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| Research Interest: Gastrointestinal inflammation with specific interests in lymphoepithelial cell interactions in H. pylori infection and inflammatory bowel disease. The ultimate goal of understanding the pathogenesis of these diseases is to enhance the design of immunotherapies for the treatment or prevention of chronic gastrointestinal inflammation. Currently, Dr. Ernst is pursuing two main projects. The goal of the first is to understand the role of Th1 cells in the pathogenesis of gastroduodenal disease in humans infected with H. pylori. These studies entail a characterization of the T cell response in gastric mucosa. Dr. Ernst has shown that Th1 responses dominate in the normal and infected stomach, largely in association with the local production of IL-12 and IL-18. These Th1 cell release mediators that promote inflammation, for example but stimulating the production of neutrophil chemokines by the epithelial cells. In addition, activated Th1 cells can target the epithelium by inducing apoptosis and epithelial cell death. This is done directly by cytolytic cytokines produced by both CD4+ and CD8+ T cells as well as the effects of these cytokines on epithelial cell expression of Fas. The latter results in an increase in Fas-mediated killing by adjacent T cells expressing Fas ligand. A novel aspect of this work is the role of reactive oxygen species in selecting for Th1 cells. Studies are being carried out to examine the impact that oxidative stress has on Th cell differentiation and function. In the second project, Dr. Ernst is using mouse models of chronic colitis to study lymphoepithelial cell interactions. Similar to the events in the stomach, Th1 cells predominate in several models of colitis and lead to epithelial cell death. This occurs directly, via Fas/Fas ligand interactions as well as indirectly, by oxidative stress that is induced by activated T cells. Some of the pathogenic events in both models are prevented by anti-inflammatory cytokines including IL-10. Regulatory T cells in the gut appear to produce high levels of IL-10 and may be important in preventing autoimmune diseases including colitis. Thus, other studies involve the characterization of regulatory T cells in the gut and their induction by luminal antigen. Dr. Ernst is also a member of the Beirne B. Carter Center for Immunology Research and the Cancer Center and has active collaborations with scientists in these groups. Representative Publications: Fan XJ, Crowe SE, Behar S, Gunasena H, Ye G, Haeberle H, Van Houten N, Gourley WK, Ernst PB, and Reyes VE: The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage. J. Exp. Med. 187(10):1659-1669, 1998. Ito K, Takaishi K, Jin Y, Song F, Denning TL, and Ernst PB: Staphylococcal enterotoxin B stimulates expansion of autoreactive T cells that induce apoptosis in intestinal epithelial cells: regulation of autoreactive responses by IL-10. J. Immunol. 164(6):2994-3001, 2000. Ernst PB, and Gold BD: The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer. Annu. Rev. Microbiol. 54:615-40, 2000. Wang J, Brooks EG, Bamford KB, Denning TL, Pappo J, and Ernst PB: Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion. J. Immunol. 167(2):926-934, 2001. Denning TL, Qi H, Konig R, Scott K, Naganuma M, Ernst PB: CD4+ Th cells resembling regulatory T cells that inhibit chronic colitis differentiate in the absence of interactions of interactions between CD4 and class II MHC. Journal of Immunology . 2003. In Press. |
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