The B cell dilemma: Diversity or fidelity?

Abstract

The ability of B lymphocytes to diversify immunoglobulin (Ig) genes is central to the generation of high-affinity, class-switched antibodies and the establishment of effective humoral immunity. This diversification is achieved through three DNA remodeling processes that occur at defined stages of B cell development and maturation: V(D)J recombination, somatic hypermutation (SHM), and class switch recombination (CSR). These reactions all rely on the induction of programmed DNA lesions at Ig genes and their productive resolution by ubiquitous DNA repair pathways. However, such physiological sources of genotoxic stress render B cells vulnerable to genome instability, including mutations and chromosomal translocations that drive malignancies. Therefore, B cells have evolved complex regulatory networks that ensure efficient Ig gene diversification while minimizing the risk of unproductive or deleterious repair outcomes. In this review, we integrate foundational studies with recent mechanistic advances to outline how B cells exploit, coordinate, and constrain DNA repair to balance immune receptor diversification with the preservation of genome integrity.