It is estimated that upwards of 10 million Americans have some form of autoimmune disorder. It is clear that both genetic and environmental factors contribute to the development and progression of autoimmune diseases. Recently considerable interest has focused on environmental factors that may contribute to the development of autoimmune disorders. In specific disorders such as systemic lupus erythematosus, women of childbearing age are affected at a rate 9-10 times that of men, and data both from human and animal studies suggest that estrogens can have an adverse impact on the course of the autoimmune process. Several chemicals have been shown to have estrogenic effects, and one mechanism by which environmental toxicants might influence the appearance or severity of autoimmune diseases is by mimicking the effects of estrogen. Heavy metals such has mercury have also been shown to induce systemic autoimmunity in both human and animal models. Epidemiologic and experimental data suggest that a common genetic background confers susceptibility to various autoimmune diseases. In addition, an extensive overlap exists between genomic regions linked to various autoimmune disorders. A panel of 17 murine congenic strains each carrying a genomic region containing an autoimmune susceptibility locus (from the NOD, NZM2410, NZW, and MRL autoimmune-prone strains) have been produced at the University of Florida, and are being used to functionally and genetically characterize these loci. This panel covers 33 percent of the murine genome and 63 percent of the common autoimmune regions. We propose to develop this panel of congenic strains as a model to study gene/environment interactions in autoimmunity. As a proof of principle, we will use 17- betaestradiol, chlordecone, and mercuric chloride as environmental agents (EA).
In Specific Aim 1, we will screen the panel to find autoimmune loci showing specific interactions with any of these 3 EA.
In Specific Aim 2, these EA/locus interactions will be analyzed by screening cDNA arrays, which will map pathways of genes with altered mRNA levels in response to the expression of the autoimmune locus under that EA exposure.
In Specific Aim 3, these insights into the EA/autoimmune locus effector mechanisms will be used to functionally characterize the immunopathology associated with these interactions. The main advantages of the model that we propose to develop are: 1) a great reduction of both genetic and functional complexity, 2) a significant overlap between autoimmune ideases for the genomic regions tested in each strains, and 3) a growing body of genetic and functional data associated with each of the strains.
| Blenman, Kim R M; Bahjat, Frances R; Moldawer, Lyle L et al. (2004) Aberrant signaling in the TNFalpha/TNF receptor 1 pathway of the NZM2410 lupus-prone mouse. Clin Immunol 110:124-33 |
