Pathogens have short replication times, are quite diverse in their genetic makeup, and evolve quickly, generating enormous antigenic variation. An adequate defense must therefore be capable of mounting an equally diverse response. Antibodies provide the diversity required for successful host defense. The timing of the antibody response and its necessary adjustment to changes in the antigenic makeup of the pathogen pose unique demands on the organization and regulation of the adaptive immune system. A unique mechanism has evolved that allows not only virtually limitless variation in the set of antibodies that can be produced (called the repertoire), but also rapid improvement in the quality of those antibodies, to meet the demands posed by an ongoing viral or bacterial infection. Because optimal antibody production by B cells requires assistance from T cells, we will see below that the molecular mechanisms underlying lymphocyte diversity are fundamentally similar for B and T cells.

B cells, which are responsible for antibody production, make use of a unique mechanism by which the genetic information required for synthesis of immunoglobulin heavy and light chains is stitched together from separate DNA sequences, or Ig gene segments, to create a functional transcription unit. The recombination mechanism that combines Ig gene segments itself dramatically expands the variability in sequence precisely where these genetic elements are joined together. This mechanism for generating a diverse array of antibodies is fundamentally different from meiotic recombination, which occurs only in germ cells, and from alternative splicing of exons (see Chapter 8). Because this recombination mechanism occurs in somatic cells but not in germ cells, it is known as somatic gene rearrangement or somatic recombination. This unusual recombination mechanism, unique to antigen-specific receptors on B and T lymphocytes, makes it possible to specify an enormously diverse set of receptors with minimal expenditure of DNA coding space. The discovery of somatic recombination is detailed in Classic Experiment 23-1.

The ability to combine discrete genetic elements at will (combinatorial diversity), in addition to the generation of yet more sequence diversity in the encoded receptors by the underlying recombination mechanisms themselves, allows adaptive immune responses against a virtually limitless array of antigens, including molecules encoded by the host. Thus there are mechanisms at work not only to create this enormous diversity, but also to impose tolerance to curtail unwanted reactivity against “self” components; the result of such reactivity is autoimmunity. Neither mechanism is perfect: the adaptive immune system cannot generate receptors for all foreign substances. Furthermore, the unavoidable price we pay for how we generate B- and T-cell receptors is the likelihood of self-reactive receptors (autoimmunity).