B careful: Humoral responses and COVID-19 severity

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Science Immunology  04 Dec 2020:
Vol. 5, Issue 54, eabf8870
DOI: 10.1126/sciimmunol.abf8870


Neutralizing antibody responses to SARS-CoV-2, though often of limited longevity, have generally been assumed to be protective against COVID-19 disease.

Prior analyses on thoracic lymph nodes and peripheral blood suggested a dysregulated humoral immune response early in COVID-19, including defective bcl-6+ follicular helper T cell TNF-α production and loss of transitional and follicular B cells in severe disease. The cumulative data from recent publications suggested association of an aberrant extrafollicular (EF) B cell response with COVID-19 disease course. Prior work by Woodruff et al. characterized a unique group of IgD and CD27 double-negative (DN) EF B cells in systemic lupus erythematosus, associating the CXCR5negCD21negCD11c+ (DN2) subset with increased disease activity and poor clinical outcomes.

By applying this knowledge to high-dimensional B cell phenotyping stratified according to clinical COVID-19 disease severity, the authors not only validate previously known immune associations including elevated plasma IL-6 concentration, but also reveal that patients with life-threatening COVID-19 demonstrate significant expansion of peripheral blood DN2 cells, activated naïve B cells, and antibody secreting cells (ASCs). They delineate a CD21negCD11cneg (DN3) B cell population that, when elevated in blood with two other EF populations including DN2 cells, associates with critical illness and high mortality in COVID-19 patients despite early neutralizing antibody responses. Elevated plasma C-reactive protein (CRP) also correlated with COVID-19 disease severity. The cumulative data offer a new perspective on pathogenic B cell responses in COVID-19 and support hypothesis-driven testing of the combined serum and B-lineage immune signature as a biomarker panel to screen for high-risk COVID-19 disease during infection and therapeutic interventions. These studies also provide insights into B cell effector pathways to consider in targeted immune therapies and COVID vaccine development.

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