MERCURY-INDUCED ACCELERATION OF SPONTANEOUS AUTOIMMUNITY IN PRE-NEPHRITIC (NZBxSWR)F1 (SNF1) FEMALE MICE (B90)

Abstract

Abstract Mercury exposure in susceptible mice has been known to induce autoimmunity, including the proliferation of autoantibodies, Th2-dominated antibody responses and immune complex disease. We investigated whether the immunostimulating effects of mercury can accelerate the induction of autoimmunity in SNF1 mice, a model that closely resembles human SLE nephritis. Previous studies from our laboratory have shown that dysregulation of the idiotypic network is key in the development of renal immune complex deposits in SNF1 females. In this study, six week-old pre-nephritic SNF1 females were exposed to 10 mg/L of either mercuric chloride or methylmercury in drinking water and examined for modulations in pathogenic immunophenotypes, autoantibody titers and clinical evidence of disease. We found increased populations of splenic T-cells and B-cells reactive with a pathogenic idiotypic determinant (IdLNF1) in mice exposed to mercury which, interestingly, also showed reductions in the percentage and absolute numbers of regulatory phenotypes (CD4+CD25+GITR+). Splenic lymphocytes from exposed mice showed increased proliferative responses to IdLNF1. LPS-induced proliferation was also increased in exposed mice, regardless of mercurial species used. We found modulations in serum antibody levels, including increased titers of anti-double stranded DNA autoantibodies. Clinically, mice exposed to mercury showed increased proteinuria and are currently being evaluated for glomerular damage and nephritis. The results of this study support the hypothesis that low-level exposure to metal xenobiotics such as mercury may trigger or accelerate autoimmune disease especially in a background of genetic susceptibility.