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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Region size is indicated by size and color of the region circle.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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h, Integrating scRNA-seq reference data localizes single-cell transcriptomes to spatial regions.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These data are used to generate network plots visualizing colocalization of cell types together in ACD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Cell-type nodes close together and linked by connecting lines are more often located in the same spots.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In ACD, mature enterocytes colocalize with TRM(2) CD8 T cells (lower red box), while TFH-like CD4 T cells localize with B cells, Treg cells and plasma cells (upper red box).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These immune-rich regions and LAs showed gene expression patterns associated with B cells (CD19, MS4A1 (CD20)), plasma cells (IGHM, IGHA1, TXNDC5) and T cells (CD3D, CCR7, CXCL13).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Signals of cellular proliferation (MKI67, REG1A) were highly localized in specific clusters.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In health, cellular proliferation was limited to stem-cell and lower-crypt regions, while in ACD, proliferative markers were more dispersed, including in immune-rich and LA regions (Supplementary Fig. 6c,d).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In ACD, villus top regions showed increases in interferon-stimulated genes, markers of proliferation, and IL32 (Fig. 6f), analogous to epithelial scRNA-seq results.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TCR genes, tissue-residency markers (ITGAE, CXCR6, KLRB1), and cytotoxic CD8 markers (GZMA, KLRD1, KLRK1) were increased in ACD, suggesting tissue-resident cytotoxic CD8 T cell enrichment in villi.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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We integrated spatial transcriptomics with scRNA-seq data to predict cell-type locations in mucosa (Supplementary Figs. 6e–j and 7).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In ACD, TA cell signatures expanded from crypt bases to most villus regions, while mature EC signatures were restricted to superficial epithelial layers.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In ACD, LAs showed highly localized enrichment of TFH-like CD4 T cell (CXCR5, CXCL13) and B cell (CD19, MS4A1; Fig. 6b and Supplementary Fig. 7a) signatures.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Plasma cell signatures were expanded in neighboring immune-rich regions.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In ACD, CD8 TRM(2) cell signatures were highly enriched in villus tip regions, colocalized with mature enterocytes (Fig. 6h and Supplementary Figs. 6h–j and 7b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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To further study LAs in CD, we performed further spatial transcriptomics experiments on duodenal biopsy samples in participants with and without CD (dataset 5; Fig. 7 and Extended Data Fig. 9a–c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Analysis of spatial regions recapitulated our description of key transcriptional regions in the duodenal mucosa (Fig. 7a,b and Extended Data Fig. 9c), with enrichment of proliferating areas at crypt bases, MUC5AC and PGC epithelium, immune-rich areas containing plasma cells, and LAs (Fig. 7c–f).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These LAs were enriched in both ACD and TCD.Fig.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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7TFH–B cell interactions are highly localized in LAs in the celiac lesion.a, UMAP overlay of all spatial transcriptomics tissue-covered spots with transcriptome-driven clustering analysis, colored by region.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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b, Bubble plot showing the expression of selected genes defining spatial regions.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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c,d, Local neighborhood enrichment of intestinal mucosal regions in ACD versus HCs (c) and TCD versus HCs (d).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Color indicates enrichment (log fold change) of cells in CD versus HCs in that UMAP neighborhood.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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e, Proportion of intestinal mucosa formed in different regions in HCs, ACD and TCD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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f, Proportion of immune-rich and LA regions in HCs, ACD and TCD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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g,h, Detailed examination of a representative LA in ACD (seen in 5/10 CD sections).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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g, Hematoxylin and eosin (H&E)-stained section of duodenal biopsy with LA circled.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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h, Spatial regions overlaid onto the section show the LA near the lower-crypt/stem-cell niche region, and near the muscularis mucosa.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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i, Predicted cell-type locations in regions overlaid onto the section.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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j–l, Bubble plots of gene expression within LAs and other regions, paired with gene expression overlaid onto an ACD section with LA, including TFH/Treg cell gene signatures (j), B/plasma cell gene signatures (k), and chemokines and associated receptors (l).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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m, Stromal cell gene expression overlaid onto a representative ACD section with LA.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
a, UMAP overlay of all spatial transcriptomics tissue-covered spots with transcriptome-driven clustering analysis, colored by region.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
b, Bubble plot showing the expression of selected genes defining spatial regions.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
c,d, Local neighborhood enrichment of intestinal mucosal regions in ACD versus HCs (c) and TCD versus HCs (d).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Color indicates enrichment (log fold change) of cells in CD versus HCs in that UMAP neighborhood.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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e, Proportion of intestinal mucosa formed in different regions in HCs, ACD and TCD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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f, Proportion of immune-rich and LA regions in HCs, ACD and TCD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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g,h, Detailed examination of a representative LA in ACD (seen in 5/10 CD sections).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
g, Hematoxylin and eosin (H&E)-stained section of duodenal biopsy with LA circled.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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h, Spatial regions overlaid onto the section show the LA near the lower-crypt/stem-cell niche region, and near the muscularis mucosa.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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i, Predicted cell-type locations in regions overlaid onto the section.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
j–l, Bubble plots of gene expression within LAs and other regions, paired with gene expression overlaid onto an ACD section with LA, including TFH/Treg cell gene signatures (j), B/plasma cell gene signatures (k), and chemokines and associated receptors (l).
