The present proposal is aimed at an in depth study of the hypothesis that mercury in its various forms may be responsible for the induction of autoimmune responses followed by autoimmune disease in genetically predisposed individuals, even when they are exposed to lower levels of mercury than generally considered """"""""safe"""""""". We have established that Brown Norway (BN) rats have a predisposition to certain autoimmune responses, e.g. to spermatozoa and antigens of the kidney glomerular basement membrane (GBM). We postulate that mercury acts in these animals by increasing their immunological responsiveness to self (e.g. by polyclonal B cell stimulation) or decreasing hameostatic immunological controls (e.g. by acting on T suppressor cells and/or affecting the idiotype-anti-idiotype network). We also suggest that within the BN strain there may be populations at an increased risk because of their sex, age or immune status. This project specifically intends to fill existing gaps in the literature regarding: 1. The relationship between dose and autoimmune effects of mercuric chloride. In dose-effect experiments we will administer decreasing amounts of mercuric chloride to BN rats and evaluate their autoimmune responses to antigens of the GBM. Dose-effects will be assessed in male vs. female, young vs. old, thymectomized vs. control rats as well as in pregnant rats and their offspring. 2. The kinetics of autoimmune responses to GBM evoked by mercuric chloride, evaluated both in the humoral and cellular compartments of the immune system. 3. The cellular populations involved in autoimmune responses to GBM, identified by flow cytofluorometric analysis and by transfer of selected lymphocyte populations. 4. The regulatory mechanisms (suppressor T cells and/or idiotype network) of anti-GBM autoimmune responses, as determined by transfer experiments and evaluation of anti-idiotypic immunity. 5. The genetics of mercuric chloride-induced autoimmune responses to GBM, evaluated by studies of hybrids, backrosses and congenic animals between good responder and poor responder strains. The results obtained in this study may also apply to other metals and eventually justify immunological investigations in humans at risk of a new kind of environmental hazard, i.e. metal-induced autoimmune disease.
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