Exposure to toxins and chemicals, including drugs, can produce aberrant immune reactions which may include autoimmunity. The observation which continues to elude explanation in chemical-induced autoimmunity is the restriction of autoantibody responses to a single, or a limited number of intracellular antigens, the specificity of which appears dependent in part upon the chemical involved. The investigator has shown that the heavy metal mercury induces a genetically restricted autoantibody response in mice that predominantly targets the nucleolar protein fibrillarin. This murine autoantibody response bears remarkable similarity to the anti-fibrillarin response in human scleroderma. Although the investigator's preliminary studies show that interaction of viable cells or isolated nuclei with mercuric chloride leads to modification of the molecular properties of fibrillarin, anti- fibrillarin autoantibodies do not appear to be directed against a fibrillarin-mercury complex. This suggests that mercury modification of fibrillarin may influence antigen processing of T cell responses associated with anti-fibrillarin autoantibody production. This is supported by additional preliminary studies showing that mercury causes apoptotic-like cell death in macrophages which is associated with proteolytic activity. Preliminary studies show that addition of exogenous fibrillarin to lysates from HgCl2 killed, but not untreated (control) macrophages results in proteolytic cleavage of the protein. This proteolytic activity is inhibited by serine protease inhibitors, showing it to be unrelated to apoptosis cysteine proteases of the ICE/CED-3 family. It is the aim of this proposal to test the hypothesis that this combination of interaction with mercury and digestion by protease leads to enhanced immunogenicity of fibrillarin, which stimulates autoreactivity among T and B cells and autoantibody production in mice of the appropriate H-2 genotype. Mercury modification of fibrillarin will be examined by mutation of the fibrillarin sequence to determine the residues responsible for the observed change in the molecular properties of fibrillarin upon interaction with mercury. Purified wild type and mutated fibrillarin, in the presence and absence of mercury, will be tested for their ability to elicit T cell and B cell responses to determine if mercury modified fibrillarin is sufficient to elicit an autoimmune response with properties similar to that produced by mercury in vivo. The significance of the protease digestion of fibrillarin in the autoimmune response will be determined by isolation of the protease to allow examination of the expression and cellular localization of the protease. The protease will also be used for the digestion of wild type and mutated fibrillarin to examine the potential of proteolytic fragments to stimulate T and B cells from mice sensitive and resistant to mercury-induced autoimmunity. By analyzing the ability of mercury modified fibrillarin to interact with cells of the lymphoid system insights might be gained as to how an immunotoxin renders a self antigen immunogenic. Such observations may be of significance in understanding immunotoxicity of other heavy metals and xenobiotics in general.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Scripps Research Institute
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