Exposure to toxins can be associated with the development of autoimmunity. An environmental toxin, mercury, has been recently shown to induce glomerulonephritis in rats, mice and rabbits. Autoantibody production and pathology in rats and mice treated with mercuric chloride have been found associated with histocompatibility phenotype, particularly class II antigens. In preliminary studies we have found that in mice, mercuric chloride exposure results in a restricted autoantibody response which targets the nucleolus, particularly the 34 kDa nucleolar antigen fibrillarin, a component of the U3 snRNP particle and a disease specific target of autoantibodies in human scleroderma. Mercuric chloride induces a proliferative response in lymphocytes. We believe that such proliferation, followed by associated with cell death, is a source of immunologic nucleolar material which leads to autoantibody production. It is the aim of this proposal to examine the fate of fibrillarin during cell proliferation following mercuric chloride exposure, and to relate these findings to fibrillarin biology in cells proliferating in the absence of mercuric chloride. Using indexes of cell function such as DNA, RNA and protein synthesis, and immunofluorescence, immunoprecipitation and Western blotting analysis with autoantibodies from scleroderma patients and mice treated with mercuric chloride and a murine antifibrillarin monoclonal autoantibody we will follow the epitope expression, cellular localisation and structure of fibrillarin following lymphocyte stimulation by mercuric chloride. Autoantibodies to other defined cell constituents will be used as reference points in nuclear structure. Identical parameters of fibrillarin biology will be analysed in proliferating lymphocytes following stimulation by mitogens and in mammalian cell culture lines. By analysing the fate of this nucleolar antigen during cell proliferation to mercuric chloride and to natural mitogens an understanding of how a nuclear self- antigen may be rendered immunogenic will be reached. Such observations may have significance on the mechanism of immunogenicity in autoimmunity in general.
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