研究揭示引起乳糜泻的分子机制
2020-02-14   阅读:276   来源:自然

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。

研究人员报道了一个小鼠模型,其可在主动的乳糜泻中再现肠道上皮和固有层中白细胞介素15(IL-15)的过表达,表达易感的HLA-DQ8分子,并在摄入麸质后发展为绒毛状萎缩。绒毛萎缩的进展需要IL-15在上皮和固有层中的过表达,这证明了IL-15在乳糜泻发病中的位置依赖性核心作用。另外,CD4+T细胞和HLA-DQ8对于促进细胞毒性T细胞介导的肠上皮细胞裂解起到关键作用。研究人员还证明了细胞因子干扰素-γ(IFNγ)和转谷氨酰胺酶2(TG2)在组织破坏中的作用。通过重现麸质、遗传因素以及IL-15引起的组织炎症之间的复杂相互作用,该小鼠模型增加了人们对乳糜泻的了解,并为研发新的治疗策略提供了机会。
 
据介绍,乳糜泻是一种复杂的、多基因炎症性肠病,是由于暴露于饮食麸质引起的,这种情况发生在表达HLA-DQ8或HLA-DQ2单倍型的遗传易感个体中。目前已经广泛意识到开发非饮食疗法的必要性,但是还没有与病理生理相关的麸质和HLA依赖的临床前模型。此外,尽管人类中的研究已使人们对乳糜泻的发病机理有了重要的了解,但尚无直接证明疾病易感性HLA分子以及适应性免疫和先天免疫在组织损伤发展中的各自作用。
 
附:英文原文

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

编辑:小柯机器人

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