Rheumatic fever is a sequela of group A streptococcal infection primarily in children. Manifestations of the disease include carditis, arthritis and chorea. Our hypothesis is that autoimmune mechanisms due to molecular mimicry between the group A streptococcus and human tissues are responsible for the disease. Our data support this hypothesis. We have identified host and streptococcal antigens which react with anti-strep/heart antibodies and T cells, and we have identified streptococcal and human cardiac myosin epitopes which produce carditis and valvulitis in animal models of disease. Despite our progress, we do not know how these crossreactive autoantibodies function in the pathogenesis of acute rheumatic fever(ARF) or the exact nature and antigenic specificities of the T cells in rheumatic carditis. Therefore, the goal and objectives propose to answer questions about the potential role of antibody in disease and to investigate the nature of the T cells which are crossreactive and appear to be responsible for valvulitis. The objectives are 1) to produce a panel of cytotoxic/crossreactive monoclonal antibodies (mAbs) from humans and transgenic mice and passively transfer IgM and IgG mAbs to test for tissue deposition in vivo; 2) to determine the nucleotide sequences of crossreactive antibody V, D, and J region genes; 3) to produce transgenic mice containing the VDJ genes(H and L) of human and mouse crossreactive and/or cytotoxic mAbs; 4) to investigate the Lewis rat model of valvulitis by producing and characterizing T cell clones from rats immunized with rM6 protein and cardiac myosin and in passive transfer experiments determine if these T cells produce disease; 5) to compare valves immunohistochemically from rheumatic carditis and Lewis rat valvulitis to identify similarities. These studies will attempt to define the steps in the pathogenesis of rheumatic carditis and will continue to support the growing body of evidence that infectious agents play a role in the development of autoimmunity in man.
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