production Delayed umbilical cord separation Yes (severe phenotype only) Yes Yes Yes Yes Leukocytosisneutrophilia Yes Yes Yes No (mild neutropenia) Yes CDG IIc, Congenital disorder of glycosylation IIc, OMIM, Online Mendelian Inheritance in Man. From Leung DYM. Pediatric Allergy: Principles and Practice. 2nd ed. Philadelphia: Saunders; 2010. p. 139. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 170 u Disorders of Phagocyte Function 1301 Prognosis The severity of infectious complications correlates with the degree of 2 integrin deficiency. Patients with severe deficiency may die in infancy, and those surviving infancy have a susceptibility to severe life threatening systemic infections. |
6,445 | Patients with moderate deficiency have infrequent life threatening infections and relatively long survival. CHDIAK HIGASHI SYNDROME Chdiak Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by increased susceptibility to infection caused by defective degranulation of neutrophils, a mild bleeding diathesis, partial oculocutaneous albinism, progressive peripheral neuropathy, and a tendency to develop a life threatening form of hemophagocytic lymphohistiocytosis (see Chapter 556.2). CHS is caused by a fundamental defect in granule morphogenesis that results in abnormally large granules in multiple tissues. Pigmen tary dilution involving the hair, skin, and ocular fundi results from pathologic aggregation of melanosomes. Neurologic deficits are associated with a failure of decussation of the optic and auditory nerves. Patients exhibit an increased susceptibility to infection that can be explained only in part by defects in neutrophil function. The patients have progressive neutropenia as well as abnormalities in natural killer (NK) function, again related to granule dysfunction. Genetics and Pathogenesis LYST (for lysosomal traffic regulator), the gene variant in CHS, is located at chromosome 1q2 q44. The LYSTCHS protein is thought to regulate vesicle transport by mediating protein protein inter action and protein membrane associations. Loss of function may lead to indiscriminate interactions with lysosomal surface proteins, yielding giant granules through uncontrolled fusion of lysosomes with each other. Almost all cells of patients with CHS show some oversized and dys morphic lysosomes, storage granules, or related vesicular structures. Melanosomes are oversized, and delivery to the keratinocytes and hair follicles is compromised, resulting in hair shafts devoid of pigment granules. This abnormality in melanosomes leads to the macroscopic impression of hair and skin that is lighter than expected from parental coloration. The same abnormality in melanocytes leads to the partial ocular albinism associated with light sensitivity. Beginning early in neutrophil development, spontaneous fusion of giant primary granules with each other or with cytoplasmic mem brane components results in huge secondary lysosomes with reduced contents of hydrolytic enzymes, including proteinases, elastase, and cathepsin G. This deficiency of proteolytic enzymes may be responsible for the impaired killing of microorganisms by CHS neutrophils. Clinical Manifestations Patients with CHS have light skin and silvery hair and frequently com plain of solar sensitivity and photophobia that is associated with rotary nystagmus. Other signs and symptoms vary considerably, but frequent infections and neuropathy are common. The infections involve mucous membranes, skin, and respiratory tract. Affected children are susceptible to gram positive bacteria, gram negative bacteria, and fungi, with S. aureus being the most common offending organism. The neuropathy may be sensory or motor in type, and ataxia may be a prominent fea ture. Neuropathy often begins in the teenage years and becomes the most prominent problem. Patients with CHS have prolonged bleeding times with normal plate let counts, resulting from impaired platelet aggregation associated with a deficiency of the dense granules containing adenosine diphosphate and serotonin. The most life threatening complication of CHS is the develop ment of an accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and |
6,446 | lymph nodes. The onset of the accelerated phase, which can occur at any age, is now recognized to be a genetic form of hemophagocytic lym phohistiocytosis. This occurs in 85 of patients and usually results in death. Laboratory Findings The diagnosis of CHS is established by finding large inclusions in all nucleated blood cells. These can be seen on Wright stained blood films and are accentuated by a peroxidase stain. Because of impaired egress from the bone marrow, cells containing the large inclusions may be missed on peripheral blood smear but readily identified on bone marrow examination. The patients have progressive neutropenia and abnormal platelet, neutrophil, and NK function. Treatment High dose ascorbic acid (200 mgday for infants; 2,000 mgday for adults) may improve the clinical status of some children in the stable phase. Although controversy surrounds the efficacy of ascorbic acid, given the safety of the vitamin, it is reasonable to administer ascorbic acid to all patients. The only curative therapy to prevent the accelerated phase is HSCT. Normal stem cells reconstitute hematopoietic and immunologic func tion, correct the NK cell deficiency, and prevent conversion to the accelerated phase, but cannot correct or prevent the neuropathy. If the patient is in the accelerated phase with active hemophagocytic lympho histiocytosis, HSCT often fails to prevent death. While HSCT can cure the neutrophil defect and hemophagocytic lymphohistiocytosis, it does nothing for neurologic complications. MYELOPEROXIDASE DEFICIENCY Myeloperoxidase (MPO) deficiency is an autosomal recessive disorder of oxidative metabolism and is one of the most common inherited dis orders of phagocytes, occurring at a frequency approaching 1 per 2,000 individuals. MPO is a green heme protein located in the azurophilic lysosomes of neutrophils and monocytes and is the basis for the green ish tinge to pus accumulated at a site of infection. Clinical Manifestations MPO deficiency is usually clinically silent. Rarely, patients may have disseminated candidiasis, usually in conjunction with diabetes mel litus. Acquired partial MPO deficiency can develop in acute myelog enous leukemia and in myelodysplastic syndromes. Laboratory Findings Deficiency of neutrophil and monocyte MPO can be identified by his tochemical analysis. Severe MPO deficiency can cause the dihydrorho damine (DHR) flow cytometric assay for chronic granulomatous disease (CGD) to be falsely positive. Unlike CGD, eosinophils in severe MPO deficiency will still reduce DHR and yield a normal reaction. Treatment There is no specific therapy for MPO deficiency. Aggressive treatment with antifungal agents should be provided for candidal infections. The prognosis is usually excellent. CHRONIC GRANULOMATOUS DISEASE CGD is characterized by neutrophils and monocytes capable of normal chemotaxis, ingestion, and degranulation, but unable to kill catalase positive microorganisms because of a defect in the generation of microbicidal oxygen metabolites. CGD is a rare disease, affecting 4 5 per 1 million individuals; it is caused by four genes: one X linked and three autosomal recessive inheritance (Table 170.4). Genetics and Pathogenesis Activation of the phagocyte NADPH oxidase requires stimulation of the neutrophils and involves assembly from cytoplasmic and integral mem brane subunits (see Fig. |
6,447 | 168.3). Oxidase activation initiates with phos phorylation of a cationic cytoplasmic protein, p47phox (47 kDa phagocyte oxidase protein). Phosphorylated p47phox, together with two other cyto plasmic components of the oxidase, p67phox and the low molecular weight guanosine triphosphatase Rac2, translocates to the membrane, where they combine with the cytoplasmic domains of the transmembrane flavocyto chrome b558 to form the active oxidase complex. The flavocytochrome is a heterodimer composed of p22phox and highly glycosylated gp91phox. The Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1302 Part XII u Immunology gp91phox glycoprotein catalyzes electron transport through its NADPH binding, flavin binding, and heme binding domains. Defects in any of these NADPH oxidase components can lead to CGD. Approximately 65 of patients with CGD are males who inherit their disorder as a result of pathogenic variants in CYBB, an X chromosome gene encoding gp91phox. Approximately 35 of patients inherit CGD in an autosomal recessive fashion resulting from pathogenic variants in the NCF1 gene on chromosome 7, encoding p47phox. Defects in the genes encoding p67phox (NCF2 on chromosome 1) and p22phox (CYBA on chromosome 16) are inherited in an autosomal recessive manner and account for approximately 5 of cases of CGD. The CGD phagocytic vacuoles lack microbicidal reactive oxygen species and remain acidic, so bacteria are not killed or digested prop erly (Fig. 170.4). Hematoxylin eosinstained sections from patients tissues show multiple granulomas that give CGD its descriptive name. Clinical Manifestations Although the clinical presentation is variable, several features suggest the diagnosis of CGD. These include any patient with recurrent pneumonia, lymphadenitis, hepatic, subcutaneous, or other abscesses, osteomyelitis at multiple sites, family history of recurrent infections, or any infection with an unusual catalase positive organism requires evaluation (Fig. 170.5). Other clinical features include chronic colitis or enteritis, gastric outlet or ureteral obstruction from granulomas, or bloodstream infec tion caused by Salmonella, Burkholderia cepacia, or Candida. The onset of clinical signs and symptoms usually occurs in early infancy, although a few patients with very rare CGD subtypes have presented later in life. The attack rate and severity of infections are exceedingly variable; however, the infection incidence decreases in the second decade, coincident with maturation of the lymphocyte and humoral immunity. The most common pathogen is S. aureus, but any catalase positive microorganism may be involved. Other organisms frequently causing infections include Serratia marcescens, B. cepacia, Aspergillus, Candida albicans, Nocardia, and Salmonella. There may also be increased susceptibility to mycobacteria, including the bacille Calmette Gurin vaccine. Pneumonia, lymphadenitis, osteomyeli tis, and skin infections are the most common illnesses encountered. Bacteremia or fungemia occurs but is much less common than focal infections and usually only occurs when local infections have been inappropriately treated for long periods. Patients may have sequelae of chronic infection, including anemia of chronic disease, poor growth, lymphadenopathy, hepatosplenomegaly, chronic purulent dermatitis, restrictive lung disease, gingivitis, hydronephrosis, esophageal |
6,448 | dys motility, and pyloric outlet narrowing. Perirectal abscesses and recur rent skin infections, including folliculitis, cutaneous granulomas, and discoid lupus erythematosus, also suggest CGD. Fig. 170.4 Pathogenesis of chronic granulomatous disease (CGD). The manner in which the metabolic deficiency of the CGD neutrophil predisposes the host to infection is shown schematically. Normal neu trophils stimulate hydrogen peroxide (H2O2) in the phagosome con taining ingested Escherichia coli. Myeloperoxidase is delivered to the phagosome by degranulation, as indicated by the closed circles. In this setting, H2O2 acts as a substrate for myeloperoxidase to oxidize halide to hypochlorous acid and chloramines that kill the microbes. The quan tity of H2O2 produced by the normal neutrophil is sufficient to exceed the capacity of catalase, an H2O2 catabolizing enzyme of many aerobic microorganisms, including Staphylococcus aureus, most gram negative enteric bacteria, Candida albicans, and Aspergillus. When organisms such as E. coli gain entry into CGD neutrophils, they are not exposed to H2O2 because the neutrophils do not produce it, and the H2O2 gener ated by microorganisms themselves is destroyed by their own catalase. When CGD neutrophils ingest streptococci, which lack catalase, the or ganisms generate enough H2O2 to result in a microbicidal effect. As in dicated (middle), catalase positive microbes such as E. coli can survive within the phagosome of the CGD neutrophil. (Adapted from Boxer LA. Quantitative abnormalities of granulocytes. In: Beutler E, Lichtman MA, Coller BS, et al., eds. Williams Hematology. 6th ed. New York: McGraw Hill; 2001. p. 845.) Table 170.4 Classification of Chronic Granulomatous Disease COMPONENT AFFECTED INHERITANCE SUBTYPE FLAVOCYTOCHROME b SPECTRUM NBT SCORE ( POSITIVE) INCIDENCE ( OF CASES) gp91phox X X910 0 0 60 X91 Low 80 100 (weak) 5 X91 Low 5 10 1 X91 0 0 1 p22phox A A220 0 0 4 A22 N 0 1 p47phox A A470 N 0 25 p67phox A A670 N 0 5 A67 N 0 1 p40phox A A40 N 100 1 In this nomenclature, the first letter represents the mode of inheritance (X linked X or autosomal recessive A), whereas the number indicates the phox component that is genetically affected. The superscript symbols indicate whether the level of protein of the affected component is undetectable (0), diminished (), or normal (), as measured by immunoblot analysis. Can be weakly positive. NBT, Nitroblue tetrazolium. From Dinauer MC, Newburger PE, Borregaard N. Phagocyte system and disorders of granulopoiesis and granulocyte function. In: Orkin SH, Fisher DE, Ginsburg D, et al., eds. Nathan and Oskis Hematology and Oncology of Infancy and Childhood. 8th ed. Philadelphia: Elsevier; 2015. Table 22.12, p. 833. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 170 u Disorders of Phagocyte Function 1303 Granuloma formation and inflammatory processes are a hallmark of CGD and may be the presenting symptoms that prompt testing for CGD if they cause pyloric outlet obstruction, bladder outlet |
6,449 | or ure ter obstruction, or rectal fistulas and granulomatous colitis simulating Crohn disease. More than 80 of CGD patients have positive serology for Crohn disease. Persistent fever, especially with splenomegaly and cytopenia, warrants an evaluation for secondary macrophage activa tion syndrome. This has been seen in CGD and may require treatment with corticosteroids and discontinuation of interferon treatment. Laboratory Findings The diagnosis is most often made by performing flow cytometry using DHR to measure oxidant production through its increased fluorescence when oxidized by hydrogen peroxide (H2O2). The nitroblue tetrazolium dye test is frequently cited in the literature but is only rarely used clini cally. The X linked carrier state is usually easily diagnosed in the mother by DHR fluorescence through a bimodal response to stimulation. It is important to test the mother as some extremely lyonized carriers with 5 positive cells may have chronic clinical problems as well. Ideally, at least the first patient in a kindred should have DNA analysis to facilitate prenatal diagnosis and for genetic counseling purposes. A few individuals have been described with apparent CGD caused by severe glucose 6 phosphate dehydrogenase deficiency, leading to insuf ficient NADPH substrate for the phagocyte oxidase. The erythrocytes of these patients also lack the enzyme, leading to chronic hemolysis. Treatment HSCT is the only known cure for CGD, although gene therapy has been transiently successful in a few patients and is the topic of active research. HSCT transplant for all patients with CGD is strongly recom mended if a suitable sibling or unrelated donor can be identified. The long term outcome for survival late into adulthood is not good, even in the hands of experienced CGD physicians. Curative therapy at an early age is strongly recommended by many experts. Patients with CGD should be given daily oral TMPSMX because it reduces the number of bacterial infections. A placebo controlled study found that interferon 50 gm2 three times per week significantly reduces the number of hospitalizations and serious infections, although the mechanism of action is unclear. Itraconazole (200 mgday for patients weighing 50 kg and 100 mgday for patients 50 kg and 5 years old) administered prophylactically reduces the frequency of fungal infections. Management of infection is dramatically different than in normal chil dren. CGD patients are always at risk for deep seated, indolent bacterial infections that can become widespread if not treated properly. They also develop the same kinds of infections that occur in normal children, so determination of the appropriate treatment can be difficult. The ESR can be quite helpful. If the child does not have a deep seated infection, the ESR will be normal or will normalize within several days with standard man agement. If it does not, however, a search for deep tissues is warranted, as is consideration of empirical antibiotics. Cultures should be obtained, but are usually negative. Because all neutrophil functions in CGD except killing are normal, there is often an exuberant inflammatory reaction to a very small number of organisms. Thus blood cultures |
6,450 | and direct cultures of biopsy samples are usually negative unless there are many organisms. Most abscesses require surgical drainage for therapeutic and diagnostic purposes. Prolonged use of antibiotics is required even for common bac terial infections. A simple pneumonia may require 6 8 weeks or more of parenteral antibiotics. Infections should be treated for at least 1 week past normalization of ESR to prevent recurrence. Severe pneumonias can be cleared completely but may require many months of parenteral antibiotics. Especially because cultures are often not helpful, many support an anti biotic sensitivity by sedimentation rate response approach to treatment. The ESRs are often 40 80 mmhr or more with severe infection and will decrease monotonically over a week or so after starting antibacterial drugs. It is important to check the ESR daily or every other day because of mod erate variability in this test, and changes in treatment need to be based on trends rather than individual values. If there is a clear downward trend over 3 10 days, continue with antibacterials alone. If this is not the case, parenteral voriconazole should be added to cover Aspergillus. Failure of the ESR to decrease suggests another antimicrobial approach needs to be tried. This sequential addition of antimicrobials offers some insight into the nature of the infection. If both antibacterials and antifungal are started at the same time, one cannot know what caused a response. Because of the rarity of this disorder, it is critical to seek counsel from someone with significant direct experience with management of several CGD patients. Granulocyte transfusions have been used, but their ben efit is unclear. The ESR should be regularly monitored in well patients and whenever they appear ill. A high ESR itself is usually not enough to trigger treatment. However, in the presence of symptoms, one should search for sources at least by contrast CT of the sinus, chest, and abdomen. If the patient is unstable or has very high fevers, B. cepacia should be considered and empirically covered. This organism can cause septic shock quickly, unlike the usual smoldering infections seen in CGD. The patient can be treated with antibiotics until the ESR is normal and radiographic evidence of infection has been cleared, if possible. The overall incidence of infection decreases in the second decade of life as nonneutrophil immunity matures, but increased risk of infection is lifelong. Corticosteroids may be useful for the treatment of children with antral and urethral obstruction or severe granulomatous colitis. Corticosteroids can also be helpful in pneumonia to shrink granulomas in the lung and promote drainage. Short (4 6 days) pulses of 1 2 mgkg of prednisone are recommended, with rapid taper to avoid long term side effects and risk of fungus. Pulses can be repeated if clinical effect has not been achieved. Genetic Counseling Identifying a patients specific genetic subgroup by DNA analysis is useful primarily for genetic counseling and prenatal diagnosis. In X linked CGD, all possibly affected females should be tested by DHR to exclude |
6,451 | carrier state. Diagnosis by DNA is strongly recommended in suspected carriers with normal DHR who are related to a known proband, because rarely DHR testing is normal in obligate carriers and may indicate that the patient has a spontaneous mutation and the mother may not be a carrier at all. Counseling is best done by a physi cian who has direct knowledge of the clinical manifestations of CGD. Prognosis The overall mortality rate for CGD is about two patient deaths per year per 100 cases, with the highest mortality among young children. The development of effective infection prophylaxis regimens, close surveil lance for signs of infections, and aggressive surgical and medical inter ventions have improved the prognosis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 170.5 Chest radiograph of a 10 year old boy with chronic granu lomatous disease shows a left sided pulmonary infiltrate and cavitary lung lesion. Biopsy revealed an Aspergillus fumigatus infection. (From Chinn IK, Chinen J, Shearer WT. Primary immunodeficiency diseases. In Cherry JD, Harrison GJ, Kaplan SL, et al., eds. Feigin and Cherrys Textbook of Pediatric Infectious Diseases. 8th ed. Philadelphia: Elsevier; 2019. Fig. 67.6, p. 652.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1304 Part XII u Immunology Leukopenia refers to an abnormally low number of white blood cells (WBCs) in the circulating blood secondary to a paucity of lympho cytes, granulocytes, or both. Because there are marked developmen tal changes in normal values for WBC counts during childhood, normal ranges must be considered in the context of age. For new borns, the mean WBC count at birth is high, followed by a rapid fall beginning at 12 hours through the first week of life. Thereafter, values are stable until 1 year of age, after which a slow, steady decline in the WBC count continues throughout childhood until adult values are reached during adolescence. Evaluation of patients with leukopenia begins with a thorough history, physical examination, and at least one confirmatory complete blood count with differential. Further evalua tion then depends on whether the leukopenia represents a decreased number of neutrophils, lymphocytes, or both cell populations (Table 171.1). Treatment depends on the etiology and clinical manifesta tions of the leukopenia. NEUTROPENIA Neutropenia is defined as a decrease in the absolute number of cir culating segmented neutrophils and bands in the peripheral blood. The absolute neutrophil count (ANC) is determined by multiply ing the total WBC count by the percentage of segmented neutro phils plus bands. Normal neutrophil counts must be stratified for age and race. Neutrophils predominate at birth but rapidly decrease in the first few days of life. During infancy, neutrophils constitute 2030 of circulating leukocyte populations. Near equal numbers of neutrophils and lymphocytes are found in the peripheral circu lation at 5 years of age, and the characteristic 70 predominance of neutrophils that occurs in |
