Kawasaki syndrome (KS) is currently the most common cause of acquired heart disease in children. Early treatment of KS with intravenous gammaglobulin significantly reduces, but does not eradicate, the occurrence of cardiovascular complications. Thus, discovery of the etiology and pathogenesis of KS is of critical importance. The current proposal will expand upon preliminary data from our lab that suggests the marked immune activation associated with acute KS is caused by a superantigen(s), e.g., a variant staphylococcal toxic shock syndrome toxin (TSST-KS) or streptococcal pyrogenic exotoxin C (SPEC) that activates macrophages and induces the selective stimulation of T cells bearing Vbeta2 gene segments.
The specific aims will be: First, to assess the role of antibody repertoire as a risk factor for KS. We will assay anti-toxin antibody levels in sera from acute vs convalescent KS patients, their family members and age-matched controls by using both functional assays of toxin neutralization and ELISA. We postulate that the selective deficiency of antibodies against TSST-KS and/or SPEC predispose to acute KS> Second, to correlate the isolation of toxin-producing bacteria with various established parameters of immune activation in acute KS. The demonstration that isolation of toxin secreting S. aureus is accompanied by the activation of macrophages and Vbeta2+ T cells will strengthen the argument that superantigens play a role in the pathogenesis of KS. Third, to determine whether the selective stimulation of T cells in patients with KS, complicated by the development of coronary artery disease, is oligoclonal or diverse, we will clone and sequence their T Cell Receptor Vbeta2 and control Vbeta gene transcripts amplified PCR. Fourth, to determine whether TSST-KS has different immunologic properties than staphylococcal TSST1 when tested on T cells, B cells, and/or vascular endothelial cells. We postulate that as the result of several critical mutations between variant TSST-KS vs staphylococcal TSST1, the cause of Toxic Shock Syndrome (TSS), that TSST-KS may exhibit different immunologic properties which account for at least some of the differences in the immunologic features distinguishing acute KS vs TSS. The importance of our proposed studies is that it should contribute directly to an understanding of the pathogenesis and etiology of KS. The elucidation of immune mechanisms underlying this disease will have important implications for the development of more effective therapeutic approaches to the treatment of KS as well as other diseases where similar pathologic mechanisms may exist. Furthermore, identification of the causative agent and unique populations of T cells associated with KS may allow us to more readily diagnose this disease and institute early therapy to prevent heart disease.
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