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IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease
Open accessAbstract
Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes 1,2. The need to develop non-dietary treatments is now widely recognized 3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease 4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.
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“Under stress or inflammatory conditions, such as in celiac disease, iIELs upregulate the expression of activating NKG2D and CD94/NKG2C receptors, (which recognize MICA/B and HLA-E, respectively) while losing the expression of the inhibitory receptors CD94/NKG2A [302, 306-308].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [308]
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Metadata
- Authors
- Abadie, V., Kim, S. M., Lejeune, T., Palanski, B. A., Ernest, J. D., Tastet, O., Voisine, J., Discepolo, V., Marietta, E. V., Hawash, M. B. F., Ciszewski, C., Bouziat, R., Panigrahi, K., Horwath, I., Zurenski, M. A., Lawrence, I., Dumaine, A., Yotova, V., Grenier, J.-C., Murray, J. A., Khosla, C., Barreiro, L. B., & Jabri, B.
- Affiliations
- University of Chicago (US)
- Université de Montréal (CA)
- Stanford University (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Mayo Clinic (US)
- ORCID
- Venue
- Nature
- Published
- 2020-02-12
- Volume
- 578
- Issue
- 7796
- Pages
- 600-604
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7047598
- OpenAlex
- W3005574648
- Cited by
- 231
- References
- 43
- Citations by year
- 2026: 21 · 2025: 52 · 2024: 39 · 2023: 27 · 2022: 33 · 2021: 32 · 2020: 25
- FWCI
- 26.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (T32AI007090)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100619, T32DK007074, R01DK067180, P30DK042086, R01DK063158)
- Topics
- Health Sciences › Medicine › Gastroenterology › Celiac Disease Research and Management
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Wheat and Barley Genetics and Pathology
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- celiac disease, IL-15, gluten, HLA-DQ8, villous atrophy, mouse model, CD4+ T cells, cytotoxic T lymphocytes, interferon-gamma, tissue transglutaminase, intestinal epithelial damage, lamina propria, HLA-DQ2, innate immunity, adaptive immunity
- MeSH terms
- Animals, Celiac Disease, Female, Glutens, HLA-DQ Antigens, Humans, Interferon-gamma, Male, Mice, Transgenic, Microfilament Proteins, CD4-Positive T-Lymphocytes, Interleukin-15, Mice
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