6,452 | adulthood is usually attained during puberty. For White children 12 months old, the lower limit of nor mal for the ANC is 1,500L; for Black children 12 months old, the lower limit of normal is 1,200L. The relatively lower limit of nor mal in Black individuals likely reflects the prevalence of the Duffy negative (Fy) blood group, which is enriched in populations in the malarial belt of Africa and is associated with ANCs 200 600L less than those who are Duffy positive. Neutropenia may be characterized as mild (ANC 1,000 1,500L), moderate (ANC 500 1,000L), or severe (ANC 500L). ANC 200 is also termed agranulocytosis. This stratification aids in predicting the risk of pyogenic infection in patients who have neu tropenia resulting from disorders of bone marrow production, because only patients with severe neutropenia have a significantly increased susceptibility to life threatening infections. Neutropenia associated with monocytopenia, lymphocytopenia, or hypogam maglobulinemia increases the risk for infection compared with isolated neutropenia. Patients with neutropenia caused by increased destruction (e.g., autoimmune) may tolerate very low ANCs without increased frequency of infection, because of their often robust ability to generate additional neutrophils from their functioning marrow when needed. Acute neutropenia evolves over a few days and is often a result of rapid neutrophil use and compromised neutrophil production. Chronic neutropenia by definition lasts longer than 3 months and arises from reduced production, increased destruction, or excessive splenic sequestration of neutrophils. The etiology of neutropenia can be classified as either an acquired disorder or extrinsic insult (Table 171.2) or more rarely an inherited, intrinsic defect (Table 171.3). Clinical Manifestations of Neutropenia Individuals with neutrophil counts 500L are at substantial risk for developing infections, primarily from their endogenous flora as well as from nosocomial organisms. However, some patients with isolated chronic neutropenia may not experience many seri ous infections, probably because the remainder of the immune system remains intact or because neutrophil delivery to tissues is preserved, as in autoimmune neutropenias (AINs). In contrast, children whose neutropenia is secondary to acquired disorders of production, as occurs with cytotoxic therapy, immunosuppressive drugs, or radiation therapy, are likely to develop serious bacterial infections because many arms of the immune system are markedly compromised and the ability of the marrow to robustly generate new phagocytes is impaired. Neutropenia associated with addi tional monocytopenia or lymphocytopenia is more highly associ ated with serious infection than neutropenia alone. The integrity of skin and mucous membranes, the vascular supply to tissues, and nutritional status also influence the risk of infection. The most common clinical presentation of profound neutro penia includes fever, frequent infections, aphthous stomatitis, and gingivitis. Infections frequently associated with neutropenia include cellulitis, furunculosis, perirectal inflammation, colitis, sinusitis, warts, and otitis media, as well as more serious infec tions such as pneumonia, deep tissue abscess, and sepsis. The most common pathogens causing infections in neutropenic patients are Staphylococcus aureus and gram negative bacteria. Isolated neu tropenia does not heighten a patients susceptibility to parasitic or viral infections or to bacterial |
6,453 | meningitis but does increase the risk of fungal pathogens causing disease. The usual signs and symp toms of local infection and inflammation (e.g., exudate, fluctuance, regional lymphadenopathy) may be diminished in the absence of neutrophils because of the inability to form pus, but patients with agranulocytosis still experience fever and feel pain at sites of inflammation. Laboratory Findings Isolated absolute neutropenia has a limited number of causes (see Tables 171.2 to 171.6). The duration and severity of the neutropenia greatly influence the extent of laboratory evaluation. Patients with chronic neutropenia since infancy and a history of recurrent fevers and chronic gingivitis should have WBC counts and differential counts determined 3 times a week for 6 8 weeks to evaluate for peri odicity suggestive of cyclic neutropenia. Bone marrow aspiration and biopsy should be performed on select patients to assess cellu larity and myeloid maturation. Additional marrow studies, such as cytogenetic analysis and flow cytometry for detecting leukemia and other malignant disorders, should be obtained for patients with sus pected intrinsic defects in the myeloid progenitors and for patients with suspected malignancy. Children of African or Arabic descent with mild to moderate neutropenia should have Duffy null, Fy(ab) variant, screening completed. Selection of further laboratory tests is determined by the duration and severity of the neutropenia and the associated findings on physical examination (see Table 171.1). Acquired Neutropenia Infection Related Neutropenia Transient neutropenia often accompanies or follows viral infec tions and is the most frequent cause of neutropenia in childhood (Table 171.4). Viruses causing acute neutropenia include influen zas A and B, SARSCoV2, adenovirus, respiratory syncytial virus, enteroviruses, human herpesvirus 6, measles, rubella, and varicella. Parvovirus B19 and hepatitis A or B may also cause neutropenia, Chapter 171 Leukopenia Thomas F. Michniacki and Kelly J. Walkovich Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 171 u Leukopenia 1305 but are more often associated with pure red cell aplasia or multiple cytopenias, respectively. Viral associated acute neutropenia often occurs during the first 24 48 hours of illness and usually persists for 3 8 days, which generally corresponds to the period of viremia. The neutropenia is related to virus induced redistribution of neu trophils from the circulating to the marginating pool. In addition, neutrophil sequestration may occur after virus induced tissue dam age or splenomegaly. Significant neutropenia also may be associated with severe bacterial, protozoal, rickettsial, or fungal infections (see Table 171.4). Bacterial sepsis is a particularly serious cause of neutropenia, especially among younger infants and children. Premature neonates are especially prone to exhausting their marrow reserve and rapidly succumbing to bacte rial sepsis. Chronic neutropenia often accompanies infection with Epstein Barr virus, cytomegalovirus, or HIV and certain immunodeficiencies Table 171.1 Diagnostic Approach for Patients with Leukopenia EVALUATION ASSOCIATED CLINICAL DIAGNOSES INITIAL EVALUATION History of acute or chronic leukopenia General medical history including prior serious, recurrent |
6,454 | or unusual infections and malignancy Congenital syndromes (severe congenital neutropenia, cyclic neutropenia, Shwachman Diamond, Wiskott Aldrich, Fanconi anemia, dyskeratosis congenita, glycogen storage disease type Ib, disorders of vesicular transport, GATA2 haploinsufficiency, and primary immunodeficiencies)Physical examination: stomatitis, gingivitis, dental defects, warts, lymphedema, congenital anomalies Spleen size Hypersplenism History of drug exposure Drug associated neutropenia Complete blood count with differential and reticulocyte counts Neutropenia, aplastic anemia, autoimmune cytopenias IF ANC 1,000L Evaluation of Acute Onset Neutropenia Repeat blood counts in 3 4 wk Transient myelosuppression (e.g., viral) Serology and cultures for infectious agents Active or chronic infection with viruses (e.g., EBV, CMV), bacteria, mycobacteria, rickettsia Discontinue drug(s) associated with neutropenia Drug associated neutropenia Test for antineutrophil antibodies Autoimmune neutropenia Measure quantitative immunoglobulins (IgG, IgA, IgM, IgE), lymphocyte subsets Neutropenia associated with disorders of immune function IF ANC 500L ON THREE SEPARATE TESTS Bone marrow aspiration and biopsy, with cytogenetics Severe congenital neutropenia, cyclic neutropenia, Shwachman Diamond syndrome, myelokathexis; chronic benign or idiopathic neutropenia; reticular dysgenesis Glucocorticoid stimulation test Chronic benign or idiopathic neutropenia, some autoimmune neutropenias Serial CBCs (3wk for 6 wk) Cyclic neutropenia Exocrine pancreatic function Shwachman Diamond syndrome Skeletal radiographs Shwachman Diamond syndrome, cartilage hair hypoplasia, Fanconi anemia IF ALC 1,000L Repeat blood counts in 3 4 wk Transient leukopenia (e.g., viral) IF ALC 1,000L THREE SEPARATE TESTS HIV antibody or RNA test HIV infection, AIDS Quantitative immunoglobulins (IgG, IgA, IgM, IgE), vaccine titers, lymphocyte subsets; qualitative lymphocyte proliferation to mitogensantigens Congenital or acquired disorders of immune function IF THERE IS PANCYTOPENIA Bone marrow aspiration and biopsy Bone marrow replacement by malignancy, fibrosis, granulomata, storage cells; aplastic anemia Bone marrow cytogenetics and flow cytometry Myelodysplasia, leukemia Copper, vitamin B12 and folate levels Vitamin deficiencies ALC, Absolute lymphocyte count; ANC, absolute neutrophil count; CBC, complete blood count; CMV, cytomegalovirus; EBV, Epstein Barr virus. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1306 Part XII u Immunology such as X linked agammaglobulinemia (XLA), hyper IgM syndrome and AIDS. The neutropenia associated with AIDS likely arises from a combination of viral bone marrow suppression, antibody mediated destruction of neutrophils, and effects of antiretroviral or other drugs. Drug Induced Neutropenia Drugs constitute a common cause of neutropenia (Table 171.5). The incidence of drug induced neutropenia increases dramatically with age; only 10 of cases occur among children and young adults. The majority of cases occur among adults 65 years, likely reflecting the more frequent use of multiple medications in that age group. Almost any drug can cause neutropenia. The most common offending drug classes are antimicrobial agents, antithyroid drugs, antipsychotics, antiepileptics, antipyretics, and antirheumatics. Drug induced neu tropenia has several underlying mechanisms (immune mediated, toxic, idiosyncratic, hypersensitivity, idiopathic) that are distinct from the severe neutropenia that predictably occurs after administration of antineoplastic drugs or radiotherapy. Drug induced neutropenia from immune mechanisms usually develops abruptly, is accompanied by fever, and |
6,455 | lasts for about 1 week after the discontinuation of the drug. The process likely arises from effects of drugs such as propylthiouracil or penicillin that act as haptens to stimulate antibody formation, or drugs such as qui nine that induce immune complex formation. Other drugs, includ ing the antipsychotic drugs such as the phenothiazines, can cause neutropenia when given in toxic amounts, but some individuals, such as those with preexisting neutropenia, may be susceptible to levels at the high end of the usual therapeutic range. Late onset neu tropenia can occur after rituximab therapy. Idiosyncratic reactions, Table 171.2 Causes of Neutropenia Extrinsic to Marrow Myeloid Cells CAUSE ETIOLOGIC FACTORSAGENTS ASSOCIATED FINDINGS Infection Viruses, bacteria, protozoa, rickettsia, fungi Clinical features and laboratory findings of the infectious agent Drug induced Phenothiazines, sulfonamides, anticonvulsants, penicillins, aminopyrine Usually none; occasional hypersensitivity reaction (fever, lymphadenopathy, rash, hepatitis, nephritis, pneumonitis, aplastic anemia) or antineutrophil antibody Immune neutropenia Alloimmune, autoimmune Myeloid hyperplasia with left shift in bone marrow (may appear to be arrested at metamyelocyte or band stage) Reticuloendothelial sequestration Hypersplenism Anemia, thrombocytopenia Bone marrow replacement Myelofibrosis, malignancy (leukemia, lymphoma, metastatic solid tumor, etc.) Anemia, thrombocytopenia, marrow fibrosis, malignant cells in bone marrow sites of extramedullary hematopoiesis Cancer chemotherapy or radiation therapy Suppression of myeloid cell production Anemia, thrombocytopenia, bone marrow hypoplasia Table 171.3 Acquired Disorders of Myeloid Cells CAUSE ETIOLOGIC FACTORSAGENTS ASSOCIATED FINDINGS Aplastic anemia Stem cell destruction and depletion Pancytopenia Vitamin B12, copper, or folate deficiency Malnutrition; congenital deficiency of B12 absorption, transport, and storage; vitamin avoidance Megaloblastic anemia, hyper segmented neutrophils Acute leukemia, chronic myelogenous leukemia Bone marrow replacement with malignant cells Pancytopenia, leukocytosis Myelodysplasia Dysplastic maturation of stem cells Bone marrow hypoplasia with megaloblastoid red cell precursors, thrombocytopenia Prematurity with birthweight 2 kg Impaired regulation of myeloid proliferation and reduced size of postmitotic pool Maternal preeclampsia Chronic idiopathic neutropenia Impaired myeloid proliferation andor maturation None Paroxysmal nocturnal hemoglobinuria Acquired stem cell defect secondary to PIGA gene variant Pancytopenia, thrombosis (hepatic vein thrombosis) Table 171.4 Infections Associated with Neutropenia Viral Cytomegalovirus, dengue, Epstein Barr virus, hepatitis viruses, HIV, influenza, measles, parvovirus B19, rubella, varicella, HHV 6, SARSCoV2 Bacterial Brucella, paratyphoid, pertussis, tuberculosis (disseminated), tularemia, Shigella, typhoid; any form of sepsis Fungal Histoplasmosis (disseminated) Protozoan Malaria, leishmaniasis (kala azar) Rickettsial Anaplasma (formerly Ehrlichia) phagocytophilum, psittacosis, Rocky Mountain spotted fever, typhus, rickettsialpox HHV 6, Human herpesvirus 6. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 171 u Leukopenia 1307 for example to chloramphenicol, are unpredictable with regard to dose or duration of use. Hypersensitivity reactions are rare and may involve arene oxide metabolites of aromatic anticonvulsants. Fever, rash, lymphadenopathy, hepatitis, nephritis, pneumonitis, and aplastic anemia are often associated with hypersensitivity induced neutropenia. Acute hypersensitivity reactions such as those caused by phenytoin or phenobarbital may last for only a few days if the offending drug is discontinued. Chronic hypersensitivity may |
6,456 | last for months to years. Once neutropenia occurs, the most effective therapeutic measure is withdrawal of nonessential drugs, particularly drugs most com monly associated with neutropenia. Usually, the neutropenia will resolve soon after withdrawal of the offending drug. If the neutro penia fails to improve with drug withdrawal and the patient is symp tomatic with infection or stomatitis, subcutaneous administration of recombinant human granulocyte colony stimulating factor (G CSF; filgrastim, 5 gkgday) should be considered. Drug induced neutropenia may be asymptomatic and noted only as an incidental finding or because of regular monitoring of WBC counts during drug therapy. For patients who are asymptomatic, continuation of the suspected offending drug depends on the relative risks of neu tropenia vs discontinuation of a possibly essential drug. If the drug is continued, blood counts should be monitored for possible pro gression to agranulocytosis. Neutropenia usually and predictably follows the use of anticancer drugs or radiation therapy, especially radiation directed at the pel vis or vertebrae, secondary to cytotoxic effects on rapidly replicating myeloid precursors. A decline in the WBC count typically occurs 7 10 days after administration of the anticancer drug and may persist for 1 2 weeks. The neutropenia accompanying malignancy or following cancer chemotherapy is frequently associated with compromised cel lular immunity and barrier compromise secondary to central venous lines and mucositis, thereby predisposing patients to a much greater risk of infection than found in disorders associated with isolated neutropenia. Patients with chemotherapyradiation related neutro penia and fever must be treated aggressively with broad spectrum antibiotics. Nutrition Related Neutropenia Poor nutrition can contribute to neutropenia. Ineffective myelopoi esis may result in neutropenia caused by acquired dietary copper, vitamin B12, or folic acid deficiency. In addition, megaloblastic pancytopenia also can result from extended use of antibiotics such as trimethoprimsulfamethoxazole that inhibit folic acid metabo lism and from the use of phenytoin, which may impair folate absorp tion in the small intestine, or from surgical resection of the small intestine. Neutropenia also occurs with starvation and marasmus in infants, with anorexia nervosa, and occasionally among patients receiving prolonged parenteral nutrition without vitamin supple mentation. Patients receiving prolonged parenteral nutrition and supplemental lipids are additionally at risk for neutropenia given hepatosplenomegaly related sequestration and marrow infiltration by abnormal macrophages filled with blue staining pigment gran ules and atypical lipid vacuoles; these cells are termed sea blue histiocytes. Immune Mediated Neutropenia Immune mediated neutropenia is usually associated with the presence of circulating antineutrophil antibodies, which may mediate neutro phil destruction by complement mediated lysis or splenic phagocytosis of opsonized neutrophils, or by accelerated apoptosis of mature neu trophils or myeloid precursors. Alloimmune neonatal neutropenia occurs after transplacental transfer of maternal alloantibodies directed against antigens on the infants neutrophils, analogous to Rh hemolytic disease. Prenatal sen sitization induces maternal IgG antibodies to neutrophil antigens on fetal cells. The neutropenia is often severe and infants may present within the first 2 weeks of life with skin or umbilical infections, fever, and pneumonia caused by the usual |
6,457 | microbes that cause neonatal dis ease. By 7 weeks of age, the neutrophil count usually returns to normal, reflecting the decay of maternal antibodies in the infants circulation. Treatment consists of supportive care and appropriate antibiotics for clinical infections, plus G CSF for severe infections without neutrophil recovery. Mothers with autoimmune disease may give birth to infants who develop transient neutropenia, known as neonatal passive AIN. The duration of the neutropenia depends on the time required for the infant to clear the maternally transferred circulating IgG antibody. It persists in most cases for a few weeks to a few months. Neonates almost always remain asymptomatic. AIN of infancy is a benign condition with an annual incidence of approximately 1 per 100,000 among children between infancy and 10 years of age. Antineutrophil antibodies are inappropriately created by the child during an inflammatory episode, most com monly a mild viral infection. Patients usually have severe neu tropenia on presentation, with ANC 500L, but the total WBC count is generally within normal limits. Monocytosis or eosino philia may occur but does not impact the low rate of infection. The median age of presentation is 8 11 months, with a range of 2 54 months. The diagnosis is often evident when a blood count incidentally reveals neutropenia in a child with a minor infection or when a routine complete blood count is obtained at the 12 month well child visit. Occasionally, children may present with more severe infections, including abscesses, pneumonia, or sepsis. The diagnosis may be supported by the presence of antineutrophil antibodies in serum; however, the test has frequent false negative and false positive results, so the absence of detectable antineu trophil antibodies does not exclude the diagnosis, and a positive result does not exclude other conditions. Therefore the diagnosis is best made clinically based on a benign course and, if obtained, a normal or hyperplastic myeloid maturation in the bone mar row. There is considerable overlap between AIN of infancy and chronic benign neutropenia. Table 171.5 Forms of Drug Induced Neutropenia IMMUNOLOGIC TOXIC HYPERSENSITIVITY Paradigm drugs Aminopyrine, propylthiouracil, penicillins Phenothiazines, clozapine Phenytoin, phenobarbital Time to onset Days to weeks Weeks to months Weeks to months Clinical appearance Acute, often explosive symptoms Often asymptomatic or insidious onset May be associated with fever, rash, nephritis, pneumonitis, or aplastic anemia Rechallenge Prompt recurrence with small test dose Latent period; high doses required Latent period; high doses required Laboratory findings Antineutrophil antibody may be positive; bone marrow myeloid hyperplasia Bone marrow myeloid hypoplasia Bone marrow myeloid hypoplasia Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1308 Part XII u Immunology Treatment is not generally necessary because the disease is only rarely associated with severe infection and usually remits spontane ously. Low dose G CSF may be useful for severe infections, to pro mote wound healing following surgery, or to |
6,458 | avert emergency room visits or hospitalizations for febrile illnesses. Longitudinal studies of infants with AIN demonstrate median duration of disease ranging from 7 30 months. Affected children generally have no evidence or risk of other autoimmune diseases. AIN in older children can occur as an isolated process, as a mani festation of other autoimmune diseases, or as a secondary complication of infection, drugs, or malignancy. In primary AIN, low circulating neutrophil counts are the only hematologic finding, and associated diseases or other factors that cause neutropenia are absent. Secondary AIN associated with immune dysregulation or other factors is more often identified in older children and is less likely to remit spontane ously. AIN is distinguished from other forms of neutropenia by the demonstration of antineutrophil antibodies (with caveats previously discussed) and myeloid hyperplasia on bone marrow examination. The most common antineutrophil antibody targets are human neutrophil antigens 1a, 1b, and 2. Treatment of AIN relies on management of any underlying dis orders. In addition, judicious use of appropriate antibiotics for bacterial infections is generally beneficial, as is family and primary care provider education. Regular dental hygiene, always strongly recommended, is even more important. Infections tend to be less frequent in AIN than with the corresponding degree of neutropenia from other causes, probably because tissue delivery of neutrophils is greater than that in conditions resulting from impaired produc tion. Prophylactic antibiotics may be helpful for the management of recurrent minor infections. For patients with serious or recur rent infections, G CSF is generally effective at raising the ANC and preventing infection. Very low doses (1 2 gkgday) are usually effective, and administration of standard doses can lead to severe bone pain from marrow expansion. Neutropenia Secondary to Bone Marrow Replacement Various acquired bone marrow disorders lead to neutropenia, usu ally accompanied by anemia and thrombocytopenia. Hematologic malignancies, including leukemia, lymphoma, and metastatic solid tumors, suppress myelopoiesis by infiltrating the bone marrow with tumor cells. Neutropenia may also accompany aplastic ane mia, myelodysplastic disorders, or preleukemic syndromes, which are characterized by multiple cytopenias and often macrocytosis. Treatment requires management of the underlying disease. Neutropenia Secondary to Reticuloendothelial Sequestration Splenic enlargement resulting from intrinsic splenic disease (stor age disease), portal hypertension, or systemic causes of splenic hyperplasia (inflammation or neoplasia) can lead to neutropenia. Most often the neutropenia is mild to moderate and is accompanied by corresponding degrees of thrombocytopenia and anemia. The reduced neutrophil survival corresponds to the size of the spleen, and the extent of the neutropenia is inversely proportional to bone marrow compensatory mechanisms. Usually, the neutropenia can be corrected by successfully treating the underlying disease. In select cases, splenectomy may be necessary to restore the neutrophil count to normal, but results in increased risk of infections by encapsu lated bacterial organisms. Patients undergoing splenectomy should receive appropriate preoperative immunizations and may benefit from antibiotic prophylaxis after splenectomy to help mitigate the risk of sepsis. Splenectomy should be avoided in patients with com mon variable immunodeficiency (CVID), autoimmune lymphopro liferative |
