Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity

摘要 由于COVID-19大流行被认为对儿童的影响有限， 特别影响儿童的综合征（MIS-C）最近出现。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COVID-19成年人不同， 然而，大多数儿童表现出胃肠道症状，但没有明显的呼吸系统受累。 一部分患者发生冠状动脉瘤，如KD所示。重要的是，虽然大量的 关于成人对SARS-CoV-2的反应的研究正在报道中，关于免疫反应的知识空白， SARS-CoV-2在儿童中的发病率仍然很高。 我们假设，一个全面的系统分析方法，结合高分辨率 需要免疫学测定来有效地鉴定最相关的免疫因子， COVID-19相关MIS-C的发病机制，并确定其后续结果。为这些 基于上述原因，我们组建了一支经验丰富的多学科团队，研究COVID-19相关MIS-C。我们将 利用儿科临床研究的专业知识以及高分辨率多组学的应用， 分析工具来表征MIS-C的免疫系统失调。为此，我们将 检查纵向样本，并将结果与匹配的健康对照进行比较， 没有接触过SARS冠状病毒2这项研究提供了一个独特的机会，仔细剖析 免疫系统的不同组成部分对最严重形式的SARS-CoV的贡献- 2个孩子的回答 我们的具体目标是：1）确定与MIS-C相关的临床变量和风险因素， 建立纵向样品生物储存库，2）鉴定与以下相关的先天免疫参数： SARS-CoV-2感染相关MIS-C，以及3）表征特异性抗SARS-CoV 2适应性免疫 MIS-C患者的反应。 该提案将解决儿童MIS-C发病机制的主要知识差距。项目建成 这些目标将有助于更好地理解失调的免疫途径，并识别新的免疫途径。 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.