Mercury-induced autoimmune glomerulonephritis in inbred rats. I. Kinetics and species specificity of autoimmune...

The nephropathy observed in rats after administration of mercuric chloride can be used to clarify the mechanisms underlying renal autoimmunity induced by chemicals. As a necessary preliminary step in the study of this animal model, we have investigated the kinetics and species-specificity of autoimmune responses to renal antigens. By a recently developed enzyme-linked immunosorbent assay (ELISA), circulating autoantibodies to the glomerular basement membrane of the kidney (anti-GBM) have been detected within 8 days after the initiation of mercuric chloride treatment. Anti-GBM antibodies reach a peak by 15 days and then decrease rapidly in the following 2 weeks. Extensive cross-reactions between rat and human GBM antigens have been detected by ELISA, indicating a high degree of conservation of some renal autoantigens and suggesting certain similarities between the autoimmune response induced in rats by mercuric chloride and that observed in human glomerulonephritis caused by anti-GBM. Dose-response studies have been performed to ascertain whether anti-GBM responses are correlated with massive kidney damage and release of renal antigens. We have noted that a wide range of levels of mercuric chloride are capable of stimulating the production of anti-GBM and that animals receiving this chemical in as low a concentration as 0.02 mg/100 g body weight (i.e. a dose ten times lower than those causing massive nephrotoxic effects) still have anti-GBM specifically bound to their kidneys. Thus, it is possible that the administration of mercury compounds to BN rats results in kidney autoimmunity not only because of the release of renal autoantigens, but also through the activation of specific lymphocytes and/or disruption of regulatory networks. Finally, we have observed that both BN and MAXX rats produce anti-GBM after mercuric chloride treatment, while M520 rats do not. Since the MAXX strain was initially obtained from a cross of BN and Lewis rats and shares antigens of the major histocompatibility complex with the BN strain, our findings stress the importance of genetic factors in chemical-induced autoimmunity and suggest that a similar situation may occur in human subjects exposed to environmental chemicals.