6,459 | disease, and other immunodeficiency syndromes because of the higher risk of sepsis. Inherited Neutropenia Intrinsic disorders of proliferation or maturation of myeloid precursor cells are rare. Table 171.6 presents a classification based on genetics (Fig. 171.1) and molecular mechanisms; other organ involvement or physical features may suggest an etiology (Table 171.7). Primary Disorders of Granulopoiesis Cyclic neutropenia is an autosomal dominant congenital granulopoi etic disorder occurring with an estimated incidence of 0.5 1 cases per 1 million population. The disorder is characterized by regular, periodic oscillations, with the ANC ranging from normal to 200L, mirrored by reciprocal cycling of monocytes. Cyclic neutropenia is sometimes termed cyclic hematopoiesis because of the secondary cycling of other blood cells, such as platelets and reticulocytes. The mean oscillatory period of the cycle is 21 days (4 days). During the neutropenic nadir, many patients develop malaise, fever, oral and genital ulcers, gingivitis, periodontitis, or pharyngitis, and occasionally lymph node enlarge ment. More serious infections occasionally occur, including pneu monia, mastoiditis, and intestinal perforation with peritonitis leading to life threatening clostridial sepsis. Before the availability of G CSF, approximately 10 of patients developed fatal clostridial or gram negative infections. Cyclic neutropenia arises from a regulatory abnor mality involving early hematopoietic precursor cells and is almost invariably associated with pathologic variants in the neutrophil elastase gene, ELANE, that lead to accelerated apoptosis as a result of abnor mal protein folding. Many patients experience abatement of symptoms with age. The cycles tend to become less noticeable in older patients, and the hematologic picture often begins to resemble that of chronic idiopathic neutropenia. Cyclic neutropenia is diagnosed by obtaining blood counts 3 times a week for 6 8 weeks. The requirement for repeated blood counts is necessary because some of the elastase variants overlap with those in patients who have severe congenital neutropenia (SCN). Dem onstrating oscillation or a lack thereof in the blood counts helps to identify patients risks for progression to myelodysplastic syndrome (MDS)acute myelogenous leukemia (AML), a risk that is only asso ciated with SCN. The diagnosis can be confirmed with genetic studies demonstrating a pathologic variant in ELANE. Affected patients with neutrophil nadirs 200L are treated with G CSF, and their cycle of profound neutropenia changes from a 21 day period with at least 3 5 days of profound neutropenia to 9 11 days with 1 day of less profound neutropenia. The dose needed to maintain nadirs 500L is usually 2 4 gkgday administered daily or every other day. SCN is a rare, genetically heterogeneous, congenital granulopoietic disorder with an estimated incidence of 1 2 cases per 1 million popula tion. The disorder is characterized by an arrest in myeloid maturation at the promyelocyte stage in the bone marrow, resulting in ANCs con sistently 200L and may occur sporadically, with autosomal domi nant or recessive inheritance. The dominant form is caused most often by pathologic variants in ELANE, which accounts for 6080 of SCN cases, whereas recessive forms arise from variants in HAX1 (the form |
6,460 | also known as Kostmann disease) or G6PC3 (encoding a myeloid specific isoform of glucose 6 phosphatase). Pathologic alterations in GFI1, CSF3R, and JAGN1 additionally may lead to the condition. HAX1 variants may be associated with neurologic deficits, and G6PC3 with heart defects, urogenital abnormalities, and venous angiectasia. In addition to severe neutropenia, peripheral blood counts generally show monocytosis and many also exhibit eosinophilia; chronic inflam mation may lead to secondary anemia and thrombocytosis. Patients who have SCN experience frequent episodes of fever, skin infections (including omphalitis), oral ulcers, gingivitis, pneumonia, and perirec tal abscesses, typically appearing in the first few months of life. Infec tions often disseminate to the blood, meninges, and peritoneum and are usually caused by S. aureus, Escherichia coli, and Pseudomonas spe cies. Without filgrastim therapy, most patients die of infectious compli cations within the first 1 2 years of life despite prophylactic antibiotics. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 171 u Leukopenia 1309 Table 171.6 Intrinsic Disorders of Myeloid Precursor Cells SYNDROME INHERITANCE (GENE) CLINICAL FEATURES (INCLUDING STATIC NEUTROPENIA UNLESS OTHERWISE NOTED) PRIMARY DISORDERS OF MYELOPOIESIS Cyclic neutropenia AD (ELANE) Periodic oscillation (21 day cycles) in ANC Severe congenital neutropenia AD (primarily ELANE, also GFI1 and others) Risk of MDSAML AR (G6PC3, HAX1, JAGN1, CSF3R) (HAX1 Kostmann syndrome) G6PC3: cardiac and urogenital anomalies, venous angioectasias; HAX1: neurologic abnormalities, risk of MDSAML XL (WAS) Neutropenic variant of Wiskott Aldrich syndrome DISORDERS OF MOLECULAR PROCESSING Shwachman Diamond syndrome Ribosomal defect: AR (SBDS, DNAJC21, EFL1, SRP54) Pancreatic insufficiency, metaphyseal dysostosis, bone marrow failure, MDSAML Telomere biology disorders dyskeratosis congenita Telomere length abnormality: XL (DKC1), AD or AR (ACD, RTEL1, TERC, TERT), AD (NAF1, TINF2), AR (CTC1, NHP2, NOP10, PARN, STN1, WRAP53) Nail dystrophy, leukoplakia, abnormal and carious teeth, lacey reticulated hyperpigmentation of the skin, bone marrow failure, various malignancies, Coats plus syndrome (CTC1 and STN1) DISORDERS OF VESICULAR TRAFFICKING Chdiak Higashi syndrome AR (LYST) Partial albinism, giant granules in myeloid cells, platelet storage pool defect, impaired NK cell function, HLH Griscelli syndrome, type II AR (RAB27a) Partial albinism, impaired NK cell function, neurologic impairment, HLH Cohen syndrome AR (COH1) Partial albinism, pigmentary retinopathy, developmental delay, facial dysmorphism Hermansky Pudlak syndrome, type II AR (AP3B1) Cyclic neutropenia, partial albinism, HLH p14 deficiency AR (MAPBPIP) Partial albinism, coarse facial features, decreased B and T cells VPS45 defects AR (VPS45) Neutrophil dysfunction, bone marrow fibrosis, nephromegaly DISORDERS OF METABOLISM Glycogen storage disease, type 1b AR (G6PT1) Hepatic enlargement, growth retardation, impaired neutrophil motility Methylmalonicpropionic acidemia aciduria AR (CLPB) Mutase or cobalamin transporters propionyl coenzyme A carboxylase Ketoacidosis, metabolic stroke, depressed consciousness, megaloblastic anemia 3 Methylglutaconic aciduria AR (CLPB) Nonspecific finding indicative of mitochondrial dysfunction or associated with known syndromes Barth syndrome XL (TAZ) Episodic neutropenia, dilated cardiomyopathy, methylglutaconic aciduria Pearson syndrome Mitochondrial (DNA deletions) Episodic neutropenia, pancytopenia; defects in exocrine pancreas, liver, and |
6,461 | kidneys NEUTROPENIA IN DISORDERS OF IMMUNE FUNCTION Common variable immunodeficiency Familial, sporadic (TNFRSF13B) Hypogammaglobulinemia, other immune system defects IgA deficiency Unknown (Unknown or TNFRSF13B) Decreased IgA Severe combined immunodeficiency AR, XL (multiple loci) Absent humoral and cellular immune function Hyper IgM syndrome XL (HIGM1) Absent IgG, elevated IgM, autoimmune cytopenias WHIM syndrome AD (CXCR4) Warts, hypogammaglobulinemia, infections, myelokathexis Cartilage hair hypoplasia AR (RMRP) Lymphopenia, short limbed dwarfism, metaphyseal chondrodysplasia, fine sparse hair Schimke immunoosseous dysplasia AR (SMARCAL1) Lymphopenia, pancytopenia, spondyloepiphyseal dysplasia, growth retardation, renal failure X linked agammaglobulinemia XL (Bruton tyrosine kinase (BTK)) Agammaglobulinemia, neutropenia in 25 GATA2 haploinsufficiency AD (GATA2) Pulmonary alveolar proteinosis, lymphedema, monocytopenia, decreased B and NK cells, risk for severe fungalmycobacterialviral infections, susceptibility to leukemiaMDS, MonoMAC syndrome AD, Autosomal dominant; AML, acute myelogenous leukemia; ANC, absolute neutrophil count; AR, autosomal recessive; HLH, hemophagocytic lymphohistiocytosis; MDS, myelodysplastic syndrome; NK, natural killer; XL, X linked. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1310 Part XII u Immunology More than 95 of SCN patients respond to filgrastim (G CSF) treatment with an increase in the ANC and a decrease in infec tions. Doses required to achieve an ANC 1,000L vary greatly. A starting dose of filgrastim at 5 gkgday is recommended; the dose should be gradually increased, if necessary, to as high as 100 gkg day to attain an ANC of 1,000 2,000L. The 5 of patients who do not respond to filgrastim or who require high doses (8 gkgday) should be considered for hematopoietic stem cell transplantation (HSCT). Along with infections, patients with SCN are at risk for developing MDS associated with monosomy 7 and AML. For this reason, regular monitoring with blood counts and yearly bone mar row surveillance, including karyotyping and fluorescence in situ hybridization, should be performed on all SCN patients. Although clonal cytogenetic abnormalities may spontaneously remit, their appearance should be considered a strong indication for HSCT, which is much more likely to be successful before progression to MDSAML. Disorders of Molecular Processing Shwachman Diamond syndrome (SDS) is an autosomal recessive disorder classically characterized by neutropenia, pancreatic insuf ficiency, and short stature with skeletal abnormalities. SDS is most commonly caused by pro apoptotic pathologic variants of the SBDS gene, which encodes a protein that plays a role in ribosome bio genesis and RNA processing. The initial symptoms are usually ste atorrhea and failure to thrive because of malabsorption secondary to pancreatic insufficiency, which usually develops by 4 months of age, although the gastrointestinal symptoms may be subtle in some patients and go unrecognized. Patients have also been reported to have respiratory problems with frequent otitis media, pneumonia, and eczema. Virtually all patients with SDS have neutropenia, with the ANC periodically 1,000L. Some children have hypogamma globulinemia, defects in chemotaxis, or a reduction in the number or function of B, T, and natural killer (NK) cells that may |
6,462 | contrib ute to the increased susceptibility to pyogenic infection. The diag nosis of SDS is based on clinical phenotype; approximately 90 of patients have pathologic variants identified in SBDS with additional disease causing variants now recently discovered in DNAJC21, EFL1, and SRP54. SDS may progress to bone marrow hypoplasia or MDSAML; identification of increasing TP53 variants or cytoge netic abnormalities, particularly isochromosome i(7q) and del(20q), often precede conversion to MDS, so routine bone marrow moni toring is warranted. Treatment includes pancreatic enzyme replace ment, plus G CSF in patients with severe neutropenia. Telomere biology disorders (TBDs), including dyskeratosis congenita, are disorders of telomere length that most often present as bone marrow failure rather than isolated neutropenia. Various pathologic variants have now been identified to cause such condi tions (see Table 171.6), including alterations in ACD, PARN, DKC1, RTEL1, TERC, and TERT. Moreover, the classic phenotype includes nail dystrophy, leukoplakia, malformed teeth, and reticulated hyperpigmentation of the skin, although many patients, particularly young ones, do not exhibit these clinical features. Pulmonary and hepatic fibrosis is also a concern in individuals with TBDs. Patients are at risk for not only hematologic dysplasiamalignancy but addi tionally neoplasms involving the gastrointestinal tract, skin, and head and neck. Early and routine screening for these malignancies can be lifesaving. Vesicular Trafficking Disorders This group of rare primary immunodeficiency syndromes (see Table 171.6) derives from autosomal recessive defects in the biogenesis or trafficking of lysosomes and related endosomal organelles. The syn dromes share phenotypic characteristics, including defects in melano somes contributing to partial albinism, abnormal platelet function, and immunologic defects involving not only neutrophil number, but also the function of neutrophils, B lymphocytes, NK cells, and cytotoxic T lymphocytes. The syndromes share a high risk of hemophagocytic lym phohistiocytosis (HLH) as a result of defects in T and NK cells. Chdiak Higashi syndrome has characteristic giant cytoplasmic granules in neutrophils, monocytes, and lymphocytes, and is a disor der of subcellular vesicular dysfunction caused by pathologic variants in the LYST gene, with resultant giant granules in all granule bearing cells. Patients have increased susceptibility to infections, mild bleed ing diathesis, progressive peripheral neuropathy, and predisposition to life threatening HLH. The only curative treatment is HSCT, but trans plant does not treat all aspects of the disorder. Griscelli syndrome type II also features neutropenia, partial albi nism, and a high risk of HLH, but peripheral blood granulocytes do not show giant granules. Patients often have hypogammaglobulinemia. The disorder is caused by alterations in RAB27a, which encodes a small guanosine triphosphatase that regulates granule secretory pathways. The only curative treatment is HSCT. Disorders of Metabolism Recurrent infections with neutropenia are a distinctive feature of gly cogen storage disease (GSD) type Ib. As in classic von Gierke disease (GSDIa), glycogen storage in GSDIb causes massive hepatomegaly and severe growth retardation. Pathologic variants in glucose 6 phosphate transporter 1, G6PT1, inhibit glucose transport in GSDIb, resulting in both defective neutrophil motility and increased apoptosis associated with neutropenia and recurrent bacterial infections. Treatment |
6,463 | with Fig. 171.1 Genes with germline variants associated with severe congenital neutropenia. Data based on 650 patients with severe congenital neutropenia registered in the European and North American Branches of the Severe Chronic Neutropenia International Registry. Pathogenic variants in JAGN1, LAMTOR2, GFI1, LYST, USB1, or mito chondrial DNA. (From Skokowa J, Dale DC, Touw IP, Zei dler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primers. 2017;3:17032. Fig. 3.) ELANE 45 Other variants 6 CXCR4 2VPS13B 2 TCIRG1 2 WAS 2 TAZ 4 G6PT 12 SBDS 14 Digenic multiple 2 HAX1 7 G6PC3 2 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 171 u Leukopenia 1311 G CSF can correct the neutropenia but does not correct the underlying functional neutrophil defects. Neutropenia in Disorders of Immune Dysfunction Congenital immunologic disorders that have severe neutropenia as a clinical feature include XLA, CVID, the severe combined immuno deficiencies (SCIDs), autoimmune lymphoproliferative syndrome, hyperimmunoglobulin M syndrome, WHIM (warts, hypogam maglobulinemia, infections, myelokathexis) syndrome, GATA2 haploinsufficiency, and a number of even rarer immunodeficiency dis orders (see Table 171.6). Unclassified Neutropenic Disorders Chronic benign neutropenia of childhood represents a common group of disorders characterized by mild to moderate neutropenia that does not lead to an increased risk of pyogenic infections. Spontane ous remissions are often reported, although these may represent mis diagnosis of AIN of infancy, in which remissions often occur during Table 171.7 Main Organ Associated Features and Genetic Subtypes of Congenital Neutropenia SYSTEM HEMATOLOGIC OR ASSOCIATED FEATURES DISEASE GENE Bloodbone marrow maturation Maturation arrest Severe congenital neutropenia Severe congenital neutropenia WiskottAldrich syndrome Neutropenia G6PC3 G CSF receptor ELANE HAX1 WAS G6PC3 Extracellular domain of CSF3R No maturation arrest GSDIb WHIM Shwachman Diamond disease Cohen disease Hermansky Pudlak type 2 G6PT1 CXCR4 SBDS VPS13B AP3B1 Myelokathexis WHIM CXCR4 Pancreas External pancreatic insufficiency Shwachman Diamond disease SBDS Eyes Congenital cataract Charcot Marie Tooth Dynamin 2 Retinochoroidal dystrophy Cohen disease VPS13B Heart Heart: arrhythmias Neutropenia G6PC3 G6PC3 Dilated cardiomyopathy Barth diseases TAZ Cardiomyopathy Shwachman Diamond disease SBDS Various cardiac abnormalities Shwachman Diamond disease WHIM Neutropenia G6PC3 SBDS CXCR4 G6PC3 Skin Skin xerosis eczema Shwachman Diamond disease SBDS Skin: prominent superficial veins Neutropenia G6PC3 G6PC3 Skin poikiloderma SCN with poikiloderma type Clericuzio 16ORF57 Skin: Partial or complete albinism Hermansky Pudlak type 2 AP14 defect Chdiak Higashi disease Griscelli disease AP3B1 AP14 LYST RAB27A Hair: fine, sparse, and light colored Cartilage hair hypoplasia RMRP Bone Metaphyseal dysplasia Shwachman Diamond disease Cartilage hair hypoplasia SBDS RMRP Facial dysmorphia Cohen disease VPS13B Central nervous system Mental retardation Kostmann disease Shwachman Diamond disease Cohen disease HAX1 SBDS VPS13B Muscle Weakness Neutropenia G6PC3 Axonal Charcot Marie Tooth disease G6PC3 Dynamin 2 Metabolic pathway Fasting intolerance and glycogenosis Glycogen storage disease type Ib SLC37A4 Inner ear Inner ear defect GFI 1severe chronic neutropenia Reticular dysgenesia GFI1 AK2 Urogenital tract Uropathy Neutropenia G6PC3 G6PC3 Cryptorchidism Cohen |
6,464 | disease Neutropenia G6PC3 VPS13B G6PC3 G CSF, Granulocyte colony stimulating factor; SCN, severe congenital neutropenia; WHIM, warts, hypogammaglobulinemia, infections, myelokathexis. From Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26. Table 2. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1312 Part XII u Immunology childhood. Chronic benign neutropenia may be sporadic or inherited in either dominant or recessive form. Because of the relatively low risk of serious infection, patients usually do not require any therapy. Idiopathic chronic neutropenia is characterized by the onset of neutropenia after 2 years of age, with no identifiable etiology. Patients with an ANC persistently 500L may have recurrent pyogenic infec tions involving the skin, mucous membranes, lungs, and lymph nodes. Bone marrow examination reveals variable patterns of myeloid forma tion with arrest generally occurring between the myelocyte and band forms. The diagnosis overlaps with chronic benign and AINs. Treatment The management of acquired transient neutropenia associated with malignancies, myelosuppressive chemotherapy, or immunosuppres sive chemotherapy differs from that of congenital or chronic forms of neutropenia. In the former situation, infections sometimes are her alded only by fever, and sepsis is a major cause of death. Early recogni tion and treatment of infections may be lifesaving. Therapy of severe chronic neutropenia is dictated by the clinical manifestations. Patients with benign neutropenia and no evidence of repeated bacterial infec tions or chronic gingivitis require no specific therapy. Superficial infec tions in children with mild to moderate neutropenia may be treated with appropriate oral antibiotics. In patients who have invasive or life threatening infections, broad spectrum intravenous antibiotics should be started promptly. Subcutaneously administered G CSF can provide effective treatment of severe chronic neutropenia, including SCN, cyclic neutropenia, and chronic symptomatic idiopathic neutropenias. Treatment leads to dra matic increases in neutrophil counts, resulting in marked attenuation of infection and inflammation. Doses range from 2 5 gkgday for cyclic, idiopathic, and AINs, to 5 100 gkgday for SCN. The long term effects of G CSF therapy include a propensity for the development of moderate splenomegaly, reduced bone density, thrombocytopenia, and rarely vas culitis; only patients with SCN are at risk for MDSAML. Patients with SCN or SDS who develop MDS or AML respond only to HSCT; chemotherapy is ineffective. HSCT is also the treatment of choice for aplastic anemia or familial HLH. LYMPHOPENIA The definition of lymphopenia, as with neutropenia, is age dependent and can have acquired or inherited causes. The absolute lymphocyte count (ALC) is determined by multiplying the total WBC count by the percentage of total lymphocytes. For children 12 months old, lym phopenia is defined as an ALC 3,000 cellsL. For older children and adults, an ALC 1,000 cellsL is considered lymphopenia. In isola tion, mild to moderate lymphopenia is generally a benign condition often detected |
