![]() ![]() B ND cells are mature naive B cells that do not express surface IgM but do express surface IgD, make up roughly 2.5% of total B cells, are enriched in autoreactive specificities ( Duty et al., 2009), and confirmed to be in an anergic state in healthy humans ( Chang et al., 2008 Quách et al., 2011 Smith et al., 2015 Smith et al., 2019 Szodoray et al., 2016). ![]() Importantly, anergic B cells are hyporesponsive to antigen stimulation as evidenced by the lack of activation marker expression, nominal protein phosphorylation downstream of the BCR, reduced calcium signaling, and minimal proliferation or differentiation to antibody secreting cells ( Franks and Cambier, 2018).Īlthough the identification of a naturally occurring anergic B cell subset was first shown in mouse models ( Merrell et al., 2006 Goodnow et al., 1988 Benschop et al., 2001), human peripheral blood has also been demonstrated to harbor an autoreactive anergic B cell population termed “B ND cells” ( Duty et al., 2009). Anergy is thought to be established when autoreactive naive B cells receive signals through the BCR in response to chronic self-antigen exposure in the absence of a secondary signal from T cells or pathogen-associated molecular patterns (PAMPs Cambier et al., 2007 Franks and Cambier, 2018). In healthy individuals, peripheral B cell tolerance holds weakly autoreactive B cells in a functionally inert state termed “anergy,” whereby cells are restrained intrinsically and extrinsically from signaling through their B cell antigen receptor (BCR Yarkoni et al., 2010 Cambier et al., 2007). Nevertheless, nearly 40% of B cells that emigrate from the bone marrow and 20% of mature naive peripheral B cells in healthy humans are weakly autoreactive ( Wardemann et al., 2003). Mechanisms of central B cell tolerance prevent the development of naturally arising high-affinity autoreactive B cells in healthy individuals ( Wardemann et al., 2004 Meffre, 2011 Meffre and O’Connor, 2019 Pelanda and Torres, 2012 Lang et al., 2016 Nemazee, 2017). Thus, autoreactive B ND cells are released from peripheral tolerance with SARS-CoV-2 infection, likely as a consequence of robust systemic inflammation. The phenotypic and functional B ND cell alterations significantly correlate with increased inflammation in 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. 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 asked whether SARS-CoV-2–associated inflammation impairs B ND cell peripheral tolerance. ![]() In vitro evidence suggests inflammatory stimuli can breach peripheral B cell tolerance in this subset. B ND cells are a B cell subset in healthy individuals harboring autoreactive but anergic B lymphocytes. 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. ![]()
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