Xenobiotics autoimmune diseases

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Immunotoxicology is the study of undesired effects resulting from the interactions of xenobiotics with the immune system (Figure 19.1). There is evidence that some xeno-biotics can cause immune suppression. Xenobiotics can also interact with the immune system to either cause or exacerbate allergic disease. Finally there is growing concern that xenobiotics could have some involvement in autoimmune disease. This chapter provides a brief overview of the immune system, chemicals associated with immune suppression and immune pathologies, and approaches to testing for these effects. 

Finally there is growing concern that the developing immune system may be particularly vulnerable to xenobiotic exposures and that perinatal and/or in utero exposures may have a lifelong impact on susceptibility to infectious, allergic, or autoimmune disease. As in other areas of toxicology, tests designed to assess the risk of immuno-toxicity for adults may not be sufficient to protect children and research is currently underway to determine how best to meet this need. 

Xenobiotics can also cause autoimmune diseases, conditions where healthy body tissue is attacked by an impacted immune system that does not discriminate between self-antigens and foreign antigens. 

Exposures to xenobiotics have been associated with the onset of several autoimmune diseases. Lupus (systemic lupus erythematosus or SLE), scleroderma (systemic sclerosis), rheumatoid arthritis, and other maladies... 

Immunotoxic chemicals can interfere with the body s ability to ward off disease, can induce and exacerbate allergic responses, and contribute to autoimmune diseases. The complexity of the immune system and its interaction with other body systems makes it particularly vulnerable to attack by xenobiotics. Studies that have been carried out, however, have demonstrated that a wide variety of chemicals are immunotoxic and that chemical mixtures such as those contained in air polluted with the products of combustion, industrial emissions, and tobacco smoke is immunotoxic. Such polluted air can induce immunostimulative responses and bring on allergic reactions in previously sensitized individuals. 

Pollard KM, Lee DK, Casiano CA, Bluthner M, Johnston MM, Tan EM. The autoimmunity-inducing xenobiotic mercury interacts with the autoantigen fibrillarin and modifies its molecular and antigenic properties. J Immunol 1997 158 3521-3528. Kubicka-Muranyi M, Kremer J, Rottmann N, Lubben B, Albers R, Bloksma N, Luhrmann R, Gleichmann E. Murine systemic autoimmune disease induced by mercuric chloride T helper cells reacting to self proteins. Int Arch Allergy Immunol 1996 109 11-20. 

The passage of immunomodulators across the BBB has been the subject of much research activity, especially because of the known impairment in BBB functioning in autoimmune diseases such as multiple sclerosis (MS). " It is generally considered that basic mechanisms of brain inflammation involve massive, yet transient, dismption of BBB functioning that plays an important role in the acute episodes of several autoimmune diseases. This may indicate that individuals with an inherited susceptibility to autoimmune responses are a high-risk group for low-level exposure to xenobiotics. 

These fatty acids play an important role also in the amelioration of autoimmune diseases, such as arthritis, and in the inhibition of the rapid proliferation of cancer cells. However, PUFA in membrane lipids are vulnerable to free radical-initiated oxidation, generated by xenobiotics or normal aerobic cellular metabolism that results in the formation of lipid peroxides [84]. 

Exposures to xenobiotics have been associated with the onset of several autoimmune diseases. Lupus [systemic lupus erythematosus (SLE)], scleroderma (systemic sclerosis), rheumatoid arthritis, and other maladies have been strongly associated with exposures to single chemicals and mixtures of chemicals. The single chemicals include sihca dust, VC, mercuric chloride, trichloroethylene, HCB, hydrazine, and tartrazine. Mixtures include epoxy resins, hair dyes, paint thinners and other (unspecified) organic solvent mixtures, industrial emissions, airborne particulate matter, and hazardous waste-site emissions [27-32],... 

Studies of xenobiotic-induced immune dysregulation in animal models. Hydralazine and procainamide-induced autoimmunity HgClj and gold salt-induced autoimmunity The impact of genetic studies in our understanding of immunological-mediated toxic-induced renal disease ... 

He XS, Ansari AA, Gershwin ME (2001) Xenobiotic considerations for the development of autoimmune liver diseases bad genes and bad luck. Rev Environ Health, 16 191— 201. 

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