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

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, 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.

From online data collection to identification of disease mechanisms: The IL-1ß, IL-6 and TNF-α cytokine triad is associated with post-acute sequelae of COVID-19 in a digital research cohort

“…We performed autoantibody screens and correlated autoantibody positivity with clinical symptoms. We included rheumatoid factor, antinuclear antibodies and anti-phospholipid antibodies in our assessment[20]. While the control cases without prior COVID-19 infection did not show positivity for any of the tested specificities, the percentage of participants with positive test results for one or more autoantibodies amounted to 20% of prior COVID-19 cases (Figure 3A and B).…”

“…A striking feature of COVID-19 are systemic manifestations of autoimmunity mirrored by elevated levels of different autoantibody classes [20][21][22][23][24][25][26], a feature that is shared by many viral infections including SARS-CoV and Mers [45,46]. While autoantibody positivity correlates with COVID-19 severity, the potential pathophysiological relevance for PASC is unclear.…”

“…Another potential biological correlate of PASC may be autoimmune tissue damage. Already in the early phases of the pandemic, it became obvious that the SARS-CoV-2 virus shifts adaptive immunity towards autoreactivity [19,20]. There is now a large body of evidence that diverse autoantibody classes are produced in acute COVID-19 as well as post-COVID-19 multisystem inflammatory syndrome in children [20][21][22][23][24][25][26][27].…”

“…Already in the early phases of the pandemic, it became obvious that the SARS-CoV-2 virus shifts adaptive immunity towards autoreactivity [19,20]. There is now a large body of evidence that diverse autoantibody classes are produced in acute COVID-19 as well as post-COVID-19 multisystem inflammatory syndrome in children [20][21][22][23][24][25][26][27]. Moreover, many reports suggest that patients may experience de novo or worsening of preexisting autoimmune conditions such as autoimmune cytopenias, Guillain-Barré syndrome or systemic lupus erythematodes [28,29].…”

Rapid hypermutation B cell trajectory recruits previously primed B cells upon third SARS-CoV-2 mRNA vaccination

“…Interestingly, even B cells with low or absent IGHV affinity maturation can generate antibodies that specifically recognize and neutralize the ancestral strain of SARS-CoV-2 (6,11,(13)(14)(15)). Yet, a continued evolution of the humoral response appears to take place over at least six months after infectioneven without re-infectionas demonstrated by sustained acquisition of IGHV somatic hypermutation despite waning antibody titers (16)(17)(18)(19)(20)(21). There is emerging evidence that these rather mitigated B cell maturation dynamics may also be characteristic for vaccine-induced anti-SARS-CoV-2 immune responses (22,23).…”