The Pathogenesis of Kawasaki Disease

描述（由申请方提供）：川崎病（KD）是一种日益被认识到的、可能致命的幼儿急性血管炎，可能导致冠状动脉瘤（CAA）形成。 本研究的目的是了解KD的发病机制。 在过去的3年中，我们发现，有一个显着的浸润上呼吸道和CAA的伊加浆细胞在急性KD，强烈建议的KD剂进入呼吸道门户。 我们证明了KD动脉壁中的伊加反应是寡克隆的，因此是抗原驱动的。 我们发现CD 8 T淋巴细胞和巨噬细胞在急性KD中浸润CAA，这与对细胞内病原体如病毒的免疫反应一致。 我们还发现，急性KD CAA中的巨噬细胞产生基质金属蛋白酶-9，其可以通过破坏细胞外基质而促进CAA的形成。我们假设在急性KD期间，巨噬细胞吞噬并被KD试剂激活和/或产生导致发病的蛋白质。 在该提案中，我们提供了初步数据，表明我们从急性KD动脉组织中流行的伊加基因序列产生的合成KD抗体与急性KD组织中巨噬细胞表达的抗原结合。 其他初步数据表明，在急性KD CAA的巨噬细胞浸润区域正在进行广泛的血管生成。 总的来说，这些数据表明巨噬细胞在KD发病机制中的重要作用。 我们将1）确定巨噬细胞分泌的血管生成介质的不平衡是否有助于KD血管病变，2）产生合成抗体并确定它们是否识别KD组织中的抗原，以及3）鉴定与KD合成抗体反应的抗原。 这些研究将深入了解巨噬细胞在KD发病机制中的作用，将确定急性KD中重要的抗原-抗体相互作用，并可能改善这种潜在破坏性儿童疾病的诊断和治疗。

DESCRIPTION (provided by applicant): Kawasaki Disease (KD) is an increasingly recognized, potentially fatal acute vasculitis of young children that may lead to coronary artery aneurysm (CAA) formation. The goal of my research is to understand the pathogenesis of KD. During the past 3 years, we showed that there is a marked infiltration of the upper respiratory tract and CAA by IgA plasma cells in acute KD, strongly suggesting a respiratory portal of entry of the KD agent. We demonstrated that the IgA response in the KD arterial wall is oligoclonal, and thus antigen-driven. We found that CD8 T lymphocytes and macrophages infiltrate CAA in acute KD, consistent with an immune response to an intracellular pathogen such as a virus. We also showed that macrophages in acute KD CAA produce matrix metalloproteinase-9, which can contribute to CAA formation by disrupting extracellular matrix. We hypothesize that during acute KD, macrophages engulf and are activated by the KD agent and/or produce proteins that result in pathogenesis. In this proposal, we provide preliminary data indicating that a synthetic KD antibody, which we generated from a prevalent IgA gene sequence in acute KD arterial tissue, binds to an antigen expressed by macrophages in acute KD tissues. Other preliminary data indicate extensive angiogenesis is ongoing in areas of macrophage infiltration in acute KD CAA. Collectively, these data indicate an important role of macrophages in KD pathogenesis. We will 1) determine whether an imbalance of angiogenic mediators secreted by macrophages contributes to KD vasculopathy, 2) generate synthetic antibodies and determine if they recognize antigens in KD tissues, and 3) identify the antigen reacting with the KD synthetic antibody. These studies will provide insight into the role of macrophages in the pathogenesis of KD, will identify important antigen-antibody interactions in acute KD, and may lead to improved diagnosis and treatment of this potentially devastating childhood illness.