6,465 | only in the evaluation of other illnesses. However, severe lymphopenia can result in serious, life threatening illness. Lymphocyte subpopulations can be measured by flow cytometry, which uses the pattern of lymphocyte antigen expression to quantitate and classify T, B, and NK cells. Acquired Lymphopenia Acute lymphopenia is most often a result of infection andor is iat rogenic from lymphocyte toxic medications and treatments (Table 171.8). Microbial causes include viruses (e.g., respiratory syncytial virus, cytomegalovirus, influenza, measles, hepatitis, COVID 19), bac terial infections (e.g., tuberculosis, typhoid fever, histoplasmosis, bru cellosis), and malaria. The mechanisms behind infection associated lymphopenia are not fully elucidated but probably include lymphocyte redistribution and accelerated apoptosis. Corticosteroids are a com mon cause of medication induced lymphopenia, as are lymphocyte specific immunosuppressive agents (e.g., antilymphocyte globulin, alemtuzumab, rituximab), chemotherapy drugs, and radiation. In most cases, infectious and iatrogenic causes of acute lymphopenia are reversible, although full lymphocyte recovery from chemotherapy and lymphocyte specific immunosuppressive agents may take several months to years. Prolonged lymphopenia (see Table 171.8) may be caused by recurrent infection, persistent infections (mostly notably HIV), malnutrition, mechanical loss of lymphocytes through protein losing enteropathy or thoracic duct leaks, or systemic diseases such as lupus erythematosus, rheumatoid arthritis, sarcoidosis, renal failure, lymphoma, and aplastic anemia. Inherited Lymphopenia Primary immunodeficiencies and bone marrow failure syndromes are the main cause of inherited lymphopenia in children (see Table 171.8). Primary immunodeficiency may result in a severe quantitative defect, as in XLA and SCID, or a qualitative or progressive defect, as in Wiskott Aldrich syndrome and CVID. XLA is characterized by a near absence of mature B cells because of a pathologic alteration in BTK that results in a dysfunctional tyrosine kinase. SCIDs are a geneti cally heterogeneous group of disorders characterized by abnormalities of thymopoiesis and T cell maturation. Newborn screening for severe T cell deficiency, by analysis of T cell receptor excision circles (TRECs) from dried blood spot Guthrie cards, aids in the rapid identification and treatment of infants with SCID and other T cell disorders. Quanti tative defects in lymphocytes can also be appreciated in select forms of inherited bone marrow failure such as reticular dysgenesis, SCN sec ondary to GFI1 variants, and dyskeratosis congenita. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 171.8 Causes of Lymphocytopenia ACQUIRED Infectious diseases AIDS, hepatitis, influenza, sepsis, tuberculosis, typhoid, COVID 19 Iatrogenic Corticosteroids, cytotoxic chemotherapy, high dose PUVA, immunosuppressive therapy, radiation, thoracic duct drainage chylothorax Systemic diseases Hodgkin disease, lupus erythematosus, myasthenia gravis, protein losing enteropathy, renal failure, sarcoidosis Other Aplastic anemia, dietary deficiencies, thermal injury INHERITED Aplasia of lymphopoietic stem cells Cartilage hair hypoplasia, ataxia telangiectasia, SCID, thymoma, Wiskott Aldrich syndrome PUVA, Psoralen and ultraviolet A irradiation; SCID, severe combined immunodeficiency. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 172 u Leukocytosis 1313 Leukocytosis is an elevation in the total leukocyte or white |
6,466 | blood cell (WBC) count that is 2 standard deviations (SDs) above the mean for age. It is most often caused by elevated numbers of neutrophils (i.e., neutrophilia), although marked increases in monocytes, eosinophils, basophils, and lymphocytes can be seen. Before extensive evaluation, it is important to assess for spurious elevations in the WBC count caused by platelet clumping (secondary to insufficient sample anticoagulation or the presence of EDTA dependent agglutinins), high numbers of cir culating nucleated red blood cells (RBCs), and the presence of cryo globulins by review of the peripheral smear. Malignancy, namely leukemia and lymphoma, is a primary concern for patients with leukocytosis. For discussion of WBC elevation caused by immature leukocytes in acute and chronic leukemias, see Chapter 544. Nonmalignant WBC counts exceeding 50,000L have histori cally been termed a leukemoid reaction. Unlike leukemia, leukemoid reactions show relatively small proportions of immature myeloid cells, consisting largely of band forms, occasional metamyelocytes, and pro gressively rarer myelocytes, promyelocytes, and blasts. Leukemoid reactions are most often neutrophilic and are frequently associated with severe bacterial infections, including shigellosis, salmonellosis, and meningococcemia; physiologic stressors; and certain medications. The presence of a left shift, defined as having 5 immature neu trophils in the peripheral blood, is consistent with marrow stress. Higher degrees of left shift with more immature neutrophil precursors are indicative of serious bacterial infections and may be a dire sign of depletion of the bone marrow reserve pool of neutrophils. Marked left shift may occasionally be encountered with trauma, burns, surgery, acute hemolysis, or hemorrhage. NEUTROPHILIA Neutrophilia is an increase in the total number of blood neutrophils that is 2 SD above the mean count for age. Elevated absolute neutro phil counts represent disturbances of the normal equilibrium involv ing bone marrow neutrophil production, migration out of the marrow compartments into the circulation, and neutrophil destruction. Neu trophilia may arise either alone or in combination with enhanced mobilization into the circulating pool from either the bone marrow storage compartment or the peripheral blood marginating pool, by impaired neutrophil egress into tissues, or by expansion of the circulat ing neutrophil pool secondary to increased granulopoiesis. Myelocytes are not released to the blood except under extreme circumstances. Acute Acquired Neutrophilia Neutrophilia is usually an acquired, secondary finding associated with inflammation, infection, injury, or an acute physical or emo tional stressor (Table 172.1). Bacterial infections, trauma (especially with hemorrhage), and surgery are among the most common causes encountered in clinical practice. Neutrophilia may also be associated with heat stroke, burns, diabetic ketoacidosis, vaccines, pregnancy, or cigarette use. Drugs commonly associated with neutrophilia include epinephrine, corticosteroids, and recombinant growth factors such as recombinant human granulocyte colony stimulating factor (G CSF) and recom binant human granulocyte macrophage colony stimulating factor (GM CSF). Epinephrine causes release into the circulation of a seques tered pool of neutrophils that normally marginate along the vascular endothelium. Corticosteroids accelerate the release of neutrophils and bands from a large storage pool within the bone marrow and impair the migration of neutrophils |
6,467 | from the circulation into tissues. G CSF and GM CSF cause acute and chronic neutrophilia by mobilizing cells from the marrow reserves and stimulating neutrophil production. Acute neutrophilia in response to inflammation and infections occurs because of release of neutrophils from the marrow storage pool. The postmitotic marrow neutrophil pools are approximately 10 times the size of the blood neutrophil pool, and about half of these cells are bands and segmented neutrophils. Exposure of blood to foreign sub stances such as hemodialysis membrane activates the complement system and causes transient neutropenia, followed by neutrophilia sec ondary to release of bone marrow neutrophils. Reactive neutrophils often have toxic granulation and Dhle bodies present. Chronic Acquired Neutrophilia Chronic acquired neutrophilia is usually associated with continued stimulation of neutrophil production resulting from persistent inflam matory reactions or chronic infections (e.g., tuberculosis), vasculitis, postsplenectomy states, Hodgkin disease, chronic myelogenous leu kemia, chronic blood loss, sickle cell disease, some chronic hemolytic anemias, and prolonged administration of corticosteroids (see Table 172.1). Chronic neutrophilia can arise after expansion of cell pro duction secondary to stimulation of cell divisions within the mitotic precursor pool, which consists of promyelocytes and myelocytes. Sub sequently, the size of the postmitotic pool increases. These changes lead to an increase in the marrow reserve pool, which can be readily mobilized for release of neutrophils into the circulation. The neutro phil production rate can increase greatly in response to exogenously administered hematopoietic growth factors, such as G CSF, with a maximum response taking at least 1 week to develop. Lifelong Neutrophilia Congenital or acquired asplenia is associated with lifelong neutro philia. Some patients with trisomy 21 also have neutrophilia. Uncom mon genetic disorders that present with neutrophilia include leukocyte function disorders such as leukocyte adhesion deficiency and Rac2 deficiency (see Chapter 170) and systemic disorders such as familial cold urticaria, periodic fever syndromes, and familial myeloprolifera tive disease (see Table 172.1). Rare patients with an autosomal domi nant hereditary neutrophilia have been reported. Evaluation of persistent neutrophilia requires a careful history, physical examination, and laboratory studies to search for infectious, inflammatory, and neoplastic conditions. The leukocyte alkaline phosphatase score of circulating neutrophils can differentiate chronic myelogenous leukemia, in which the level is uniformly almost zero, from reactive or secondary neutrophilia, which features normal to elevated levels. ADDITIONAL FORMS OF LEUKOCYTOSIS Monocytosis The average absolute blood monocyte count varies with age, which must be considered in the assessment of monocytosis. Given the role of monocytes in antigen presentation and cytokine secretion and as effec tors of ingestion of invading organisms, it is not surprising that many clinical disorders give rise to monocytosis (Table 172.2). Typically, monocytosis occurs in patients recovering from myelosuppressive che motherapy and is a harbinger of the return of the neutrophil count to normal. Monocytosis is occasionally a sign of an acute bacterial, viral, protozoal, or rickettsial infection and may also occur in some forms of chronic neutropenia and postsplenectomy states. Chronic inflamma tory conditions can stimulate sustained monocytosis, as can preleuke |
6,468 | mia, chronic myelogenous leukemia, and lymphomas. Eosinophilia Eosinophilia is defined as an absolute eosinophil count 1500 cellsL. The majority of eosinophilic conditions are reactive, including infec tions (especially parasitic diseases), connective tissue disorders, allergic and hyperinflammatory diseases, pulmonary disorders, and dermato logic conditions (see Chapter 169). Drug reaction with eosinophilia and systemic symptoms (DRESS) is a particularly important condition Chapter 172 Leukocytosis Thomas F. Michniacki and Kelly J. Walkovich Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1314 Part XII u Immunology to consider in those with prominent eosinophilia as severe cases are associated with significant morbidity and mortality (see Chapter 686.2). Hypereosinophilic syndrome and systemic mastocytosis are additional important causes of an elevated eosinophil count. However, persistent eosinophilia can also herald a malignancy such as leukemia, lymphoma, or carcinoma. Basophilia Basophilia is defined as an absolute basophil count 120 cellsL. Baso philia is a nonspecific sign of a wide variety of disorders and is usually of limited diagnostic importance. Basophilia is most often present in hypersensitivity reactions and frequently accompanies the leukocytosis of chronic myeloid leukemia. Lymphocytosis The most common cause of lymphocytosis is an acute viral illness, as part of the normal T cell response to the infection. In infectious mono nucleosis, the B cells are infected with the Epstein Barr virus, and the T cells react to the viral antigens present in the B cells, resulting in atypical lymphocytes with characteristic large, vacuolated morphology. Other viral infections classically associated with lymphocytosis are cytomega lovirus and viral hepatitis. Chronic bacterial infections such as tubercu losis and brucellosis may lead to a sustained lymphocytosis. Pertussis is accompanied by marked lymphocytosis in approximately 25 of infants infected before 6 months of age. Thyrotoxicosis and Addison disease are endocrine disorders associated with lymphocytosis. Persistent or pro nounced lymphocytosis suggests acute lymphocytic leukemia. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography Table 172.1 Causes of Neutrophilia TYPE CAUSE EXAMPLE Acute acquired Bacterial infections Neutrophil disorder Leukocyte adhesion defects Surgery Acute stress Burns, diabetic ketoacidosis, heat stroke, postneutropenia rebound, exercise Drugs Corticosteroids, epinephrine, hematopoietic growth factors, lithium Chronic acquired Chronic inflammation Inflammatory bowel disease, rheumatoid arthritis, vasculitis, cigarette exposure Persistent infection Tuberculosis Persistent stress Chronic blood loss, hypoxia, sickle cell and other chronic hemolytic anemias Drugs Corticosteroids, lithium; rarely ranitidine, quinidine Other Postsplenectomy, tumors, Hodgkin disease, pregnancy, Sweet syndrome Lifelong Congenital asplenia Hereditary disorders Familial cold urticaria, hereditary neutrophilia, leukocyte adhesion deficiencies, periodic fever syndromes Table 172.2 Causes of Monocytosis CAUSE EXAMPLE Infections Bacterial Brucellosis, subacute bacterial endocarditis, syphilis, tuberculosis, typhoid Nonbacterial Fungal infections, kala azar, malaria, Rocky Mountain spotted fever, typhus Hematologic disorders Congenital and acquired neutropenias, hemolytic anemias Malignant disorders Acute myelogenous leukemia, chronic myelogenous leukemia, juvenile myelomonocytic leukemia, Hodgkin disease, non Hodgkin lymphomas, preleukemia Chronic inflammatory diseases Inflammatory bowel disease, polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus Miscellaneous Cirrhosis, drug reaction, postsplenectomy, recovery from |
6,469 | bone marrow suppression Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 173 u Complement System 1315 173.1 Complement Components, Pathways, and Evaluation Anete Sevciovic Grumach The complement system (CS) forms a network of soluble and cell sur facebound components, pattern recognition proteins (PRPs), prote ases, receptors, effectors, and regulators to perform multiple sensor and effector functions as part of the innate immune system (Tables 173.1 and 173.2). It represents an essential part of immunity, having a major role in host defense against pathogens, homeostasis, and inflam mation, such as promoting phagocytic removal of senescent cells, molecular debris, and weak or superfluous synapses during brain for mation. Complement acts not only in the extracellular space but also within cells and subcellular compartments, where it is involved in the regulation of basic processes of the cell, suggesting that complement directs both innate and adaptive immune responses. Cells are generally protected from amplification and effector insult by a group of comple ment regulators, which are expressed on their surface or mobilized from the circulation. However, if the equilibrium between complement activation and regulation is disturbed, complement can harm the host and precipitate or worsen adverse processes that result in diseases. Circulating complement proteases are zymogens and, once acti vated, they initiate an amplification cascade through cleavage of spe cific targets andor interaction with other proteins. Depending on the activating surface, the CS can be triggered by the classical (CP), lec tin (LP), and alternative (AP) pathways. Each pathway is triggered by different interactions. The CP is initiated by immune complexes through binding of complement protein C1q to immune complexes containing IgM or IgG, in solution or bound to antigens on the cell surface. Certain bacteria, RNA viruses, and the lipid A component of bacterial endotoxin as pathogen associated molecular patterns (PAMPs) on microbial surfaces can activate C1q directly and trigger the full complement cascade. The LP is activated when mannose binding lectin (MBL), or ficolins, recognize unique carbohydrate structures present on the surface of pathogens or altered glycosylation patterns (DAMPs, dangerassociated molecular patterns) on abnormal host cells. The mannose binding lectin associated serine proteases (MASPs) cleave C2 and C4, following the same sequence as CP. The AP is rapidly activated after contact with pathogens, independent of antibody; however, antibody will accelerate the rate of activation. The fluid phase C3 convertase complex C3(H2O)Bb is generated with the spontaneous hydrolysis of C3, referred to as tick over. An amplifica tion loop leads to rapid opsonization stabilized by properdin. Therefore each of these pathways converge toward the cleavage of the abundant plasma protein C3 by a C3 convertase, followed by the formation of a C5 convertase, which cleaves C5 into C5a and C5b, and induces the acti vation of the common lytic effector terminal pathway (TP). The inter action among C5b, C6, C7, C8, and C9 is nonenzymatic and |
6,470 | depends on changes in molecular configuration. The subsequent insertion of TP components into the cell wall leads to lysis via the membrane attack complex (MAC), which is composed of complement proteins C5b to C9. Cell membrane receptors bind complement components or fragments to mediate complement activity, and a large array of serum and mem brane regulatory proteins control the activation of CS (Fig. 173.1). The circulating components and regulators together comprise approximately 15 of the globulin fraction and 4 of the total serum proteins. The normal concentrations of serum complement components vary by age; newborn infants have mild to moderate deficiencies of all components. CLASSICAL AND LECTIN PATHWAYS The CP sequence begins with fixation of C1, by way of C1q, to the Fc non antigen binding part of the antibody molecule after antigen antibody interaction. On binding, the C1 complex changes conformation, activat ing the C1r and C1s protease subunits; the C1s subcomponent becomes an active enzyme, C1 esterase. The activation leads to cleavage of C2 and C4 and the formation of the CP C3 convertase (C4bC2a). As part of the innate immune response, broadly reactive natu ral antibodies and C reactive protein (CRP), which react with car bohydrates from microorganisms and with dying cells, can substitute for specific antibodies in the fixation of C1q and initiate reaction of the entire sequence. Endogenous substances, including uric acid crystals, amyloid deposits, DNA, and components of damaged cells, such as apoptotic blebs and mitochondrial membranes, can activate C1q directly. In this case, however, the ligand C1q complex interacts strongly with the inhibitors C4 binding protein and factor H, allowing some C3 mediated opsonization and phagocytosis but limiting the full inflammatory response typically triggered by microbes. Section 4 Complement System Chapter 173 Complement System Anete Sevciovic Grumach Table 173.1 Nomenclature for Complement Components EXAMPLES Classical pathway components are labeled with a C and a number C1, C2, C4 Alternative pathway components are lettered B, P, D Some components are called factors Factor B, factor D Activated components or complexes have a bar over to indicate activation C4bC2a Cleavage fragments are designated with a small letter C3a, C3b Cell membrane receptor CR1, CR2, CR3, CR4 Table 173.2 Components of Complement System SERUM COMPONENTS THAT ARE THE CORE OF THE COMPLEMENT SYSTEM Classical pathway: C1q, C1r, C1s, C4, C2, C3 Alternative pathway: factor B, factor D Lectin pathway: Mannose binding lectin (MBL), ficolins 123, MBL associated serine proteases (MASPs) 123 Membrane attack complex: C5, C6, C7, C8, C9 Regulatory protein, enhancing: properdin Regulatory proteins, downregulating: C1 inhibitor (C1 INH), C4 binding protein (C4 bp), factor H, factor I, vitronectin, clusterin, carboxypeptidase N (anaphylatoxin inactivator) MEMBRANE REGULATORY PROTEINS CR1 (CD35), membrane cofactor protein (MCP; CD46), decay accelerating factor (DAF, CD55), CD59 (membrane inhibitor of reactive lysis) MEMBRANE RECEPTORS CR1 (CD35), CR2 (CD21), CR3 (CD11bCD18), CR4 (CD11cCD18) C3a receptor, C5a receptor, C1q receptors, complement receptor of the immunoglobulin superfamily (CRIg) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, |
6,471 | 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1316 Part XII u Immunology C1q synthesized in the brain and retina fixes to superfluous syn apses, which then can be cleared through C1q receptors on microglia, clearing the way for fresh synapses to populate the developing nervous system. Recognition molecules in the LP are MBL, ficolins, or collectins (CL 11 or kidney collectin or CL K1; CL 10, collectin liver 1). MBL is the prototype of the collectin family of carbohydrate binding proteins (lectins) that play an important part in innate, nonspecific immunity; its structure is homologous to that of C1q. Three ficolins have been identified in humans: L ficolin (ficolin 2), H ficolin (ficolin 3), and M ficolin (ficolin 1). Ficolins show specificity for N acetylglucosamine residues in complex oligosaccharides, but not for mannose or high mannose type oligosaccharides. Individual members display addi tional specificities, e.g., H ficolin binds to N acetyl d galactosamine and d fucose, M ficolin binds to sialic acid, and L ficolin recognizes lipoteichoic acid and 1,3 d glucan, the major component of yeast and fungal cell walls. These lectins, in association with MASP 1, 2, and 3, can bind to mannose, lipoteichoic acid, and other carbohy drates on the surface of bacteria, fungi, parasites, and viruses. There, MASPs then function like C1s to cleave C4 and C2 and activate the complement cascade. The peptide C4a has weak anaphylatoxin activ ity and reacts with mast cells to release the chemical mediators of immediate hypersensitivity, including histamine. The activation of C3 and C5 also liberates potent chemotactic fragments (i.e., the anaphyla toxins C3a and C5a) that recruit immune cells to the site of activation and prime them. Fixation of C4b to the complex permits it to adhere to neutrophils, macrophages, B cells, dendritic cells, and erythrocytes. MASP 2 can activate clotting by generating thrombin from prothrom bin, which could prevent microbial spread. Cleavage of C3 and generation of C3b is the next step in the sequence. The serum concentration of C3 is the highest of any component, and its activation is the most crucial step in terms of biologic activity. Cleavage of C3 can be achieved through the C3 convertase of the CP, C142, or of the AP, C3bBb. Once C3b is fixed to a complex or dead or dying host cell, it can bind to cells with receptors for C3b (complement receptor 1, CR1), including B lymphocytes, erythrocytes, and phagocytic cells (neutrophils, monocytes, and macrophages). Efficient phagocytosis of most microorganisms, especially by neutrophils, requires binding of C3 to the microbe. The severe pyogenic infections that frequently occur in C3 deficient patients illustrate this point. The biologic activity of C3b is controlled by cleavage by factor I to iC3b, which promotes phagocytosis on binding to the iC3b receptor (CR3) on phagocytes. Further degradation of iC3b by factor I and proteases yields C3dg, then C3d; C3d binds to CR2 on B lymphocytes, thereby serving as a co stimulator of |
