Elucidating the immunology of autoantibody formation and function in COVID-19

阐明 COVID-19 中自身抗体形成和功能的免疫学

• 批准号: 10639707
• 负责人: Eric Meffre
• 金额: $ 75.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639707
• 关键词: 2019-nCoV; Acute; Acute Respiratory Distress Syndrome; Address; Antibodies; Antibody Repertoire; Antigen-Antibody Complex; Antigens; Authorization documentation; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Binding; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; Cell secretion; Clinical; Clinical Data; Communicable Diseases; Connective Tissue; Connective Tissue Diseases; Convalescence; Critical Illness; Defect; Dengue Virus; Development; Disease; Emigrant; Evolution; Fc domain; Follow-Up Studies; Frequencies; Generations; Goals; Hospitalization; IgG autoantibodies; Immune; Immune System Diseases; Immune response; Immunoglobulin G; Immunologics; Immunology; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Intervention; Lung; Mass Spectrum Analysis; Measurement; Methods; Molecular; Natural experiment; Outcome; Pathogenicity; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Pneumonia; Population; Predisposition; Production; Property; Pulmonology; Recontacts; Regulation; Resources; Rheumatology; Role; SARS-CoV-2 infection; Sampling; Sampling Studies; Serum; Severity of illness; Structure; System; Testing; Time; Variant; Viral; Virus Diseases; Work; acute infection; autoreactive B cell; autoreactivity; cohort; coronavirus disease; cytokine; glycosylation; humanized mouse; immunoregulation; multidisciplinary; receptor; severe COVID-19

Project Summary Surprisingly little is known about the regulation of B cell tolerance during infection; thus, the overarching goal of our studies is to characterize autoantibodies in COVID-19, focusing on their inflammatory capacity and abnormal regulation of B cell tolerance during infection. The scale of the COVID-19 pandemic, synchrony between infection and autoimmune manifestations, and mobilization of resources has allowed us to generate large numbers of banked samples paired with well-annotated clinical data - creating a once-in-a-lifetime opportunity to study the mechanisms involved in regulation of B cell tolerance and generation of IgG autoantibodies (AAb) and pro-inflammatory immune complexes (IC). The pathogenic roles of AAb in COVID-19 are now widely recognized with anti-cytokine antibodies targeting type I interferons identified in ~10% of critically ill patients, and rare in those with milder disease. More than half of patients in our COVID-19 cohorts have evidence of at least one AAb; the overwhelming majority of those who are AAb positive during SARS-COV-2 infections have no known cause for autoimmunity. The clinical correlates and immunologic basis of this loss of tolerance and aberrant AAb formation in infection are as yet unexplored. Elucidating the role of Fc glycosylation and impairments in the establishment of B cell tolerance in development of AAbs has not yet been attempted but may lead to a paradigm shift in our understanding of the immune and autoimmune responses to both COVID-19 and viral infection more broadly. Hence, in cohorts totaling >1300 patients with acute COVID-19 infection and >3000 samples, we propose to test the hypothesis that patients with severe infections and poor outcomes have pathogenic IgG AAb that may appear over the course of hospitalization and become part of the antibody repertoire even in convalescence. We will also test whether IgG AAbs in patients with severe COVID-19 have different Fc domain repertoires and glycosylation that favor inflammation. Finally, we postulate that serum AAb in patients with COVID-19 result from the activation of naïve self-reactive clones that escape early B cell tolerance checkpoints. We will determine if naïve B cell selection defects are induced by infection or are likely already present at the time of acute infection. Hence, our work may ultimately inform the role of early immune-modulating interventions not only in COVID-19, but in severe infections and ARDS more broadly, particularly pneumonia in ICU settings.

项目摘要 令人惊讶的是，关于感染过程中B细胞耐受性的调节知之甚少。因此， 我们研究的总体目的是表征Covid-19中的自身抗体，重点是 它们在感染过程中对B细胞耐受性的炎症能力和异常调节。规模 Covid-19的大流行，感染与自身免疫性表现之间的同步 动员资源使我们能够生成大量的银行样本配对 借助良好的临床数据 - 创造了一个千载难逢的机会来研究 涉及调节B细胞耐受性和IgG自身抗体（AAB）的机制 和促炎性免疫复合物（IC）。 AAB在Covid-19中的致病作用现在为 靶向I型I型I类干扰素在〜10％中鉴定出的抗周期代因子抗体广泛认可 重症患者，在米勒病患者中很少见。我们一半以上的患者 COVID-19人群至少有一个AAB的证据。绝大多数的人 在SARS-COV-2感染期间，AAB阳性是自身免疫性的已知原因。这 临床相关性和免疫学基础的耐受性丧失和异常AAB形成 感染还出乎意料。 阐明FC糖基化和损害在B细胞建立中的作用 尚未尝试在AABS开发中的耐受性，但可能导致范式转变 在我们对Covid-19和病毒的免疫和自身免疫反应的理解中 感染更广泛。因此，在总计> 1300例急性共证患者的同类中， 和> 3000个样本，我们建议检验以下假设：严重感染和 不良结果具有致病性IgG AAB，可能会在住院和 即使在康复中也成为抗体库的一部分。我们还将测试IgG是否 严重的COVID-19患者的AABS具有不同的FC结构域库和糖基化的AAB。 偏爱注射。最后，我们假设Covid-19患者的血清AAB 从逃脱早期B细胞耐受性检查点的幼稚的自反应克隆的激活。 我们将确定幼稚的B细胞选择缺陷是通过感染诱导的还是很可能已经 急性感染时存在。 因此，我们的工作最终可能会为早期免疫调节干预措施的作用提供信息 不仅在Covid-19，而且在严重的感染和ARDS中，尤其是肺炎 在ICU设置中。