Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity

导致人类系统性自身免疫的免疫细胞和分泌途径

基本信息

批准号：
10209399
负责人：
Maria Virginia Pascual
金额：
$ 241.93万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-25 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10209399
关键词：
20 year old 2019-nCoV Address Adult Adult Respiratory Distress Syndrome Affect Aneurysm Antibodies B-Lymphocytes Biological Biological Assay Blood COVID-19 COVID-19 pandemic Cells Child Childhood China Clinical Clinical Data Clinical Research Complement Coronary artery Data Diagnosis Disease Disease Progression Exanthema Exposure to Feces Fever Goals Human Immune Immune response Immune system Immunologic Factors Immunology procedure Immunophenotyping Immunosuppression In Vitro Infection Inflammatory Knowledge Laboratories Mucocutaneous Lymph Node Syndrome Myocardial dysfunction Myocarditis Natural Immunity Outcome Pathogenesis Pathway interactions Patients Phenotype Play Pneumonia Proteome Reporting Resolution Resources Respiratory System Risk Factors Role Sampling Shock Siblings Swab Symptoms Syndrome Systemic disease Systems Analysis T cell response Technology Time Toxic Shock Syndrome Urine Viral Viral Load result Virus adaptive immune response age group age related analytical tool biobank body system epigenome experience expression cloning gastrointestinal symptom high throughput technology immune activation insight minority children multidisciplinary multiple omics new therapeutic target novel marker pandemic disease patient subsets pediatric patients respiratory response systemic autoimmunity transcriptome treatment response

项目摘要

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.

抽象的由于人们认为 COVID-19 大流行对儿童的影响有限，因此严重的多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 COVID-19 的成年人不同，然而，大多数儿童表现出胃肠道症状，但并未出现明显的呼吸道受累。一部分患者会出现冠状动脉瘤，如川崎病中所见。重要的是，虽然大量正在报道成人对 SARS-CoV-2 反应的研究，但关于对 SARS-CoV-2 的免疫反应的知识差距儿童中的 SARS-CoV-2 数量仍然不成比例地大。我们假设综合系统分析方法结合了高分辨率需要免疫测定来有效地识别最相关的免疫因素 COVID-19 相关 MIS-C 的发病机制并确定其后续结果。对于这些因此，我们组建了一支经验丰富的多学科团队来研究与 COVID-19 相关的 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和分析工具来表征 MIS-C 背后的免疫系统失调。为此，我们将检查纵向样本并将结果与匹配的健康对照的结果进行比较之前没有接触过 SARS-CoV-2。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形式的 SARS-CoV 的贡献 2 儿童反应。我们的具体目标是 1) 定义与 MIS-C 相关的临床变量和风险因素，以及建立纵向样本生物样本库，2) 识别与相关的先天免疫参数 SARS-CoV-2 感染相关的 MIS-C，以及 3) 表征特异性抗 SARS-CoV2 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空白。项目完成情况目标将导致更好地理解失调的免疫途径并识别新的这种新综合征的生物标志物和治疗靶点。