Genetic influences and T-cell activation in Kawasaki Disease

描述（由申请人提供）：川崎病（KD）是一种自限性急性血管炎，是儿童获得性心脏病的最常见原因。冠状动脉瘤在未经治疗的儿童中发生率高达25%，但通过及时给予高剂量静脉注射丙种球蛋白（IVIG）可以在很大程度上预防。KD的病因尚不清楚，但怀疑是感染引起的。我们的实验室已经确定了影响疾病易感性和结果的单核苷酸多态性。在一项尚未发表的研究中，我们的合作者、日本东京理化学研究所的Yoshi Onuochi发现了一种新的、功能性的单核苷酸多态性（SNP），它在IL-2信号传导和t细胞活化中发挥作用。该研究结合了我们实验室收集的DNA和日本KD患者的DNA，进行了全基因组连锁、关联和重测序。该SNP强烈影响KD易感性以及冠状动脉瘤的形成。该项目的首要目标是了解这种SNP如何影响急性KD的免疫激活和恢复。为了了解KD中免疫介导的损伤，我们需要了解在这种自限性疾病的过程中免疫级联是如何激活和失活的。尸检研究表明，在KD急性期死亡的儿童中，t细胞，特别是CD8+细胞毒性t细胞（CTL）浸润到动脉瘤的冠状动脉壁。这表明t细胞活化和t细胞浸润在特定的区室中是KD发病的关键因素。受新SNP影响的t细胞活化增加可能是急性期促炎t细胞扩增更大、更持久的原因，从而导致更严重的疾病。此外，不能及时调节这些促炎t细胞可能导致冠状动脉损伤增加。我们组建了一个多学科的团队，包括一名KD专家、一名细胞免疫学家和一名分子生物学家，通过共聚焦显微镜来表征t细胞活化，并克隆急性KD患者的t细胞并进行表型分析。比较不同细胞表型和基因型的分布将使我们能够确定功能性SNP在影响急性KD中促炎T细胞和调节性T细胞产生方面的影响。了解新的SNP与免疫调节之间的联系将对KD患者的治疗具有重要意义，因为环孢素A （cyclosporin A, CsA）通过干扰涉及该基因的t细胞激活途径介导免疫抑制。与公共卫生有关

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 In an as yet unpublished study combining genome-wide linkage, association, and re-sequencing using both DNA collected by our laboratory and DNA from Japanese KD patients, our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 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.