Lead (Pb) and mercury (Hg) are two toxicants that can influence immunosuppression or enhancement of select immune functions. Hg can induce autoimmune reactivities in multiple species; however, this characteristic of Pb has not been established. At relatively low doses (<10muM) Hg and Pb can induce a MHC class II-dependent T cell proliferative response, enhanced MHC class II expression on B cells, and heighten immunoglobulin production by B cells. It is important to note that both Hg and Pb preferentially enhance the functions of Th2 cells over those of Th1 cells. Since Th1 cells are responsible for cell- mediated immunity, that is, activation of macrophages for enhanced intracellular killing of pathogens, this could explain why Pb and Hg inhibit host resistance to numerous pathogens/parasites. On the other hand, enhanced activity from Th2 cells could explain the autoimmune aspects of Hg (and possibly Pb), in that Th2 cells produce IL-4 and IL-5 which can increase B cell production of antibodies. Chronic T cell activation leading to excessive B cell activation (the bystander effect) has been a leading theory of autoimmune induction. Although all of these modifications could explain the manner by which these metals induce autoimmunity, the mechanisms by which these metals produce these reactivities remain unknown. This proposal is designed to address the mechanisms involved in the modification of T cell, B cell and macrophage activation, differentiation and proliferation. Our hypothesis is that Hg and Pb produce similar end results (immunomodulation) but they alter different biochemical/molecular pathways to achieve these modifications. We postulate that Pb modifies plasma membrane structure function and thus changes cell-cell interactions known to be critical in T cell/macrophage and T cell/Be cell associations. On the other hand, Hg alters cellular thiols which in turn modify signal transduction events. To evaluate this hypothesis we will compare the effects of Pb and Hg on various immunologic, biochemical, and molecular parameters of human and mouse cells. Since lipids and glycoproteins are responsible for maintaining the cell's barrier and the site where all activation events are initiated, we will evaluate lymphocyte plasma membrane structure including phospholipid composition, membrane fluidity, protein/receptor topography, and expression and movement of surface molecules (antigens) known to be involved in cell interactions and/or T cell activation. Additionally, we will quantify intracellular events such as calcium fluxes, PKC activity, and gene expression. Analysis of cytokine production will be measured at the mRNA and protein level. This approach should identify the mechanisms by which Pb and Hg are immunomodulatory and assist evaluation of their health hazard and the molecular basis for the risks in exposure. Species differences are apparent and comparative analyses should be helpful.
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