Bouziat Romain, Hinterleitner Reinhard, Brown Judy J, Stencel-Baerenwald Jennifer E, Ikizler Mine, Mayassi Toufic, Meisel Marlies, Kim Sangman M, Discepolo Valentina, Pruijssers Andrea J, Ernest Jordan D, Iskarpatyoti Jason A, Costes Léa M M, Lawrence Ian, Palanski Brad A, Varma Mukund, Zurenski Matthew A, Khomandiak Solomiia, McAllister Nicole, Aravamudhan Pavithra, Boehme Karl W, Hu Fengling, Samsom Janneke N, Reinecker Hans-Christian, Kupfer Sonia S, Guandalini Stefano, Semrad Carol E, Abadie Valérie, Khosla Chaitan, Barreiro Luis B, Xavier Ramnik J, Ng Aylwin, Dermody Terence S, Jabri Bana
Department of Medicine, University of Chicago, Chicago, IL, USA.
Committee on Immunology, University of Chicago, Chicago, IL, USA.
Science. 2017 Apr 7;356(6333):44-50. doi: 10.1126/science.aah5298.
Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (T1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pT) conversion and promoting T1 immunity to dietary antigen. Initiation of T1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pT conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.
病毒感染被认为会引发导致针对膳食麸质和乳糜泻（CeD）的辅助性T细胞1（T1）免疫反应启动的病理过程。为了验证这一假设并深入了解病毒诱导的对膳食抗原耐受性丧失的潜在机制，我们开发了一种病毒感染模型，该模型利用两种感染肠道但免疫病理结果不同的呼肠孤病毒株。呼肠孤病毒是一种引发保护性免疫的无毒病原体，但我们发现它仍然可以通过抑制外周调节性T细胞（pT）转化并促进对膳食抗原的T1免疫反应，在口服耐受性的诱导和效应部位破坏肠道免疫稳态。对膳食抗原的T1免疫反应的启动依赖于干扰素调节因子1，并且与由1型干扰素介导的pT转化抑制无关。最后，我们在人类中的研究支持一种看似无害的病毒——呼肠孤病毒感染在触发CeD发展中所起的作用。