6,472 | antigen induced B cell activation. ALTERNATIVE PATHWAY The AP can be activated by C3b generated through CP activity or proteases from neutrophils or the clotting system. It can also be acti vated by a form of C3 created by a low grade, spontaneous reaction of native C3 with a molecule of water, or a tick over that occurs constantly in plasma. Once formed, C3b or the hydrolyzed C3 can bind to any nearby cell or to factor B. Factor B attached to C3b in the plasma or on a surface can be cleaved to Bb by the circulating protease factor D. The complex C3bBb becomes an efficient C3 convertase, which gener ates more C3b through an amplification loop. Properdin can bind to C3bBb, increasing stability of the enzyme and protecting it from inac tivation by factors I and H, which modulate the loop and the pathway. Certain activating surfaces promote AP activation if C3b is fixed to them, including bacterial teichoic acid and endotoxin, virally infected cells, antigenimmunoglobulin A complexes, and cardiopulmonary bypass and renal dialysis membranes. These surfaces act by protecting the C3bBb enzyme from the control otherwise exercised by factors I and H. Rabbit red blood cell (RBC) membrane is such a surface, which serves as the basis for an assay of serum AP activity. Conversely, sialic acid on the surface of microorganisms or cells prevents the formation of an effective AP C3 convertase by promoting the activity of factors I and H. Significant activation of C3 can occur through the AP, and the resultant biologic activities are qualitatively the same as those achieved through activation by C142. MEMBRANE ATTACK COMPLEX The sequence leading to cytolysis begins with the attachment of C5b to the C5 activating enzyme from the CP, C4b2a3b, or from the AP, C3bBb3b. C6 is bound to C5b without being cleaved, stabilizing the activated C5b fragment. The C5b6 complex then dissociates from C423 and reacts with C7. C5b67 complexes must attach promptly to the membrane of the parent or a bystander cell, or they lose their activity. Next, C8 binds, and the C5b678 complex then promotes the addition of multiple C9 molecules. The C9 polymer of at least 3 6 molecules forms a transmembrane channel, and lysis ensues. CONTROL MECHANISMS Without control mechanisms acting at multiple points, there would be unbridled consumption of components, which would generate severe, potentially lethal host damage. Cells are generally protected from ampli fication and effector insult by a panel of complement regulators, which are expressed on their surface or recruited from circulation At the first step, C1 inhibitor (C1 INH) inhibits C1r and C1s enzymatic activity and thus the cleavage of C4 and C2. C1 INH also inhibits MASP 2, fac tors XIa and XIIa of the clotting system, and kallikrein of the contact system. Activated C2 has a short half life, and this relative instability limits the effective life of C42 and C423. The AP enzyme that activates C3, C3bBb, also has a short half life, although it |
6,473 | can be prolonged by the binding of properdin to the enzyme complex. Properdin can also bind directly to microbes and promote assembly of the AP C3 convertase. The serum contains the enzyme carboxypeptidase N, which cleaves the N terminus arginine from C4a, C3a, and C5a, thereby limit ing their biologic activity. Factor I inactivates C4b and C3b; factor H accelerates inactivation of C3b by factor I; and an analogous fac tor, C4 binding protein (C4 bp), accelerates C4b cleavage by factor I, thus limiting assembly of the C3 convertase. Three protein constitu ents of cell membranes (CR1, membrane cofactor protein MCP, and decay accelerating factor DAF) promote the disruption of C3 and C5 convertases assembled on those membranes. Another cell membraneassociated protein, CD59, can bind C8 or both C8 and C9, thereby interfering with the insertion of the MAC (C5b6789). The serum proteins vitronectin and clusterin can inhibit attachment of the C5b67 complex to cell membranes, bind C8 or C9 in a full MAC, or lgM, lgG Immune complexes Classical pathway Lectin pathway MBL, ficolins, MASP Factor D Factor B Bb Ba C3 C3b Properdin C3a C5 C5b9 (MAC) C5a C4bC2a C3 convertase C4bC2aC3b C5 convertase C1INH Factor HI Factor HI CD55 (DAF) MCP CR1 CRIg C4, C2 C3 C3b C3a C3bBb C3 convertase (C3b)2Bb C5 convertase C3 C3b C3a C4bp, Factor I Protein S CD59 C1q, C1r, C1s Alternative pathway Mannose rich surface in microbials Bacteria, bacterial toxin, thick over Fig. 173.1 Activation and control of the complement system. C1INH, C1 inhibitor; C4 bp, C4 binding protein; CD59, cell membraneassociated protein; CR1 (CD35), complement receptor 1; CRIg, complement recep tor of the immunoglobulin superfamily; DAF, CD55, decay accelerating factor; MASP, mannose binding lectinassociated serine protease; MAC, membrane attack complex; MCP, membrane cofactor protein. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 173 u Complement System 1317 interfere with the formation or insertion of this complex. Vitronectin also promotes macrophage uptake of dying neutrophils. The genes for the regulatory proteins factor H, C4 bp, MCP, DAF, CR1, and CR2 are clustered on chromosome 1. PARTICIPATION IN HOST DEFENSE Neutralization of virus by antibody can be enhanced with C1 and C4 and further enhanced by the additional fixation of C3b through the classical or alternative pathway. Complement may therefore be par ticularly important in the early phases of a viral infection when the antibody titer is limited. Antibody and the full complement sequence can also eliminate infectivity of at least some viruses by the production of typical complement holes, as seen by electron microscopy. Fixation of C1q can opsonize (promote phagocytosis) through binding to the phagocyte C1q receptor. C4a, C3a, and C5a can bind to mast cells and thereby trigger the release of histamine and other mediators, leading to vasodilation and the swelling and redness of inflammation. C5a can enhance macrophage phagocytosis of C3b |
6,474 | opsonized particles and induce macrophages to release the cytokines tumor necrosis factor and interleukin 1. C5a is a major chemotactic factor for neutrophils, monocytes, and eosino phils, which can efficiently phagocytize microorganisms opsonized with C3b or cleaved C3b (iC3b). Further inactivation of cell bound C3b by cleavage to C3d and C3dg removes its opsonizing activity, but it can still bind to B cells. Fixation of C3b to a target cell can enhance its lysis by natural killer cells or macrophages (Fig. 173.2). Insoluble immune complexes can be solubilized if they bind C3b, apparently because C3b disrupts the orderly antigen antibody lattice. Binding C3b to a complex also allows it to adhere to C3 receptors (CR1) on RBCs, which then transport the complexes to hepatic and splenic macrophages for removal. This phenomenon may at least par tially explain the immune complex disease found in patients who lack C1, C4, C2, or C3. The CS serves to link the innate and adaptive immune systems. C4b or C3b coupled to immune complexes promotes their binding to antigen presenting macrophages, dendritic cells, and B cells. The cou pling of antigens to C3d allows binding to CR2 on B cells, which greatly reduces the amount of antigen needed to trigger an antibody response. Neutralization of endotoxin in vitro and protection from its lethal effects in experimental animals require C1 INH and later acting components of complement, at least through C6. Activation of the entire complement sequence can result in lysis of virus infected cells, tumor cells, and most types of microorganisms. Bactericidal activ ity of complement has not appeared to be important to host defense, except for the occurrence of Neisseria infections in patients lacking later acting components of complement. Complement Evaluation Good quality blood sampling requires that after clotting (about 20 120 minutes), the serum must be separated by centrifugation as soon as possible, and stored under controlled conditions. In case complement testing cannot be performed on the day of blood sampling, the serum and plasma samples must be stored in a deep freezer (20C) for up to 3 months or in an ultra deep freezer (70C) for a longer storage until analysis. If the analysis will be done by a specialized laboratory, the samples must be shipped on dry ice by courier. Repeated freezing and thawing should be avoided because of the risk of in vitro activation. The serum is sufficient for the analysis of the total function of comple ment proteins and regulators as well as of autoantibodies. A quantita tion of activation products requires the use of EDTA plasma because it blocks the in vitro activation of the CS by way of its Mg2 and Ca2 complexing properties. Heparin and citrate are less useful. The utiliza tion of the less invasive dried blood spot (DBS) based assays can also be used for diagnosis; enzyme activities could be retained, facilitating the samples transportation. The indication for using assays for complement evaluation is to detect genetic, acquired, or the effect of complement inhibitory |
6,475 | ther apy. Functional assays can screen and direct the following steps for the evaluation of specific protein deficiencies (Fig. 173.3). Assays including hemolysis of RBCs (CH50, AP50) check the activation of classical and alternative pathways. In both cases, CH50 and AP50, the functional result is the lytic destruction of erythrocytes on membrane insertion of C5b 9 (MAC). Low but not absent CH50 results could reflect comple ment consumption due to active immune complex disease, diminished hepatic production due to liver disease, and immaturity of hepatic production seen in young infants. Screening with hemolytic assays is not adequate for C9, properdin, MBL, MASP 2, or ficolin deficiencies. In patients with these defects, the hemolytic assay value may be minimally decreased or normal. An alternative assay, popular in Europe, is a plate based activation assay, which more specifically detects complement Fig. 173.2 Sequence of activation of the components of the classical and lectin pathways of complement and interaction with the alternative pathway. Functional activities gener ated during activation are enclosed in boxes. The multiple sites at which inhibitory regulator proteins (not shown) act are indicated by asterisks. Ab, Antibody (immunoglobulin G or M class); Ag, antigen (bacterium, virus, tumor, or tissue cell); B, D, P, factors B, D, and properdin; C CRP, carbohydratecarbohydrate reactive protein; MBL, mannose binding lec tin; MASP, MBL associated serine protease. Classical and lectin pathways Alternative pathway LectinMBL or ficolinMASPCCRP C3AgAb Dying cells C1qrs C1 C14b C1423b C3bBbC3b(P) Opsonization, clearance of dying cells Opsonization, clearance of dying cells C5 C5b67 C6 C8, C9 Reaction with bystander cells C5b67 C5b9 C7 C5a Vascular permeability, chemotaxis AgSurfaceC3b5b Vascular permeability C3a C142a C3bBb(P) C4 C4a C2 C3 activating surface C3b, B, DP C2b Vascular permeability Cytolysis Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1318 Part XII u Immunology activation through CP, LP, and AP (CS screen test). Although the result target of these enzyme linked immunosorbent assays (ELISAs) is principally the same as for the lytic assays, it is based on detecting full assembly of C5b 9 by using an antibody to a C9 neoantigen when serum is added to microtiter wells coated with the activation agent for the different pathways (e.g., IgM for CP, mannan for LP, and lipopoly saccharides for AP). Once an abnormal CH50 or AP50 has been confirmed, immu nochemical tests can be used to define the serum levels of specific components, the second step for defining complement deficiencies. Normal concentrations of single components do not exclude func tional defects. The functional activity of a single component can be tested. Sera depleted of the actual component and patients fresh serum are mixed to see whether the activity can be restored by using hemo lysis as a result. Reduced functional activity of individual complement components either reflects a deficiency state, or indicates consuming complement activation. To distinguish primary or acquired defects, |
6,476 | activation products generated by CS activation could be measured. Different approaches can be applied for this aim: detection of split fragments, generated after enzymatic cleavage of certain components, e.g., C4 (C4a, C4bc, C4d), C3 (C3a, C3bc, iC3b, C3d), factor B (Ba, Bb), and C5 (C5a), or the identification of protein complexes where activated components are bound to their respective regulators, like C1rs C1 inhibitor, the properdin containing AP convertase, C3bBbP, and sC5b 9 (soluble terminal complement complex). Detection of complement activation products like C3d and C4d on red cells using flow cytometry has been used to evaluate in vivo complement activation in autoimmune diseases and trauma. The terminal C5b 9 complement complex exists in two forms, the MAC and the soluble form (sC5b 9). The in vitrogenerated surface bound C5b 9 must not be confused with sC5b 9, which is found in plasma and if increased is a useful marker of complement activation in vivo reflecting diseases with dis turbed complement function. sC5b 9 can be quantified by ELISA and is based on the same C9 neoepitope principle. In the case of efficient C5 blockade, there should ideally be no sC5b 9 present. C4 levels have been used as a screening test for C1 INH deficiency in hereditary angioedema (HAE); this test does not substitute quanti tative andor functional evaluation of C1 INH. C4 concentrations can be within normal range between episodes in approximately 510 of the patients. Also, a defective C1 INH protein can reflect only a func tional assay with normal quantitative values. Deficiency of factor I or H permits persistence of the classical and alternative pathway conver tase and thus consumption of C3, with reduction in the CH50 value. If multiple components are decreased, it is possible that sample handling was improper, a regulatory protein was deficient, or autoantibodies were present. Flow cytometry is the standard technique for the diag nosis of paroxysmal nocturnal hemoglobinuria (PNH) by detecting reduced levels of CD55 and CD59 on blood cells. Autoantibodies to complement components could simulate defi ciencies and assays for their detection would be relevant according to clinical information. They are often associated with specific dis eases, e.g., anti C1q antibody is associated with hypocomplementemic urticarial vasculitis andor proliferative systemic lupus erythematosus (SLE) nephritis. Assessment of cell surface expression of receptors and tissue deposi tion of complement proteins or fragments are further steps for comple ment evaluation. Specific gene panels are another accessible tool that could supply additional information (Table 173.3). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 173.2 Complement Pathway Deficiencies Anete Sevciovic Grumach Most genetically determined complement deficiencies are inherited in an autosomal recessive fashion. Exceptions are properdin deficiency, which is X linked, and C1 INH deficiency, which is autosomal domi nant. In most cases, it is possible to predict the effects of a particular deficiency based on understanding the normal physiologic function of that protein. Increased susceptibility to infections caused by encap sulated bacteria and autoimmunity are the most common presenta tions of complement deficiencies. Deficiency |
6,477 | of components of TP and properdin deficiency are associated with neisserial infections. When there is an imbalance between complement activation and regulation, complement can quickly attack the host and trigger andor exacerbate adverse processes that result in diseases and clinical complications. Genetic variants in the complement factor H (CFH) and complement factor I (CFI) genes have been associated with atypical hemolytic ure mic syndrome (aHUS) and aging macular degeneration (AMD). A distinct clinical manifestation is described for deficiency of C1 INH causing recurrent angioedema. CLASSICAL PATHWAY DEFICIENCIES Patients deficient in the initial components of the CP are prone to auto immune connective tissue diseases (Table 173.4). Most patients with pri mary C1q deficiency have SLE; some have SLE like syndrome without typical SLE serology, a chronic rash with underlying vasculitis, or mem branoproliferative glomerulonephritis (MPGN). The association with SLE is due to compromised clearance of apoptotic debris and impaired B cell tolerance. Some C1q deficient children have serious infections, including septicemia and meningitis. Only a few patients with inherited deficiencies of C1r and C1s have been described. It is thought that nei ther component is stable without the other so that a pathogenic variant in one often leads to diminished levels of both. Glomerulonephritis and lupus have been reported in C1rC1s deficient patients. C1q, C1r, C1s, C2, C4 deficiencies CH50 AP50 LP Factor B, Factor D deficiencies MBL, MASP2 deficiencies C3, C5, C6, C7, C8 deficiencies Fig. 173.3 Laboratory screening of complement system. LP, Lectin pathway; MBL, mannose binding lectin; MASP, MBL associated serine protease. Table 173.3 The Steps for Complement System Evaluation COMPLEMENT EVALUATION EXAMPLES Total complement activity CH50, AP50, lectin pathway Quantification of single components C3, C4, MBL, properdin Functional activity of single components Functional C1 inhibitor Products of complement activation C3d; C3dg Autoantibodies to complement components Anti C1q; nephritic factor Cell surface expression CD55; CD59; CR34 Tissue deposition of complement proteins or fragments Deposition of C3 or factor H in injury burns Genetic evaluation Next generation sequencing or specific gene panels Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 173 u Complement System 1319 Complement component C4 is a central protein in the classical and lectin pathways within the CS. C4A and C4B genes encode the two isoforms of the component C4, an essential element for the effector arm of the humoral immune response. The two isotypes of C4, which differ by only four amino acids, demonstrate differential chemical reactivities: C4A displays a higher affinity for amino groupcontain ing antigens or immune complexes, and C4B for hydroxyl group containing antigens. The presence of one C4A or C4B gene is called heterozygous C4A or C4B deficiency, whereas the presence of no functional C4A or C4B genes causes complete C4A or C4B deficiency and is called homozygous C4 deficiency. Homozygous deficiencies of complement C4A or C4B are detected in 110 of populations. |
6,478 | Homozygous deficiency of C4A is associated with an increased fre quency of SLE; whereas homozygous C4B deficiency has been asso ciated with increased susceptibility to bacterial and enveloped viral infections. Within each C4 gene, there can be deletions or duplica tions or simple inactivating variants; therefore interpretation of a serum level is difficult. C2 deficiency is found with a frequency of 110,000 in the White population. The lowest frequency of autoimmunity (1042), among the proteins of the CP, is observed in C2 deficient patients. Individu als with C2 deficiency also carry the risk of life threatening septicemic illnesses, usually caused by pneumococci; however, most have not had problems, presumably because of protective effects of other comple ment pathways. The genes for C2, factor B (AP), and C4 are situated close to each other on chromosome 6, and a partial depression of factor B levels can occur in conjunction with C2 deficiency. Patients with C1, C2, or C4 deficiency have an increased occur rence of autoantibodies; antinuclear antibodies are present in 75 of patients with C1 or C4 deficiency and 2555 of patients with C2 deficiency. Anti dsDNA antibodies are present in 20 of patients with C1qC4 deficiency and 33 of patients with C2 deficiency. Individu als with heterozygous C2 or C4 deficiency often remain asymptomatic. Also, there is an increased incidence of bacterial infections associated with deficiency of components in CP, including meningitis, pneumo nia, arthritis, or septicemia. Other infections such as epiglottitis, and peritonitis have been described. The most common organisms identi fied in C2 deficient patients have been Streptococcus pneumoniae and Haemophilus influenzae type b. C3 Deficiency C3 deficiency is rare and the disease manifests early in life. Severe infec tions (pneumonia, meningitis, osteomyelitis, or bacteremia) caused by encapsulated bacteria (H. influenzae, Neisseria meningitidis) occur. The infections reflect the impairment in the C3b opsonization, generation of chemotactic factor, influence in B cell stimulation, and failure of complete complement activation. MPGN is noted in approximately 30 of the cases of C3 deficiency. Slightly more common is a partial deficiency of C3, termed hypomorphic C3. This partial deficiency has been seen in some autoimmune disorders. Rare C3 gain of function (GOF) variants may lead to aHUS and endothelial damage in the glom erulus. One common and several rare variants in C3 have been associ ated with increased risk of AMD. A unique feature of C3 deficiency is a vasculitic rash that may appear during infections; symptoms of serum sickness may occasionally be seen. These unusual findings are due to the lack of immune complex solubilization by C3. They typically are transient in nature but can cause confusion with lupus, particularly in the presence of glomerulonephritis. DEFICIENCY OF TERMINAL COMPONENTS (C5, C6, C7, C8, C9) Terminal components are shared by the classical, lectin, and alterna tive pathways, and are ultimately responsible for the formation of the MAC. The risk of developing meningococcal sepsis or meningitis is markedly increased in people who have a deficiency of one terminal component. In contrast to |
6,479 | the immunocompetent population (median age for meningococcal infection: 3 years), the onset of symptoms in patients with terminal deficiencies is 17 years. However, infections generally lead to lower mortality, may be recurrent, and have a milder course than in an immunocompetent person. Rarely, SLE or other autoimmune disorders has been identified in these defects. Dissemi nated Neisseria gonorrhoeae infections have also been described; an increased frequency of other bacterial infections is not observed. A terminal component deficiency should be suspected if there is a family history of meningococcal infections, repeated neisserial infections, or if the causative meningococcal serotype is W 135, X, Y, or Z, which less frequently cause infections in healthy individuals. Early vaccina tion of children could change the profile of serotypes causing infection in those patients. Table 173.4 Pathway Deficiencies of Complement System DEFICIENCY INHERITANCE ASSOCIATED SYMPTOMSDISORDERS C1q, C1rs (often combined), C2, C4 (total C4 deficiency) AR SLE, systemic infections with encapsulated organisms; heterozygous C2 deficiency may have a reduced CH50 but remain asymptomatic C4A or C4B Complex Susceptibility to infections andor autoimmunity (SLE); mostly asymptomatic C3 GOF AD aHUS (210 of the cases) C3 AR Pyogenic infections, neisserial infections, glomerulonephritis, AMD C5, C6, C7, C8C8 AR Neisserial infections; recurrent meningitis C9 AR Neisserial infections (mostly asymptomatic) Factor B AR Neisserial and pneumococcal infections, aHUS (14 of the cases) Factor D AR Bacterial infections MBL Polymorphism Bacterial infections (mostly asymptomatic) and susceptibility to autoimmunity in some cases Ficolin 3 (H ficolin) Polymorphism Various clinical phenotypes MASP 1 AR 3MC syndrome MASP 2 AR Respiratory infections, mostly asymptomatic AR, Autosomal recessive non codominant. AR, Autosomal recessive; AD, Autosomal dominant; C4A and C4B, isotypes encoded by C4A and C4B genes, respectively; GOF, gain of function; SLE, systemic lupus erythematosus; aHUS, atypical hemolytic uremic syndrome; AMD, aging macular degeneration; 3MC, Mingarelli, Malpuech, Michels and Carnevale. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1320 Part XII u Immunology C6 deficiency occurs more frequently in African Americans and in people from South Africa. Two variations of C6 deficiency have been described. In one case, a splice defect leads to a smaller than usual pro tein, C6SD. This protein functions less efficiently than wild type C6; however, it is not clear whether bearing C6SD leads to compromised host defense. The other variation is combined C6 and C7 deficiency. C7 deficiency is rare and in the few reported cases, the clinical presenta tions have varied. C8 is composed of three chains: , , and . C8 deficiency is more common in White people, whereas C8 deficiency is more common among African Americans. Approximately 1 patient in 1000 carries a homozygous common nonsense variant causing C9 deficiency as described in Japan and Korea. It is more difficult to diagnose than most of the other complement deficiencies because the CH50 is diminished but not absent. Lytic activity can be |
