Autoimmune Determinants of Human Cardiac Myosin

Abstract: Myocarditis and rheumatic carditis are sequelae of viral or bacterial infections, respectively, and occur in humans and animal models following viral infection, group A streptococcal infection, or immunization with cardiac myosin(CM). Myocarditis may be a precursor of dilated cardiomyopathy and heart failure. The pathogenesis of these diseases may have a common denominator related in part to molecular mimicry between the infectious pathogen and the host autoantigen CM or to immune responses against CM released from cardiomyocytes during infection. Although CM can induce myocarditis and valvulitis in animals, the role of CM in the molecular pathogenesis of disease in humans is not well defined. The goal of the proposed work is to define the autoimmune response to human CM in humans and in CM-induced animal models of myocarditis to understand how an intracellular molecule such as myosin can act through immunological mimicry of exogenous foreign antigens or endogenous self antigens to cause disease. We will investigate links between innate and adaptive immunity to CM and use animal models to provide clues for studies in humans. We will test the hypothesis that autoimmune carditis may arise due to the influence of molecular mimicry, which may lead to the involvement of other heart proteins/antigens through innate immunity, mimicry or epitope spreading. In aims 1 and 2, we plan to evaluate a group of myocarditis patients longitudinally where we can determine immunological parameters of recovery and disease which may be important in understanding and developing individualized treatment plans in the future. In order to decipher pathogenic reactivity in patients we plan: 1)To produce human monoclonal antibodies from selected patients with myocarditis and cardiomyopathy to determine mimicry and the role of antibody in the pathogenesis of myocarditis and cardiomyopathy; 2)To evaluate human T cell responses and to produce T cell clones to CM epitopes using synthetic peptides of human CM in carditis and cardiomyopathy and correlate epitopes with disease; 3) To determine the ability of CM to act as an endogenous ligand and stimulate innate immunity 4) To investigate our previously established Lewis rat CM peptide-induced model of severe myocarditis for parameters of inflammatory heart disease including the role of molecular mimicry, cytokines, regulatory T cells, Th17 cells and antibody in the induction of and protection against myocarditis. Our work will provide a better understanding of pathogenic and protective immune mechanisms in animal models of myocarditis and cardiomyopathy and their relationship to human disease.