classswitching

Class switch recombination (CSR) is a process in B lymphocytes that changes the antibody heavy-chain constant region from the default IgM (and IgD on naive B cells) to other isotypes such as IgG, IgA, or IgE. This switch alters antibody effector functions without changing antigen specificity, which is determined by the variable region of the heavy chain.

CSR is initiated when B cells receive help from T helper cells and become activated in germinal centers or extrafollicular sites. Transcription of the target constant-region gene (germline transcription) opens the corresponding switch region. Activation-induced cytidine deaminase (AID) then deaminates cytosines within switch regions, creating DNA lesions. The breaks are repaired by non-homologous end joining, resulting in recombination between the donor Sμ region and a downstream acceptor S region (Sγ, Sα, Sε, etc.). The intervening DNA is excised and the VDJ variable region remains linked to a downstream constant region, yielding an antibody isotype with identical antigen specificity but different effector properties. CSR can occur in sequence, allowing successive isotype changes.

Isotype choice is shaped by cytokines and receptor signals. CD40–CD40L interactions from T helper cells are essential for CSR, providing survival and activation signals. Cytokines bias switching toward specific isotypes, for example, IL-4 promotes IgG and IgE responses in various contexts, while transforming growth factor-beta favors IgA production. The process is coordinated with somatic hypermutation, which introduces mutations in the variable region to improve antigen affinity.

CSR has major implications for immune function. Different isotypes engage different Fc receptors and activate complement to tailor the immune response, including mucosal defense with IgA and potent pathogen neutralization with IgG. Defects in CSR or AID lead to immunodeficiencies, such as Hyper-IgM syndrome, and may predispose to infections. Aberrant CSR can contribute to lymphomagenesis via chromosomal translocations involving immunoglobulin heavy-chain loci.