Genetic influences and T-cell activation in Kawasaki Disease

描述（由申请方提供）：川崎病（KD）是一种自限性急性血管炎，是儿科获得性心脏病的最常见原因。冠状动脉瘤发生在高达25%的未经治疗的儿童，但可以在很大程度上预防及时给予大剂量静脉注射丙种球蛋白（IVIG）。KD的病因尚不清楚，尽管怀疑是感染性触发因素。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，使用我们实验室收集的DNA和日本KD患者的DNA，结合全基因组连锁，关联和重新测序，我们的合作者，日本东京理研研究所的Yoshi Onuochi发现了一种新的功能性单核苷酸多态性（SNP），它在IL-2信号传导中发挥作用，从而激活T细胞。该SNP强烈影响KD的易感性以及冠状动脉瘤的形成。该项目的主要目标是了解这种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如何激活和失活。尸检研究表明，在KD急性期死亡的儿童中，T细胞，特别是CD 8+细胞毒性T细胞（CTL）浸润到动脉瘤的冠状动脉壁中。这表明，T细胞活化和T细胞浸润在选定的区室是关键参与KD的发病机制。受新型SNP影响的T细胞的活化增加可能是急性期期间促炎性T细胞更大和更长时间扩增的原因，从而导致更严重的疾病。此外，未能及时调节这些促炎性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团队，包括KD专家，细胞免疫学家和分子生物学家，通过共聚焦显微镜表征T细胞活化，并从急性KD患者中克隆和表型T细胞。比较不同细胞表型与基因型的分布将允许我们确定功能性SNP在影响急性KD中促炎性T细胞与调节性T细胞的产生中的影响。了解新的SNP和免疫调节之间的联系将对KD患者的治疗具有重要意义，因为环孢菌素A（CsA）通过干扰涉及该基因的T细胞活化途径介导免疫抑制。 在发达国家，川崎是获得性小儿心脏病的主要原因，如果不及时治疗，25%的患者会导致严重的冠状动脉损伤。该提案旨在了解患者遗传学如何在急性期形成免疫反应。这些研究可能会导致新的治疗方法，将防止心脏损伤。

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 In an as yet unpublished study combining genome-wide linkage, association, and re-sequencing using both DNA collected by our laboratory and DNA from Japanese KD patients, our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