Two types of DNA rearrangements in immunoglobulin genes

During the differentiation of antibody-producing cells, two types of DNA rearrangements occur. First, the V(L) and J(L) or the V(H) and J(H) gene segments are joined to generate a contiguous coding sequence for the entire light-chain or heavy-chain variable region. We have designated this type of DNA rearrangement V(D)J joining. A second type of DNA rearrangement, C(H) or class switching, occurs in the heavy-chain gene family. In the mouse, this gene family contains at least eight closely linked heavy-chain constant-region genes (C(μ), C(δ), C(γ1), C(γ3), C(γ2b), C(γ2a), C(α), and C(ε). During the development of a B cell, IgM (Cμ) is initially expressed; later, the B cell or its progeny may switch to expression of any of the other classes or subclasses of immunoglobulins. In molecular terms, these distinct stages of B-cell differentiation are mediated by the two types of DNA rearrangements discussed above. The V(D)J joining generates the functional V(H) gene 5' of the Cμ gene, leading to the synthesis of μ chains and IgM molecules. Later the B cell or its clonal progeny can undergo a class-switch DNA rearrangement in which another heavy-chain constant-region gene replaces the Cμ gene adjacent to the same functional V(H) gene. For example, a transcript can now be made that contains the V(H) and Cμ genes, leading to the synthesis of α chains and IgA molecules. In the functional gene, each domain of the immunoglobulin chain (the variable region and one or more constant-region domains) is encoded by a separate exon, so that RNA splicing is required to generate the final V + C immunoglobulin mRNA from transcripts of the rearranged gene.