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Primary pathogensare capable of causing pathological changes associated with disease in a healthy individual, whereasopportunistic pathogenscan only cause disease when the individual is compromised by a break in protective barriers or immunosuppression.
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Infections and disease can be caused by pathogens in the environment or microbes in an individual’sresident microbiota.
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Infections can be classified aslocal,focal, orsystemicdepending on the extent to which the pathogen spreads in the body.
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Asecondary infectioncan sometimes occur after the host’s defenses or normal microbiota are compromised by aprimary infectionor antibiotic treatment.
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Pathogens enter the body throughportals of entryand leave throughportals of exit. The stages of pathogenesis includeexposure,adhesion,invasion,infection, andtransmission.
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Virulence factorscontribute to a pathogen’s ability to cause disease.
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Exoenzymesandtoxinsallow pathogens to invade host tissue and cause tissue damage. Exoenzymes are classified according to the macromolecule they target and exotoxins are classified based on their mechanism of action.
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Bacterial toxins includeendotoxinandexotoxins. Endotoxin is the lipid A component of the LPS of the gram-negative cell envelope. Exotoxins are proteins secreted mainly by gram-positive bacteria, but also are secreted by gram-negative bacteria.
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Bacterial pathogens may evade the host immune response by producingcapsulesto avoid phagocytosis, surviving the intracellular environment of phagocytes, degrading antibodies, or throughantigenic variation.
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Viral pathogens use adhesins for initiating infections and antigenic variation to avoid immune defenses.
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Influenza viruses use bothantigenic driftandantigenic shiftto avoid being recognized by the immune system.
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Fungal and parasitic pathogens use pathogenic mechanisms and virulence factors that are similar to those of bacterial pathogens
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Fungi initiate infections through the interaction of adhesins with receptors on host cells. Some fungi produce toxins and exoenzymes involved in disease production and capsules that provide protection of phagocytosis.
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Protozoa adhere to target cells through complex mechanisms and can cause cellular damage through release of cytopathic substances. Some protozoa avoid the immune system through antigenic variation and production of capsules.
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Helminthic worms are able to avoid the immune system by coating their exteriors with glycan molecules that make them look like host cells or by suppressing the immune system.
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Epidemiologyis the science underlying public health.
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Morbiditymeans being in a state of illness, whereasmortalityrefers to death; bothmorbidity ratesandmortality ratesare of interest to epidemiologists.
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Incidenceis the number of new cases (morbidity or mortality), usually expressed as a proportion, during a specified time period;prevalenceis the total number affected in the population, again usually expressed as a proportion.
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Sporadic diseasesonly occur rarely and largely without a geographic focus.Endemic diseasesoccur at a constant (and often low) level within a population.Epidemic diseasesandpandemic diseasesoccur when an outbreak occurs on a significantly larger than expected level, either locally or globally, respectively.
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Koch’s postulatesspecify the procedure for confirming a particular pathogen as the etiologic agent of a particular disease. Koch’s postulates have limitations in application if the microbe cannot be isolated and cultured or if there is no animal host for the microbe. In this case, molecular Koch’s postulates woul...
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In the United States, theCenters for Disease Control and Preventionmonitorsnotifiable diseasesand publishes weekly updates in theMorbidity and Mortality Weekly Report.
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Early pioneers of epidemiology such as John Snow, Florence Nightingale, and Joseph Lister, studied disease at the population level and used data to disrupt disease transmission.
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Descriptive epidemiologystudies rely on case analysis and patient histories to gain information about outbreaks, frequently while they are still occurring.
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Retrospective epidemiologystudies use historical data to identify associations with the disease state of present cases.Prospective epidemiologystudies gather data and follow cases to find associations with future disease states.
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Analytical epidemiologystudies are observational studies that are carefully designed to compare groups and uncover associations between environmental or genetic factors and disease.
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Experimental epidemiologystudies generate strong evidence of causation in disease or treatment by manipulating subjects and comparing them with control subjects.
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Reservoirsof human disease can include the human and animal populations, soil, water, and inanimate objects or materials.
