| First Author | Abadie V | Year | 2020 |
| Journal | Nature | Volume | 578 |
| Issue | 7796 | Pages | 600-604 |
| PubMed ID | 32051586 | Mgi Jnum | J:293300 |
| Mgi Id | MGI:6445877 | Doi | 10.1038/s41586-020-2003-8 |
| Citation | Abadie V, et al. (2020) IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578(7796):600-604 |
| abstractText | 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 haplotypes(1,2). The need to develop non-dietary treatments is now widely recognized(3), 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 disease(4), 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-gamma (IFNgamma) 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. |
