SARS-CoV-2 infection relaxes peripheral B cell tolerance

B-ND cells demonstrate phenotypical and functional changes indicative of a loss of anergy with severe SARS-CoV-2 infection, and these changes correlate with increased systemic inflammation and autoreactive antibodies. Together, this data suggests that viral infection relaxes peripheral B cell tolerance. Severe SARS-CoV-2 infection is associated with strong inflammation and autoantibody production against diverse self-antigens, suggesting a system-wide defect in B cell tolerance. B-ND cells are a B cell subset in healthy individuals harboring autoreactive but anergic B lymphocytes. In vitro evidence suggests inflammatory stimuli can breach peripheral B cell tolerance in this subset. We asked whether SARS-CoV-2-associated inflammation impairs B-ND cell peripheral tolerance. To address this, PBMCs and plasma were collected from healthy controls, individuals immunized against SARS-CoV-2, or subjects with convalescent or severe SARS-CoV-2 infection. We demonstrate that B-ND cells from severely infected individuals are significantly activated, display reduced inhibitory receptor expression, and restored BCR signaling, indicative of a breach in anergy during viral infection, supported by increased levels of autoreactive antibodies. The phenotypic and functional B-ND cell alterations significantly correlate with increased inflammation in severe SARS-CoV-2 infection. Thus, autoreactive B-ND cells are released from peripheral tolerance with SARS-CoV-2 infection, likely as a consequence of robust systemic inflammation.