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Contact transmissioncan bedirectorindirectthrough physical contact with either an infected host (direct) or contact with a fomite that an infected host has made contact with previously (indirect).
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Vector transmission occurs when a living organism carries an infectious agent on its body (mechanical) or as an infection host itself (biological), to a new host.
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Vehicle transmissionoccurs when a substance, such as soil, water, or air, carries an infectious agent to a new host.
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Healthcare-associated infections (HAI), ornosocomial infections, are acquired in a clinical setting. Transmission is facilitated by medical interventions and the high concentration of susceptible, immunocompromised individuals in clinical settings.
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TheWorld Health Organization (WHO)is an agency of the United Nations that collects and analyzes data on disease occurrence from member nations. WHO also coordinates public health programs and responses to international health emergencies.
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Emerging diseasesare those that are new to human populations or that have been increasing in the past two decades.Reemerging diseasesare those that are making a resurgence in susceptible populations after previously having been controlled in some geographic areas.
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Nonspecific innate immunityprovides a first line of defense against infection by nonspecifically blocking entry of microbes and targeting them for destruction or removal from the body.
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The physical defenses of innate immunity include physical barriers, mechanical actions that remove microbes and debris, and the microbiome, which competes with and inhibits the growth of pathogens.
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The skin, mucous membranes, and endothelia throughout the body serve as physical barriers that prevent microbes from reaching potential sites of infection. Tight cell junctions in these tissues prevent microbes from passing through.
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Microbes trapped in dead skin cells ormucusare removed from the body by mechanical actions such as shedding of skin cells, mucociliary sweeping, coughing,peristalsis, and flushing of bodily fluids (e.g., urination, tears)
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The resident microbiota provide a physical defense by occupying available cellular binding sites and competing with pathogens for available nutrients.
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Numerouschemical mediatorsproduced endogenously and exogenously exhibit nonspecific antimicrobial functions.
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Many chemical mediators are found in body fluids such as sebum, saliva, mucus, gastric and intestinal fluids, urine, tears, cerumen, and vaginal secretions.
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Antimicrobial peptides (AMPs)found on the skin and in other areas of the body are largely produced in response to the presence of pathogens. These include dermcidin, cathelicidin, defensins, histatins, and bacteriocins.
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Plasmacontains various proteins that serve as chemical mediators, includingacute-phase proteins,complement proteins, andcytokines.
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Thecomplement systeminvolves numerous precursor proteins that circulate in plasma. These proteins become activated in a cascading sequence in the presence of microbes, resulting in theopsonizationof pathogens, chemoattraction of leukocytes, induction of inflammation, and cytolysis through the formation of amembrane att...
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Cytokinesare proteins that facilitate various nonspecific responses by innate immune cells, including production of other chemical mediators, cell proliferation, cell death, and differentiation.
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Cytokines play a key role in the inflammatory response, triggering production of inflammation-eliciting mediators such as acute-phase proteins,histamine, leukotrienes,prostaglandins, andbradykinin.
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Theformed elementsof the blood include red blood cells (erythrocytes), white blood cells (leukocytes), andplatelets (thrombocytes). Of these, leukocytes are primarily involved in the immune response.
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All formed elements originate in the bone marrow as stem cells (HSCs) that differentiate throughhematopoiesis.
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Granulocytesare leukocytes characterized by a lobed nucleus and granules in the cytoplasm. These includeneutrophils (PMNs),eosinophils, andbasophils.
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Neutrophils are the leukocytes found in the largest numbers in the bloodstream and they primarily fight bacterial infections.
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Eosinophils target parasitic infections. Eosinophils and basophils are involved in allergic reactions. Both release histamine and other proinflammatory compounds from their granules upon stimulation.
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Mast cellsfunction similarly to basophils but can be found in tissues outside the bloodstream.
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Natural killer(NK) cells are lymphocytes that recognize and kill abnormal or infected cells by releasing proteins that trigger apoptosis.
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Monocytesare large, mononuclear leukocytes that circulate in the bloodstream. They may leave the bloodstream and take up residence in body tissues, where they differentiate and become tissue-specificmacrophagesanddendritic cells.
