Exposure to low doses of mercury can cause systemic autoimmunity in a number of species, including humans. The response has been particularly well described in mice, where both haplotype-specific and non-specific effects are seen. Haplotype-specific effects appear to largely determine autoantibody specificity, while both MHC and non-MHC loci mediate the magnitude of response. The specific autoantibody response to fibrillarin is clearly not only T-cell -dependent, but is MHC restricted. Mercury has been shown to be taken up by macrophages and to be concentrated in lysosomes. Although a Th2 response by cytokine profiles, the anti-fibrillarin response is critically dependent on IFN-gamma and not IL-4, again suggesting the importance of macrophages in antigen presentation. Recent data suggest that mercury may induce a break in tolerance to fibrillarin through the development of a novel intramolecular disulfide bond bridged by a mercury molecule. Of interest, however, is the finding that autoantibody specificity is limited to mercury-unmodified fibrillarin. Other experiments suggest that T cell epitopes initially require exposure to mercury but later become mercury independent. Taken together, these results suggest that mercury alters antigen processing but raise questions as to the relative role of macrophages and B cells in the initiation and perpetuation of the mercury-induced antifibrillarin response. This proposal has three Specific Aims: 1) to determine whether and how mercury-modified antigens are immunogenic; 2) to determine the role of B cells in T cell priming and epitope spreading of the antifibrillarin response; and 3) to determine the role of non-mercury-induced apoptosis in amplifying the response following induction of autoimmunity by mercury exposure. Successful completion of these specific aims will provide important insights into the in vitro and in vivo effects on antigen processing of a ubiquitous heavy metal toxin and may have relevance to other heavy metals known to cause immune perturbations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES010315-01
Application #
6078900
Study Section
Special Emphasis Panel (ZES1-JPM-B (R))
Program Officer
Serrate-Sztein, Susana
Project Start
1999-09-30
Project End
2002-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611