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* Department of Microbiology and Immunology, and
Biostatistics Consulting Center, Temple University School of Medicine, Philadelphia, PA 19140;
Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; and
Department of Chemistry, University of Connecticut, Storrs, CT 06269
The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs, or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar Ab production and immune system activation. Regulatory components of the innate immune system such as NKT cells and TLRs can also modulate the autoimmune process. We examined the interplay among environmental chemicals and NKT cells in the regulation of autoimmunity. Additionally, we studied NKT and TLR ligands in a tolerance model in which preadministration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. We also studied the effect of Sphingomonas capsulata, a bacterial strain that carries both NKT cell and TLR ligands, on metal-induced autoimmunity. Overall, NKT cell activation by synthetic ligands enhanced the manifestations of metal-induced autoimmunity. Exposure to S. capsulata exacerbated autoimmunity elicited by mercury. Although the synthetic NKT cell ligands that we used are reportedly similar in their ability to activate NKT cells, they displayed pronounced differences when coinjected with environmental agents or TLR ligands. Individual NKT ligands differed in their ability to prevent or break tolerance induced by low-dose mercury treatment. Likewise, different NKT ligands either dramatically potentiated or inhibited the ability of TLR9 agonistic oligonucleotides to disrupt tolerance to mercury. Our data suggest that these differences could be mediated by the modification of cytokine profiles and regulatory T cell numbers.
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1 This work was supported by National Institutes of Health Grants ES-09409 and ES-12646 to M.M. and Grant AI-057519 to A.H. J.M. is a Lupus Research Institute Fellow and is supported by Public Health Service Grant P30 DK078392.
2 Address correspondence and reprint requests to Dr. Marc Monestier, Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140. E-mail address: marcm{at}temple.edu
3 Abbreviations used in this paper: ANoA, anti-nucleolar autoantibody; 
-GalCer, -galactosyl ceramide; DC, dendritic cell; ODN, oligodeoxynucleotide; Treg, CD4+CD25+Foxp3+ regulatory T cell.
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