The central theme of our research concerns the cellular and biochemical/molecular mechanisms controlling lymphocyte activation and function. We focus on lymphocyte signaling pathways as targets for toxic metals, in our effort to understand how toxic metals contribute to aberrations within the immune system, leading either to immunosuppressive states or to autoimmune disease.

      Under the umbrella of this theme, we are actively studying the immunotoxicology of metals (mercury, lead) and metalloids (arsenic). Animal studies clearly have established a connection between mercury administration and systemic (lupus-like) autoimmune disease in rodents, while in humans there is evidence that Hg promotes an autoimmune-like syndrome. However, the mechanisms underlying mercury-mediated autoimmune reactions remain poorly understood and we seek a better understanding of them.

      Cell culture as well as animal models are used to elucidate the influences of mercury exposure on the biochemical signaling pathways controlling cell death. In recent years it has become clear that cell death is a natural process—one just as important as cell growth in controlling cell populations and tissue formation. Cell turnover by a process known as apoptotic cell death occurs extensively in the immune system. In fact, a decreased ability to undergo apoptosis has been linked to autoimmune disease susceptibility. Thus, certain autoimmune diseases may arise when self-reactive lymphocytes don’t die when they are supposed to die.

       Accordingly, the working hypothesis guiding much of the research is that low concentrations of mercury disrupt the biochemical signaling pathways controlling this apoptotic death. Specifically, our studies have focused on CD95-mediated apoptosis, where we have found that low concentrations of ionic mercury (i.e., ~0.2uM) attenuate CD95 agonist-induced apoptosis by targeting a signaling event upstream of caspase-3 activation.

       Interestingly, Tumor Necrosis Factor-induced apoptosis is not attenuated by mercury, indicating that there is some specificity to the effects of mercury on apoptotic signaling pathways. By non-specifically crosslinking cell surface receptors (via sulfhydryl interactions), bivalent mercury (i.e., Hg²⁺) may initiate signaling events that interfere with the CD95 pathway (see figure). Crosslinking of cell surface receptors by Hg²⁺ stimulates marked phosphorylation of proteins on tyrosine residues. We believe that cross talk between tyrosine kinase signaling and the CD95 apoptotic pathway serves as the basis for Hg2+ interference.

McNeely SC, Xu X, Taylor BF, Zacharias W, McCabe MJ Jr, States JC. 2006. Exit from arsenite-induced mitotic arrest is p53 dependent. Environ Health Perspect. Sep;114(9):1401-1406.

Taylor BF, McNeely SC, Miller HL, Lehmann GM, McCabe MJ Jr, States JC. 2006. p53 suppression of arsenite-induced mitotic catastrophe is mediated by p21CIP1/WAF1. J Pharmacol Exp Ther. Jul;318(1):142-151.

Ziemba SE, Mattingly RR, McCabe MJ Jr, Rosenspire AJ. 2006. Inorganic mercury inhibits the activation of LAT in T-cell receptor-mediated signal transduction. Toxicol Sci. Jan;89(1):145-153.

Ziemba SE, McCabe MJ Jr, Rosenspire AJ. 2005. Inorganic mercury dissociates preassembled Fas/CD95 receptor oligomers in T lymphocytes. Toxicol Appl Pharmacol. Aug 15;206(3):334-342.

Joseph CL, Havstad S, Ownby DR, Peterson EL, Maliarik M, McCabe MJ Jr, Barone C, Johnson CC. 2005. Blood lead level and risk of asthma. Environ Health Perspect. Jul;113(7):900-904.

Farrer DG, Hueber SM, McCabe MJ Jr. 2005. Lead enhances CD4+ T cell proliferation indirectly by targeting antigen presenting cells and modulating antigen-specific interactions. Toxicol Appl Pharmacol. Sep 1;207(2):125-137.

McCollum G, Keng PC, States JC, McCabe MJ Jr. 2005. Arsenite delays progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells. J Pharmacol Exp Ther. May;313(2):877-887

McCabe MJ Jr, Eckles KG, Langdon M, Clarkson TW, Whitekus MJ, and Rosenspire AJ. 2005. Attenuation of CD95-induced apoptosis by inorganic mercury: caspase-3 is not a direct target of low levels of Hg(2+). Toxicol Lett. Jan 15;155(1):161-170

McCabe MJ Jr. 2003. Mechanisms and consequences of silica-induced apoptosis. Toxicol Sci. Nov;76(1):1-2. No abstract available.

McCabe MJ Jr, Whitekus MJ, Hyun J, Eckles KG, McCollum G, and Rosenspire AJ. 2003. Inorganic mercury attenuates CD95-mediated apoptosis by interfering with formation of the death inducing signaling complex. Toxicol Appl Pharmacol. Jul 15;190(2):146-156.

Guity P, McCabe MJ Jr, Pitts DK, Santini RP, and Pounds JG. 2002. Protein kinase C does not mediate the inhibitory action of lead on vitamin D3-dependent production of osteocalcin in osteoblastic bone cells. Toxicol Appl Pharmacol. Jan 15;178(2):109-116.

Lawrence DA, and McCabe MJ Jr. 2002. Immunomodulation by metals. Int Immunopharmacol. Feb;2(2-3):293-302.

States JC, Reiners JJ Jr, Pounds JG, Beauerle BD, McNeely SC, Mathieu P, McCabe MJ Jr. 2002. Arsenite disrupts mitosis and induces apoptosis in SV40-transformed human skin fibroblasts. Toxicol Appl Pharmacol. Apr 15;180(2):83-91.

McCabe MJ Jr, Singh KP, and Reiners JJ Jr. 2001. Low Level Lead Exposure in Vitro Stimulates the Proliferation and Expansion of Alloantigen-Reactive CD4(high) T Cells. Toxicol Appl Pharmacol Dec 15;177(3):219-231.

Mattingly, R. R., Felczak, A., Chen C., McCabe, Jr., M. J. and Rosenspire A. J. 2001. Low Concentrations of Inorganic Mercury Inhibit Ras Activation During T Cell Receptor-Mediated Signal Transduction. Toxicol. Appl. Pharmacol. 176: 162-168, 2001.

McCabe, M.J., Jr., Singh, K.P., Reddy, S., Chelladurai, B.S., Pounds, J.G., Reiners, J.J., Jr., and States, J.C. 2000. Sensitivity of myelomonocytic leukemia cells to arsenite-Induced cell cycle disruption, apoptosis and enhanced differentiation is dependent on the inter-relationship between arsenic concentration, duration of treatment, and cell cycle phase. J. Pharmacol. Exper. Therapeut. 295 (2): 724-733.