Source: (Janeway 1999).

Source: (Janeway 1999).

generating mechanisms randomly select one each of the V, D, and J regions during the somatic development of lymphocytes. This is what is transcribed, while the remaining alternative segments in these regions are discarded from the genome and from the cell. The repertoire from which this random selection process chooses provides a huge variety of possible VDJ combinations, and hence different lineages. Table 11-1 shows the number of functional gene segments in human V regions.

The total number of possible different receptors is enormous, and the total number of different lymphocytes circulating in an individual at any time is on the order of 108 (Janeway 1999). The V and C (constant) regions are connected by the short J region and, in the heavy chain, also a D region. It is the C region that determines the class of antibody and how it destroys the pathogen once it is identified and bound, whereas the variable region determines which antigen the antibody or TCR binds. Sequence variation is greater in the V region, and there are many related genes in tandem in the V region, whereas the C region has more standard genelike function. Because the former determine antigen-binding specificity of the coded molecule, this means there is a comparable diversity in the molecules.

This somatic recombination is triggered by the products of the recombination-activating genes Rag1 and Rag2. The V, D, and J gene segments are flanked by recombination signal sequences (RSSs) that consist of conserved heptamer and nonamer sequences separated by 12- or 23-base-pair spacer sequences. The Rag genes encode a recombinase that catalyzes site-specific cleavage of DNA between the RSSs; two coding ends of the excised pieces are then joined in an imprecise way, with additions of random nucleotides and/or short deletions, yielding a unique new combination of V(D)J segments (Roitt, Brostoff et al. 1998) (see Figure 11-6).

Diversity in immunoglobulins can result from any one or a combination of five different processes; the different possible combinations of Ig heavy and light chains, gene conversion, recombination of V, D, and J genes (V and J for the light chains), variability in joins, or somatic hypermutation introducing mutations into the V regions of activated B cells in a way that is not yet completely understood but that involves regions of numerous point mutations, mutational hot spots, and a mechanism in which DNA breaks initiate error-prone DNA synthesis by faulty DNA polymerases in V(D)J regions (Diaz and Casali 2002). The triggering mechanisms are not yet known, but generally are well within the familiar repertoire of evolution (mutation, duplication), gene expression (context-dependent transcription, splicing), and development (combinatorial signaling).

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