{"doi":"10.3389/fimmu.2023.1294532","title":"Editorial: Does selection against autoreactive B cells limit affinity maturation to pathogens?","abstract":"largely keeps this problem in check by the elimination of strong autoreactivities during central tolerance in B cells, and in thymic development of T cells (Nemazee, 2017;Klein et al., 2019). In B-cells, this pruning of autoreactive specificities is accomplished through a variety of mechanisms including deletion of autoreactive cells, inactivation of the cell responsiveness to activation (anergy), and swapping of the light chain (Receptor Editing) (Nemazee, 2017). Finally, by requiring multiple \"danger\" signals to initiate an immune response, the immune system is able to \"tolerate\" low affinity self-reactive cells whose deletion may lead to significant holes in the lymphocytic repertoire. These danger signals include the role of toll receptors that interact with pathogen debris during an infection to amplify activation signals (Miyake, 2007). Thus, through a combination of somatic diversity-generating mechanisms, and checkpoints to prune autoreactive specificities, the vertebrate adaptive immune system has managed to strike a balance that yields an efficacious yet tolerant adaptive response against a sea of potential pathogens.antigens through somatic hypermutation (SHM). This process alters B cell receptors specificities by introduction of point mutations throughout the variable regions of the heavy and light chains (Wagner and Neuberger, 1996;Diaz and Casali, 2002). SHM is coordinated with positive selection for increased affinity of B cell receptors in transient structures known as germinal centers (GC) that develop in secondary lymphoid organs during an immune response (Berek et al., 1991;Gatto and Brink, 2012). SHM is another opportunity for the generation of not just higher affinity receptors to foreign antigen but also of autoreactive B cell receptors that need to be purged from the memory B cell compartment. Because of the multitude of tolerance checkpoints to eliminate autoreactivities generated either during V(D)J recombination or during SHM in B cells, the existence of repertoire gaps or \"holes\" that inhibit immune responses to certain pathogens is very likely. Similarly, many pathogens exploit these repertoire holes through molecular mimicry, thus avoiding detection by adaptive immune cells (Rojas et al., 2018). The notion that B cell receptors can mutate away from autoreactivity towards high affinity to foreign pathogens was initially proposed by Jerne (1971), and later by Diaz and Klinman (2000) but experimental evidence is needed. The focus of this issue is to explore the extent by which autoreactivity and tolerance mechanism may prevent effective B cells responses in GC's to important pathogens.An insightful exploration of this topic is provided by Young et al. In their review, multiple studies are summarized, including their own, that demonstrate this conflict is in play in GC's and the outcome depends on whether self-reactivity and increased affinity can be decoupled allowing high affinity receptors to be \"redeemed\" and participate in the immune response. Furthermore, they describe evidence that when this decoupling is not achievable, the outcome of these 'unredeemable' B-cell specificities is their elimination from the repertoire (Sabouri et al., 2014). This is a key finding as it demonstrates that such a conflict can effectively inhibit the immune response to some pathogens.By using site directed back mutation of the broadly neutralizing lineage, CH103-106, Li et al. provide experimental evidence that SHM controlling autoreactivity and neutralization can be decoupled, thus opening the door for the possibility that at least some bnAb immune responses directed to the CD4 binding site of HIV-1 are 'redeemable, and could be manipulated by empirical or rational immunogen design to exploit this non-overlap between self and non-self. This is also consistent with the proposal (Verkoczy and Diaz, 2014) that autoreactivity decoupling from neutralization may potentiate more potent broadly neutralizing (bnAb) antibody ","journal":"Frontiers in Immunology","year":2023,"id":412249,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":469215,"name":"Laurent Verkoczy","orcid":"0000-0001-7497-6645","position":1,"is_corresponding":false},{"id":546747,"name":"Marilyn Diaz","orcid":"0000-0002-3046-2746","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-19T01:21:50.261851Z","pmid":"37860006","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}