Lupus-like extrafollicular B cell responses and autoreactivity are hallmarks of severe COVID-19

Abstract

Abstract In late 2019, the emergence of the coronavirus SARS-CoV-2 resulted in a global pandemic, costing over 2 million lives. A hallmark of the disease resulting from SARS-CoV-2 infection, COVID-19, has been it’s heterogeneity in presentation. To understand the immunological underpinnings of this variability in symptoms, we performed a deep characterization of the B cell responses generated in patients within the NIH-defined mild/moderate or severe/critical categories. Somewhat surprisingly, patients with severe disease had higher neutralizing antibody titers than their mild/moderate counterparts, but showed strong evidence of extrafollicular B cell activation by flow cytometry – previously described in humans primarily in autoimmune disease. Further analysis of the B cell repertoire through single cell VDJ sequencing revealed low (or fully absent) levels of somatic hypermutation in the antibody secreting cell compartment, phenocopying the low selective pressures previously associated with extrafollicular responses. Together, these findings suggested the possible relaxation of peripheral tolerance in severe patients. This was confirmed through clinical autoreactivity testing, revealing more than 70% of the most severe COVID-19 patients, despite no history of autoimmunity, test positive for anti-nuclear antibodies or rheumatoid factor. Altogether, these findings provide the immunological context for an emerging consensus in the literature whereby severe COVID-19 is characterized by robust extrafollicular B cell activation, resulting not only in neutralizing antibody production, but also autoreactive B cell targeting with the potential for direct involvement in severe disease pathology.