Maturation trajectories and transcriptional landscape of plasmablasts and autoreactive B cells in COVID-19

Schultheiß, Christoph; Paschold, Lisa; Willscher, Edith; Simnica, Donjete; Wöstemeier, Anna; Muscate, Franziska; Wass, Maxi; Eisenmann, Stephan; Dutzmann, Jochen; Keyßer, Gernot; Gagliani, Nicola; Binder, Mascha

In parasite and viral infections, aberrant B cell responses can suppress germinal center reactions thereby blunting long-lived memory and may provoke immunopathology including autoimmunity. Using COVID-19 as model, we set out to identify serological, cellular and transcriptomic imprints of pathological responses linked to autoreactive B cells at single-cell resolution. We show that excessive plasmablast expansions are prognostically adverse, correlate with auto-antibody production, but do not hinder the formation of neutralizing antibodies. While plasmablasts followed 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 auto-antibodies in COVID-19 and that may persist beyond recovery. Immunomodulatory interventions discouraging such adverse responses may be useful in selected patients to shift the balance from autoreactivity towards long-term memory.