CHEMICAL-INDUCED AUTOIMMUNITY

Chemical-induced autoimmunity represents an important and interesting problem for at least three reasons: (1) many chemicals, including drugs, may induce such manifestations in a few susceptible individuals; (2) since the causative agent is known, there is a unique opportunity to elucidate some of the mechanisms at work in the appearance of autoimmunity; (3) as far as the pharmaceutical industry is concerned, tests presently available cannot predict this type of potentially deleterious effects of a drug. Chemicals may induce either hypersensitivity or autoimmune reactions. The former is the consequence of a humoral and/or T-cell-mediated response towards the chemical itself (or a metabolite). The latter is due to an immune response against an autoantigen. In man, it is often difficult to distinguish the former from the latter. In this review, we have first considered chemical-induced, organ-specific autoimmunity and then chemical-induced systemic autoimmunity. Numerous drugs are known to induce immune-mediated hepatitis or cytopenia. Recent advances were made in the understanding of the mechanisms involved in drug-induced hepatitis. The autoantibodies produced by patients treated with drugs such as tienilic acid recognize the enzyme that is used for the metabolism of the drug. Autoantibody production probably occurs as a consequence of fixation of a reactive metabolite on the enzyme. Many questions remain to be answered, especially the actual pathogenic role of the autoantibodies, as well as the possible role of autoreactive T cells. Experimental models of systemic autoimmunity have been developed in rats and mice using mercurials, gold salts or D-penicillamine, all known to induce various autoimmune disorders in exposed susceptible individuals. Experiments performed in the rat, mainly with HgCl2, showed that susceptibility is genetically controlled and that this agent induces a polyclonal activation of B cells, resulting in the production of pathogenic autoantibodies. The occurrence of autoimmunity is probably due to two different effects of the chemical. HgCl2 first induces very rapidly a decrease in IFN gamma production and an increase in IL4 production in the susceptible (Brown-Norway) strain. This agent also induces the appearance of autoreactive T cells that recognize normal class II molecules. Due to the effect on cytokine production, those T cells are Th2 cells that will activate polyclonally normal B cells, leading to an increased production of IgE and IgG1 immunoglobulins, some of which are autoantibodies. It has also been shown that, in the resistant (Lewis) strain, autoreactive T cells are also induced. Those T cells, however, are now Th1 cells because HgCl2 has a different effect on cytokine production in that strain. Interestingly, Th1-autoreactive T cells induce immunosuppression in the Lewis rat. Finally, it is shown that, in F-1 hybrids between Brown-Norway and Lewis rats, prior injection of HgCl2 or gold salts may prevent the appearance of a T-cell-mediated autoimmune disease by switching the response from Th1 to Th2. This observation may explain why some chemicals that may induce autoimmunity may also have a beneficial effect.