Fig. 10.13 The primary antibody repertoire is diversified by three processes that modify the rearranged immunoglobulin gene. First panel: the primary antibody repertoire is initially composed of IgM-containing variable regions (red) produced by V(D)J recombination and constant regions (blue) from the μ gene segment. The range of reactivity of this primary repertoire can be further modified by somatic hypermutation, by class switch recombination at the immunoglobulin loci, and in some species by gene conversion (not shown). Second panel: somatic hypermutation results in mutations (shown as black lines) being introduced into the heavy-chain and light-chain V regions (red), altering the affinity of the antibody for its antigen. Third panel: in class switch recombination, the initial μ heavy-chain C regions (blue) are replaced by heavy-chain regions of another isotype (shown as yellow), modifying the effector activity of the antibody but not its antigen specificity.
hypermutation, and cells with mutations that improve affinity for antigen are selected.
Somatic hypermutation introduces mutations that change anywhere from one to a few amino acids in the immunoglobulin, producing closely related B-cell clones that differ subtly in specificity and antigen affinity (Fig. 10.13). These mutations in the V genes are initiated by an enzyme called activation-induced cytidine deaminase, or AID, which is expressed only by germinal center B cells. Before describing the enzymatic mechanisms initiated by AID, we first present a general overview of this process in which random mutations can improve antibody affinity.
The immunoglobulin V-region genes accumulate mutations at a rate of about one base pair change per 103 base pairs per cell division, while the rate of mutations in the rest of the cell’s DNA is much lower: around one base pair change per 1010 base pairs per cell division. Somatic hypermutation also affects some DNA flanking the rearranged V gene, but does not generally extend into the C-region exons. Since each V region is encoded by about 360 base pairs and about three out of every four base changes will alter the amino acid encoded, there is about a 50% chance during each B-cell division that a mutation will occur to the receptor.