PATHOGENESIS KAWASAKI DISEASE

川崎病（Kawasaki Disease， KD）是一种急性、潜在致命的幼童血管炎，主要影响冠状动脉。KD影响所有国家和种族的儿童，在美国和日本已经取代急性风湿热成为儿童获得性心脏病的最常见原因。仅在芝加哥儿童纪念医院，1998年就诊断出65例新的急性KD病例。尽管KD在美国已成为一个重要的儿科问题，但病因和发病机制仍不明确。我们的长期目标是确定KD的发病机制。本提案的总体目标是研究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，急性KD患者的IgA1浆细胞浸润血管壁。初步数据表明，急性KD患者血管壁上的IgA基因是寡克隆的，这表明KD患者的IgA反应是针对特定抗原的，这些抗原可能是导致疾病的潜在病原体，也可能是通过分子模仿机制针对宿主抗原。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浆细胞数量明显增加。其他初步数据表明，急性KD血清中IgA1异常糖基化，因此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，IgA在发病机制中起着重要作用。我们打算确定寡克隆IgA反应是否是KD的特征。我们还将确定KD血清中IgA 1的糖基化谱。我们将利用我们建立的急性致命性KD病例组织库来确定IgA浆细胞在KD组织中的分布。我们还将表征浸润浆细胞中IgA的糖基化谱，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，并在炎症性疾病中由浆细胞产生。这些研究将阐明IgA和IgA浆细胞在KD发病机制中的作用，并将对这一日益被认识到的潜在致命性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.