Dual role of plasmablasts as immune regulators or amplifiers in COVID-19

COVID-19 induces a marked plasmablast (PB) expansion, whose functional role remains unclear. We performed B-cell immunophenotyping and multiplex cytokine analysis in a prospective cohort of 50 COVID-19 patients. PB expansion occurred early and correlated with both maximal disease severity and inflammatory markers. A retrospective cohort of 282 steroid-naïve patients was used to validate PB dynamics, model trajectories, and perform transcriptomic profiling. Two PB trajectories emerged: a transient one and a persistent, amplified one, the latter associated with a sixfold increase in 30-day mortality (p < 0.001). In severe cases, PB upregulated purine metabolism genes; in non-severe cases, they expressed interferon and CIITA-mediated MHC-II programs. BAFF levels at day 7 correlated with severity suggesting a role in sustaining PB expansion. PB exhibit functional duality in COVID-19-acting as immune regulators in non-severe cases and as inflammation amplifiers in severe disease. BAFF emerges as a potential therapeutic target in PB-driven immune dysregulation. Trial registration.ClinicalTrials.govNCT04327180 and NCT04341792.