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Vaccine Safety Forum: Summaries of Two Workshops GENETIC FACTORS AFFECTING DEVELOPMENT OF AUTOIMMUNITY15 If adverse reactions to vaccines are autoimmune reactions, as discussed in the previous section, then susceptibility to adverse events after vaccination might depend in part on an inherited or genetic susceptibility to such reactions. If so, the study of such disorders might provide insight into genetic susceptibility and expression. Autoimmune disorders, which affect between 10 and 20 percent of the population (Miller, 1995) are thought to be caused by many different genetic and environmental factors acting together. Reflecting these issues, the second session of the workshop addressed genetic variability in immune factors, and the interaction of these factors with environmental agents. According to Miller, the genes likely to be involved in the development of autoimmune disorders are those that code for the production of MHC molecules, those that encode other proteins involved with antigen processing, and T-cell receptors. Genes that code for or regulate the production of immunoglobulins or cytokines are also likely candidates, as are genes that regulate the metabolism of drugs and toxins. Because most autoimmune disorders are more prevalent in women than men, sex chromosome genes also likely play a role in their development. Much of the research documenting genetic risk factors associated with autoimmune disorders have focused on the MHC genes, which in humans are known as human leukocyte antigen (HLA) genes. Different HLA gene subtypes have been shown to be associated with an increased risk for different autoimmune disorders. The interaction of genes can also influence the risk for autoimmune disorders. Researchers have shown that people who have the HLA genetic marker called DQ2 in conjunction with a gene for a certain subtype of immunoglobulin have a much increased risk for autoimmune-mediated myositis, a muscle destroying condition with many etiologies, compared with the risk if they have just one of those genes (Miller, 1995) Environmental triggers of autoimmune disorders (as discussed above) can also interact with genetic factors. Environmental agents that have been implicated in some autoimmune diseases include infectious organisms, foods, dietary supplements, drugs, toxic agents and other substances, occupational exposures, foreign cells, and medical devices. It is not known for certain how these factors trigger autoimmune disorders. Hypothetical mechanisms include the following: These agents could foster an increased or altered expression of self-antigens, they could cause direct inhibitory or stimulatory effects on 15 This section is based on information by Frederick Miller and Howard Urnovitz.
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Vaccine Safety Forum: Summaries of Two Workshops components of the immune system, or they could cause a combination of these effects. Studies suggest that the duration and number of exposures to the same or different agents, as well as the dosage and route of administration of the agent, affect the risks of developing specific autoimmune disorders (Miller, 1997). Research suggests that the same autoimmune syndrome can be induced by different environmental agents, even though each agent is associated with different HLA risk factors. In contrast, a similar syndrome induced by different agents can sometimes be associated with the same genetic risk factor (Love and Miller, 1993). A lupus-like syndrome can be caused by the heart medication procainamide in association with the HLA subtype DR6, for example, or by the high blood pressure drug hydralazine in association with the HLA subtype DR4. In contrast, two scleroderma-like syndromes, one due to contaminated rapeseed oil and another associated with ingestion of certain manufacturing batches of L-tryptophan, are both associated with the HLA subtype DR4 (Miller, 1997). Genetic factors that also might influence the risk of developing autoimmune disorders and other possible adverse reactions from vaccines are human endogenous retroviruses (HERVs). HERVs are genetic sequences that resemble retroviruses and that may either be a precursor or a product of viruses whose genes have become inserted into all human DNA. HERVs usually cannot actively infect cells, like viruses can, but evidence suggests that their genes can be expressed, possibly to the point of generating proteins, in certain tissues under certain circumstances. Factors proposed to possibly influence HERV expression include hormones, X rays, compounds generated by the immune system in response to infection, viruses, and steroids (Urnovitz and Murphy, 1996). A mouse model also suggests that certain genes can influence the expression of specific endogenous retroviruses (ERVs). In this mouse model, mice that have a gene that fosters expression of ERVs develop an age-dependent paralyzing disorder when they are infected with a virus that, without ERV expression, is normally harmless (Murphy et al., 1983). The possibility that ERVs can be part of the disease process, as in the previously mentioned mouse model, has prompted one workshop speaker to consider the possibility that HERVs play a role in certain human diseases or in adverse events following vaccination. Because HERVs have the enzyme needed to copy and incorporate viral genetic material into human DNA, HERVs theoretically might copy and incorporate the viral genetic material presented in vaccines or natural infections (Urnovitz et al., 1996). Urnovitz hypothesized that these fragments normally would not be expressed but that an infection by another organism, certain hormones, or injury might activate them.
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