研究揭示引起乳糜瀉的分子機制
作者：
小柯機器人發布時間：2020/2/14 15:17:59
近日，美國芝加哥大學Bana Jabri、加拿大及蒙特婁大學Valérie Abadie等研究人員合作發現，IL-15、麩質和HLA-DQ8一同引起乳糜瀉的組織破壞。2020年2月12日，國際知名學術期刊《自然》在線發表了這一成果。
研究人員報導了一個小鼠模型，其可在主動的乳糜瀉中再現腸道上皮和固有層中白細胞介素15（IL-15）的過表達，表達易感的HLA-DQ8分子，並在攝入麩質後發展為絨毛狀萎縮。絨毛萎縮的進展需要IL-15在上皮和固有層中的過表達，這證明了IL-15在乳糜瀉發病中的位置依賴性核心作用。另外，CD4+T細胞和HLA-DQ8對於促進細胞毒性T細胞介導的腸上皮細胞裂解起到關鍵作用。研究人員還證明了細胞因子幹擾素-γ（IFNγ）和轉穀氨醯胺酶2（TG2）在組織破壞中的作用。通過重現麩質、遺傳因素以及IL-15引起的組織炎症之間的複雜相互作用，該小鼠模型增加了人們對乳糜瀉的了解，並為研發新的治療策略提供了機會。
據介紹，乳糜瀉是一種複雜的、多基因炎症性腸病，是由於暴露於飲食麩質引起的，這種情況發生在表達HLA-DQ8或HLA-DQ2單倍型的遺傳易感個體中。目前已經廣泛意識到開發非飲食療法的必要性，但是還沒有與病理生理相關的麩質和HLA依賴的臨床前模型。此外，儘管人類中的研究已使人們對乳糜瀉的發病機理有了重要的了解，但尚無直接證明疾病易感性HLA分子以及適應性免疫和先天免疫在組織損傷發展中的各自作用。
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
Source: https://www.nature.com/articles/s41586-020-2003-8