Beyond the Classical View: Early Emergence of Class Switch Recombination-Associated Molecular Features During B-Cell Development in the Bone Marrow

Class switch recombination (CSR) is a fundamental mechanism of humoral immunity that enables activated B lymphocytes to switch from the expression of IgM to other immunoglobulin isotypes, such as IgG, IgA, or IgE, thereby changing the effector functions while preserving antigen specificity. Traditionally, CSR has been considered a late event in B-cell differentiation, occurring predominantly in germinal centers following antigen encounter and activation-induced cytidine deaminase (AID) expression. In this classical model, B-cell development in the bone marrow is largely separated from antigen-dependent antibody diversification in peripheral lymphoid organs. However, transcriptomic, epigenomic, and functional studies suggest that several molecular components and regulatory features associated with CSR may already emerge during early stages of B-cell ontogeny. Evidence from mouse models and molecular studies indicates that immature and transitional B cells can express low levels of AID, while transcriptional and regulatory features linked to CSR may already be established before antigen-driven B-cell activation. In this review, we first summarize the classical process of CSR, including the molecular events and requirements necessary for its activation in mature B cells. We then discuss evidence indicating that components and regulatory features associated with CSR can emerge during early B-cell development. Furthermore, we examine how transcriptional regulation and enhancer activity within the IgH locus may contribute to the establishment of these features throughout ontogeny. Finally, we discuss the potential biological implications of early CSR-associated molecular activity for immune repertoire formation, central tolerance, genomic integrity, and B-cell malignancies.