Journal article
Immune–epithelial–stromal networks define the cellular ecosystem of the small intestine in celiac disease
- Abstract:
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The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 57.5MB, Terms of use)
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- Publisher copy:
- 10.1038/s41590-025-02146-2
Authors
- Funder identifier:
- https://ror.org/00c489v88
- Grant:
- SGL025\1066
- Publisher:
- Springer Nature
- Journal:
- Nature Immunology More from this journal
- Volume:
- 26
- Issue:
- 6
- Pages:
- 947-962
- Publication date:
- 2025-05-06
- Acceptance date:
- 2025-03-25
- DOI:
- EISSN:
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1529-2916
- ISSN:
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1529-2908
- Language:
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English
- Keywords:
- Pubs id:
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2100687
- Local pid:
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pubs:2100687
- Deposit date:
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2025-03-27
Terms of use
- Copyright holder:
- FitzPatrick et al.
- Copyright date:
- 2025
- Rights statement:
- Copyright © 2025, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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