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Phagocytes are cells that recognize pathogens and destroy them through phagocytosis.
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Recognition often takes place by the use of phagocyte receptors that bind molecules commonly found on pathogens, known aspathogen-associated molecular patterns (PAMPs).
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The receptors that bind PAMPs are calledpattern recognition receptors, orPRRs.Toll-like receptors(TLRs) are one type of PRR found on phagocytes.
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Extravasationof white blood cells from the bloodstream into infected tissue occurs through the process oftransendothelial migration.
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Phagocytes degrade pathogens throughphagocytosis, which involves engulfing the pathogen, killing and digesting it within aphagolysosome, and then excreting undigested matter.
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Inflammationresults from the collective response of chemical mediators and cellular defenses to an injury or infection.
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Acute inflammationis short lived and localized to the site of injury or infection.Chronic inflammationoccurs when the inflammatory response is unsuccessful, and may result in the formation ofgranulomas(e.g., with tuberculosis) and scarring (e.g., with hepatitis C viral infections and liver cirrhosis).
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The five cardinal signs of inflammation areerythema,edema, heat, pain, and altered function. These largely result from innate responses that draw increased blood flow to the injured or infected tissue.
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Feveris a system-wide sign of inflammation that raises the body temperature and stimulates the immune response.
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Both inflammation and fever can be harmful if the inflammatory response is too severe.
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Adaptive immunityis an acquired defense against foreign pathogens that is characterized byspecificityandmemory.The first exposure to an antigen stimulates aprimary response, and subsequent exposures stimulate a faster and strongsecondary response.
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Adaptive immunity is a dual system involvinghumoral immunity(antibodies produced by B cells) andcellular immunity(T cells directed against intracellular pathogens).
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Antigens, also calledimmunogens, are molecules that activate adaptive immunity. A single antigen possesses smallerepitopes, each capable of inducing a specific adaptive immune response.
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An antigen’s ability to stimulate an immune response depends on several factors, including its molecular class, molecular complexity, and size.
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Antibodies(immunoglobulins) are Y-shaped glycoproteins with two Fab sites for binding antigens and an Fc portion involved in complement activation and opsonization.
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The five classes of antibody areIgM,IgG,IgA,IgE, andIgD, each differing in size, arrangement, location within the body, and function. The five primary functions of antibodies are neutralization, opsonization, agglutination, complement activation, and antibody-dependent cell-mediated cytotoxicity (ADCC).
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Major histocompatibility complex (MHC)is a collection of genes coding for glycoprotein molecules expressed on the surface of all nucleated cells.
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MHC Imolecules are expressed on all nucleated cells and are essential for presentation of normal “self” antigens. Cells that become infected by intracellular pathogens can present foreign antigens on MHC I as well, marking the infected cell for destruction.
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MHC IImolecules are expressed only on the surface ofantigen-presenting cells(macrophages, dendritic cells, and B cells). Antigen presentation with MHC II is essential for the activation of T cells.
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Antigen-presenting cells (APCs)primarily ingest pathogens by phagocytosis, destroy them in the phagolysosomes, process the protein antigens, and select the most antigenic/immunodominant epitopes with MHC II for presentation to T cells.
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Cross-presentationis a mechanism of antigen presentation and T-cell activation used by dendritic cells not directly infected by the pathogen; it involves phagocytosis of the pathogen but presentation on MHC I rather than MHC II.
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Immature T lymphocytes are produced in the red bone marrow and travel to the thymus for maturation.
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Thymic selectionis a three-step process of negative and positive selection that determines which T cells will mature and exit the thymus into the peripheral bloodstream.
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Central toleranceinvolves negative selection of self-reactive T cells in the thymus, andperipheral toleranceinvolvesanergyandregulatory T cellsthat prevent self-reactive immune responses and autoimmunity.
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TheTCRis similar in structure to immunoglobulins, but less complex. Millions of unique epitope-binding TCRs are encoded through a process of genetic rearrangement of V, D, and J gene segments.
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T cells can be divided into three classes—helper T cells, cytotoxic T cells,andregulatory T cells—based on their expression of CD4 or CD8, the MHC molecules with which they interact for activation, and their respective functions.
