Although plasmablasts followed interleukin-4 (IL-4) and BAFF-driven developmental trajectories, were polyclonal, and not enriched in autoreactive B cells, we identified two memory populations (CD80+/ISG15+ and CD11c+/SOX5+/T-bet+/−) with immunogenetic and transcriptional signs of autoreactivity that may be the cellular source of autoantibodies in COVID-19 and that may persist beyond recovery. Here, ISG15 is linked to COVID-19.