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

Abstract

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.

Tracing Self-Reactive B Cells in Normal Mice

“…We wish to suggest that purging the B cell repertoire of all reactivity is a poor evolutionary strategy. Deletion of all B cells that react with self-epitopes would result in substantial "holes" in the Ab repertoire that could easily be exploited by microbial pathogens (22,(63)(64)(65). In contrast, self-reactive B cell compartments might be beneficial to immune protection by providing BCR repertoires that are normally unavailable in non-self-reactive compartments (55,(65)(66)(67).…”

“…Deletion of all B cells that react with self-epitopes would result in substantial "holes" in the Ab repertoire that could easily be exploited by microbial pathogens (22,(63)(64)(65). In contrast, self-reactive B cell compartments might be beneficial to immune protection by providing BCR repertoires that are normally unavailable in non-self-reactive compartments (55,(65)(66)(67). Although the association between Guillain-Barre syndrome and an infection with Campylobacter jejuni suggests a link between the development of autoimmune diseases and the activation of self-reactive B cells with foreign Ags (68), recent reports by Goodnow (69)(70)(71) and Meffre (72) suggest an alternative fate of self-reactive B cells; in response to cross-reactive, foreign Ags, those self-reactive B cells that increased an affinity to the foreign Ags but reduced an affinity to self-antigens are selected during germinal center responses (71) and enter into memory compartment (69)(70)(71)(72).…”

Generation of High Quality Memory B Cells

“…In regard to the recruitment to the GCs, difficulties are due to; i) a very low affinity of the naïve anti-stem precursors for the native HA antigen; ii) the subsequent problem in receiving sufficient T cell help; iii) the possibly anergic state of these precursor B cells because of poly-reactivity ( 54 ). In regard to problem iii), studies using the model antigen HEL system provided significant insight into how we can awaken such anergic B cells ( 55 , 56 ).…”

Aggregation of protein therapeutics enhances their immunogenicity: causes and mitigation strategies

“…These are mice that express the human ortholog of the protein of interest and therefore establish central tolerance towards it. Both T cells and B cells go through negative selection processes during development to eliminate autoreactive cells that recognize native epitopes; 45,46 a process referred to as central tolerance. For T cells, there is also active maintenance of peripheral tolerance in the form of regulatory T cells (Tregs).…”