Minding the gap: The impact of B‐cell tolerance on the microbial antibody repertoire

: B lymphocytes must respond to vast numbers of foreign antigens, including those of microbial pathogens. To do so, developing B cells use combinatorial joining of V-, D-, and J-gene segments to generate an extraordinarily diverse repertoire of B-cell antigen receptors (BCRs). Unsurprisingly, a large fraction of this initial BCR repertoire reacts to self-antigens, and these "forbidden" B cells are culled by immunological tolerance from mature B-cell populations. While culling of autoreactive BCRs mitigates the risk of autoimmunity, it also opens gaps in the BCR repertoire, which are exploited by pathogens that mimic the forbidden self-epitopes. Consequently, immunological tolerance, necessary for averting autoimmune disease, also acts to limit effective microbial immunity. In this brief review, we recount the evidence for the linkage of tolerance and impaired microbial immunity, consider the implications of this linkage for vaccine development, and discuss modulating tolerance as a potential strategy for strengthening humoral immune responses.