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Nature. 2020 Feb;578(7796):600-604. doi: 10.1038/s41586-020-2003-8. Epub 2020 Feb 12.

IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease.

Author information

1
Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. vabadie@medicine.bsd.uchicago.edu.
2
Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada. vabadie@medicine.bsd.uchicago.edu.
3
Department of Medicine, University of Chicago, Chicago, IL, USA. vabadie@medicine.bsd.uchicago.edu.
4
Department of Medicine, University of Chicago, Chicago, IL, USA.
5
Committee on Immunology, University of Chicago, Chicago, IL, USA.
6
Department of Biology, University of San Francisco, San Francisco, CA, USA.
7
Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
8
Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
9
Department of Chemistry, Stanford University, Stanford, CA, USA.
10
Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.
11
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
12
Department of Immunology, Mayo Clinic, Rochester, MN, USA.
13
Department of Dermatology, Mayo Clinic, Rochester, MN, USA.
14
Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
15
Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
16
Stanford ChEM-H, Stanford University, Stanford, CA, USA.
17
Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
18
Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA.
19
Department of Medicine, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.
20
Committee on Immunology, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.
21
Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.
22
Department of Pathology, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.
23
University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu.

Abstract

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 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, 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 disease4, 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.

PMID:
32051586
DOI:
10.1038/s41586-020-2003-8

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