B Cells Can Switch the Isotype of Immunoglobulin They Make
In the immunoglobulin heavy-chain locus, the exons that encode the µ chain lie immediately downstream of the rearranged VDJ exon (Figure 23-20, top). They are followed by exons that specify the δ chain. Transcription of a newly rearranged immunoglobulin heavy-chain locus yields a single primary transcript that includes the µ and δ constant regions. The splicing of this large transcript determines whether a µ chain or a δ chain will be produced. Downstream of the µ and δ exons are the exons that encode all the other heavy-chain isotypes. Upstream of each cluster of exons (with the exception of the δ locus) encoding one of the different isotypes is a repetitive sequence (switch region) that is recombination-prone, presumably because of its repetitive nature. Because each B cell necessarily starts out with surface IgM, recombination involving these sites, if it occurs, results in class switching from IgM to one of the other isotypes encoded downstream in the array of constant-region genes (see Figure 23-20). The intervening DNA is deleted.
FIGURE 23-20 Class-switch recombination in the immunoglobulin heavy-chain locus. Class-switch recombination involves switch sites, which are repetitive sequences (colored circles) upstream of each of the heavy-chain constant-region genes. Recombination requires activation-induced deaminase (AID) as well as cytokines (e.g., IL-4) produced by certain helper T cells. Recombination eliminates the segment of DNA between the switch site upstream of µ exons and the constant region to which switching occurs. Class switching generates antibody molecules with the same specificity for antigen as that of the IgM-bearing B cell that mounted the original response, but with different heavy-chain constant regions and therefore different effector functions.
In the course of its differentiation, a B cell can switch Ig classes sequentially. Importantly, the light chain is not affected by this process, nor is the rearranged VDJ segment with which the B cell started out on this pathway. Class-switch recombination thus generates antibodies with different constant regions, but identical antigenic specificity because the variable region has not changed. Each immunoglobulin isotype is characterized by its own unique constant region. As discussed previously, these constant regions determine the functional properties of the various isotypes. Class-switch recombination is dependent on the activity of activation-induced deaminase (AID) and on the presence of antigen as well as on helper T cells. Somatic hypermutation and class-switch recombination occur concurrently, and their combined effect allows fine-tuning of the adaptive immune response with respect to the affinity of the antibodies produced and the effector functions employed.