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Activated helper T cells differentiate intoTH1, TH2, TH17, ormemory T cell subtypes. Differentiation is directed by the specific cytokines to which they are exposed. TH1, TH2, and TH17 perform different functions related to stimulation of adaptive and innate immune defenses. Memory T cells are long-lived cells that can...
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Once activated, cytotoxic T cells target and kill cells infected with intracellular pathogens. Killing requires recognition of specific pathogen epitopes presented on the cell surface using MHC I molecules. Killing is mediated byperforinandgranzymesthat induce apoptosis.
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Superantigensare bacterial or viral proteins that cause a nonspecific activation of helper T cells, leading to an excessive release of cytokines (cytokine storm) and a systemic, potentially fatal inflammatory response.
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B lymphocytesorB cellsproduce antibodies involved in humoral immunity. B cells are produced in the bone marrow, where the initial stages of maturation occur, and travel to the spleen for final steps of maturation into naïve mature B cells.
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B-cell receptors (BCRs)are membrane-bound monomeric forms of IgD and IgM that bind specific antigen epitopes with their Fab antigen-binding regions. Diversity of antigen binding specificity is created by genetic rearrangement of V, D, and J segments similar to the mechanism used for TCR diversity.
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Protein antigens are calledT-dependent antigensbecause they can only activate B cells with the cooperation of helper T cells. Other molecule classes do not require T cell cooperation and are calledT-independent antigens.
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T cell-independent activationof B cells involves cross-linkage of BCRs by repetitive nonprotein antigen epitopes. It is characterized by the production of IgM byplasma cellsand does not produce memory B cells.
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T cell-dependent activationof B cells involves processing and presentation of protein antigens to helper T cells, activation of the B cells by cytokines secreted from activated TH2 cells, and plasma cells that produce different classes of antibodies as a result ofclass switching.Memory B cellsare also produced.
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Secondary exposures to T-dependent antigens result in a secondary antibody response initiated by memory B cells. The secondary response develops more quickly and produces higher and more sustained levels of antibody with higher affinity for the specific antigen.
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Adaptive immunity can be divided into four distinct classifications:natural active immunity, natural passive immunity, artificial passive immunity,andartificial active immunity.
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Artificial active immunity is the foundation forvaccinationand vaccine development. Vaccination programs not only confer artificial immunity on individuals, but also fosterherd immunityin populations.
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Variolationagainst smallpox originated in the 10thcentury in China, but the procedure was risky because it could cause the disease it was intended to prevent. Modern vaccination was developed by Edward Jenner, who developed the practice of inoculating patients with infectious materials from cowpox lesions to prevent sm...
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Live attenuated vaccinesandinactivated vaccinescontain whole pathogens that are weak, killed, or inactivated.Subunit vaccines, toxoid vaccines,andconjugate vaccinescontain acellular components with antigens that stimulate an immune response.
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Anallergyis an adaptive immune response, sometimes life-threatening, to anallergen.
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Type I hypersensitivityrequires sensitization of mast cells with IgE, involving an initial IgE antibody response and IgE attachment to mast cells. On second exposure to an allergen, cross-linking of IgE molecules on mast cells triggers degranulation and release of preformed and newly formed chemical mediators of inflam...
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Type II hypersensitivitiesresult from antibodies binding to antigens on cells and initiating cytotoxic responses. Examples includehemolytic transfusion reactionandhemolytic disease of the newborn.
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Type III hypersensitivitiesresult from formation and accumulation ofimmune complexesin tissues, stimulating damaging inflammatory responses.
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Type IV hypersensitivitiesare not mediated by antibodies, but by helper T-cell activation of macrophages, eosinophils, and cytotoxic T cells.
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Autoimmune diseasesresult from a breakdown in immunological tolerance. The actual induction event(s) for autoimmune states are largely unknown.
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Some autoimmune diseases attack specific organs, whereas others are more systemic.
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Organ-specific autoimmune diseases includeceliac disease,Graves disease,Hashimoto thyroiditis,type I diabetes mellitus,andAddison disease.
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