Genetic influences and T-cell activation in Kawasaki Disease

University Of California, San Diego, La Jolla CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Kawasaki disease (KD) is a self-limited, acute vasculitis that is the most common cause of pediatric acquired heart disease. Coronary artery aneurysms occur in up to 25% of untreated children, but can be largely prevented with timely administration of high dose intravenous gamma globulin (IVIG). The etiology of KD is unknown, although an infectious trigger is suspected. Our laboratory has identified single nucleotide polymorphisms that influence both disease susceptibility and outcome. In an as yet unpublished study combining genome-wide linkage, association, and re-sequencing using both DNA collected by our laboratory and DNA from Japanese KD patients, our collaborator, Yoshi Onuochi at Riken Institute in Tokyo, Japan, has discovered a novel, functional single nucleotide polymorphism (SNP) that plays a role in IL-2 signaling and thus T-cell activation. This SNP strongly influences susceptibility to KD as well as formation of coronary artery aneurysms. The over-arching goal of this project is to understand how this SNP influences immune activation and recovery in acute KD. To understand immune-mediated injury in KD, we need to understand how the immune cascade activates and de-activates during the course of this self-limited disease. Autopsy studies demonstrate the infiltration of T-cells, particularly CD8+ cytotoxic T-cells (CTL), into the coronary artery wall of aneurysms in children who die during the acute phase of KD. This suggests that T-cell activation and T-cell infiltration in selected compartments are critically involved in the pathogenesis of KD. Increased activation of T-cells influenced by the novel SNP may be responsible for a greater and more prolonged expansion of pro- inflammatory T-cells during the acute phase, thus leading to greater disease severity. In addition, failure to promptly regulate these pro-inflammatory T-cells may lead to increased coronary artery damage. We have assembled a multi-disciplinary team including a KD expert, a cellular immunologist, and a molecular biologist to characterize T-cell activation by confocal microscopy and to clone and phenotype T-cells from acute KD patients. Comparing the distribution of different cell phenotypes to genotype will allow us to determine the impact of the functional SNP in influencing the generation of pro-inflammatory vs. regulatory T cells in acute KD. Understanding the connection between the novel SNP and immune regulation will have important implications for treatment of KD patients since cyclosporin A (CsA) mediates immunosuppression by interfering with the T-cell activation pathway that involves this gene.Relevance to Public Health [unreadable] [unreadable] Kawasaki disease is the leading cause of acquired pediatric heart disease in developed countries, which if left untreated, results in serious coronary artery damage in 25% of patients. This proposal seeks to understand how patient genetics shapes the immune response during the acute phase. These studies may lead to new treatments that will prevent heart damage. [unreadable] [unreadable] [unreadable]