Silencing and activating anergic B cells*

Abstract Despite the existence of central tolerance mechanisms, including clonal deletion and receptor editing to eliminate self‐reactive B cells, moderately self‐reactive cells still survive in the periphery (about 20% of peripheral B cells). These cells normally exist in a functionally silenced state called anergy; thus, anergy has been thought to contribute to tolerance by active‐silencing of potentially dangerous B cells. However, a positive rationale for the existence of these anergic B cells has recently been suggested by discoveries that broadly neutralizing antibodies for HIV and influenza virus possess poly‐ and/or auto‐reactivity. Given the conundrum of generating inherent holes in the immune repertoire, retaining weakly self‐reactive BCRs on anergic B cells could allow these antibodies to serve as an effective defense against pathogens, particularly in the case of pathogens that mimic forbidden self‐epitopes to evade the host immune system. Thus, anergic B cells should be brought into a silenced or activated state, depending on their contexts. Here, we review recent progress in our understanding of how the anergic B cell state is controlled in B cell–intrinsic and B cell–extrinsic ways.