Kawasaki syndrome (KS) is currently the most common cause of acquired heart disease in the United States and Japan. Left untreated, approximately 30% of children develop coronary artery (CA) abnormalities. Early treatment of KS with intravenous gammaglobulin (IVGG) significantly reduces the occurrence of cardiovascular complications due to KS. Thus, the development of an objective laboratory test for diagnosis of KS is critical. The current proposal will test the hypothesis that KS is caused by a superantigen e.g. a bacterial toxin that induces the selective stimulation of T cells bearing specific T cell receptor (TCR) Vbeta gene segments. Furthermore, we postulate that this expansion of T cells will be unique and not found in other diseases associated with systemic inflammation.
The specific aims will be: First, to determine whether KS is associated with the selective expansion of T cells, we will assess the TCR Vbeta gene usage of T cells from peripheral blood and tissue infiltrates of KS patients vs patients with other diseases that may mimic KS. As part of these studies, we will examine whether TCR Vbeta gene usage correlates with disease response in KS patients. Thus, we will compare the TCR Vbeta gene usage with different clinical outcomes e.g. development of CA abnormalities, response to IVGG therapy, ethnic background, etc. Second, to determine whether the selective stimulation of T cells in KS is clonotypic or diverse, we will clone and sequence the KS TCR transcripts amplified by PCR. Third, to determine the capacity of antibodies in KC sera to inhibit the T cell mitogenic effects of various staphylococcal and streptococcal exotoxins. We expect to find that convalescent but not acute sera from KS patients will contain IgG to streptococcal erythrogenic toxin B. Furthermore, the lack of IgG to erythrogenic toxin B during acute KS may predispose to the selective expansion of T cells expressing Vbeta2 and Vbeta8 gene segments. The pathogenesis and etiology of KS is poorly understood. It is hoped that these studies will contribute to an understanding of the pathogenesis of KS. The elucidation of immune mechanisms underlying this disease should have important consequences for the development of more effective therapeutic approaches to the treatment of KS and other diseases where similar pathologic mechanisms may exist. In particular, identification of an unique population of T cells associated with KS may allow us to more readily diagnose and institute early therapy of this disease.
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