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

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

doi:10.1016/j.isci.2021.103325

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

iScience. 2021 Nov 19;24(11):103325. doi: 10.1016/j.isci.2021.103325. Epub 2021 Oct 23.

Authors

Affiliations

¹ Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany.
² I. Department of Medicine and Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³ Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
⁴ Mid-German Heart Center, Department of Cardiology and Intensive Care Medicine, University Hospital, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
⁵ Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
⁶ Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.

Abstract

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 and correlate with autoantibody production but do not hinder the formation of neutralizing antibodies. 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. Immunomodulatory interventions discouraging such adverse responses may be useful in selected patients to shift the balance from autoreactivity toward long-term memory.

Keywords: Immunology; Transcriptomics; Virology.