6,480 | generated in the absence of C9. The neisserial disease can occur, although the penetrance appears to be less than that with other terminal component deficiencies. ALTERNATIVE PATHWAY DEFICIENCIES The AP is a highly conserved surveillance system that is continuously turning over (tick over) due to a labile thioester bond in C3 and thus does not require antibodies or lectins for activation. Properdin is a positive regulator of AP activity and works by stabilizing AP conver tases. Properdin deficiency is rare, hereditary, and is the only X linked complement deficiency. A small number of patients have been iden tified with properdin deficiency; these patients are unusually suscep tible to Neisseria infections. There is a particularly high fatality rate for meningococcal disease in properdin deficient patients, in contrast with the protection from early death seen in patients with terminal complement component deficiencies. It manifests with either complete absence of the molecule (type I), partial deficiency (type II), or a nor mal level of dysfunctional protein (type III). Properdin deficient indi viduals are susceptible to meningococcal disease, which is frequently complicated by sepsis and most commonly occurs in adolescence. Factor D and Factor B deficiencies were described in few cases and the association with Neisseria infections was also identified. Systemic streptococcal infections have also been involved in factor D deficiency. GOF pathogenic variants in factor B are associated with the aHUS. LECTIN PATHWAY DEFICIENCIES The LP is focused on the recognition of repetitive carbohydrate pat terns found on the surface of microbial pathogens. Lectin pattern recognition molecules (PRMs), which include MBL, ficolin 1, fico lin 2, ficolin 3, collectin 10, and collectin 11, activate the pathway in an analogous manner to antibodies in the CP. MASPs, which act in a similar fashion to C1r and C1s, associate with MBL and activate C4 and C2 by proteolytic cleavage (see Fig.173.1). Among White populations, approximately 57 of people have inherited MBL deficiency. LP impairment due to insufficient production of any of these components is common and may be associated with no clear clinical phenotype. However, MBL insufficiency is, in combination with other factors, associated with more severe forms of sepsis and fatal outcomes. The deficiency appears to represent a modest risk factor for infection, typi cally revealed in a high risk setting. Similarly, it may subtly alter the course or contribute to the overall risk of developing several autoim mune diseases. MBL deficiency has been associated as an additional severity influence for common variable immunodeficiency, cystic fibrosis, and hepatitis. In contrast, low MBL levels have been described as protective for mycobacterial infection. MBL deficiency is not typi cally associated with absent levels, and it has been difficult to define the normal range in healthy people. MASP 1, the most abundant protease of the LP, has a central role in pathway activation via MASP 2. MASP 1 may be involved in coagu lation, renal, gastrointestinal, and myocardial ischemiareperfusion related pathology; there is no firm evidence for this type of pathology in humans. The Malpuech, Michels, Mingarelli, |
6,481 | Carnevale (3MC) syndrome is a rare, autosomal recessive genetic disorder associated with patho genic variants in the MASP13; COLEC11; or COLEC10 genes. The number of 3MC patients with known pathogenic variants in these three genes reported so far remains very small. The clinical manifestations of the 3MC syndrome consist of developmental delay, facial dysmorphia, and various skeletal anomalies. Developmental defects include cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss. Excess or unusual infections and autoimmunity have not yet been described in this syndrome. The proposed mechanism was revealed by an unexpected role for these proteins in cuing neural crest cell migration. MASP 2 deficiency was initially described in a patient with seri ous infections and autoimmune disease. MASP 2 deficiency has been included in the classification of primary immunodeficiencies. Asymp tomatic individuals have been described; the frequency is 610,000, sug gesting that the phenotype is mild. Healthy individuals homozygous for p.D120G have also been found by chance in genetic association stud ies. These findings suggest that MASP 2 deficiency could no longer be associated to a specific clinical phenotype. In contrast, increased levels of MBL or MASP 2 may contribute to poor disease outcome associated with mycobacterial infections or pneumococcal meningitis. Complete ficolin 3 (or H ficolin) deficiency was initially associ ated with increased susceptibility to infections and necrotizing entero colitis. A heterogeneous range of clinical manifestations have been described in patients with complete ficolin 3 deficiency, and the first case described was later diagnosed with Wiskott Aldrich syndrome. Respiratory and nervous system involvement in the few reported cases of FCN3 deficiency raises awareness regarding the significance of fico lin 3 in respiratory and nervous immunity. DEFICIENCIES OF COMPLEMENT REGULATION The CS has several levels of regulation at the initiation, amplification (formation of convertases), and membrane attack phases, thereby pre venting inadvertent tissue damage. Deficiency of complement inhibi tors leads to dysregulation either in the fluid phase or on cell surfaces and consequent recurrent infections (mostly bacterial), inflamma tory disorders, and presentations with a broader clinical phenotype. These include angioedema (C1 INH deficiency), kidney and eye dis eases (factor H, factor I, or CD46MCP deficiency), protein losing enteropathy (CD55DAF deficiency), and PNH (CD55 CD59 defi ciency). In addition, there are seven complement receptors (C1qR, C3aR, C5aR, CR1, CR2, CR3, and CR4). The same disease spectrum may be caused and shaped by a broad variety of different alterations in comple ment activators andor regulators. The individual complement profile of a patient (sometimes referred to as complotype) often determines the course and severity of the disease. Disorders such as AMD, aHUS, or C3 glomerulopathy (C3G) are among the most well described examples in this context. Approximately 50 of patients with aHUS have genetic pathogenic variants of factors H and I, C3, factor B, andor MCP, and deletion of complement factor Hrelated proteins 1 and 3 (CFHR1CFHR3). Approximately 20 of patients with aHUS have pathologic variants in more than one gene and patients with autoantibodies to regulatory proteins also |
6,482 | comprise a significant subset. The majority of aHUS cases are sporadic and occur in the absence of prior family history. Further more, even in familial forms of aHUS, penetrance is incomplete. Thrombomodulin (CD141) also has a regulatory role and binds to factor H and C3b, thereby inhibiting complement activation. Interest ingly, pathologic variants in factor H, MCP, and factor I have also been reported in C3 MPGN, as well as preeclampsia and hemolysis, elevated liver enzyme levels, and low platelet levels (HELLP) syndrome. Several complement proteins, their activation products, and regula tors have also been related to AMD, particularly, C3 and factors H and I. Hereditary Angioedema HAE comprises a group of diseases characterized by recurrent angio edema without wheals, showing an autosomal dominant inheritance pattern. It was first recognized in patients with heterozygous defi ciencies of C1 INH and the estimated prevalence is 1:50,000 (Chap ter 189.1). Patients with angioedema without wheals have also been described with normal C1 INH levels. Several pathogenic variants Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 173 u Complement System 1321 were associated with this group of patients with primary angioedema: factor XII (FXII HAE), plasminogen (PLG HAE), angiopoietin 1 (ANGPT1 HAE), kininogen 1 (KNG1 HAE), myoferlin (MYOF HAE), and heparan sulfate glucosamine 3 O sulfotransferase 6 (HS HAE). However, a significant proportion do not have a defined molecular explanation. The angioedema is self limited and recurrent, affecting the deep layers of skin and mucosa, commonly causing swelling of extremities (hands, feet, limbs), face, lips, tongue, genitalia, bowels, and the upper airway. The involvement of the gastrointestinal tract causes severe abdominal pain, distension, vomiting, and, less frequently, diarrhea. The symptoms can be misdiagnosed, and unnecessary surgery may be performed. The obstruction of upper airways due to edema of the glot tis is associated with asphyxia if the attacks are not prevented. Swelling attacks are transitory and usually last from 2 5 days, but their severity and frequency vary widely from patient to patient. Approximately 5 of people who carry a C1 INH pathologic variant are asymptomatic. In the most frequent subtype, HAE with C1 INH deficiency (HAE C1INH, OMIM 106100), the first HAE episodes occur at a mean age of 10 years; however, the onset of symptoms may occur at an early age (Chapter 189.1). This type of HAE is classified as type I when there is low quantitative and functional C1 INH levels (85 of the cases) and type II for decreased functional C1 INH values. A typical func tional level is approximately 2540 of normal in both types. Attacks, when identified, are triggered by stress, trauma, hormones (estrogen), infections, extreme temperatures, and alcohol. Although many patients can identify triggers, many episodes have no identifiable trigger, which increases anxiety and contributes to feelings of loss of control. The symptoms are preceded by prodromes, such as |
6,483 | erythema marginatum, irritability, nausea, and flulike symptoms. Consumption of C2 and C4 increases the risk for the development of SLE. Positive family his tory occurs in 75 of the cases and de novo pathogenic variants are described in 25 of the cases. The third type of HAE referred to as HAE with normal C1 INH (pre viously called type III), is not a complement deficiency. It is characterized by normal serum levels and functional activity of C1 INH. It has been described primarily in females; however, both sexes are affected. Acquired C1 INH deficiency is rarer than HAE C1 INH (1:9) and is clinically indistinguishable from inherited C1 INH deficiency except that onset is later in life (40 years old). Patients with acquired C1 INH deficiency require careful surveillance for malignancy; B cell malignancies, autoimmunity, and monoclonal gammopathies are the most common. The laboratory features are similar to those of hereditary C1 INH deficiency, except that C1q levels are diminished in these patients. AntiC1 INH can be detected in approximately 70 of the cases. C4 Binding Protein Deficiency C4 binding protein deficiency has been described in one family. The proband presented with angioedema, vasculitis, and arthritis. The manifestations were thought to relate to uncontrolled activation of the CP and the release of anaphylatoxins. Factor H Deficiency Factor H (CFH), which is present at high concentrations (500 gmL) in plasma, works in both the liquid and solid phases and attenuates the activity of C3 convertase in the AP and acts as a cofactor for factor I in the cleavage of C3b and C4b. It is a multifunctional molecule that has the function of decay acceleration and plays a very important role in regulat ing complement activation. Infections, aHUS, glomerulonephritis, and macular degeneration are the main disease phenotypes seen in patients with factor H deficiency. Infections occur due to secondary consump tion of C3 with consequent partial deficiency. Diagnosis is suggestive when C3 has diminished levels and low but not absent CH50 and AP50 is found. The antigenic levels of factor H are typically low. Several people with MPGN were identified with factor H defi ciency. CFH deficiency was found to be the underlying basis for the pathophysiologic changes in 1530 of patients with aHUS. aHUS is a thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, and renal failure, which occurs in the absence of its usual cause (infection with a Shiga toxinproducing organism). It is called atypical because it lacks the common trigger of infectious diar rhea. CFH deficiency probably affects the ability to protect the fenes trated endothelium in the glomerulus from complement mediated damage. Recurrent aHUS also has been seen in patients with anti bodies to factor H, defining an acquired form as well. This form may be slightly more amenable to therapy. Both autosomal recessive and heterozygous pathogenic variants have been seen. The age at onset is quite young in most cases, and the disease is recurrent. Mortality is not uncommon. These patients have a diminished C3 level, although |
6,484 | the antigenic level of factor H typically is normal or elevated. Normal C3 levels are sometimes seen, and the only way in which this disorder can be identified is with direct genetic analysis. A common tyrosine histidine polymorphism of factor H was identi fied as a significant risk factor for macular degeneration with a higher risk of the development of macular degeneration and blindness sub sequently. In macular degeneration, the central region of the retina is gradually destroyed by a process that leaves deposits of protein that contain factor H and terminal complement components. It has been hypothesized that the abnormal factor H provides less protection to the choroidal vessels, allowing smoldering complement activation with gradual damage to the endothelium. FACTOR I DEFICIENCY Not only factor H but also factor I is a key regulator of the AP. Defi ciency of factor I results in uncontrolled activation of the AP with subsequent secondary C3 deficiency and a reduction in circulating factor H levels. Distinct clinical manifestations have been associated with factor I deficiency. Marked susceptibility to infections relates to the role of factor I as a cofactor for C3bBb dissociation. When factor I is lacking, C3bBb continues to cleave C3 resulting in secondary C3 deficit. Both the CH50 and the AP50 are depressed but not absent, and C3 antigen levels are low. In factor I deficiency, infections are similar to those seen in true C3 deficiency. Neisserial disease has been reported, as well as infections with encapsulated organisms such as S. pneumoniae and H. influenzae. Partial factor I deficiency has been described. aHUS, or MPGN II, has also been associated with factor I deficiency, probably related to the capacity of complement regulatory proteins to protect vascular endothelium from activating complement after microtrauma. These cases of factor I deficiency are difficult to identify because complement studies often give normal results. C3 may be depressed but is not necessarily affected. The pathogenic variants inactivate certain binding sites like surface bound C3b and polyanion surfaces such as the fenestrated endothelium of the glomerulus, which exposes the basement membrane. A third phenotype resembles an autoinflammatory process and has been described in a small number of patients. Central nervous system inflammation has been the hallmark. Partial factor I deficiency has also been previously associated with clin ical manifestations including recurrent tonsillitis, urinary infections, otitis, pyelonephritis, severe meningitis, and sepsis. Membrane Cofactor Protein (CD46) Deficiency MCP is a membrane protein, and its defect is intrinsic to the kidney. Deficiencies of MCP are associated with a later onset of atypical HUS compared with factor H and factor I deficiencies and it accounts for approximately 10 of all cases. There is no other known phenotype for MCP deficiency. Findings on traditional complement analysis are normal, although the mechanism is thought to be the same as for factor H and factor I deficiencies. Considering the local defect, renal trans plantation can be successful. CD59 Deficiency CD59 is the key membrane regulator of the TP that prevents inser tion of |
6,485 | the MAC into host tissue. It is expressed on most hemato poietic cells and endothelial cells, where it confers protection from intravascular complement mediated lysis. Isolated CD59 deficiency manifests by chronic hemolytic anemia, recurrent stroke, and severe Guillain Barrlike neurologic symptoms with hemolysis. This defect Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1322 Part XII u Immunology in CD59 was suspected in cases of chronic hemolysis because of the phenotypic resemblance to PNH. PNH is caused by acquired somatic variants of phosphatidylinositol glycan class A (PIG A) or phospha tidylinositol glycan class M (PIG M) in a clone of bone marrow pro genitor cells. The protein product of PIG A is an anchoring structure for C8 binding protein, DAF (CD55), and CD59. Glycosylphosphati dylinositol (GPI) anchored proteins protect hematopoietic cells from complement mediated lysis. PNH is characterized by recurrent epi sodes of hemoglobinuria secondary to intravascular hemolysis and can be associated with thrombosis and aplastic anemia. The red cells are the most vulnerable because they have no ability to repair membrane dam age. When the cells develop from the variant bearing progenitor, they lack all GPI anchored membrane proteins, although the major features relate to loss of CD59. The diagnosis of PNH is made by flow cytometry for CD59 or CD55 (DAF). Decay Accelerating Factor (CD55) Deficiency DAF (CD55) is a membrane bound regulator that dissociates both classical and alternative C3 convertases. In certain kindreds, DAF defi ciency has been associated with protein losing enteropathy, whereas in others, all of the members have been completely healthy, with the defi ciency being identified at the time of blood donation or cross matching for a transfusion. The Cromer blood group antigens reside on DAF. The RBCs of people with the Cromer null phenotype, Inab, lack DAF but do not appear to show increased susceptibility to hemolysis. This find ing suggests that CD59 is substantially more important in regulating red cell lysis by complement. DEFICIENCIES OF COMPLEMENT RECEPTORS CR1 Deficiency CR1 (CD35) is a multiple modular protein that binds C3bC4b opsonized foreign antigens, mediating the immune adherence phe nomenon. No cases of complete inherited CR1 deficiency have been reported; however, acquired mild C1R deficiency is quite common in patients with immune complex diseases and serum sickness. Similarly, a polymorphic variant of CR1 with diminished levels and function has been described, although it does not appear to be a risk factor for auto immune disease. CR3CR4 Deficiency CR3CR4 deficiency (LFA 1) is a defect in the 3 2 integrin adhesion molecules. Pathogenic variants in the common chain (CD18) lead to failure to express adequate chains: CD11a, CD11b, and CD11c. Leu kocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of 2 integrin sub unit of the leukocyte cell adhesion molecule (Table 173.5; see Chapter 170). The leukocyte cell adhesion molecule |
6,486 | is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and medi ates cell cell and cell extracellular matrix adhesion. LAD is character ized by a delayed separation of the umbilical cord, recurrent bacterial and fungal infections, and impaired pus formation and wound healing associated with heavy mortality; bone marrow transplantation often is recommended. The infections are characteristic in that necrosis pre dominates, with little neutrophilic infiltrate. With some residual 2 integrin expression, the patient may be able to survive without a bone marrow transplant and infections are common. The manifestations of the disorder are due to the combined effects of ineffective opsonization and an inability to traverse the vascular endo thelium to phagocytose bacteria. 2 Integrins are essential for the firm adhesion step and diapedesis. Lacking 2 integrins, the neutrophils remain in the vascular space, where they are unable to participate in the defense against bacteria. This explains the lack of pus at sites of active infection. Two other forms of LAD are recognized: LAD type II is due to a defect in fucosylation of selectin ligands and LAD type III is due to an activation defect of integrins. The major manifestations are the infection pattern just described and a moderate to severe bleeding ten dency secondary to impaired activation of platelet adhesion molecules. LAD III results from pathogenic variants in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with integrins in hematopoietic cells. In LAD III, the adhesive functions of inte grins on both leukocytes and platelets are disrupted, most likely due Table 173.5 Protein Regulators and Receptor Deficiencies of Complement System DEFICIENCY INHERITANCE ASSOCIATED SYMPTOMSDISORDERS C1 inhibitor AD HAE with C1 INH deficiency C4 binding protein Unknown Atypical Morbus Behet, angioedema, protein S deficit Properdin X linked recessive Meningitis (Neisseria) Factor H AR Membranoproliferative glomerulonephritis, AMD, aHUS (2030 of the cases) Factor I AR Pyogenic infections, neisserial infections, glomerulonephritis, aHUS (510 of the cases), central nervous system inflammation CFHR1 (FHR3) Complex aHUS, C3G, AMD, RA, SLE Thrombomodulin (CD141) AD aHUS (35 of the cases) CD46MCP Most often heterozygous or compound heterozygous pathogenic variants aHUS (1015 of the cases) CD55DAF AR Protein losing enteropathy CD55 (DAF) or CD59 AR PNH CD59 AR Chronic hemolysis and relapsing peripheral demyelinating disease, cerebral infarction CR2 (CD21) AR Infections, associated with CVID CR3 (CD18CD11b); CR4 (CD18CD11c, LFA 1) AR LAD CFHR1, Complement factor H related 1; MCP, membrane cofactor protein; DAF, decay accelerating factor; LFA 1, integrin called lymphocyte function associated antigen 1; AR, autosomal recessive; AD, autosomal dominant; aHUS, atypical hemolytic uremic syndrome; C3G, C3 glomerulopathy; SLE, systemic lupus erythematosus; AMD, aging macular degeneration; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; PNH, paroxysmal nocturnal hemoglobinuria; CVID, common variable immunodeficiency; LAD, leukocyte adhesion deficiency. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 173 u Complement System 1323 to defects in activation |
