Kawasaki Syndrome (K.S.) is an acute vasculitis of childhood that results in coronary artery damage in 20% of patients. This complication is prevented by the early administration of gammaglobulin. Recently, we have demonstrated that during acute K.S. there is marked T cell and B cell activation in association with circulating cytotoxic IgM antibodies directed against gamma interferon (Gamma-INF) inducible antigens of vascular endothelial cells. The current proposal will test the hypothesis that a lymphocytotropic virus results in immunoregulatory abnormalities which trigger a cascade of events that result in tissue injury, particularly vasculitis. These events include the secretion of mediators (e.g., Gamma-IFN, IL-1, etc) which causes the expression of neoantigens on endothelial cells, and the production of cytotoxic antibodies to these neoantigens. Two related areas will be studied: First, we will assess the role of the immunoregulatory abnormalities in the pathogenesis of blood vessel injury in K.S. Specifically, we will: i) examine the presence and the target specificity of antibodies directed to endothelial cell antigens inducible by mediators of activated T cell and monocytes; ii) determine whether sera from acute K.S. are cytotoxic to other cell types activated with Gamma-IFN, IL-1 or other immune mediators; iii) examine the in vivo relevance of these findings by immunopathologic studies and by correlating the production of IL-1, Gamma-IFN and anti-endothelial cell antibodies with the clinical course, (fever, coronary artery disease) of K.S. patients treated with aspirin (ASA) alone or with ASA plus intravenousgGammaglobulin; iv) determine whether sera from other vasculitides (e.g., systemic lupus) contain antibodies directed against inducible endothelial cell antigens. Second, the possibility that K.S. is triggered by a lymphocytotropic virus will be explored by screening culture supernatants of K.S. peripheral blood lymphocytes (PBL) for reverse transcriptase and DNA polymerase activity by standard techniques. We will determine the divalent cation requirements, template and primer specificity, and transmissibility of the polymerase activity to establish T and/or B cell lines. Freshly isolated PBL and cultured PBL will be examined by electron microscopy for viral particles. It is hoped that these studies will contribute to a better understanding of the etiology and pathogenesis of K.S., provide a basis for more objective criteria for the diagnosis of this disease, and result in a more specific treatment of children with this potentially life-threatening disease.
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