Role of hepatitis E virus (HEV) infection in the induction of autoimmune hepatitis (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在自身免疫性肝炎的启动和持续中所起的作用。顺应这一点，我们已经发现了HEV与AIH发病率之间的临床联系。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，这两个机制可能导致HEV感染环境下AIH的发展。该项目的第一部分主要集中于解决患有或不患有AIH的患者HEV特异性T细胞反应模式的差异。我们还将识别和实验验证HEV和自身蛋白的交叉反应T细胞表位。HEV感染可导致病原体特异性T细胞对具有序列或结构相似性的自身抗原产生交叉反应。虽然已经描述了许多与病毒相关的自身免疫状况的例子，但关于病毒感染后自身免疫反应是如何触发和持续的，人们知之甚少。人类系统中存在不同层次的病毒特异性T细胞和潜在的交叉反应候选表位，这一实验验证可能为免疫发病机制和开发新的自身免疫性肝炎治疗策略提供新的见解。该项目的第二部分集中在确定来自正在进行凋亡的活化T细胞的凋亡自我表位的作用和功能。严密控制的细胞死亡过程的失败可能会由于自身表位呈递给自身反应性CD8+T细胞而启动免疫反应。在HIV和丙型肝炎病毒感染的患者中，出现了大量针对凋亡自身表位的自身反应性CD8+T细胞。此外，组织中高水平的凋亡细胞的存在与不同的自身免疫性疾病有关。然而，自身凋亡表位在AIH中的作用从未被提及。深入了解细胞凋亡的作用，特别是细胞凋亡表位与自身免疫之间的可能联系，可能为设计创新的治疗策略提供重要的平台。此外，识别针对细胞凋亡表位的多功能CD8+T细胞有助于预测AIH的高危人群。

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.