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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m, Stromal cell gene expression overlaid onto a representative ACD section with LA.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These lamina propria LAs were located adjacent to stem cell niches and muscularis mucosa (Fig. 7g–i), with enrichment of TFH-like CD4 T cell, Treg cell and B cell gene signatures.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Plasma cell signatures were more widely dispersed in immune-rich regions (Fig. 7i–k and Extended Data Fig. 9d,e).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Genes for chemokines and receptors, including CXCR5, CCR7, CCL19, CCL21, CXCL13 and CXCL14 were enriched specifically within LAs (Fig. 7l), as were genes associated with S3 stromal cells, and pro-inflammatory stroma seen in inflammatory bowel disease (Fig. 7m).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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We examined the expression of chemokines, cytokines and tumor necrosis factor (TNF) superfamily members, as well as receptor–ligand coexpression, within regions in the spatial transcriptomics dataset (Fig. 8a,b and Supplementary Fig. 8).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Signaling pathway expression was region dependent, indicating highly localized mucosal signaling circuits (Fig. 8a).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Within CD-specific LAs, chemokine signaling circuits involving CXCR5–CXCL13, CCR7–CCL19, CXCR4 and integrins ITGB2 and ITGAM were upregulated (Fig. 8a and Supplementary Fig. 8a,b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TNF superfamily receptor–ligand pathways were upregulated in LAs, including TNF, lymphotoxins A and B, CD40, TNFRSF8 (CD30), TNFRSF6B, TNFRSF18 (GITR) and TNFRSF4 (OX40) (Supplementary Fig. 8c,d).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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There was also evidence of IL2 and IL21 signaling, as well as possible involvement of IL23A and IL26 pathways (Supplementary Fig. 9e,f).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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LAs found in CD were enriched with signaling pathways involving CXCR4, CXCR5 and CXCL13 (Figs. 7l and 8a,b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Single-cell examination of CXCL13, CCR7 and ITGB2 signaling interactions in dataset 1 implicated TFH-like CD4 T cell, B cell and myeloid cell interactions as drivers of these signaling pathways in LAs (Fig. 8b).Fig.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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8A spatially resolved model of mucosal immunological responses in CD.a, Bubble plot of region-specific receptor–ligand expression within the duodenal mucosa.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Scaled receptor–ligand (RL) expression indicated by color; proportion of regions expressing the receptor–ligand genes indicated by bubble size.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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b, Circos plots of selected receptor–ligand pair expression between cell types in CD (dataset 1).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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c, A proposed schematic for the spatially resolved cellular ecosystems within the duodenal mucosa in CD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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LTo, lymphoid tissue organizer.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Figure created with BioRender.com.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
a, Bubble plot of region-specific receptor–ligand expression within the duodenal mucosa.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Scaled receptor–ligand (RL) expression indicated by color; proportion of regions expressing the receptor–ligand genes indicated by bubble size.
