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

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. MurrayChaitan Khosla, Luis B. Barreiro, Bana Jabri

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)600-604
Number of pages5
JournalNature
Volume578
Issue number7796
DOIs
StatePublished - Feb 27 2020

ASJC Scopus subject areas

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    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., ... Jabri, B. (2020). IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature, 578(7796), 600-604. https://doi.org/10.1038/s41586-020-2003-8