PATHOGENESIS KAWASAKI DISEASE

川崎病（KD）是一种幼儿急性、可能致命的血管炎，主要影响冠状动脉。 KD影响所有国家和种族的儿童，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。 本实验室最近的研究表明，IgA 1浆细胞浸润血管壁在急性KD。 初步数据表明，IgA基因在血管壁中的急性KD是寡克隆的，这表明IgA反应在KD是针对特定的抗原，无论是那些潜在的病原体引起的疾病，或宿主抗原的分子模拟机制。 初步数据还表明，IgA浆细胞存在于显着增加的数量在呼吸道和消化道的KD患者相比，年龄匹配的控制。其他初步数据表明，急性KD血清中的血清IgA 1异常糖基化，因此可能具有改变的性质。 我们的假设是KD是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。 我们建议确定寡克隆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。 我们将使用我们建立的急性致死性KD病例组织库来确定KD组织中IgA浆细胞的分布。 我们还将描述浸润浆细胞中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，并将对这种日益认可的潜在致命儿童疾病的潜在诊断和治疗策略产生重要影响。

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.