Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity

摘要 由于新冠肺炎疫情被认为对儿童影响有限，出现了严重的多发性炎症 最近出现了专门影响儿童的综合症(MIS-C)。Mis-C表型包括 典型/非典型川崎病(KD)和中毒性休克综合征的组合。与患有新冠肺炎的成年人不同， 然而，大多数儿童表现出胃肠道症状，但没有出现明显的呼吸道损害。 部分患者发展为冠状动脉动脉瘤，如KD所见。重要的是，虽然一大群人 关于成人对SARS-CoV-2免疫反应的研究正在报道中，关于免疫反应的知识空白 儿童中的SARS-CoV-2病毒仍然不成比例地大。 我们假设一个综合的系统分析方法结合了高分辨率 需要免疫学检测来有效地识别与免疫因素最相关的因素。 目的：探讨新冠肺炎相关管理信息系统C的发病机制，并确定其后续转归。为了这些 原因是，我们已经组建了一个经验丰富的多学科团队来研究新冠肺炎相关的管理信息系统-C。我们会 利用儿科临床研究方面的专业知识以及高分辨率多组学和 分析工具，以表征免疫系统失调的基础上的MIS-C。为此，我们将 检查纵向样本，并将结果与匹配的健康对照组进行比较 没有接触过SARS-CoV-2病毒。这项研究提供了一个独特的机会来仔细剖析 免疫系统的不同组成部分对最严重的SARS-CoV的贡献- 2儿童的反应。 我们的具体目标是：1)明确与管理信息系统相关的临床变量和风险因素； 建立纵向样本生物库，2)确定与以下疾病相关的先天免疫参数 SARS-CoV-2感染相关的MIS-C；3)特异性抗SARS-CoV2获得性免疫的特性 管理信息系统-C患者的反应。 这项建议将解决儿童在MIS-C发病机制方面的主要知识空白。项目竣工 目标将导致更好地理解失调的免疫途径，并识别新的 这一新综合征的生物标志物和治疗靶点。

Abstract As the COVID-19 pandemic was considered to have a limited impact in children, a severe multi-inflammatory syndrome that specifically affects children (MIS-C) has recently emerged. MIS-C phenotypes include a combination of typical/atypical Kawasaki disease (KD) and toxic shock syndrome. Unlike adults with COVID-19, however, most children display gastrointestinal symptoms but fail to present significant respiratory involvement. A subset of patients develops coronary artery aneurysms, as seen in KD. Importantly, while a large body of studies on adult responses to SARS-CoV-2 is being reported, knowledge gaps about the immune responses to SARS-CoV-2 in children remain disproportionally large. We hypothesize that a comprehensive systems analysis approach that incorporates high-resolution immunologic assays is required to efficiently identify the most relevant immune factors that contribute to the pathogenesis of COVID-19 related-MIS-C and to determine its subsequent outcomes. For these reasons, we have assembled an experienced multidisciplinary team to study COVID-19 related MIS-C. We will leverage expertise in pediatric clinical research together with application of high-resolution multi-omics and analytical tools to characterize the immune system dysregulation underlying MIS-C. Towards this end, we will examine longitudinal samples and will compare the results with those of matched healthy controls with and without previous exposure to SARS-CoV-2. This study offers a unique opportunity to carefully dissect the contributions of the different components of the immune system to the most severe form of SARS-CoV- 2 responses in children. Our specific Aims are 1) to define the clinical variables and risk factors associated with MIS-C and establish a longitudinal sample biorepository, 2) to identify innate immunity parameters associated with SARS-CoV-2 infection-related MIS-C, and 3) to characterize specific anti-SARS-CoV2 adaptive immune responses in patients with MIS-C. This proposal will address major knowledge gaps in MIS-C pathogenesis in children. Completion of the project goals will lead to better understanding of dysregulated immune pathways and to the identification of novel biomarkers and therapeutic targets for this new syndrome.