Heavy metals (such as Cd, Hg, Ni, Zn, Cu, and Pb) are increasingly important contaminants of air, water, and soils. One of the critical biological systems which can be altered by exposure to heavy metals is the immune system, where inappropriate changes in immune capacity can result in immunodeficiency or autoimmune disease. While there is a great deal of interest in the mechanisms by which heavy metals alter immunity, there remain many unresolved issues. In preliminary studies, the investigators have examined the contributions that MT (a small, cysteine-rich metalloprotein that is rapidly induced in cells following heavy metal exposure) might make to altered immune activity. Metallothionein may be responsible for some of the forms of humoral immunosuppression associated with metal exposure. For example, the investigators have found that MT suppresses specific T-dependent humoral responses, and that some aspects of macrophage function are altered by MT. They have also found that monoclonal antibodies to MT developed in our laboratory can block some in vivo immunomodulatory activities of MT. The investigator's findings suggest that MT induced by heavy metal exposure (or indeed by exposure to other toxicants) is responsible for decreases in immunity as a consequence of antigen-presenting cell/helper T-cell interactions. The central parameters of the humoral response that are potential targets of the suppressive effect of MT will be evaluated. These experiments will establish the mechanisms by which suppressive effects occur.
The Specific Aims are to: (1) explore the dynamics of in vivo MT interactions with the immune system and to determine if suppression of humoral immunity is found in both T-dependent and -independent responses, (2) to examine the effects of MT on the role that T-lymphocytes play in regulation of the humoral immune response, (3) to determine whether the interactions of helper T-cells and macrophages are altered by MT, and (4) to establish whether patterns of B-cell differentiation are altered by the presence of MT. This research will have important implications both for the identification of individuals at particular risk for immune disease as a consequence of heavy metal exposure, and for the diagnosis and treatment of individuals exposed to excessive levels of these important environmental toxins.
| Rice, James M; Zweifach, Adam; Lynes, Michael A (2016) Metallothionein regulates intracellular zinc signaling during CD4(+) T cell activation. BMC Immunol 17:13 |
| Emeny, Rebecca T; Kasten-Jolly, Jane; Mondal, Tapan et al. (2015) Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint. Cell Stress Chaperones 20:1013-22 |
| Devisscher, Lindsey; Hindryckx, Pieter; Lynes, Michael A et al. (2014) Role of metallothioneins as danger signals in the pathogenesis of colitis. J Pathol 233:89-100 |
| Lynes, Michael A; Hidalgo, Juan; Manso, Yasmina et al. (2014) Metallothionein and stress combine to affect multiple organ systems. Cell Stress Chaperones 19:605-11 |
| Pietrosimone, Kathryn M; Yin, Xiuyin; Knecht, David A et al. (2012) Measurement of cellular chemotaxis with ECIS/Taxis. J Vis Exp : |
| Emeny, Rebecca T; Marusov, Gregory; Lawrence, David A et al. (2009) Manipulations of metallothionein gene dose accelerate the response to Listeria monocytogenes. Chem Biol Interact 181:243-53 |
| Hadjout, Nacima; Yin, Xiuyun; Knecht, David A et al. (2007) Automated real-time measurements of leukocyte chemotaxis. J Immunol Methods 320:70-80 |
| Lynes, Michael A; Kang, Y James; Sensi, Stefano L et al. (2007) Heavy metal ions in normal physiology, toxic stress, and cytoprotection. Ann N Y Acad Sci 1113:159-72 |
| Lynes, Michael A; Fontenot, Andrew P; Lawrence, David A et al. (2006) Gene expression influences on metal immunomodulation. Toxicol Appl Pharmacol 210:9-16 |
| Lynes, Michael A; Yin, Xiuyun (2006) Metallothionein and anti-metallothionein, complementary elements of cadmium-induced renal disease. Toxicol Sci 91:1-3 |
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