Final Source of Diversity Is Combinatorial Association of Heavy and Light Chains

In humans, there is the potential to generate 8262 heavy-chain genes and 320 light-chain genes as a result of variableregion gene rearrangements. Assuming that any one of the possible heavy-chain and light-chain genes can occur randomly in the same cell, the potential number of heavy- and light-chain combinations is 2,644,240. This number is probably higher than the amount of combinatorial diversity actually generated in an individual, because it is not likely that all VH and VL will pair with each other. Furthermore, the recombination process is not completely random; not all VH, D, or VL gene segments are used at the same frequency. Some are used often, others only occasionally, and still others almost never.

Although the number of different antibody combining sites the immune system can generate is difficult to calculate with precision, we know that it is quite high. Because the very large number of new sequences created by junctional

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FIGURE 5-14

Experimental evidence for somatic mutation in variable regions of immunoglobulin genes. The diagram compares the mRNA sequences of heavy chains and of light chains from hybridomas specific for the phOx hapten. The horizontal solid lines represent the germ-line VH and VK Ox-1 sequences; dashed lines represent sequences derived from other germ-line genes. Blue shading shows the areas where mutations clustered; the blue circles with vertical lines indicate locations of mutations that encode a different amino acid than the germ-line sequence. These data show that the fre quency of mutation (1) increases in the course of the primary response (day 7 vs. day 14) and (2) is higher after secondary and tertiary immunizations than after primary immunization. Moreover, the dissociation constant (Kd) ofthe anti-phOx antibodies decreases during the transition from the primary to tertiary response, indicating an increase in the overall affinity of the antibody. Note also that most of the mutations are clustered within CDR1 and CDR2 of both the heavy and the light chains. [Adapted from C. Berek and C. Milstein, 1987, Immunol. Rev. 96:23.]

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flexibility, P-nucleotide addition, and N-nucleotide addition are within the third CDR, they are positioned to influence the structure of the antibody binding site. In addition to these sources of antibody diversity, the phenomenon of somatic hypermutation contributes enormously to the repertoire after antigen stimulation.

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