Immunoglobulin maturation

In the B cell lineage in the bone marrow, the three immunoglobulin loci are recombined to produce specific variable regions that can recognize specific antigens (reviewed in Christie et al. 2022). A specific heavy chain is produced by recombination among about 57 variable (V) segments, 23 diversity (D) segments, and 6 joining (J) segments, a process called VDJ recombination (reviewed in Mikocziova et al. 2021). The light chains are produced by recombination between 41 (IGK) or 34 (IGL) V segments and 5 J segments, a process called VJ recombination (reviewed in Mikocziova et al. 2021). The term V(D)J recombination refers to recombination at all of the three loci. V(D)J recombination is initiated by DNA cleavage catalyzed by the RAG1:RAG2 recombinase complex at sites flanking the V, D (if present), and J segments followed by repair of double-strand breaks (reviewed in Schatz and Ji 2011, Yu 2022, Christie et al. 2022).

The initial class of the recombined heavy chain is usually IgM, as the M-type C-terminal segment is the most upstream in the array of C-terminal segments at the IGH locus. In germinal centers (reviewed in Victora and Nussenzweig 2022), a process called class switch recombination (CSR) occurs in which the region encoding the variable domain is recombinationally joined to a gene segment encoding the C-terminal constant domain (reviewed in Xu et al. 2012, Matthews et al. 2014, Liu et al. 2024). Activation-induced cytosine deaminase (AICDA, also called AID) deaminates cytidine residues at the Cmu site upstream of the M-type segment and at specific sites, switch regions, flanking the downstream C-terminal segments (reviewed in Matthews et al. 2014, Yu 2022). DNA repair enzymes act on the resulting G:U mismatches to create and resolve double-strand breaks. This produces recombination events that eliminate the M-type segment and in some cases additional segments to generate one of the eight other class types.

The affinity of immunoglobulins for antigens is further enhanced by somatic hypermutation and affinity selection in germinal centers (reviewed in Haberman et al. 2019, Young and Brink 2021, Victora and Nussenzweig 2022). Functionally, higher-affinity B cells are selected based on their ability to capture antigen from follicular dendritic cells (reviewed in Tolar 2017, Papa and Vinuesa 2018, Nakagawa and Calado 2021). The B cell then proteolytically processes the antigen and displays antigen peptides on MHC II complexes to follicular helper T cells, which secrete helper cytokines (principally IL4 and IL21) to maintain the viability of the B cell and cause it to proliferate (reviewed in Crotty et al. 2019). A program of somatic hypermutation is triggered in which AICDA deaminates cytidine residues in the variable regions of immunoglobulin loci (reviewed in Yu 2022). The deamination and subsequent error-prone repair produce mutations (reviewed in Pilzecker and Jacobs 2019, Hao et al. 2024). The mutant immunoglobulins are then re-selected for affinity as described above.