The purpose of this proposal is to resolve the underlying cellular and biochemical mechanisms for heavy metal modulation of humoral immunity. Our hypothesis as to how heavy metals alter humoral immunity is by 1) disrupting intercellular communication between helper T cells and B cells and/or 2) altering the function of B cell ion channels or the fidelity of signalling via second messenger systems, both of which are intimately tied to B lymphocyte activation. Cd and Hg have been chosen for study because Cd and Hg contamination of the environment poses a significant health issue, Cd and Hg have been shown to exert immunomodulatory activities on humoral immune responses in vivo and in vitro, little is known about the biochemical basis for the immunomodulatory effects of Cd and Hg on humoral immunity, and in non-lymphoid systems, both Cd and Hg have been shown to exert selective effects on specific biochemical pathways that are intimately involved in lymphocyte activation.
The specific aims of this project are to: 1) determine the effects of Cd and Hg on B cell growth and differentiation; 2) determine the effects of Cd and Hg on helper T cell growth and lymphokine production; 3) Evaluate the effects of Cd and Hg on helper T cell-B cell interaction and B cell activation and 4) Measure the effects of Cd and Hg on the early biochemical responses of B cells, thereby resolving the underlying biochemical pathways whose alterations result in changes in humoral immunity. Heavy metal modulation of humoral immunity will be studied using in a well- defined in vitro system in which B cells are induced to grow and differentiate in response to cloned helper T cells and lymphokines. Individual events in helper T cell-dependent B cell activation will be studied for their sensitivity to metal intoxication. After having defined the effects of Hg and Cd on helper T cell and B cell immunobiology, the biochemical basis for the biological alterations will be sought. It is likely that Cd exerts profound, direct influences on numerous biochemical pathways by its displacement of Ca++ from its normal ligands. Specific B cell activation pathways which are Ca++-regulated or -dependent will be evaluated for their sensitivity to Cd poisoning. Cd and Hg can also exert toxic effects via their interaction with sulfhydryl groups on proteins that are integral elements of lymphocyte activation cascades (e.g. protein kinase C) thereby altering the function of proteins involved in lymphocyte activation. Because the activities of plasma membrane ion channels are central to lymphocyte activation and targets of metal toxicity, metal- induced alterations in B cell ion channel function will be determined by patch clamp technology. These studies will provide fundamental knowledge concerning the biochemical basis for metal-induced alterations in B lymphocyte function.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Toxicology Subcommittee 2 (TOX)
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Dartmouth College
Schools of Medicine
United States
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