Once bound, AID initiates switch recombination by deaminating some cytosines to uracil in the vicinity of these switch sequences. Excision of these uracils is thought to lead to double-strand breaks in the participating switch regions, which are then joined by a form of nonhomologous end joining (discussed in Chapter 5).
Thus, whereas the primary Ig repertoire in humans (and mice) is generated by V(D)J joining mediated by V(D)J recombinase, the secondary antibody repertoire is generated by somatic hypermutation and class switch recombination, both of which are mediated by AID. Figure 24–31 lists the main mechanisms that we have discussed in this chapter that diversify Igs.
Each B cell clone makes Ig molecules with a unique antigen‑binding site. Initially, the Ig molecules are inserted into the plasma membrane and serve as B cell receptors (BCRs) for antigen. Antigen binding to the BCRs, together with co‑stimulatory signals from helper T cells, activates the B cells to proliferate and differentiate into either memory cells or antibody‑secreting effector cells. The effector cells secrete large amounts of antibodies with the same antigen‑binding site as the BCRs.
A typical Ig molecule is composed of four polypeptide chains—two identical heavy chains and two identical light chains. Parts of both the heavy and light chains form the two identical antigen‑binding sites. There are multiple classes of Ig (IgA, IgD, IgE, IgG, and IgM), each with a distinctive heavy chain, which determines the
Figure 24–30 An example of the DNA rearrangement that occurs in class switch recombination. A B cell making IgM molecules with a V region encoded by a particular assembled VDJ DNA sequence is stimulated to switch to making IgA molecules with the same V region. In the process, it deletes the DNA between the VDJ sequence and the cα-coding sequence. Specific DNA sequences (switch sequences) located upstream of each ch-coding sequence (except cδ, as B cells don't switch from cμ to cδ) can recombine with one another, with the deletion of the intervening DNA, as shown here. As discussed in the text, the recombination process depends on AID, the same enzyme that is involved in somatic hypermutation. When switching from IgM to IgG or Ige, the c-region coding sequences downstream of cγ or cδ, which remain after the DNA deletion, are removed during rNA splicing.
combinatorial joining of gene segments combinatorial joining of L and H chains
Figure 24–31 The main mechanisms of Ig diversification in mice and humans.
Those shaded in green occur during B cell development in the bone marrow, whereas the two mechanisms shaded in red occur when B cells are stimulated by foreign antigen and helper T cells in germinal centers in peripheral lymphoid organs, either late in a primary response or in a secondary response.
biological properties of the Ig class. Each light and heavy chain is composed of a number of Ig domains. The amino acid sequence variation in the variable domains of both light and heavy chains is concentrated in several small hypervariable regions, which form loops at one end of these domains to produce the antigen‑binding site.
Igs are encoded by loci on three different chromosomes, each of which is responsible for producing a different polypeptide chain—a κ light chain, a λ light chain, or a heavy chain. Each locus contains separate gene segments that encode different parts of the variable region of the particular Ig chain. Each light‑chain locus contains one or more constant‑ (C‑) region coding sequences and sets of variable (V) and joining (J) gene segments. The heavy‑chain locus contains sets of C‑region coding sequences and sets of  V, diversity (D), and J gene segments.