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

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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.