Multiple Sclerosis (MS) is an inflammatory disease characterized by recurrent episodes of immune-mediated attack of central nervous system (CNS) myelin leading to axon damage and progressive disability. T helper (Th) cells specific for CNS antigens are thought to orchestrate the autoimmune attack of myelin in this disease. Our lab is studying how members of the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors may modulate the activity of autoaggressor T cells during experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our data have indicated that the PPARa isoform of this receptor is expressed at higher levels in T cells of male mice and that activation of this protein by either endogenous or synthetic ligands inhibits the development of Th1 responses that are important for the initiation of EAE. The sexual dimorphism in expression of this receptor may thus explain why sex-based differences exist in the pattern of MS and other T cell-mediated autoimmune diseases. Our studies have also revealed that PPARd, another PPAR isoform, may limit the development of Th1 and Th17 inflammation and EAE progression. Current research is directed towards understanding the cellular and molecular basis of action of these nuclear receptors in EAE.
Dunn, S.E., Bhat, R., Straus, D., Sobel, R.A., Axtell, R. Johnson, A., Nguyen, K., Mukundan, L., Moshkova, M., Dugas, J., Chawla, A., and Steinman, L.S. Peroxisome proliferator activated receptor-delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity. J. Exp. Med., in press.
Mukundan L., Odegaard, J.I., Morel, C.R., Heredia, J.E., Mwangi, J.W., Ricardo-Gonzalez, R.R., Goh, Y.P., Eagle, A.R., Dunn, S.E., Awakuni, J.U., Nguyen, K.D., Steinman, L., Michie, S.A., Chawla, A. PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med. 15:1266-72, 2009.
Dunn, S.E., Ousman, S., Sobel, R.A., Zuniga, L., Baranzini, S.E., Youssef, S., Crowell, A., Loh, J., Oksenberg, J., and Steinman, L. Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med. 204: 321-330, 2007.
Weber, M.S., Prod’homme, T., Youssef, S., Dunn S.E., Rundle, C.D., Lee, L., Patarroyo, J.C., Stuve, O., Sobel, R.A., Steinman, L., and Zamvil, S.S. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med. 13: 935-943, 2007.
Dunn, S.E., Youssef, S., Goldstein, M.J., Prod’homme, T., Weber, M., Zamvil, S.S., and Steinman, L. Isoprenoids determine Th1/Th2 fate in pathogenic T cells providing a mechanism of modulation of autoimmunity by atorvastatin. J. Exp. Med., 203: 401-12, 2006.