Redemption of autoreactive B cells

Autoreactive antibodies can be pathogenic in a myriad of diseases. Consequently, the adaptive immune system actively removes or inactivates self-reactive B cells, while promoting the survival of B cells that recognize exogenous antigens, including microbial pathogens (1, 2). These physiological mechanisms of immune tolerance are often defective in autoimmune diseases (3, 4), and much effort is currently being expended learning how to mitigate autoreactive B-cell responses in the setting of autoimmune diseases. An unwelcome consequence of tolerizing selection is reduction in the potential diversity of the primary B-cell repertoire that limits the availability of B cells capable of generating protective responses against pathogens (5). An example of immunological censoring by tolerance is apparent in the protective antibodies elicited by HIV-1 infection, called broadly reactive neutralizing antibodies (bnAbs) (6). The majority of bnAbs are either polyreactive (reactive with many unrelated molecules), autoreactive (reactive with one specific self-antigen), or both (7), and in some cases, reactivity with host antigens is tightly linked to HIV-1–neutralizing activity (8, 9). Thus, in contrast to autoimmunity where the goal is to reduce autoreactive B-cell responses, vaccinologists are trying to activate and expand disfavored bnAb B-cell clonal lineages subject to control by immune tolerance (6–13). In PNAS, Sabouri et al. (14) outline a surprising pathway for the utilization or “redemption” of autoreactive anergic B cells. The authors demonstrate that B cells that recognize both foreign and self-antigens can be activated by immunization and recruited into germinal centers (GC) where hypermutation of the B-cell antigen receptor (BCR) can reduce self-reactivity while maintaining the capacity of the redeemed B cells to recognize an exogenous antigen (14). This …