AUTOIMMUNE DETERMINANTS OF HUMAN CARDIAC MYOSIN

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DESCRIPTION (Adapted from Investigator's abstract): Myocarditis is a sequela of viral or bacterial infections in humans and occurs in susceptible animal strains following coxsackievirus infection or immunization with cardiac myosin. In some instances, myocarditis may be due to molecular mimicry between an infectious pathogen and the host autoantigen cardiac myosin. Myocarditis may result from exposure of the host to mimicking epitopes which may break tolerance against cardiac myosin. Although cardiac myosin is the known autoantigen which can induce myocarditis in animals, the molecular basis of the pathogenesis of the disease in humans remains unknown. In addition, there are few studies in humans which identify the immunological epitopes defining the disease. The goal of the proposed work is to define the autoimmune response to human cardiac myosin in animal models of myocarditis and in humans with myocarditis and to test the hypothesis that the anti-myosin antibodies and T-cells in the disease are crossreactive with viral or bacterial epitopes. For these reasons, the investigators have chosen to explore the following objects: 1) To produce human anti-myosin monoclonal antibodies (Mabs) from patients with myocarditis and investigate the Mabs reactivity with human cardiac myosin and its fragments and synthetic peptides, streptococcal M protein and coxsackieviral proteins and peptides, and to investigate mAb cytotoxicity against heart cells in culture; 2) To investigate the T-cell response in myocarditis patients to human cardiac myosin, fragments and synthetic peptides, streptococcal M Protein and coxsackieviral peptides, including production of human cardiac myosin response T-cell clones; 3)a) To determine the specificity of the heart specific infiltrating T-cells/lines/clones from hearts in animals models (Lewis rats and A/J and MRL mice) of myocarditis. T-cell lines/clones will be tested for responsiveness to fragments of human cardiac myosin, streptococcal M protein, and coxsackieviral proteins and peptides and will be compared with the specificities of the human T-cell response in myocarditis, b) to study pathogenic peptides of myosin, coxsackievirus or streptococcal M protein to determine their ability to produce tolerance against coxsackieviral or myosin-induced myocarditis.