The organization of the heavy-chain locus, on chromosome 14, contains separate clusters of VH, DH, and JH gene segments and of CH genes. The heavy-chain locus differs in one important way: instead of a single C region, it contains a series of C regions arrayed one after the other, each of which corresponds to a different immunoglobulin isotype (see Fig. 5.19). While the Cλ locus contains several distinct C regions, these encode similar proteins, which function similarly, whereas the different heavy-chain isotypes are structurally quite distinct and have different functions.
B cells initially express the heavy-chain isotypes μ and δ (see Section 4-1), which is accomplished by alternative mRNA splicing and which leads to the expression of immunoglobulins IgM and IgD, as we shall see in Section 5-14. The expression of other isotypes, such as γ (giving IgG), occurs through DNA rearrangements referred to as class switching, and takes place at a later stage, after a B cell is activated by antigen in an immune response. We describe class switching in Chapter 10.
The human V gene segments can be grouped into families in which each member shares at least 80% DNA sequence identity with all others in the
Fig. 5.4 The number of functional gene segments for the V regions of human heavy and light chains. The numbers shown are derived from exhaustive cloning and sequencing of DNA from one individual and exclude all pseudogenes (mutated and nonfunctional versions of a gene sequence). As a result of genetic polymorphism, the numbers will not be the same for all people.
Fig. 5.5 The germline organization of the immunoglobulin heavyand light-chain loci in the human genome. Depending on the individual, the genetic locus for the λ light chain (chromosome 22) has between 29 and 33 functional Vλ gene segments and four or five pairs of functional Jλ gene segments and Cλ genes. The κ locus (chromosome 2) is organized in a similar way, with about 38 functional Vκ gene segments accompanied by a cluster of five Jκ gene segments but with a single Cκ gene. In approximately 50% of individuals, the entire cluster of Vκ gene segments has undergone an increase by duplication (not shown, for simplicity). The heavy-chain locus (chromosome 14) has about 40 functional VH gene segments and a cluster of around 23 DH segments lying between these VH gene segments and 6 JH gene segments. The heavy-chain locus also contains a large cluster of CH genes (see Fig. 5.19). For simplicity, all V gene segments have been shown in the same chromosomal orientation; only the first CH gene (for Cμ) is shown, without illustrating its separate exons; and all pseudogenes have been omitted. This diagram is not to scale: the total length of the heavy-chain locus is more than 2 megabases (2 million bases), whereas some of the D gene segments are only 6 bases long.
Fig. 5.6 Recombination signal sequences are conserved heptamer and nonamer sequences that flank the gene segments encoding the V, D, and J regions of immunoglobulins.