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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结