Current research activities of our laboratory are focused on autoimmune disease, with particular stress on the complex controls regulating self-tolerance and autoimmune responses. In this context we are investigating the autoimmune effects of certain environmental chemicals (xenobiotics), such as metals and polyaromatic hydrocarbons. To this purpose, we have used an animal model of autoimmunity induced by exposure to mercury. We have demonstrated changes of B and T lymphocyte subsets in the spleen and lymph nodes of Brown Norway (BN) rats with mercury-induced autoimmune glomerulonephropathy. Of particular interest was the RT6+ T cell subset, a population of peripheral T lymphocytes that appear to have important immunoregulatory properties in the BB rat model of autoimmune insulin-dependent diabetes mellitus. We have observed that in BN rats this subset decreases during exposure to mercury, a change that correlates inversely with autoimmune responses to antigens of the renal basement membranes (e.g., laminin). Lewis rats are resistant to the autoimmune effects of mercury and do not show any changes in RT6+ T lymphocytes or autoimmunity to kidney antigens. Therefore, renal autoimmune disease in genetically predisposed BN rats may be a consequence of immunotoxic interactions between this chemical and a regulatory (possibly RT6+) T cell subset. Additional studies from our laboratory, performed in F1 hybrids, congenic and chimeric rats, suggest that a combination of factors are important for the induction of autoimmunity by mercury and possibly other xenobiotics. These factors include the appropriate MHC, T cell-mediated regulation (through the cytokine network and other contact molecules) and anti-self TCR-bearing cells. We have recently begun studies of the cytokine network in mercury-induced autoimmunity. Preliminary results indicate a possible predominance of cytokines (e.g., IL-4) secreted by Th2 lymphocytes and other cells. However, there are suggestions that so-called Th1-type cytokines (e.g., IFN-g) may also be involved. Thus, studies of xenobiotic-induced autoimmunity are providing new insights into the complex interactions between cells of the immune system.

Selected References:

Kosuda, L.L., Hannigan, M.O., Bigazzi, P.E., Leif, J.H. and Greiner, D.L. Thymus atrophy and changes in thymocyte subpopulations of BN rats with mercury-induced renal autoimmune disease. Autoimmunity. 23:77-89, 1996.

Bigazzi, P.E. Autoimmunity caused by xenobiotics. Toxicology 119:1-21, 1997..

Bigazzi, P.E. and Rose, N.R. Animal models of autoimmunity. In: The Handbook of Experimental Immunology (5th ed.). (D.M. Weir, C. Blackwell, L.A. Herzenberg, L.A. Herzenberg, Eds.) Blackwell Scientific Publications, Oxford, UK, 1997.

Kosuda, L.L., Greiner,. D.L. and Bigazzi, P.E. Effects of HgCl2 on the expression of autoimmune responses and disease in diabetes-prone (DP) BB rats. Autoimmunity 26:173-187, 1997.

Bigazzi, P.E. Animal models of autoimmunity: spontaneous and induced. In: The Autoimmune Diseases (N.R. Rose and I. Mackay, Eds.). Academic Press, San Diego, CA, pp.211-244, 1998.

Kosuda, L.L., Whalen, B., Greiner,. D.L. and Bigazzi, P.E. Mercury-induced autoimmunity in Brown Norway rats: kinetics of changes in RT6+ T lymphocytes correlated with IgG isotypes of circulating autoantibodies to laminin 1. Toxicology 125: 215-231, 1998.