Exposure to toxins and chemicals can produce aberrant immune reactions that may include autoimmunity. The observation that eludes explanation is the restriction of the autoantibody response to a single, or a limited number of intracellular antigens the specificity of which appears dependent in part upon the toxin or chemical involved. We have shown that the heavy metal mercury induces a genetically restricted autoantibody response in mice that targets the nucleolar protein fibrillarin. Mercury-induced cell death results in modification of the molecular properties of fibrillarin, however mercury-modified fibrillarin is a poor antigen for HgCI2-induced antifibrillarin autoantibodies. These observations suggest that mercury-modified fibrillarin might be a source of (cryptic) T cell determinants. Immunization studies with bacterial recombinant fibrillarin, modified by mercury, where not successful in eliciting the same spectrum of antifibrillarin antibodies as HgC12-treatment. Alternative antigen sources appear more promising, including fragments of fibrillarin produced following cell death associated proteolysis, and eukaryotic cellular material resulting from HgCI2-induced cell death. The investigators propose to continue to examine the immunogenicity of fibrillarin by using eukaryotic expression systems to determine if the nature of the antigen is a limiting factor in autoantibody production. This will be achieved by examination of the fine specificity of anti-fibrillarin antibodies produced by immunization, or HgCI2-treatment. Additional studies will examine the fine specificity of fibrillarin specific T cells, to determine if cryptic epitopes are important in the autoantibody response and whether immunization elicits cryptic epitope specific T cells. The importance of T cell specificity in the anti-fibrillarin autoantibody response will be determined by examining the ability of antigen specific T cells to drive B cells to produce antibody. Analysis of the interaction between fibrillarin, mercury and cells of the lymphoid system may lead to insights into how an imunotoxin renders self-antigen immunogenic.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-SSS-3 (02))
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Tinkle, Sally S
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Scripps Research Institute
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