The Pathogenesis of Kawasaki Disease

描述(申请人提供)：川崎病(KD)是一种原因不明的传染病，难以诊断和治疗，可导致终生心脏病或死于先前健康的儿童的冠状动脉(CA)动脉瘤。我们的长期研究目标是确定KD的发病机制，以便开发诊断试验并设计基于分子发病机制的改进治疗方法。KD动脉病的一种范式认为KD是一种持续2-3个月的自限性急性脉管炎，KD的动脉闭塞是不活跃的、愈合的“疤痕”的结果。我们最近对41例KD患者的冠状动脉病变进行了广泛的光镜和电子显微镜病理学研究，这对这一模型提出了重大挑战。我们发现KD动脉病有3个相互关联的病理过程：坏死性大动脉炎(NA)、亚急性/慢性血管炎(SA/C)和腔内肌纤维母细胞增殖(LMP)。NA是唯一一个自我限制的过程，在发热开始后2周内完成。SA/C和LMP在前2周开始，但可持续数年。LMP是一种中层平滑肌细胞来源的肌成纤维细胞的增殖过程，可导致进行性动脉狭窄，并可能代表创面的异常愈合。我们的具体目标提出了KD研究的范式转变，这对KD患者具有重要的临床意义。识别KD动脉病中调节失调的分子通路可以导致靶向治疗而不是经验性治疗。患有慢性KD动脉病的儿童可能会有持续性的CA疾病，甚至随着时间的推移而恶化。虽然先前的范例表明他们的脉管炎在发病后2个月内消失，但我们发现SA/C持续存在，识别他们免疫反应失调的分子基础可能会导致一种新的治疗方法。LMP是一种活跃的增殖过程，而不是“瘢痕”，这一发现促使人们有必要了解其发病机制，并开发治疗方法来预防或减少这种严重的KD并发症。以前对KD的生物标志物研究主要集中在炎症分子上，但心血管应激标志物在鉴别诊断中可能会更好地区分KD患者和患有发热性疾病的儿童。在这项研究中，我们将：1)确认急性KD动脉病的分子发病机制；2)确定慢性KD动脉病免疫失调的分子发病机制；3)确定与发热对照组儿童相比，有CA扩张的KD儿童血浆中心血管损伤/应激诱导的分子水平升高。这些研究的结果将为KD动脉病的分子发病机制提供洞察力，并确定新的诊断工具和治疗靶点。

DESCRIPTION (provided by applicant): Kawasaki Disease (KD) is an infectious disease of unknown cause that can be difficult to diagnose and treat and can lead to lifelong heart disease or death from coronary artery (CA) aneurysms in previously healthy children. Our long-term research goal is to identify the pathogenesis of KD, so that a diagnostic test can be developed and improved therapies based on the molecular pathogenesis be designed. A paradigm of KD arteriopathy has held that KD is a self-limited acute vasculitis lasting 2-3 months after onset, and that arterial occlusion in KD was the result of inactive, healed "scar". We recently performed an extensive light and electron microscopic pathologic study of coronary arteriopathy in 41 KD cases that significantly challenges this model. We identified 3 linked pathologic processes in KD arteriopathy: necrotizing arteritis (NA), subacute/chronic vasculitis (SA/C), and luminal myofibroblastic proliferation (LMP). NA was the only self-limited process and was complete by 2 weeks after fever onset. SA/C and LMP began in the first 2 weeks but could persist for years. LMP is a medial smooth muscle cell-derived myofibroblastic proliferative process that can lead to progressive arterial stenosis, and may represent aberrant wound healing. Our specific aims propose paradigm shifts for KD research that have significant clinical implications for KD patients. Identification of dysregulated molecular pathways in KD arteriopathy can lead to target-directed rather than empiric therapies. Children with chronic KD arteriopathy can have persistent or even worsening CA disease over time. While the prior paradigm indicated that their vasculitis resolved at ~2 months after onset, we showed persistence of SA/C, and identifying the molecular basis of their dysregulated immune response could result in a new approach to treatment. The discovery that LMP is an active proliferative process instead of "scar" leads to the need to understand its pathogenesis and develop therapies to prevent or reduce this serious KD complication. Previous biomarker studies of KD have focused primarily on inflammatory molecules, but markers of cardiovascular stress would likely better distinguish KD patients from children with febrile illnesses in the differential diagnosis. In this proposal, we will: 1) identiy the molecular pathogenesis of acute KD arteriopathy; 2) determine the molecular pathogenesis of immune dysregulation in chronic KD arteriopathy, and 3) identify cardiovascular damage/stress induced molecules that are elevated in the plasma of KD children with CA dilation compared with febrile control children. The results of these studies will provide insights into the molecula pathogenesis of KD arteriopathy and identify new diagnostic tools and therapeutic targets.