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Inflammatory heart disease can result from infectious or non-infectious etiologies. When infectious causes are involved, autoimmune responses are commonly suspected to explain persistence of inflammation, leading to the suggestion that pathogens primarily affecting the target organs can lead to a secondary generation of autoimmune responses. In addressing this hypothesis, we had previously reported that Coxsackievirus B3 (CVB) infection accompanies the generation of cardiac myosin-specific T cells, which can transfer disease to naïve mice. This work led us to propose that the postinfectious phase of CVB infection involves the generation of autoreactive T cells with multiple antigen specificities. To this end, we made efforts to identify cardiac autoantigens that can potentially become immune targets in the CVB pathogenesis. First, by establishing T cell hybridoma technology, we generated T cell hybridomas for cardiac myosin that may be helpful in tracking cells expressing viral proteins in vivo. Second, we demonstrated that mitochondrial protein, branched chain α-ketoacid dehydrogenase kinase (BCKDk) can act as a target antigen in the mediation of both autoimmune myocarditis and hepatitis. Third, we identified an antigenic determinant from sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA2a) that induces mainly atrial inflammation. The implications of our observations are two-fold: (a) the new disease models (BCKDk and SERCA2a) can be used to determine inflammatory events arising from autoimmune responses in both the heart and liver, and (b) identification of immunodominant epitopes in BCKDk and SERCA2a proteins is helpful in evaluating the relevance of epitope spreading as an autoimmune mechanism in the development of CVB-induced chronic myocarditis in future studies.
A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy, Major: Integrative Biomedical Sciences, Under the Supervision of Professor Jay Reddy. Lincoln, Nebraska: September, 2017
Copyright (c) 2017 Bharathi Yalaka