Affinity Maturation Somatic Mutation of Ig Genes and Selection of High Affinity B Cells

Affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen as a T-dependent humoral response progresses and is the result of somatic mutation of Ig genes followed by selective survival of the B cells producing the antibodies with the highest affinities. The process of affinity maturation generates antibodies with an increasing capacity to bind antigens and thus to more efficiently bind to, neutralize, and eliminate microbes (Fig. 11-17). Helper T cells and CD40:CD40L interactions are required for somatic mutation to be initiated, and as a result, affinity maturation is observed only in antibody responses to T-dependent protein antigens. Some somatic mutation occurs in B cells in extrafollicular foci, but extensive somatic mutation occurs in germinal centers. As discussed earlier, the need for CD40 reflects the ability of this receptor to induce AID as well as extensive proliferation in B cells.

In proliferating germinal center B cells in the dark zone, Ig Vgenes undergo point mutations at an extremely high rate. This rate is estimated to be 1 in 103 V gene base pairs per cell division, which is about a thousand times higher than the spontaneous rate of mutation in other mammalian genes. (For this reason, mutation in Ig V genes is also called hypermutation.) The V genes of expressed heavy and light chains in each B cell contain a total of about 700 nucleotides; this implies that mutations will accumulate in expressed V regions at an average rate of almost one per cell division. Ig V gene mutations continue to occur in the progeny of individual B cells. As a result, any B cell clone can accumulate more and more mutations during its life in the germinal center. It is estimated that as a consequence of somatic mutations, the nucleotide sequences of IgG antibodies derived from one clone of B cells can diverge as much as 5% from the original germline sequence. This usually translates to up to 10 amino acid substitutions. Several features of these mutations are noteworthy. First, the mutations are clustered in the V regions, mostly in the antigen-binding complementarity-determining regions (Fig. 11-18). Second, there are far more mutations in IgG than in IgM antibodies. Third, the presence of mutations correlates with increasing affinities of the antibodies for the antigen that induced the response.

The mechanisms underlying somatic mutation in Ig genes are partially understood. It is clear that the rearranged Ig VDJ exon becomes highly susceptible to mutation, suggesting enhanced susceptibility of this region to DNA-binding factors that identify rearranged V regions for mutation. The enzyme AID, discussed before in the context of isotype switching, plays an essential role in affinity maturation. Its DNA deaminase activity converts C residues to U residues at hotspots for mutation. The U's may be changed to T's when DNA replication occurs, thus generating a common type of C to T mutation, or the U may be excised by uracil N-glycosylase, and the abasic site thus generated is repaired by an error-prone repair process, eventually generating all types of substitutions at each site of AID-induced cytidine deamination. These error-prone repair processes extend mutations to residues beyond the C residues that are targeted by AID.

Repeated stimulation by T cell-dependent protein antigens leads to increasing numbers of mutations in the Ig genes of antigen-specific germinal center B cells. Some of these mutations are likely to be useful because they will generate high-affinity antibodies. However, many of the mutations may result in a decline or even in a loss of antigen binding. Therefore, the next and crucial step

Switch region Coding germline transcript strand

Switch region Coding germline transcript strand

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