Human exposure to various chemical or pollutants is associated with an increased incidence of autoimmune diseases. Nevertheless, there are only a few useful animal models to study the mechanisms of chemically induced autoimmunity. In genetically susceptible mice, subtoxic doses of mercury elicit a complex autoimmune syndrome with production of highly specific IgG antinucleolar antibodies and a polyclonal increase in serum IgG1 and IgE. Mercury exposure affects various components of the immune system and, in this proposal; we plan to characterize the effects of mercury on B cells. Our preliminary data lead us to propose the hypothesis that mercury accelerates B cell maturation in the periphery and that mercury triggers secondary immunoglobulin gene rearrangements.
In Specific Aim 1, we will assess how mercury influences the development of peripheral B cell subsets. We are particularly interested in determining whether mercury administration results in the upregulation of RAG proteins and in secondary immunoglobulin rearrangements.
In Specific Aim 2, we will examine how mercury affects the expression and regulation of an anti-DNA transgene that has been bred onto a mercury susceptible genetic background.
In Specific Aim 3, we will generate mice that possess a site directed transgene for an antinucleolar antibody. We will characterize the regulation of these B cells and evaluate their responses to mercury exposure. ? ?
| Luning Prak, Eline T; Monestier, Marc; Eisenberg, Robert A (2011) B cell receptor editing in tolerance and autoimmunity. Ann N Y Acad Sci 1217:96-121 |
| Rowley, Benjamin; Monestier, Marc (2005) Mechanisms of heavy metal-induced autoimmunity. Mol Immunol 42:833-8 |
| Zheng, Yan; Jost, Monika; Gaughan, John P et al. (2005) ICOS-B7 homologous protein interactions are necessary for mercury-induced autoimmunity. J Immunol 174:3117-21 |
