近日，美国芝加哥大学Bana Jabri、加拿大及蒙特利尔大学Valérie Abadie等研究人员合作发现，IL-15、麸质和HLA-DQ8一同引起乳糜泻的组织破坏。2020年2月12日，国际知名学术期刊《自然》在线发表了这一成果。

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

Author: Valrie 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

Issue&Volume: 2020-02-12

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.

DOI: 10.1038/s41586-020-2003-8

Source: https://www.nature.com/articles/s41586-020-2003-8