6,487 | dependent alterations of surface integrins that enable high avidity binding to ligands on target cells, a process termed inside out signaling. MANAGEMENT OF COMPLEMENT DEFICIENCIES Prophylactic antibiotics may offer additional protection from seri ous infection. With the onset of unexplained fever, cultures should be obtained and antibiotic therapy instituted rapidly and with less strin gent indications than in an unaffected child. The parent or patient should be given a written action plan describing any predisposition to systemic bacterial infection or autoimmune disease associated with the patients deficiency, along with the recommended initial approach to management, for possible use by school, camp, or emergency depart ment physicians. Therapy for infection is not standardized, but it is usually directed to prevent infections caused by encapsulated bacteria. Early complement component deficiencies have major risks to acquire infections caused by S. pneumoniae and H. influenzae. Patients should also be vaccinated against encapsulated organisms to maintain high titers. In the case of terminal component, factor D, and properdin deficiencies, high levels of antibody after vaccination may partially compensate for the complement deficiency. Effective vac cines are available; high titers of antibody may offer protection. Repeat immunization of patients is advisable because complement deficiency can be associated with a blunted or shorter lived antibody response than normal. Immunization of household members may reduce the risk of exposing patients to these pathogens. Patients under immunosuppression for rheumatologic disorders such as SLE will require more vigilance for severe infection. Individuals with SLE and a complement defect generally respond as well to therapy as do those without complement deficiency. Management of cardiac risk factors is of heightened importance in early complement compo nentdeficient individuals because of their accelerated atherosclerosis. C1q deficiency has a poor prognosis and this protein is produced to a large extent by myeloid cells. Bone marrow transplantation has been curative and should be considered for C1q deficiency. MBL purified from plasma or recombinant material has been admin istered in trials; however, no prospective study has been performed. In addition, the role of MBL deficiency in significant infections is not well established. The treatment of HAE with C1 INH deficiency is noted in Chapter 189.1. General guidance includes avoiding the use of estrogens or drugs that can induce angioedema, such as angiotensin converting enzyme inhibitors (ACEis) and gliptins. If possible, trigger factors could be avoided. Vaccination is not contraindicated, and hepatitis A and B vaccinations are recommended. The approach includes long term pro phylaxis (LTP), short term prophylaxis (STP), and on demand therapy (Table 173.6; see Chapter 189.1). STP is used for dental procedures, surgical procedures, endoscopies, or other situations in which significant trauma may be expected. Atten uated androgens can be used for this indication; C1 INH concentrates have largely supplanted androgens in this setting. A recombinant C1 INH, conestat alfa, is effective for both HAE attacks and for STP. Fresh frozen plasma (FFP) is another alternative in this setting. Despite prophylaxis, breakthrough episodes do occur. On demand therapy should also be an option for patients |
6,488 | with sporadic attacks or who may not be on any active prophylaxis. There are several options to treat the attacks: C1 INH concentrate; ecallantide, a kallikrein inhibi tor; and icatibant, a bradykinin 2 receptor antagonist. On demand treatment and STP is the same for HAE with nor mal C1 INH. LTP shows improvement with tranexamic acid and progestins. PNHaHUS Treatment Eculizumab, a humanized monoclonal IgG24 antibody targeting C5, prevents the generation of the MAC C5b9 and is an effective treatment for PNH and aHUS. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 173.6 Therapies for Hereditary Angioedema with C1 Inhibitor Deficiency LONG TERM PROPHYLAXIS Androgens (danazol, oxandrolone, stanozolol) Avoid use If necessary: Danazol: 10 mgkgday (max 200 mgday) Oxandrolone: 0.1 mgkgday (no max) Stanozolol: 26 mgday (dose and max) after puberty (Tanner 5) Oral Antifibrinolytics (tranexamic acid, epsilon aminocaproic acid) Tranexamic acid: 10 mgkgday bid to 25 mgkgday tid Limit dosage 3 gday Oral pdC1 INH nanofiltrated Approved for 12 yr in some countries, 6 yr in others 1,000 IU in 12 yr 6 12 yr 500 IU q 3 4 days IV SC pdC1 INH nanofiltrated 60 IUkg twice weekly 12 yr SC Lanadelumab 300 mg every 2 wk After 6 mo, if no attacks: 300 mg every 4 wk 12 yr SC Berotralstat Approved in some countries for 12 yr or older 150 mgday Oral SHORT TERM PROPHYLAXIS pdC1 INH nanofiltrated 20 IUkg IV (no age limits) 1 6 hr before proceduretrigger IV rhC1 INHconestat alfa Approved for 12 yr in some countries, 2 yr in others 50 IUkg, max. 4,200 IU (50 IUkg 84 kg, 4,200 IU 85 kg) IV Androgens (danazol, oxandrolone, stanozolol) Avoid use Danazol: 10 mgkgday (max 200 mgday) Oxandrolone: 0.1 mgkgday (no max) Stanozolol: 26 mgday (dose and max) 5 days before and 23 days after proceduretrigger Oral Fresh frozen plasma May be used, if other STP medications not available 10 mLkg IV No age limits ON DEMAND THERAPY Ecallantide Approved in some countries for 12 yr 30 mg SC Self administration is not allowed due to anaphylaxis Icatibant Approved for 18 yr in some countries, 2 yr in others 30 mg3 mL Dose adjustment is needed for adolescent children 65 kg2 yr SC pdC1 INH nanofiltrated 20 IUkg IV (no age limits) rhC1 INHconestat alfa Approved for 12 yr in some countries, 2 yr in others 50 IUkg, max. 4,200 IU (50 IUkg 84 kg, 4,200 IU 85 kg) IV Fresh frozen plasma May be used if other on demand medications are not available 10 mLkg IV No age limits Commercial name for pdC1INH nanofiltered indicated for LTP is Cinryze and for STP is Berinert. IV, Intravenous; LTP, longterm prophylaxis; pd, plasma derived; rh, recombinant; SC, subcutaneous; STP, short term prophylaxis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1324 Part XII u Immunology Primary immune |
6,489 | dysregulatory diseases (PIRDs) are a recognized subset of primary immunodeficiencies that are characterized by hyperinflamma tion, organ specific and systemic autoimmunity, endocrinopathy, enter opathy, and nonmalignant lymphoproliferation. Clinical manifestations of immune dysregulation should lead to a consideration of PIRD. Genetic testing can confirm a diagnosis. Targeted treatments are available for many PIRDs and hematopoietic cell transplant (HCT) is often curative. 174.1 Tregopathies Danielle E. Arnold and Jennifer W. Leiding Tregopathies are a subset of primary immunodeficiency diseases recog nized by the International Union of Immunologic Societies. The clinical manifestations of these diseases are variable, but all involve some degree of immune dysregulation manifesting as autoimmunity, hyperinflamma tion, cancer predisposition, andor lymphoproliferative disease. PATHOPHYSIOLOGY T regulatory (Treg) cells are specialized T cells responsible for the maintenance and self tolerance of immune responses (Fig. 174.1). These cells are responsible for suppressing production of proinflam matory cytokines and growth factors and suppressing T cell prolifera tion. The transcription factor FOXP3 is essential for the regulatory function of Treg cells. Several subsets of Treg cells exist, each char acterized by unique features. Thymic derived Treg cells (tTreg) (CD4CD25FOXP3) account for 5 of total CD4 T cells in the peripheral blood. FOXP3 Treg cells can also differentiate outside of the thymus in peripheral tissues. These cells are known as peripher ally induced regulatory (pTreg) cells. A number of monogenic diseases (Table 174.1) of the immune system that affect the number andor function of Treg cells have been described. By reducing the effect of Treg cells, T cell activation and proliferation are unrestrained. This lack of regulation or inhibition manifests as immune dysregulation. Clinical symptoms of these disorders include early onset multiorgan autoim munity, endocrinopathy, enteropathy, colitis, and lymphoproliferation. Diagnosis In a patient with early onset, severe, or difficult to control autoim munity, endocrinopathy, colitis, or nonmalignant lymphoproliferative disease, a diagnosis of a Tregopathy should be considered. Next genera tion sequencing via a targeted panel andor whole exome sequencing is necessary to establish a genetic diagnosis. Treatment Targeted treatment is available for several Tregopathies (see Table 174.1). Abatacept, a CTLA4 Ig fusion protein, has been used suc cessfully in the treatment of refractory cytopenias, interstitial lung disease, and lymphoproliferation in CTLA4 haploinsufficiency and lipopolysaccharide responsive and beigelike anchor protein (LRBA) deficiency. Jakinibs are a class of medications that inhibit Janus kinase activation of certain STAT transcription factors. Jakinibs have been used successfully to treat immune dysregulatory and autoimmune symptoms in gain of function of STAT1 and STAT3 diseases. HCT can provide a curative option for many Tregopathies. IMMUNE DYSREGULATION POLYENDOCRINOPATHY, ENTEROPATHY, X LINKED SYNDROME This immune dysregulation syndrome is characterized by onset within the first few weeks or months of life with watery diarrhea (autoimmune enteropathy), an eczematous rash (erythroderma in neonates), insulin dependent diabetes mellitus, hyperthyroidism or more often hypothyroid ism, severe allergies, and other autoimmune disorders (Coombs positive hemolytic anemia, thrombocytopenia, neutropenia). Psoriasiform or ich thyosiform rashes and alopecia have also been reported. Immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is caused by |
6,490 | a pathogenic variant in the FOXP3 gene, which encodes a forkhead winged helix transcription factor (scurfin) involved in the function and development of CD4 CD25 Tregs. The absence of Tregs may predispose to abnormal activation of effector T cells. Variants in multiple other genes also produce an IPEX like syn drome (see Table 174.1; Fig. 174.2). Clinical Manifestations Watery diarrhea with intestinal villous atrophy leads to failure to thrive in most patients. Cutaneous lesions (usually eczema) and insulin dependent diabetes begin in infancy. Lymphadenopathy and splenomegaly are also present. Serious bacterial infections (meningitis, sepsis, pneumonia, osteo myelitis) may be related to neutropenia, malnutrition, or immune dysreg ulation. Laboratory features reflect the associated autoimmune diseases, dehydration, and malnutrition. In addition, serum IgE levels are elevated, Chapter 174 Immune Dysregulation Danielle E. Arnold and Jennifer W. Leiding Fig. 174.1 Immunosuppressive mechanisms underlying Treg mediated immune suppression. Tregs are characterized by expression of the cell surface markers CD4, CD25high and CD127low, and transcription factor FOXP3. Tregs modulate the immune system using their suppres sive molecules PD 1, CTLA 4, and CD39, and various surface receptors through inhibition of dendritic cell (DC) function and maturation, through the secretion of anti inflammatory cytokines such as IL 10, TGF , and IL 35, andor through direct inhibition of Teff via induction of cytolysis using granzyme and metabolic disruption. Moreover, Tregs can reduce Teff activation by limiting TCR ligand binding. DC, dendritic cell; TCR, T cell receptor; Teff, effector T cell; Treg, regulatory T cell. (From Kempkes RWM, Joosten I, Koenen HJPM, He X. Metabolic pathways involved in regulatory T cell functionality. Front Immunol. 2019;10:2839. Fig. 1.) Metabolic disruption Cytolysis with granzyme Antiinflammatory cytokines DC Teff TCRmediated activation Function and maturation CD73 CD39 CTLA4PD1 CD25 CD4 Treg FOXP3 Section 5 Immune Dysregulation Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 174 u Immune Dysregulation 1325 with normal levels of IgM, IgG, and IgA. The diagnosis is initially made clinically and confirmed by genetic testing (exome or panels). Treatment Inhibition of T cell activation by cyclosporine, tacrolimus, or sirolimus with corticosteroids is the treatment of choice, along with the specific care of the endocrinopathy and other manifestations of autoimmunity. These agents are typically used as a bridge to transplant. HCT is the only possibility for curing IPEX. Janus kinase inhibitors have been used in patients with IPEX like syndromes. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 174.2 Hemophagocytic Lymphohistiocytosis Danielle E. Arnold and Jennifer W. Leiding Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic hyperinflammatory syndrome that can be aggressive and life threatening. Classic features include fever, cytopenia, hepatospleno megaly, coagulopathy, and elevations in inflammatory markers. Primary or genetic HLH is due to pathogenic variants in genes that predispose patients to HLH by a variety of mechanisms and includes classic familial HLH due to pathogenic variants in PRF1, UNC13D, STX11, and STXBP2; |
6,491 | certain pigmentary disorders; and other primary Table 174.1 Tregopathies GENE (PROTEIN) DISORDER INHERITANCE CLINICAL PHENOTYPE DEFINITIVE OR DISEASE SPECIFIC TREATMENT FOXP3 IPEX syndrome XL Enteropathy, type 1 diabetes, eczema, FTT, autoimmune cytopenias, thyroiditis, hepatitis Tacrolimus, cyclosporine Allogeneic HCT IL2RA CD25 deficiency AR Enteropathy, eczema, lymphoproliferation, recurrent infections Allogeneic HCT CTLA 4 ALPSV CTLA4 haploinsufficiency AD Enteropathy, type 1 diabetes, autoimmune cytopenias, interstitial lung disease Sirolimus Abatacept, belatacept Allogeneic HCT LRBA LRBA deficiency AR Enteropathy, type 1 diabetes, autoimmune cytopenias, interstitial lung disease Abatacept, belatacept Allogeneic HCT BACH2 BACH2 deficiency AD Enteropathy, lymphoproliferation, recurrent respiratory tract infections, infections Allogeneic HCT STAT3 STAT3 GOF AD, GOF Enteropathy, autoimmune cytopenias, lymphoproliferation, type 1 diabetes, recurrent infections Jakinibs Allogeneic HCT STAT5B STAT5B AD, AR Eczema, growth hormone deficiency, infections, enteropathy, JIA, ITP, chronic lung disease Symptom specific therapy, HCT IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X linked; XL, X linked; FTT, failure to thrive; HCT, hematopoietic cell transplant; AR, autosomal recessive; CTLA, cytotoxic T lymphocyte protein; ALPSV, autoimmune lymphoproliferative disease V; AD, autosomal dominant; LRBA, lipopolysaccharide responsive and beigelike anchor protein; BACH, broad complex tramtrack bric a brac and Capncollar homology; STAT, signal transducer and activator of transcription; GOF, gain of function; JIA, juvenile idiopathic arthritis; ITP, immune thrombocytopenic purpura. Fig. 174.2 Clinical manifestations in the IPEX like cohorts. (Modified from Gambineri E, Ciullini Man nurita S, Hagin D, et al. Clinical, immunological, and molecular het erogeneity of 173 patients with the phenotype of immune dysregula tion, polyendocrinopathy, enteropa thy, X linked (IPEX) syndrome. Front Immunol. 2018;9:2411. Fig. 5.) Enteropathy Skin disease Endocrinopathy Hematologic disease Pulmonary Cardiovascular Renal Hepatic Lymphadenopathy Arthritisvasculitis Neurologic Serious infections 0 10 20 30 40 50 60 70 80 90 100 IPEXlike IPEX Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1326 Part XII u Immunology immunodeficiencies or immune regulatory disorders (see Chapter 556.2; Fig. 174.3). Primary HLH is seen most frequently in pediatric patients but may occur at all ages. Secondary HLH occurs in the setting of a medical condition that results in intense immune activation such as severe infection, malignancy, or rheumatologic disease. Many primary immune deficiencies (PIDs) are also associated with an increased risk of HLH, usually in the setting of infection. HLH has been reported in patients with severe combined immune deficiency and chronic granulomatous disease, but secondary HLH has been seen in a wide variety of PID. Several inborn errors of metabolism can also present with secondary HLH. Of note, patients with primary or genetic HLH often present with HLH triggered by or secondary to infection or other immune activating events. For more details see Chapter 556.2. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 174.3 Epstein Barr Virus Susceptibility Disorders Danielle E. Arnold and Jennifer W. Leiding Epstein Barr virus (EBV) is a gamma herpes family virus with a marked tropism for B cells. Most individuals experience asymptomatic infection or |
6,492 | infectious mononucleosis, a self limiting lymphoproliferative disease that is particularly common in adolescents. EBV is also an oncogenic virus and may induce several types of neoplasms, including B cell, T cell, and natural killer (NK) cell lymphomas; nasopharyngeal and gastric carcinomas; and EBV associated smooth muscle cell tumors. During primary infection, EBV infected B cells are eliminated by EBV specific cytotoxic T cells as well as other innate cytotoxic lym phocytes such as NK cells, T cells, and invariant natural killer T (iNKT) cells. However, some EBV infected B cells escape the immune response, establishing a reservoir for EBV that may reactivate anakinra IL1 IL18 IL18 binding protein Inflammasome inflammasome Macrophage IL6 Ferritin Fever Inflammation Tissue damage Cytokine storm ruxolitinib emapalumabIFNR IFNgamma sIL2R Tissue Infiltration IL6R tocilizumab perforin granzyme perforin pore XIAP PRF1 UNC13D STX11 STXBP2 LYST RAB27A AP3B1 Cell apoptosis MHC1TCR Complex alemtuzumab CD52 IL12R IL12 Cytotoxic T cell Infected B cell EBV EBV EBV NLRC4 XIAP Fig. 174.3 Hemophagocytic lymphohistiocytosis (HLH). HLH is a severe systemic inflammatory syndrome due to abnormal reciprocal macrophage and cytotoxic lymphocyte hyperactivation, resulting in cytokine storm, hemophagocytosis, and tissue infiltration by activated immune cells. Primary HLH genes associated with defective granule mediated cytotoxicity or inflammasome dysregulation are shown in red. Common nonsteroidal immu nosuppressive agents frequently used to treat HLH are also shown. EBV, Epstein Barr virus; IFN, interferon; IL, interleukin; MHC, major histocompat ibility complex; TCR, T cell receptor; XIAP, X linked inhibitor of apoptosis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 174 u Immune Dysregulation 1327 throughout an individuals life. These reactivations are typically asymptomatic in healthy individuals; however, in immunocompro mised persons, EBV reactivations and persistence and expansion of latently infected B lymphoblasts may result in symptomatic and often severe disease. PATHOPHYSIOLOGY There are several primary combined immunodeficiencies charac terized by a very high predisposition to EBV infection, some of which are listed in Table 174.2. These disorders are due to defects in pathways involved in T and B cell interaction and crosstalk (Fig. 174.4). Disruption of these pathways results in aberrant cytotoxic T cell activation, migration, proliferation, andor cytolytic activity in response to antigenic stimulation and, thus, impaired immune surveillance of B cells by T cells. Marked decrease or absence of iNKT cells, mucosal associated invariant T (MAIT) cells, andor NK cells and impaired NK cell function are also often observed. Clinical Manifestations, Diagnosis, and Treatment More than 50 of patients with EBV susceptibility disorders expe rience at least one episode of EBV lymphoproliferative disease. Patients are also susceptible to other EBV driven pathologies, including HLH and both Hodgkin and non Hodgkin lymphoma. Other severe viral infections (e.g., other herpesviruses, human herpesvirus 6 HHV 6), bacterial infections, particularly recur rent pulmonary infections, and hypogammaglobulinemia and or dysgammaglobulinemia are also common. Diagnosis for these disorders is with a full immune evaluation and |
6,493 | genetic testing. Treatment includes rituximab (anti CD20 antibody) to eliminate EBV infected B cells, treatment of infections, and immunoglobulin Table 174.2 Primary or Genetic EBV Susceptibility Disorders GENE (PROTEIN) DISORDER INHERITANCE PATHOGENESIS ADDITIONAL FEATURES DEFINITIVE OR DISEASE SPECIFIC TREATMENT MAGT1 XMEN (X linked immunodeficiency wMg2 defect, EBV infection and neoplasia) XL Defective Mg2 transporter; NKG2D expression results in defective cytotoxicity Chronic EBV infection rather than full scale HLH, viral infections, lung infections, autoimmune cytopenia, lymphoma Allogeneic HCT ITK Lymphoproliferative syndrome 1 AR Defective tyrosine kinase function; defective cytotoxic T cell expansion, and cytolytic capacity; iNKT cells Chronic EBV infection, lung infections, PJP, autoimmune cytopenia, lymphoma Allogeneic HCT CD27 Lymphoproliferative syndrome 2 AD CD27 is a co stimulatory molecule on T cells; required for normal T cell proliferation and cytotoxicity against EBV infected B cells; iNKT cells Chronic EBV infection, lung infections, uveitis, oral and anal ulcers, hypogammaglobulinemia, lymphoma Allogeneic HCT CD70 Lymphoproliferative syndrome 3 AR CD70 expressed by EBV infected B cells interacts with CD27 on T cells; required for normal expansion and cytotoxicity of T cells; NKG2D and 2B4 expression; iNKT cells Chronic EBV infection, lung infections, lymphoma Allogeneic HCT CTPS1 CTPS1 deficiency AR Enzyme involved in de novo synthesis of cytidine nucleotide triphosphate (CTP); deficiency leads to impaired T cell proliferation; iNKT cells Chronic EBV infection, viral infections, lung infections, meningitis, eczema, lymphoma Allogeneic HCT CORO1A CORO1A deficiency AR Actin regulator; T lymphopenia, impaired immunologic synapse formation and intracellular signaling; iNKT cells Chronic EBV infection rather than HLH, viral infections, lung infections, neurologic involvement, lymphoma Allogeneic HCT RASGRP1 RASGRP1 deficiency AR Activates RAS, which leads to MAPK pathway activation; defects in T cell activation, proliferation, and migration; iNKT cells Chronic EBV infection, viral infections, lung infections, autoimmune cytopenia, EBV negative lymphoproliferative disease, lymphoma Allogeneic HCT Treatment should include HLH directed therapy, treatment of infections and malignancy, and other supportive care measures as appropriate. EBV, Epstein Barr virus; AR, autosomal recessive; XL, X linked; AD, autosomal dominant; TNF, tumor necrosis factor; iNKT, invariant NK T cell; CNS, central nervous system; HSM, hepatosplenomegaly; PJP, Pneumocystis jiroveci pneumonia; HCT, hematopoietic cell transplantation. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1328 Part XII u Immunology replacement when indicated. Allogeneic HCT is the only curative treatment available. Other Primary Immunodeficiencies Associated with Epstein Barr Virus Lymphoproliferative Disease Herpesvirus infections and EBV lymphoproliferative disease are also seen to a lesser extent in several other combined immunodeficien cies associated with T cell defects, particularly those affecting T cell survival and mobilization. Classic examples include Wiskott Aldrich syndrome, DOCK8 deficiency, GATA2 haploinsufficiency, and acti vated PI3K delta syndrome, among others. Severe EBV infections may also be seen in patients with hypomorphic or leaky severe combined immunodeficiency. Any patient who presents with prolonged andor severe EBV lym phoproliferative disease or EBV positive lymphoma warrants evalua tion for an underlying primary |
