Oh P

coding ends signal ends coding ends random nucleotide i signal ends random nucleotide coding joint

Figure 11-6. Rag1 and Rag2 mediated V(D)J formation (see text). Redrawn from (Ohmori and Hikida 1998) with permission.

This somatic recombination happens in cis, that is, along the TCR and heavy and light chain Ig gene regions. At the same time, there is a trans phenomenon of allelic exclusion, by which the same region of the homologous chromosome is inactivated, so that the cell expresses only one combination of its genes (for the TCR or its Ig, depending on the cell type) derived from only one of its chromosomes. Each of these events happens independently in each of the cell lineages. At least one mechanism of allelic exclusion seems to involve asynchronous replication in mitosis (Singh et al. 2003). The earlier-replicating chromosome can in principle produce some substances or conditions that prevent recombination from occurring on the homologous chromosome. Of course, in any evolving system, there will be diversity among species. A variety of ways in which antibody diversity is generated in vertebrates is depicted in Figure 11-7. The system in sharks depends on a large number of individual complete genes, much like that of olfactory reception (Chapter 13) and the R-gene system in plants (see below). We see again our common finding: in their own way, each works well enough to have evolved.

The first stages of B cell development occur in the bone marrow, where the process of gene rearrangement takes place. This stage generates an immature B cell that carries an antigen receptor. This antigen receptor is in the form of cell surface IgM, capable of interacting with antigen. ("IgM" means that in addition to its chosen V, D, and J region, the cell is using its "|m-" or M constant chain to form the immunoglobulin). Immature B cells at this stage that do not encounter antigen either die or are inactivated (become anergic), thereby eliminating many potentially self-reactive B cells from the repertoire of antibody-producing cells, because B cells that crosslink their own IgM are programmed to die (Janeway 2001; Roitt, Brostoff et al. 1998). Cells that survive this process are subsequently free to leave the bone marrow and enter the lymphoid system, where they may encounter foreign antigen and be activated. Activated mature B cells proliferate clonally, to become either antibody-producing plasma cells or memory cells that can respond quickly to reinfection with the same pathogen. If activated in later stages of infection, the constant chain switches from M to G, etc., depending on the context. The stages of B cell development are shown schematically in Figure 11-8.

T cells are bone marrow-derived stem cells, called thymocytes when they are immature lymphocytes. They differentiate and mature in the thymus, undergoing recombinational events like those that produce the differentiated antibodies of B cells. They also undergo the same kind of selection process as B cells: 98% of thymocytes die, by apoptosis, before they mature, although, unlike B cells, T cells undergo positive as well as negative selection. The process is complicated and not well understood, but it is based on the recognition by T cells of self peptide-self MHC complexes and eliminates those that are highly self-reactive, while selecting for those that have a moderate affinity for self. This negative selection thus ensures that these cells become self-tolerant. Experimental work has also shown that T cells are unable to recognize and bind to foreign peptide-foreign MHC complexes. That is, positive selection of T cells, based on moderate affinity to self MHC, ensures that T cells recognize foreign peptide-self MHC complexes (Janeway 2001; Roitt, Brostoff et al. 1998).

Several aspects of the system are worth noting. The recombinational possibilities come about because of the number of selectable regions that can be used (thanks to a history of duplication), because there are two chromosomes for each gene complex to choose from, and because recombination is an error-prone system (especially in the D and J regions). Since each activated B or T cell expresses only a single binding variant, the proliferation of just that variant represents a kind of natural selection within the organism that favors what works without proliferating a lot of antibodies that do not work against a particular pathogen (but could generate antiself reaction). This makes the system modular in an interesting way and sequesters its specificities in controlled ways—but that do not require the organisms as a whole to "know" which of some fixed prior repertoire of antibodies to activate and which not to.

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