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IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease
Nature ( IF 43.070 ) Pub Date : 2020-02-12 , DOI: 10.1038/s41586-020-2003-8
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 Ciszewski; Romain Bouziat; Kaushik Panigrahi; Irina Horwath; Matthew A. Zurenski; Ian Lawrence; Anne Dumaine; Vania Yotova; Jean-Christophe Grenier; Joseph A. Murray; Chaitan Khosla; Luis B. Barreiro; Bana Jabri

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.
更新日期:2020-02-13

 

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