Two sources of programmed flexibility in the immune system: variation in structural and regulatory gene segments

Publisher Summary Genetic variation in humans and other diploid organisms results mainly from the presence in the population of polymorphic genes. A useful distinction, made possible by molecular genetics, is between variation in structural genes and variation in noncoding, regulatory regions. Regulatory regions are generally upstream of the corresponding structural genes, but may include introns and downstream segments. Within the immune system, polymorphism of structural segments is conspicuous only among genes encoding the antigen-handling proteins. The best known of these are the immunoglobulins, the T-cell receptors, and the class I and II major histocompatibility complex (MHC) proteins. Polymorphisms of the two proinflammatory cytokines IL-1 and tumor necrosis factor α (TNFα) are repeatedly associated with immunological diseases, which also apply to the antagonist IL-1RA and probably also to the receptor IL-1R. The association of these cytokine polymorphisms with immunological diseases occurs so regularly that they may well become a defining characteristic of these diseases. Polymorphism in upstream regulatory regions of MHC genes is conspicuous in class II MHC genes of both humans and mice. It may provide differential expression of these molecules in diverse antigen-presenting cells, and may thus influence the balance of Th1 and Th2 cytokines.

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