Diverse Functional Autoantibodies that Underlie Immune Perturbations in COVID-19

Abstract Infection with SARS-CoV-2 results in a broad spectrum of immunological and clinical outcomes for patients with COVID-19. While dysregulated innate immunity has been extensively explored in severe disease, autoantibody responses and their impact on disease trajectories remain uncharted. Here, we enrolled a cohort of 194 SARS-CoV-2 infected patients and uninfected individuals, and employed a high-throughput autoantibody discovery platform, Rapid Extracellular Antigen Profiling (REAP), to assess the prevalence of autoantibodies against 2,770 extracellular and secreted proteins in COVID-19 disease. We found that COVID-19 patients harbor dramatically expanded autoantibody repertoires compared to uninfected controls. We further established that immunomodulatory proteins including cytokines, chemokines, complements, and cell surface receptors, are frequent targets of autoantibodies. Longitudinal analysis revealed the existence of both pre-existing autoantibodies, as well as a broad subset of autoantibodies induced upon SARS-CoV-2 infection. We uncovered distinct mechanisms by which immune-targeting autoantibodies perturb immunological functions, including interference of immunoreceptor signaling, depletion of circulating leukocytes, and modulation of antiviral antibody responses. Concordantly, murine surrogates of these autoantibodies hinder immune activation and exacerbate disease severity in a mouse model of SARS-CoV-2 infection. In summary, through the lens of an unbiased proteome-scale survey for autoantibody targets, these findings implicate humoral immunopathology as an integral aspect of COVID-19 pathogenesis with diverse impacts on immune functionality and clinical outcomes.