The generation of antibody diversity through somatic hypermutation and class switch recombination

Antibody-mediated immunity is critical to the resistance of vertebrate species to pathogenic organisms. Although low-affinity immunoglobin (Ig) M antibodies circulate in the blood prior to encountering pathogens, high-affinity IgG and IgA antibodies are required to inactivate toxins, neutralize viruses, and promote the clearance of microorganisms. Individuals, such as those with hyper-IgM syndrome (HIGM), who lack the ability to make such high-affinity IgG and IgA antibodies, are unable to combat bacterial and viral infections and usually die at a young age (Revy et al. 2000; Imai et al. 2003). Prior to exposure to antigen, the initial generation of a diverse antibody repertoire is achieved early in B-lymphocyte development by the successful rearrangement of the V, D, and J gene segments to produce B cells, each of which makes a unique Ig heavy- and light-chain variable (V) region (Fig. 1A; Tonegawa 1983). These V regions encode the antigen binding sites of antibodies that are then expressed on the surface of a B lymphocyte and its clonal progeny. Following specific antigen recognition by its cognate B lymphocyte and costimulation by helper T lymphocytes, the B lymphocyte enters the germinal center of peripheral lymphoid organs to become a centroblast B cell. There, a second wave of antibody diversification occurs through somatic hypermutation (SHM) and/or gene conversion (GC) of the V region to generate high-affinity antigen binding sites (Fig. 1B; MacLennan 1994). SHM is the predominant mechanism in mice and humans, whereas GC occurs in chickens and some other species (Weill and Reynaud 1996). In the same centroblast B cell, the heavy-chain V regions encoding the antigen binding sites are rearranged down the chromosome through class switch recombination (CSR) so that they can be expressed with one of the constant (C) region genes to carry out many different effector functions and be …