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

• 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
• 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

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COVID-19的大流行被认为对儿童的影响有限，因此一种严重的多炎症 特别影响儿童的综合征（MIS-C）最近出现了。 MIS-C表型包括 典型/非典型川崎疾病（KD）和有毒休克综合征的结合。与19岁的成年人不同， 但是，大多数儿童都表现出胃肠道症状，但没有出现明显的呼吸介入。 如KD所示，一部分患者会发展出冠状动脉动脉瘤。重要的是，虽然很大 报道了成人对SARS-COV-2的反应的研究，有关免疫反应的知识差距 儿童中的SARS-COV-2仍然不成比例。 我们假设一种综合高分辨率的全面系统分析方法 需要免疫学分析以有效识别有助于的最相关的免疫因素 covid-19相关-MIS-C的发病机理，并确定其随后的结果。为此 原因，我们组建了一个经验丰富的多学科团队来研究COVID-19相关的MIS-C。我们将 利用小儿临床研究中的专业知识，以及高分辨率多词的应用 分析工具以表征MIS-C基础的免疫系统失调。为此，我们将 检查纵向样品，并将结果与​​匹配的健康对照的结果与和和 没有以前接触SARS-COV-2。这项研究提供了一个独特的机会来仔细剖析 免疫系统不同组成部分的贡献对最严重的SARS-COV形式 2个儿童回答。 我们的具体目的是1）定义与MIS-C和COS相关的临床变量和风险因素 建立一个纵向样品生物座席，2）确定与先天免疫参数 SARS-COV-2感染相关的MIS-C和3）表征特定的抗SARS-COV2自适应免疫 MIS-C患者的反应。 该建议将解决儿童MIS-C发病机理的主要知识差距。完成项目 目标将更好地理解失调的免疫途径和新颖的识别 这种新综合征的生物标志物和治疗靶标。