Autoimmune response

Muller, S., Briand, J.P., Van, R.M.H. (1988). Presence of antibodies to ubiquitin during the autoimmune response associated with systemic lupus erythematosis. Proc. Natl. Acad. Sci. USA 85,8176-8180. 

A limited study in animals also presents evidence for increased susceptibility to Streptococcus zooepidomicus (Aran d et al. 1986). Immune system effects observed in mice exposed orally to trichloroethylene included inhibition of cell-mediated immunity, delayed type hypersensitivity, and inhibition of antibody-mediated immunity (Sanders et al. 1982). Female mice appeared to be more sensitive than male mice. A study in which a susceptible strain of mice was treated with intraperitoneal injections of trichloroethylene suggests that trichloroethylene can accelerate the autoimmune response (Khan et al. 1995). The immune system may be a sensitive end point for toxic effects from low-level exposure to trichloroethylene however, no firm conclusions can be drawn from the available information. Additional human and animal studies are needed to better characterize this end point and determine the potential for immunological effects for people exposed to trichloroethylene at hazardous waste sites. 

Khan FM, Kaphalia BS, Prabhakar BS, et al. 1995. Trichloroethene-induced autoimmune response in female MRL +/+ mice. Toxicol Appl Pharmacol 134 155-160. 

Zhou XH, Paulsson G, Stemme S, Hansson GK. Hypercholesterolemia is associated with a T helper (Th) 1 Th2 switch of the autoimmune response in atherosclerotic apo E knockout mice. J Clin Invest 1998 101(8) 1717— 1725. 

Xu et al. [5] described the effect of (z>)-penicillamine on the binding of several antiacetylcholine receptor monoclonal antibodies to the Torpedo acetylcholine receptor. Penicillamine is covalently incorporated into the acetylcholine receptor through SS exchange at the cysteine residues of the a-subunit, altering the antigenic structure of the receptor. This effect on the structure of the native receptor at the neuromuscular junction may be responsible for the establishment of the autoimmune response to the acetylcholine receptor in (i))-penicillamine-induced myasthenia gravis. Cysteine and penicillamine interact to form penicillamine-cysteine mixed disulfide complexes [6] ... 

It has been estimated that 1-2 per cent of the US population suffer from autoimmune conditions, including rheumatoid arthritis, MS and some forms of diabetes. In many instances, an autoimmune response results from the inappropriate activation of a specific subset of B- and/or T-lymphocytes. The most common immunotherapeutic approach to potentially treat such diseases is to induce depletion of the individual s T- and B-cell populations. This could be achieved by administration of an antibody raised against a surface antigen present on such cells. Initial trials, for example, have shown that injection of an (unconjugated) anti-CD4 antibody (cell surface glycoprotein present on many T-lymphocytes) over 7 days significantly reduced the clinical symptoms of rheumatoid arthritis for several months. 

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. 

Atkinson, H.A. and Maisey, J., Effects of high levels of dietary oils on autoimmune responses, Biochem Soc Trans, 23, 277S, 1995. 

Nassberger, L. et al., Antibodies to neutrophil granulocyte myeloperoxidase and elastase Autoimmune responses in glomerulonephritis due to hydralazine treatment, J. Intern. Med., 229, 261, 1991. 

MS is a neurological chronic and progressive disease likely caused by an autoimmune response to various antigens present in the myelin sheath. MS is... 

A number of different drugs have been shown to induce autoimmunity in susceptible individuals. A syndrome similar to that of SLE was described in a patient administered sulfadiazine in 1945 by Hoffman (see Bigazzi, 1988). Sulfonamides were one of the first classes of drugs identified to induce an autoimmune response, while to date, over 40 other drugs have been associated with a similar syndrome. 

A rare but serious event that can result from irreversible CYP inhibition is the development of a hypersensitivity reaction. The bioactivation of a drug and the formation of a covalent adduct between the activated substrate and the enzyme can lead to hapten formation and eventually to an idiosyncratic autoimmune response (usually in the form of autoimmune hepatitis) [14]. The hapten formation is the first key step toward the autoimmune response. The CYP macromolecule is made immunogenic ( foreign ) by the covalent binding of the electrophilic metabolites, and the immune reaction follows with the production of autoantibodies against the target molecule (not necessarily alkylated). 

An autoimmune response is rarely detected during preclinical drug development because of the lack of good predictive animal models for the human immune system. Owing to their low incidence and idiosyncratic nature, autoimmune diseases quite often appear as a serious issue only after product launch [2,22]. 

Carcinogenesis Mutation Terratogenesis Tissue necrosis Autoimmune response... 

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