|
PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
b, Circos plots of selected receptor–ligand pair expression between cell types in CD (dataset 1).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
c, A proposed schematic for the spatially resolved cellular ecosystems within the duodenal mucosa in CD.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
LTo, lymphoid tissue organizer.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
|
Figure created with BioRender.com.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Villus tip regions, demonstrated region-specific activation of T cell and immune-related pathways, including increased expression of IL15, IL18, IFNG and IL32, and interactions including CXCR6–CXCL16, CCR9–CCL25, DPP4–ADA and HLA-E interactions with KLRC2 and KLRD1 (Fig. 8a and Supplementary Fig. 8).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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There was also high expression of TNF superfamily members associated with apoptotic pathways, including FASLG, TNFSF10 (TRAIL), TNFSF11 (RANKL), TNFSF12 (TWEAK) and TNFSF13 (APRIL) interactions.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Examination of single-cell signaling pathways implicated CD8 T cells in chemokine and type II interferon signaling, including CCR9–CCL25 axis interactions between progenitor ECs and cycling CD8 T cells (Fig. 8b).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Wnt signaling pathways were enriched in telocyte-rich areas and neighboring villus structures (Fig. 8a).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Such morphogen gradients may shape villus structure and morphology, perhaps driven by subepithelial telocytes.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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To understand how genetic susceptibility can drive CD inflammatory responses, we examined putative genome-wide association study (GWAS) candidate gene expression in spatial regions.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Villus, telocyte-rich and LA regions showed enriched expression of multiple GWAS candidates (Extended Data Fig. 10a).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Expression of MMP9, CTLA4, ICOS, ITGA4, GPR183, IL21 and IL21R was enriched within CD-specific LA regions (Extended Data Figs. 9e and 10a), while IL2RA, CCR1, XCR1, TNFSF11 (RANKL) and TNFRSF9 (CD137, 4-1BB) were increased in telocyte-rich regions.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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scRNA-seq data were examined for cell-type-specific expression of CD genetic susceptibility loci.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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GWAS candidate genes were most prominent in T cell subsets (Extended Data Fig. 10b), with the highest signal enrichment in cycling CD8 T cells.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Specific putative GWAS candidate genes drove these associations (Extended Data Fig. 10c), with TFH-like CD4 T cells expressing the IL21, PTPN2, ITGA4, CD28 and ICOS and TRM(2) CD8 T cells expressing CXCR6, TNFRSF9 and TNFRSF14, and showing CD-related changes in STAT expression (Extended Data Fig. 10d).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Cell-type-specific gene expression patterns were recapitulated in dataset 2 (Extended Data Fig. 10e).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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This multi-omics study provides an integrated single-cell transcriptomic and proteomic assessment of intestinal immune, epithelial and parenchymal cell populations in adult and pediatric CD, contextualized through integration with spatial transcriptomics analysis.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Our results show that perturbations of immune and epithelial cell states are spatially localized within distinct mucosal niches.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Disease-associated cell types, including gluten-specific TFH-like CD4 T cells and CD8 TRM cells, occupy distinct LA and villus niches, respectively, with cell–cell interactions best understood through spatial colocalization (Fig. 8c).
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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The application of receptor–ligand analyses implicates broader cytokine and chemokine perturbations in CD than those described previously, including IL-32, CXCL13, CCL19, CXCL16, CXCL8 and CCL25.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Our understanding of human duodenal lymphoid structures is incomplete.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Isolated gut lymphoid structures may act as immune-inductive sites.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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In CD, it remains unclear where the immune response to gluten is primed, or where subsequent antigen presentation occurs.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Both myeloid and B cell lineages have been posited as relevant antigen-presenting cells (APCs) in CD.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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The discovery of highly localized LAs where B cells and (likely gluten-specific) TFH CD4 T cells are co-located implicates these sites in gluten peptide antigen presentation.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Several aspects of the mucosal epithelial and immune response remained perturbed despite a GFD.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These findings help explain the observation that subtle abnormalities in duodenal biopsy samples remain despite treatment, with reduced villus height/crypt depth ratios on morphometric analysis.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Whether this represents subclinical inflammation from ongoing low-level antigen exposure, slow mucosal healing or a long-term (perhaps epigenetic) response to prior inflammation is unclear.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Participants often report ongoing symptoms despite a GFD, and this epithelial and immunological ‘scar’ from prior inflammation could underpin this, representing a therapeutic target.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Intestinal tissue-resident CD8 T cell perturbations, including increases in TRM(2) populations, persisted despite GFD treatment.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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Therefore, this CD8 TRM(2) state may represent a distinct T cell fate, rather than an activated phenotype alone.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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TRM cells are long-lived memory populations that persist as immunological sentinels in barrier tissues, and this result is consistent with prior work showing a permanent reshaping of γδT cell-resident populations following CD-driven inflammation.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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CD8 T cell populations exhibited changes in TCR repertoire, a finding validated in multiple datasets.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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These TCR repertoire changes, along with upregulation of TCR signaling gene sets, may indicate that TCR-dependent activation is relevant in CD, involving a separate mechanism to previously described NKG2C/NKG2D pathways, and invoke the possibility of TCR-targeted disease therapies.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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IL-15 and NK cell receptor signaling could lead to a reduction in TCR activation threshold, which could enable recognition of low-affinity antigens, either self-antigens or those of microbial or dietary origin.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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The persistence of CD8 TRM(2) cells in TCD could represent ongoing antigen exposure.
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PMC12133578
|
Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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There is a series of enterocyte transcriptional states in the human small intestine, with absorptive cellular machinery generally limited to mature ECs, consistent with murine studies.
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PMC12133578
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Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.
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The shift to progenitor states in CD may increase CCL25 expression, implicating the CCL25–CCR9 axis in disease.
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