Box 7.1
Genetics and the Immune Response

Genetic factors can influence the host’s response, including the immune system’s response, to foreign antigens in many ways—for example, metabolism of the antigen, antigen processing, alteration of self-antigens, stimulation or suppression of the immune response, the nature of the humoral immune response (e.g., different immunoglobulin subclasses), the nature of the cellular immune response (e.g., Th1 versus Th2 response), or the development of an autoimmune response/disease. There are several examples of genetic factors that have been associated with the development and severity of infectious diseases. Polymorphisms (variant gene patterns) for the HLA gene alter the risk for severe pulmonary tuberculosis. Certain polymorphisms of the gene for cytokine tumor necrosis factor are associated with more severe malaria.

The immune response is also modulated by hormonal factors. Sex hormones affect the immune response as do adrenal hormones; estrogen tends to enhance the immune response, and cortisone tends to diminish it. The immune response is also modulated by various cytokines (molecules released by immune system cells that direct actions by other immune system cells), some of which increase and others of which decrease the immune response.

Normally the human body is “immunologically tolerant” to its own self-antigens, and the immune system does not attack the body’s own tissues. However, in some circumstances this tolerance appears to be broken, resulting in autoimmune disorders. Theoretically, there are several ways in which autoimmune diseases are thought to occur:

  • Environmental agents (such as chemicals) may enter the body and alter certain native body substances (usually proteins) so that these native substances are perceived by the immune system as being foreign.

  • Antigens from an infectious agent may have a structure that is similar to that of one or more normal host antigens. When the immune system reacts to the foreign antigen, it may also “inadvertently” attack the normal host antigens that are structurally similar.

  • Genetic factors that affect the immune response may encourage an autoimmune attack. For example, autoimmune diseases are often strongly associated with certain histocompatibility antigen (HLA) genes. There is evidence that infection with Coxsackie virus is more likely to cause Type I diabetes mellitus in people with the HLA DR4 allele.

  • Estrogens may also affect the clinical expression of certain autoimmune diseases. A number of autoimmune diseases are found more frequently in females including: Hashimoto thyroiditis, Graves disease, systemic lupus erythematosus, and scleroderma. HLA B27 associated spondyloarthropathies are found more frequently in males, although it is not clear that this is caused by male sex hormones.

SOURCES: Ahmed et al., 1999; Albert and Inman, 1999; Cooper et al., 1999; Miller, 1999; Rao and Richardson, 1999.

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