创作:szx 审核:szx 03月01日
  • 构建一种表达易感性HLA-DQ8基因型的乳糜泻小鼠模型,可重现活动性乳糜泻患者的表型(肠道上皮及固有层中过表达IL-15),并在摄入谷蛋白后发展出绒毛萎缩表型;
  • 肠道上皮及固有层中同时过表达IL-15对于绒毛萎缩的发展是必需的,提示特定位点的IL-15在乳糜泻发病机制中的重要作用;
  • CD4+ T细胞及HLA-DQ8基因型对于细胞毒性T细胞介导的肠道上皮细胞裂解是必需的;
  • IFN-γ及谷氨酰胺转移酶2在乳糜泻的组织破坏中也扮演了重要角色。
乳糜泻是一种复杂的多基因肠道炎症疾病,在HLA-DQ8或HLA-DQ2基因型的个体中,饮食谷蛋白暴露可能触发乳糜泻。来自Nature上发表的一项最新研究,报道了一种新的乳糜泻小鼠模型,表达HLA-DQ8基因型,并在肠道上皮及固有层中过表达IL-15,摄入谷蛋白后可触发绒毛萎缩等乳糜泻表型。利用新模型,该研究揭示了IL-15、CD4+ T细胞、IFN-γ等关键因素在乳糜泻发病机制中的重要作用。
Nature [IF:42.778]

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



02-12, Article

Abstract & Authors:展开

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.

First Authors:
Valérie Abadie,Sangman M Kim,Thomas Lejeune

Correspondence Authors:
Valérie Abadie,Bana Jabri

All Authors:
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

Nature Reviews Gastroenterology and Hepatology期刊

Mimicking coeliac disease in mice