Author
Listed:
- Valérie Abadie
(University of Montreal
University of Montreal
University of Chicago)
- Sangman M. Kim
(University of Chicago
University of Chicago
University of San Francisco)
- Thomas Lejeune
(University of Montreal
University of Montreal)
- Brad A. Palanski
(Stanford University)
- Jordan D. Ernest
(University of Chicago
University of Chicago)
- Olivier Tastet
(University of Montreal)
- Jordan Voisine
(University of Chicago
University of Chicago)
- Valentina Discepolo
(University of Chicago)
- Eric V. Marietta
(Division of Gastroenterology and Hepatology, Mayo Clinic
Mayo Clinic
Mayo Clinic)
- Mohamed B. F. Hawash
(University of Montreal
University of Montreal)
- Cezary Ciszewski
(University of Chicago
University of Chicago)
- Romain Bouziat
(University of Chicago
University of Chicago)
- Kaushik Panigrahi
(University of Chicago)
- Irina Horwath
(Division of Gastroenterology and Hepatology, Mayo Clinic)
- Matthew A. Zurenski
(University of Chicago)
- Ian Lawrence
(University of Chicago)
- Anne Dumaine
(University of Montreal)
- Vania Yotova
(University of Montreal)
- Jean-Christophe Grenier
(University of Montreal)
- Joseph A. Murray
(Division of Gastroenterology and Hepatology, Mayo Clinic)
- Chaitan Khosla
(Stanford University
Stanford University
Stanford University)
- Luis B. Barreiro
(University of Montreal
University of Montreal
University of Chicago)
- Bana Jabri
(University of Chicago
University of Chicago
University of Chicago
University of Chicago)
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.
Suggested Citation
Valérie Abadie & Sangman M. Kim & Thomas Lejeune & Brad A. Palanski & Jordan D. Ernest & Olivier Tastet & Jordan Voisine & Valentina Discepolo & Eric V. Marietta & Mohamed B. F. Hawash & Cezary Cisze, 2020.
"IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease,"
Nature, Nature, vol. 578(7796), pages 600-604, February.
Handle:
RePEc:nat:nature:v:578:y:2020:i:7796:d:10.1038_s41586-020-2003-8
DOI: 10.1038/s41586-020-2003-8
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Citations
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Cited by:
- Kuan Zhang & Yu Zhou & Junsheng Zhang & Qing Liu & Christina Hanenberg & Ahmed Mourran & Xin Wang & Xiang Gao & Yi Cao & Andreas Herrmann & Lifei Zheng, 2024.
"Shape morphing of hydrogels by harnessing enzyme enabled mechanoresponse,"
Nature Communications, Nature, vol. 15(1), pages 1-11, December.
- Brad A. Palanski & Nielson Weng & Lichao Zhang & Andrew J. Hilmer & Lalla A. Fall & Kavya Swaminathan & Bana Jabri & Carolina Sousa & Nielsen Q. Fernandez-Becker & Chaitan Khosla & Joshua E. Elias, 2022.
"An efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease,"
Nature Communications, Nature, vol. 13(1), pages 1-13, December.
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