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Role of hepatitis E virus (HEV) infection in the induction of autoimmune hepatitis (AIH)

戊型肝炎病毒（HEV）感染在诱导自身免疫性肝炎（AIH）中的作用

基本信息

批准号：
266770423
负责人：
Professor Dr. Markus Cornberg, since 7/2015
金额：
--
依托单位：
Klinik für Gastroenterologie, Hepatologie und Endokrinologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/266770423?language=en
关键词：
Role hepatitis virus HEV infection

项目摘要

Pathogenesis of AIH is not well known and immunosuppression is the only available treatment option. There is mounting evidence supporting the contribution of viruses to the initiation and perpetuation of the autoimmune hepatitis. Complying with this, we already found clinical association between HEV and incidence of AIH. In the following research proposal we propose to address two potentially important underlying mechanisms that could lead to the development of AIH in settings of HEV infection. First part of the project is mainly focussed on addressing the differences in pattern of HEV- specific T cells responses in patients with or without AIH. We will also identify and experimentally validate the cross reactive T cell epitopes of HEV and self-proteins. HEV infection can result in activation of cross reactive pathogen specific T cells to self-antigens with sequence or structural similarity. Although many examples of viral associated autoimmune conditions have been described, little is known about how autoimmune response is triggered and perpetuated following viral infection. Experimental validation of presence of different hierarchies of virus specific T cells and potential cross reactive candidate epitopes in human system might provide new insights in to the immunopathogenesis and development of novel treatment strategies for autoimmune hepatitis.Second part of the project is focussed on determining the role and functionality of apoptotic self-epitopes derived from activated T cells which are undergoing apoptosis. Failure of tightly controlled cell death process could potentially initiate immune responses as a result of self-epitope presentation to autoreactive CD8+ T cells. Emergence of large number of autoreactive CD8+ T cells specific to apoptotic self-epitopes was previously described in HIV and HCV infected patients. Moreover, Presence of high levels of apoptotic cells in tissues has been linked to different autoimmune diseases. However the role of self-apoptotic epitopes in AIH has been never addressed. Deeper understanding of the role of apoptotic cells especially, possible connection between apoptotic epitopes and autoimmunity may provide an important platform for the design of innovative therapeutic strategies. Additionally, identification of poly functional CD8+ T cells specific to apoptotic epitopes could help predicting the individuals at high risk of developing AIH.

AIH 的发病机制尚不清楚，免疫抑制是唯一可用的治疗选择。越来越多的证据支持病毒导致自身免疫性肝炎的发生和持续。与此相符，我们已经发现 HEV 与 AIH 发病率之间存在临床关联。在下面的研究提案中，我们建议解决两个潜在的重要潜在机制，这些机制可能导致 HEV 感染情况下发生 AIH。该项目的第一部分主要致力于解决患有或不患有 AIH 的患者中 HEV 特异性 T 细胞反应模式的差异。我们还将鉴定并通过实验验证 HEV 和自身蛋白的交叉反应性 T 细胞表位。 HEV 感染可导致病原体特异性 T 细胞与具有序列或结构相似性的自身抗原发生交叉反应。尽管已经描述了许多与病毒相关的自身免疫性疾病的例子，但人们对病毒感染后如何触发和维持自身免疫反应知之甚少。对人体系统中不同层次的病毒特异性 T 细胞和潜在交叉反应候选表位的存在进行实验验证，可能会为自身免疫性肝炎的免疫发病机制和新型治疗策略的开发提供新的见解。该项目的第二部分重点是确定来自正在经历凋亡的活化 T 细胞的凋亡自身表位的作用和功能。严格控制的细胞死亡过程失败可能会由于自身表位呈递给自身反应性 CD8+ T 细胞而引发免疫反应。先前描述了在HIV和HCV感染的患者中出现大量针对凋亡自身表位的自身反应性CD8+T细胞的出现。此外，组织中高水平凋亡细胞的存在与不同的自身免疫性疾病有关。然而，自凋亡表位在 AIH 中的作用从未得到解决。更深入地了解凋亡细胞的作用，特别是凋亡表位与自身免疫之间可能的联系，可能为创新治疗策略的设计提供重要平台。此外，对凋亡表位特异性的多功能 CD8+ T 细胞的鉴定有助于预测罹患 AIH 的高风险个体。