Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

Wide heterogeneity of disease course ranging from asymptomatic spread to respiratory failure and death has become a hallmark of the SARS-CoV-2 pandemic. While this clinical spectrum is well documented, its immunologic underpinnings are less clear. We have therefore, initiated studies of the B cell responses as they would participate in both early effector responses and in the initiation of memory formation. In terms of effector responses, we were particularly interested in the engagement and clinical correlates of the extra-follicular pathway (EF), we recently described in flaring SLE. In this systemic autoimmune disease, the EF pathway is initiated by newly activated naive B cell (aN) leading to large expansion of autoantibody-producing antibody-secreting cells through the generation of an epigenetically primed B cell precursor which are double negative (DN) for naive (IgD) and memory markers (CD27) and lacking expression of CXCR5 and CD21 (DN2). These highly activated D2 cells are also distinguished by high expression of CD11c and T-bet and are TLR7-driven. Both, TLR7-stimulation which is triggered by ssRNA and the central role played by their murine counterparts (typically characterized as Age-Associated B cells), in viral clearance, strongly supported the hypothesis that DN2 cells and the global EF pathway could be prominently engaged in COVID-19 patients. Also of note, EF B cell activation is particularly prominent in SLE patients of African-American ancestry, a population disproportionately represented in severe COVID-19. In this study we find that critically-ill patients with COVID-19 robustly upregulate constituents of the extrafollicular pathway, produce enormous numbers of antibody secreting cells, and lose unique transitional B cell populations that correlate with positive prognosis. This patient cluster associates tightly with biomarkers of poor outcomes and exhibits high rates of mortality. Thus, this B cell phenotype might serve as an immunological marker of severe COVID infection at early stages and could therefore identify a patient subset likely to benefit from targeted immunomodulatory therapy aimed at alleviating disease burden.