Exposure to toxins produces aberrant immune reactions which may include the development of autoimmunity. Heavy metals are well known as immunotoxins. One of these, mercury, has been recently shown to induce autoantibody production and pathology in rats and mice treated with mercuric chloride. This has been found to be associated with histocompatibility phenotype, particularly class II antigens. We have shown 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. Mercuric chloride also induces a proliferative response in lymphocytes. We believe that such proliferation, followed by or associated with cell death, is a source of immunogenic nucleolar material which leads to autoantibody production. It is the aim of this proposal to elucidate the mechanisms which induce this specific autoimmune response by examining the fate of fibrillarin during cell proliferation or injury following mercuric chloride exposure, and to relate these findings to fibrillarin biology. Indexes of cell function such as DNA, RNA and protein synthesis will be used to assess proliferative and toxic responses. We will follow the epitope expression, cellular distribution and structure of the fibrillarin containing U3 snRNP particle following lymphocyte exposure to mercuric chloride. This will be achieved by using immunofluorescence, immunoprecipitation and Western blotting analysis with monoclonal 72B9, a unique murine anti-fibrillarin autoantibody and with autoantibodies from certain patients with scleroderma producing antifibrillarin antibodies. Autoantibodies to other defined cell constituents will be used as reference points in monitoring nuclear structure. Identical parameters of fibrillarin biology will be analyzed in proliferating lymphocytes following stimulation by mitogens and in mammalian cell culture lines. The ability of whole cells and homogenates of tissues from mercuric chloride treated mice to induce antibody production in vivo will be examined. By analyzing the fate of this nucleolar antigen during cell exposure to mercuric chloride and to natural mitogens insights might be gained as to how an immunotoxin renders a nuclear self-antigen immunogenic. Such observations may be of significance in understanding the immunotoxicology of other heavy metals and xenobiotics in general.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Toxicology Subcommittee 2 (TOX)
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Scripps Research Institute
La Jolla
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