Human dilated cardiomyopathy is responsible for approximately 10,000 deaths in the United States annually. Endomyocardial biopsy has shown that 20-30% of cardiomyopathy patients have active myocarditis. Our studies of murine Coxsackievirus B3(CB3) myocarditis have revealed many similarities between the lats-phase myocarditis in mice and human myocarditis. Both share similar pathology patterns of inflammation and are associated with circulating heart-specific autoantibodies. The disparity between the severe cardiac dysfunction in myocarditis, and the small amount of myocyte necrosis, highlights the need to define the pathogenic mechanisms responsible for myocarditis. Recently, we have discovered that a major myocardial autoantigen in murine myocarditis was the heavy chain of cardiac myosin. We have thus developed a second model of autoimune myocarditis by immunizing mice with purified cardiac myosin. Immunization with cardiac myosin produces severe myocarditis similar in appearance, time course and genetic predisposition pattern to late-phase myocarditis induced by CB3. Our hypothesis is that late-phase, post-CB3 myocarditis is an autoimmune response to unique epitopes on cardiac myosin heavy chain. It is our goal to use both murine models of myocarditis to elucidate the initiation and pathogenesis of autoimmune myocarditis. The work proposed herein will initially determine the sequence of events leading to myosin-induced autoimmune myocarditis, with respect to both the roles of antibody and T-cell-mediated immunity. We will then compare the immunopathology and antibody specificity of the two models of myocarditis. Passive transfer with antibody and adoptive transfer of myocarditis with T cell populations will be performed in both models. Since immunization with cardiac myosin produces severe myocarditis while immunization with skeletal myosin does not, the epitopes unique to cardiac myosin will be investigated. Finally, we will determine whether cardiac antigens other then myosin heavy chain may contribute to the development of autoimmune myocarditis. The addition of a simple model of myocarditis due to a known specific cardiac antigen allows us the unique opportunity to define the relative roles of humoral and cell-mediated immunity in myocarditis. lt is anticipated that these studies will form a rational basis for the development of successful therapies for myocarditis and possibly prevent the development of post-viral cardiomyopathy.
Showing the most recent 10 out of 34 publications
