LAUSR

Objectives The role of B cells in COVID‐19, beyond the production of specific antibodies against SARS-CoV-2, is still not well understood. Here, we describe the novel landscape of circulating double-negative (DN) CD27 − IgD − B cells in COVID‐19 patients, representing a group of atypical and neglected subpopulations of this cell lineage. Methods Using multiparametric flow cytometry, we determined DN B cell subset amounts from 91 COVID-19 patients, correlated those with cytokines, clinical and laboratory parameters, and segregated them by principal components analysis. Results We detected significant increments in the DN2 and DN3 B cell subsets, while we found a relevant decrease in the DN1 B cell subpopulation, according to disease severity and patient outcomes. These DN cell numbers also appeared to correlate with pro- or anti-inflammatory signatures, respectively, and contributed to the segregation of the patients into disease severity groups. Conclusion This study provides insights into DN B cell subsets’ potential role in immune responses against SARS‐CoV‐2, particularly linked to the severity of COVID‐19.