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

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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.