PATHOGENESIS KAWASAKI DISEASE

川崎病(KD)是一种急性的、可能致命的幼儿脉管炎，主要影响冠状动脉。KD影响所有国家和民族的儿童，并已取代急性风湿热成为美国和日本儿童获得性心脏病的最常见原因。仅在芝加哥的儿童纪念医院，1998年就诊断出65例新的急性KD病例。尽管KD在美国已经成为一个重要的儿科问题，但其病因和发病机制仍不清楚。我们的长期目标是确定KD的发病机制。这项建议的总体目标是研究IgA和IgA浆细胞在KD血管炎发展中的作用。我们实验室最近的研究表明，在急性KD中，IgA1浆细胞渗入血管壁。初步资料表明，川崎病急性期血管壁中的免疫球蛋白A基因是寡克隆的，提示川崎病的免疫应答是针对特定的抗原，要么是潜在病原体(S)的抗原，要么是通过分子模拟机制的宿主抗原。初步数据还表明，与年龄匹配的对照组相比，KD患者呼吸道和胃肠道中的IgA浆细胞数量显著增加。其他初步数据表明，急性KD血清中的血清IgA1糖基化异常，因此很可能具有改变的性质。我们的假设是KD是一种由粘膜病原体引发的免疫介导的血管炎，而IgA在发病机制中起着重要作用。我们建议确定寡克隆性IgA反应是否为KD的特征。我们还将测定KD血清中IgA型L的糖基化情况。我们将使用我们建立的急性致死性KD病例的组织资料库来确定KD组织中IgA浆细胞的分布。我们还将确定浸润性浆细胞中IgA的糖基化特征，并确定这些浆细胞是否产生基质金属蛋白酶(MMPs)，基质降解酶参与腹主动脉瘤的形成，并由炎症性疾病中的浆细胞产生。这些研究将阐明IgA和IgA浆细胞在KD发病机制中的作用，并将对这种日益被认识的、潜在的致命儿童疾病的潜在诊断和治疗策略具有重要意义。

Kawasaki Disease (KD) is an acute, potentially fatal vasculitis of young children which predominately affects the coronary arteries. KD affects children of all nations and ethnic groups, and has replaced acute rheumatic fever as the most common cause of acquired heart disease in children in the U.S. and Japan. At Children's Memorial Hospital in Chicago alone, 65 new acute KD cases were diagnosed in 1998. Despite the fact that KD has become a significant pediatric problem in the U.S. the etiology and pathogenesis remain undefined. Our long-term objective is to determine the pathogenesis of KD. The overall goal of this proposal is to investigate the role of IgA and IgA plasma cells in the development of KD vasculitis. Recent studies from our laboratory indicate that IgA1 plasma cells infiltrate the vascular wall in acute KD. Preliminary data indicate that IgA genes in the vascular wall in acute KD are oligoclonal, suggesting that the IgA response in KD is directed toward specific antigens, either those of the potential pathogen(s) causing the illness, or host antigens by a molecular mimicry mechanism. Preliminary data also indicate that IgA plasma cells are present in markedly increased numbers in the respiratory and GI tracts of KD patients when compared with age-matched controls. Other preliminary data indicate that serum IgA1 in acute KD sera is aberrently glycosylated and therefore is likely to have altered properties. Our hypothesis is that KD is an immune-mediated vasculitis triggered by a mucosal pathogen, and that IgA plays a prominent role in pathogenesis. We propose to determine whether an oligoclonal IgA response is characteristic of KD. We will also determine glycosylation profiles of IgA l in KD sera. We will determine the distribution of IgA plasma cells in KD tissues using our established tissue repository of acute fatal KD cases. We will also characterize glycosylation profiles of IgA in the infiltrating plasma cells and determine whether these plasma cells produce matrix metalloproteinases (MMPs), matrix-degrading enzymes that participate in abdominal aortic aneurysm formation and that are produced by plasma cells in inflammatory diseases. These studies will elucidate the role of IgA and IgA plasma cells in the pathogenesis of KD, and will have important implications for potential diagnostic and treatment strategies for this increasingly recognized, potentially fatal childhood illness.