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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008080-07
Application #
6727662
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (02))
Program Officer
Tinkle, Sally S
Project Start
1996-08-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
7
Fiscal Year
2004
Total Cost
$324,100
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Hultman, P; Taylor, A; Yang, J M et al. (2006) The effect of xenobiotic exposure on spontaneous autoimmunity in (SWR x SJL)F1 hybrid mice. J Toxicol Environ Health A 69:505-23
Lynes, Michael A; Fontenot, Andrew P; Lawrence, David A et al. (2006) Gene expression influences on metal immunomodulation. Toxicol Appl Pharmacol 210:9-16
Cauvi, David M; Cauvi, Gabrielle; Pollard, K Michael (2006) Constitutive expression of murine decay-accelerating factor 1 is controlled by the transcription factor Sp1. J Immunol 177:3837-47
Pollard, K Michael; Hultman, Per; Kono, Dwight H (2005) Immunology and genetics of induced systemic autoimmunity. Autoimmun Rev 4:282-8
Pollard, K Michael; Arnush, Marc; Hultman, Per et al. (2004) Costimulation requirements of induced murine systemic autoimmune disease. J Immunol 173:5880-7
Pollard, K Michael; Hultman, Per; Kono, Dwight H (2003) Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity. Ann N Y Acad Sci 987:236-9
Yang, Jian-Ming; Hildebrandt, Bernhard; Luderschmidt, Christoph et al. (2003) Human scleroderma sera contain autoantibodies to protein components specific to the U3 small nucleolar RNP complex. Arthritis Rheum 48:210-7
Mahler, M; Bluthner, M; Pollard, K M (2003) Advances in B-cell epitope analysis of autoantigens in connective tissue diseases. Clin Immunol 107:65-79
Pollard, K M; Pearson, D L; Hultman, P et al. (2001) Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice. Environ Health Perspect 109:27-33
Yang, J M; Baserga, S J; Turley, S J et al. (2001) Fibrillarin and other snoRNP proteins are targets of autoantibodies in xenobiotic-induced autoimmunity. Clin Immunol 101:38-50

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