6,494 | immunodeficiency. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 174.4 Chronic Active Epstein Barr Virus Danielle E. Arnold and Jennifer W. Leiding Chronic active EBV (CAEBV) is a rare systemic EBV lymphoprolifera tive disorder characterized by fever, persistent lymphadenopathy, hepa tosplenomegaly, and hepatitis in the absence of an underlying primary or secondary immunodeficiency, malignancy, or autoimmune disorder. GENETIC PREDISPOSITION CAEBV is seen primarily in persons of East Asian (Japan, Korea, China, and Taiwan) or Latin American (Indigenous people in Mexico and CentralSouth America) ancestry; in these patients, EBV is pre dominantly present in T cells or NK cells. Conversely, while rare, per sons of Western European descent typically have B cell CAEBV. The uneven geographic distribution of CAEBV suggests that underlying genetic factors may contribute to the development of CAEBV; hetero zygous pathogenic variants in HLH predisposing genes (e.g., perforin) have been identified in patients with CAEBV. Causative genetic defects have not been identified in most cases. Pathophysiology The mechanism of EBV entry into T cells or NK cells is unclear, but T cells and NK cells can express low levels of CD21, the EBV recep tor, during primary infection. The pathogenesis of CAEBV is less clear. Evidence suggests that EBV infection directly induces T cell or NK cell survival via activation of several survival promoting molecules or pathways, including upregulation of co stimulatory molecules that suppress apoptosis, activation of the NF B pathway, and upregulation of activation induced cytidine deaminase, which acts as a genomic dis ruptor and has been shown to play a role in EBV induced lymphoma genesis in B cells. Clinical Manifestations and Diagnosis Clinical manifestations of CAEBV are heterogenous, ranging from a mild and indolent clinical course to a more aggressive and potentially fatal illness due to complications such as HLH, multisystem organ failure, andor progression to leukemia or lymphoma. Clinical mani festations may by episodic, but patients typically have persistently and markedly elevated levels of EBV in the blood throughout their disease course. Infiltration of tissues by EBV positive lymphocytes may result in organ failure (liver failure is commonly seen), and EBV infected T cells and NK cells may undergo malignant transformation. The diagnostic criteria for CAEBV are listed in Table 174.3; CAEBV should be sus pected in any patient with sustained inflammation of unknown origin and chronically elevated EBV polymerase chain reaction (PCR) levels. Evaluations to determine whether EBV is predominantly present in T cells or NK cells should be undertaken, if possible, in patients with CAEBV. One method is EBV PCR on peripheral blood mononuclear cells that have been sorted by flow cytometry, although this test is not widely available. Histologic examination of tissue that has been infil trated by EBV infected lymphocytes by immune staining and in situ hybridization of EBV encoded mRNA (EBER) is another approach. Treatment Treatment options in severe cases are limited, and clinical responses are mostly transient. Some therapeutic approaches include T cell expansion CD8 T cell T cell migration SLAMF6 CD48 2B4 Mg CTP MICA Infected B |
6,495 | cell EBV EBV EBV iNKT NK cell T cell CORO1A SAP ITK CD27 RASGRP1CTPS1 MAGT1 CD70 NKG2D Fig. 174.4 Epstein Barr virus (EBV) susceptibility disorders. Combined immunodeficiencies characterized by a very high predisposition to EBV lymphoproliferative disease are shown in red. These genesproteins play essential roles in the recognition of EBV infected B cells by T cells and in cytotoxic T cell activation, migration, proliferation, andor cytotoxic activity. As such, defects in any of these components allow for EBV infected B cell immune escape. Invariant natural killer T (iNKT) cell, NK cell, and T cell numbers andor function may also be low or aberrant, respectively. Table 174.3 Chronic Active EBV (CAEBV) Diagnostic Criteria All 4 criteria must be present: 1. Sustained or recurrent infectious mononucleosis like symptoms persisting for 3 mo 2. EBV PCR 102.5 copiesg DNA in the peripheral blood or tissue lesion 3. Evidence of EBV infection of T or NK cells in the peripheral blood or affected tissues 4. Exclusion of other diagnoses: primary EBV infection, primary or secondary immunodeficiency, malignancy, autoimmune disease EBV, Epstein Barr virus; NK, natural killer; PCR, polymerase chain reaction. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 174 u Immune Dysregulation 1329 immunomodulatory therapy, combination bortezomib and ganciclo vir, and EBV specific T cells. Patients with HLH should receive HLH directed therapy. Standard antiviral therapy is not effective. Cytotoxic chemotherapy is also used to reduce disease activity and burden of EBV infected lymphocytes, primarily as a bridge to HCT. Allogeneic HCT is the only definitive therapy available with overall survival rates as high as 87 in some reports. Patients with progressive disease remain difficult to transplant. As such, some advocate rapidly proceed ing to HCT early in the disease process, although the timing of HCT remains controversial. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 174.5 Very Early Onset Inflammatory Bowel Disease Danielle E. Arnold and Jennifer W. Leiding Inflammatory bowel disease that presents in children less than 6 years of age is known as very early onset inflammatory bowel disease (VEO IBD). Monogenic defects involved in primary immunodeficiency and intestinal barrier processes are enriched in children with VEO IBD (Fig. 174.5). Targeted therapies in children with VEO IBD with a monogenic defect have been successful in treating disease manifesta tions (see Chapter 382.3). DISEASE CLASSIFICATION AND CLINICAL PRESENTATION Children diagnosed with IBD 2 years of age are referred to as infantile onset IBD and those 2 6 years as VEO IBD. Children present with classic symptoms of IBD including weight loss, failure to thrive, abdominal pain, fever, constipation, diarrhea, hematochezia. The phe notype is heterogenous with some children having mild disease and others presenting with or developing more severe disease over time. Approximately 40 have extensive pancolonic disease at presentation. Extent, location, and histology can progress or change over time. For more details see Chapter |
6,496 | 382.3. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 174.6 Autoimmune Cytopenias Danielle E. Arnold and Jennifer W. Leiding Autoimmune cytopenias are a group of disorders in which there is immune destruction of differentiated hematopoietic cells. Immune destruction can be autoantibody mediated or non autoantibody medi ated. Single lineage disease can affect red cells (autoimmune hemolytic anemia AIHA), platelets (idiopathic thrombocytopenia purpura ITP), or neutrophils (autoimmune neutropenia AIN). Bilineage or trilineage disease can affect any combination of these cell lines. Evan disease is a combination of AIHA and ITP. PATHOPHYSIOLOGY The etiology of autoimmune cytopenias as a manifestation of an inborn error of immunity is often multifactorial with autoantibody mediated destruction or cellular mediated destruction of red blood cells, plate lets, or neutrophils as the major causes of hemolysis (Table 174.4). In disorders with intrinsic B cell defects and disrupted T and B cell interactions, autoantibody production toward hematopoietic cells can Environmental trigger Intestinal microbiota Epithelial barrier ADAM17 IKBKG COL7A1 TTC7A Neutrophil defects CYBA, CYBB, NCF1, NCF2, NCF4 SLC37A4 G6PC3 ITGB2 Immune regulation FOXP3 IL2RA, IL2RB IL10, IL10RA, IL10RB CTLA4, LRBA STAT1, STAT3, STAT5b IL21, IL21R IL10, TGF Adaptive immune response RAG12 WAS ICOS PIK3R1, PTEN CTLA4, LRBA BTK DCLRE1C CD40LG AICDA IL1, IL18 Hyperactive autoinflammatory STXBP2 LYST RAGB27a MVK PLCG2 HPS1, 4, 6 SH2D1A Inflammasome dysregulation XIAP NLRC4 MEFV Treg Fig. 174.5 Very early onset inflammatory bowel disease. Complex host interactions between the environment, intestinal microbiota, and immune related genes maintain gut health. Mutations in genes involved in epithelial barrier, neutrophil function, control of inflammation, and T and B cell function can manifest as very early onset inflammatory bowel disease. IL, Interleukin; TGF, transforming growth factor; Treg, T regulatory cell. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1330 Part XII u Immunology occur. When B cell maturation is impaired, vital steps in the induction of tolerance are omitted. In addition to the humoral B cell defects that can lead to autoimmune cytopenias, intrinsic defects in T cell effector function can lead to cellular autoimmunity. Impaired T cell develop ment can cause a lack of functional effector cells against non self or dangerous antigens while allowing production of autoreactive clones with T cell receptors directed against self antigens. Additionally, T cell defects may lead to a reduction in FOXP3 Treg cells. Clinical Manifestations and Diagnosis The clinical presentation of AIHA commonly includes dizziness, fatigue, pallor, jaundice, and exertional dyspnea (see Chapter 513). Complete blood count will show anemia and reticulocytosis. Addi tional features of hemolysis include hyperbilirubinemia, elevated lactate dehydrogenase, and decreased haptoglobin levels. Direct anti globulin testing is most often positive. ITP typically presents with bleeding episodes that can range from mild bruising, petechiae, and epistaxis to oral purpura, hematuria, menorrhagia, gastrointestinal hemorrhage, or intracranial bleeding (see Chapter 533.1). Severe life threatening bleeding is rare. Laboratory findings include acute thrombocytopenia. Mean platelet volume |
6,497 | is elevated or variable indi cating that large new platelets are being generated to compensate for loss. Autoantibodies against platelet glycoproteins may be positive but are not helpful in elucidating immune thrombocytopenia as they are positive in less than 65 of patients with immune thrombocy topenia and are not predictive, specific, or prognostic. AIN pres ents with low absolute neutrophil count (see Chapter 171). Clinical manifestations include aphthous stomatitis, periodontal disease, and increased frequency of soft tissue infections. Invasive infections and sepsis are rare. Antigranulocyte antibodies can be present. Immunodeficiencies Associated with Autoimmune Cytopenias Autoimmune cytopenias, especially those that include bilineages and trilineages, are often a presenting symptom of or associated with primary immunodysregulatory disorders. Other organ specific immunodysregulatory and autoimmune conditions are often pres ent. Next generation sequencing via whole exome sequencing or panel based sequencing can aid in establishing a diagnosis. When an inborn error of immunity is suspected with the presence of auto immune cytopenias, a general immune screen should be performed including serum quantities of IgG, IgM, IgA, and IgE. Quantities of T cell, B cell, and NK cells should also be measured. Additional labs that may be helpful in narrowing a diagnosis of immunodeficiency include quantification of double negative T cells (CD4CD8), CD27IgD and CD27IgD memory B cells, serum ferritin, soluble interleukin (IL) 2 receptor, IL 18, soluble Fas ligand, vitamin B12, and folate. Treatment Targeted treatment of the primary immunodysregulatory disorder can control or resolve autoimmune cytopenias. Standard treatment of autoimmune cytopenias with or without a primary immunodysregu latory disorder include corticosteroids, intravenous immunoglobulin (IVIG), and biologic therapies such as rituximab and daratumumab (monoclonal antibody against CD38 expressed on long lived plasma cells). Control of symptoms is often more difficult and may increase the suspicion for an underlying primary immunodysregulatory disorder. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 174.4 Monogenic Causes of Autoimmune Cytopenias and Primary Immunodeficiency GENE (PROTEIN) DISORDER MOI CLINICAL PHENOTYPE IMMUNE FEATURES DEFINITIVE OR DISEASE SPECIFIC TREATMENT PIK3 defects Activated PI3K delta syndrome AD, LOF AD, GOF AD Insulin resistance, short stature, nodular lymphoid hyperplasia, lymphoma, bronchiectasis High IgM, low IgG, low CD4CD45RA Allogeneic HCT Leniolisib, sirolimus STAT3 STAT3 GOF AD, GOF Enteropathy, autoimmune cytopenias, lymphoproliferation, recurrent infections Elevated DNTs Variable decreases in IgG, IgA, IgM, B and T cell quantities Jakinibs Allogeneic HCT STAT1 STAT1 GOF AD, GOF Chronic mucocutaneous candidiasis, cerebral aneurysms, interstitial lung disease, enteropathy, colitis Variable decreases in IgG, IgA, IgM, B and T cell quantities Jakinibs Allogeneic HCT CTLA 4 CTLA4 haploinsufficiency AD Enteropathy, type 1 diabetes, autoimmune cytopenias, interstitial lung disease Low IgG, low T cell quantities Sirolimus Abatacept, belatacept Allogeneic HCT LRBA LRBA deficiency AR Enteropathy, type 1 diabetes, autoimmune cytopenias, interstitial lung disease Low IgG, low T cell quantities Abatacept, belatacept Allogeneic HCT TNFRSF6 TNFSF6 FADD CASP8 CASP10 ALPS AR GOF Lymphadenopathy, lymphoma Elevated DNTs Mycophenolate mofetil Sirolimus PI3K, Phosphoinositide 3 kinase; AD, autosomal dominant; LOF, loss of function; AD, autosomal dominant; GOF, gain of function; HCT, hematopoietic cell transplant; STAT, signal |
6,498 | transducer and activator of transcription; CTLA, cytotoxic T lymphocyte protein; LRBA, lipopolysaccharide responsive and beigelike anchor protein; ALPS, autoimmune lymphopro liferative syndrome; DNT, double negative T cell. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 174 u Immune Dysregulation 1331 174.7 Autoimmune Lymphoproliferative Syndrome Danielle E. Arnold and Jennifer W. Leiding Autoimmune lymphoproliferative syndrome (ALPS), also known as Canale Smith syndrome, is a disorder of abnormal lymphocyte apop tosis leading to polyclonal populations of T cells (double negative T cells), which express CD3 and antigen receptors but do not have CD4 or CD8 co receptors (CD3 T cell receptor , CD4CD8). These T cells respond poorly to antigens or mitogens and do not pro duce growth or survival factors (IL 2). The genetic deficit in most patients is a germline or somatic pathologic variant in the FAS gene, which produces a cell surface receptor of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF6), which, when stimulated by its ligand, will produce programmed cell death (Table 174.5). Persis tent survival of these lymphocytes leads to immune dysregulation and autoimmunity. ALPS is also caused by other genes in the Fas pathway (FASLG and CASP10). In addition, ALPS like disorders are associated with other mutations: RAS associated autoimmune lymphoprolif erative disorder (RALD), caspase 8 deficiency, Fas associated protein with death domain deficiency (FADD), and protein kinase C delta defi ciency (PRKCD). These disorders have varying degrees of immunode ficiency, autoimmunity, and lymphoproliferation. CLINICAL MANIFESTATIONS ALPS is characterized by autoimmunity, chronic persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly (in 50), and hypergammaglobulinemia (IgG, IgA). Many patients present in the first year of life, and most are symptomatic by age 5 years. Lymphadenopathy can be striking (Fig. 174.6). Splenomegaly Table 174.5 Revised Diagnostic Criteria for Autoimmune Lymphoproliferative Syndrome REQUIRED 1. Chronic (6 mo), nonmalignant, noninfectious lymphadenopathy, splenomegaly or both 2. Elevated CD3 TCR CD4 CD8 DNT cells (1.5 of total lymphocytes or 2.5 of CD3 lymphocytes) in the setting of normal or elevated lymphocyte counts ACCESSORY Primary 1. Defective lymphocyte apoptosis (in two separate assays) 2. Somatic or germline pathogenic mutation in FAS, FASLG, or CASP10 Secondary 1. Elevated plasma sFasL levels (200 pgmL) OR elevated plasma interleukin 10 levels (20 pgmL) OR elevated serum or plasma vitamin B12 levels (1500 ngL) OR elevated plasma interleukin 18 levels 500 pgmL 2. Typical immunohistologic findings as reviewed by an experienced hematopathologist 3. Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia) 4. Family history of a nonmalignantnoninfectious lymphoproliferation with or without autoimmunity A definitive diagnosis is based on the presence of both required criteria plus one primary accessory criterion. A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion. DNT, Double negative T cell; TCR, T cell receptor. From Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, eds. |
6,499 | Textbook of Pediatric Rheumatology. 7th ed. Philadelphia: Elsevier; 2016. Box 46 2. A B CD3 CT scan: Lymph node CD3? T cells CD4 CD4 FITC C D 8 P E 102101 104103100 10 2 10 1 10 4 10 3 10 0 CD8 Fig. 174.6 Clinical, radiographic, immunologic, and histologic characteristics of the autoimmune lymphoproliferative syndrome. A, Front view of the National Institutes of Health patient. B, Top left, CT scan of the neck is shown demonstrating enlarged preauricular, cervical, and occipital lymph nodes. Arrowheads denote the most prominent lymph nodes. Top right, Flow cytometric analysis of peripheral blood T cells from a patient with autoimmune lymphoproliferative syndrome (ALPS), with CD8 expression on the vertical axis and CD4 on the horizontal axis. Lower left quadrant, Contains CD4CD8 (double negative) T cells, which are usually present at 1 of T cells expressing the T cell receptor. Bottom, CD3, CD4, and CD8 staining on serial sections of a lymph node biopsy specimen from a patient with ALPS. Large numbers of DNCD3 CD4CD8 (double negative) T cells are present in the interfollicular areas of the lymph node. (Adapted from Siegel RM, Fleisher TA. The role of Fas and related death receptors in autoimmune and other disease states. J Allergy Clin Immunol. 1999;1035 Pt 1:729738.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1332 Part XII u Immunology may produce hypersplenism. Autoimmunity also produces ane mia (Coombs positive hemolytic anemia) or thrombocytopenia or a mild neutropenia. The lymphoproliferative process (lymphade nopathy, splenomegaly) may regress over time, but autoimmunity does not regress and is characterized by frequent exacerbations and recurrences. Other autoimmune features include urticaria, uveitis, glomerulonephritis, hepatitis, vasculitis, panniculitis, arthritis, pre mature ovarian failure, thyroiditis, myocarditis, pancreatitis, and CNS involvement (seizures, headaches, encephalopathy, transverse myeli tis, Guillain Barr syndrome, ataxia). Malignancies are also more common in patients with ALPS and include Hodgkin and non Hodgkin lymphomas and solid tissue tumors of thyroid, skin, heart, or lung. ALPS is one cause of Evan syn drome (immune thrombocytopenia and immune hemolytic anemia). Diagnosis Laboratory abnormalities depend on the lymphoproliferative organ response (hypersplenism) or the degree of autoimmunity (anemia, thrombocytopenia). There may be lymphocytosis or lymphopenia. Table 174.5 lists the criteria for the diagnosis. Flow cytometry helps identify the lymphocyte type (see Fig. 174.6). Functional genetic analysis for the TNFRSF6 gene often reveals a heterozygous muta tion. The differential diagnosis of ALP related syndromes is noted in Table 174.6. Table 174.6 Autoimmune Lymphoproliferative Syndrome (ALPS) Related Syndromes That Are Potentially Similar to But Genetically Distinct from ALPS or Meet Characteristics of ALPS with Undetermined Genetic Defects (ALPS U) DISEASE NOMENCLA TURE MUTATION CLINICAL FEATURES LABORATORY BIOMARKERS POTENTIAL TARGETED THERAPIES Ras associated autoimmune leukoproliferative disorder RALD Germline or somatic NRAS and KRAS pathogenic variants RAS markedly decreases Bim protein expression leading to impaired lymphoid withdrawal and T cell receptor (TCR) induced apoptosis |
6,500 | Primary immunodeficiency disorder of defective apoptosis leading to lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, and autoimmunity increased risk for hematopoietic malignancies Persistent absolute or relative monocytosis, hypergamma globulinemia, B lymphocytosis Does not exhibit elevated double negative T cells (DNTs), vitamin B12 Activating somatic mutations in KRAS or NRAS Mitogen activated pathway kinase (MAPK) inhibitors (for example, trametinib), mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) Dianzani autoimmune lymphoproliferative disease DALD No causative genes identified Overexpression of the cytokine osteopontin Perforin Exhibit autoimmunity, lymphoproliferation, splenomegaly, and defective Fas without expansion of DNT cells Absent DNTs FAS resistance but without FAS or FASL mutations Caspase 8 deficiency state CEDS Loss of function pathogenic variants in CASP8 thought to play a dual role in the induction of the nuclear factor kappa B (NF B) transcription factor during lymphocyte activation as well as in apoptosis mediated by the Fas death inducing signaling complex (DISC) Exhibits lymphoproliferation and apoptosis defects observed in ALPS, but manifests immunodeficiency rather than autoimmunity; recurrent sinopulmonary infections Increased risk for malignancy Serum Ig levels, antibody function, lymphocyte activation Defective activation of T, B and natural killer (NK) cells CASP8 deficiency Fas associated death domain deficiency FADD deficiency Autosomal recessive (AR) FADD deficiency Characterized by severe bacterial and viral infections, congenital heart defects, and recurrent episodes of fever, liver, dysfunction, and seizures FADD deficiency Common variable immunodeficiency 9 Protein kinase C delta (PRKCD) deficiency AR PRKCD primary immunodeficiency Characterized by recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity, and NK cell dysfunction IL 10 overexpression by B cells Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 174 u Immune Dysregulation 1333 Table 174.6 Autoimmune Lymphoproliferative Syndrome (ALPS) Related Syndromes That Are Potentially Similar to But Genetically Distinct from ALPS or Meet Characteristics of ALPS with Undetermined Genetic Defects (ALPS U)contd DISEASE NOMENCLA TURE MUTATION CLINICAL FEATURES LABORATORY BIOMARKERS POTENTIAL TARGETED THERAPIES Activated PI3K delta syndrome APDS, also known as PASLI Heterozygous gain of function pathogenic variants in PI3KCD or PI3KR1 Recurrent respiratory infections and increased susceptibility to viral infections with both B and T cell defects Decreased nave T cells, low IgG, IgA, and normal or elevated IgM mTOR inhibitors, PI3K inhibitors X linked immunodeficiency with magnesium defect, Epstein Barr virus (EBV) infection and neoplasia XMEN disease Loss of function pathogenic variants in magnesium transporter 1 (MAGT1); X linked Chronic high level EBV with increased EBV infected B cells and increased susceptibility to EBV associated lymphomas Mg deficiency Magnesium Gain of function mutations in signal transducer and activator of transcription 1 defect GOF STAT1 defect STAT1 gain of function pathogenic variants Chronic mucocutaneous candidiasis, recurrent Staphylococcus aureus infections, cerebral aneurysms, and multiple autoimmune features Decreased TH17 response JAKSTAT inhibitors (for example, ruxolitinib) Gain of function mutations in signal transducer and activator of transcription 3 GOF STAT3 mutations STAT3 gain of function pathogenic variants Lymphoproliferation and |
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