The Vasculitis of Kawasaki Disease

 描述(申请人提供)：川崎病(KD)是一种潜在的致命的幼年儿童脉管炎。虽然发烧、红疹、红晕、结膜注射、四肢改变和腺病的最初症状是自限性的，但我们最近对41例KD患者尸检或手术动脉组织的精液病理学研究显示，亚急性/慢性血管炎在发病后持续数月至数年。在KD的早期病理学研究中没有发现慢性KD血管炎，患有持续性冠状动脉动脉瘤的儿童在急性发热期后不接受额外的免疫调节治疗。我们假设长期的免疫激活与KD患者的持续性冠脉炎有关，在KD患儿的血清中可以检测到免疫激活的标志物。在初步研究中，我们通过对7例KD持续性动脉瘤患者(发病后6个月至6年)和7名儿童对照组的冠状动脉组织进行实时RT-PCR分析，证实了20多个免疫反应基因的上调。在单独的初步研究中，我们对8个KD和7个儿童控制的冠状动脉(发病后2.5周至5个月)进行了转录组分析，发现了1057个异常基因(Q-Value；0.05和&gt；1.5倍变化)。这些异常表达的基因包括~50个免疫反应基因，这些基因在KD血管组织中表达上调，编码细胞外蛋白，是慢性KD血管炎的候选血清标志物。在随后的一项先导性研究中，我们检测了6名患有持续性(发病3-8年)冠状动脉动脉瘤的KD儿童和6名儿童对照组的血清中这50种蛋白中的15种的水平，并确定了持续性KD血管炎的5个候选血清标记物。在这一探索性建议中，我们将：1)确定慢性KD血管炎组织中调控失调的分子途径；2)确定慢性KD血管炎的血清免疫生物标志物。这些研究的结果将为慢性KD血管炎的分子免疫发病机制提供重要的见解，并使一组慢性KD血管炎的血清生物标志物的开发能够在更大的多中心患者队列中进行测试。这样的非侵入性标记物可以识别和监测患有慢性血管炎的KD患者，以便参与未来的多中心免疫调节治疗合作试验，以降低这种严重的儿童疾病的发病率和死亡率。

 DESCRIPTION (provided by applicant): Kawasaki Disease (KD) is a potentially fatal vasculitis of young childhood. Although the initial presenting symptoms of fever, exanthem, enanthem, conjunctival injection, extremity changes, and adenopathy are self- limiting, our recent seminal pathologic study of autopsy or surgical arterial tissues from 41 KD patients demonstrated subacute/chronic vasculitis persisting for months to years after the onset. Chronic KD vasculitis was not recognized in early pathologic studies of KD, and children with persistent coronary artery aneurysms do not receive additional immunomodulatory therapies after the acute febrile phase of illness. We hypothesize that prolonged immune activation contributes to persistent coronary arteritis in KD patients, and that markers of immune activation can be detected in the sera of KD children with persistent coronary artery aneurysms. In preliminary studies, we demonstrated upregulation of more than 20 immune response genes by real-time RT- PCR analyses of coronary artery tissues from 7 KD patients with persistent aneurysms (>6 months to years after the onset) and 7 childhood controls. In separate preliminary studies, we performed transcriptome analysis of 8 KD and 7 childhood control coronary arteries (2.5 weeks to 5 months after the onset) and identified 1057 dysregulated genes (q-value <0.05 and >1.5 fold change). These dysregulated genes included ~50 immune response genes that are upregulated in KD vascular tissues and encode extracellular proteins that are candidate serum biomarkers of chronic KD vasculitis. In a subsequent pilot study, we tested sera from 6 KD children with persistent (3-8 years after onset) coronary artery aneurysms and from 6 childhood controls for levels of 15 of these 50 proteins and identified 5 candidate serum markers of persistent KD vasculitis. In this exploratory proposal, we will: 1) Identify molecular pathways dysregulated in chronic KD vasculitis tissues, and 2) Identify serum immune biomarkers of chronic KD vasculitis. The results of these studies will provide important insights into the molecular immunopathogenesis of chronic KD vasculitis, and enable development of a panel of serum biomarkers of chronic KD vasculitis that can be tested in larger multicenter patient cohorts. Such non-invasive markers could enable identification and monitoring of KD patients with chronic vasculitis for participation in future multicenter collaborative trials of immunomodulatory therapies, to reduce morbidity and mortality from this serious childhood illness.