Helicobacter pylori is an important pathogen which plays the major role in chronic gastritis, gastric and duodenal ulcers and gastric carcinomas. Although H pylori infection of the gastric epithelium elicits immune responses, insight into the mechanisms that regulate the development of those responses is limited. Recent studies have suggested that mucosal epithelial cells are active participants in immune responses to mucosal pathogens. The antral gastric epithelium constitutively expresses class II MHC molecules, and our cells have shown that these epithelial cells express other important markers which are required by antigen presenting cells. We noted that gastric epithelial cells in vitro and in vivo expressed the CD86 co-stimulatory molecule and this expression increased in parallel with the rise of local CD4+ T cell numbers and epithelial class II MHC expression increased in parallel with the rise of local CD4+ T cell numbers and epithelial c;ass II MHC expression during infection with H. pylori. Our most recent studies suggest that H pylori antigens are endocytosed by gastric epithelial cells and transported into endosomes that contain HLA-DM, a molecule which is essential in class II MHC-mediated antigen presentation and immunity to pathogens. Thus, gastric epithelial cells possess key functional elements of antigen presenting cells. Since antigen processing and presentation are pivotal events in the development of an immune response, our observations have led us to hypothesize that gastric epithelial cells are central regulators of the inflammatory and immunologic responses during H. pylori infection and that the nature of those responses is influenced by the bacteria. To examine this hypothesis we will address the following specific aims, as natural extensions of the studies performed during the initial period of funding. 1) Characterize the mechanisms of antigen internalization by gastric epithelial cells. In this aim we will (a) characterize the H. pylori antigens that are selectively internalized by human gastric epithelial cells and the mechanisms that promote their uptake; (b) define how internalized H. pylori antigens may alter various steps in the normal antigen processing (steps) and (c) identify the H. pylori peptides that are selective for presentation to T cells by gastric epithelial cells. 2) Characterize the mechanisms that allow gastric epithelial cells to influence CD4+ T cell function. In this aim we will (a) define the distribution of class II MHC in polarized gastric epithelial cells and (b) characterize the expression and function of Ii-CS, an essential co- receptor for CD44 on T cells, by human gastric epithelial cells. The overall goal of these studies is to better understand the interactions between H. pylori, the gastric epithelium and immune cells that determine the outcome of the infection. The studies may help explain why H. pylori infection persists and whether mechanisms that allow H. pylori to evade immune defenses may also permit the associated neoplasms to evade immune surveillance. Understanding the molecular basis for the regulation of the local immune response to natural infection will also facilitate the development of therapeutic or prophylactic vaccines against this clinically important pathogen.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Hamilton, Frank A
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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Beswick, Ellen J; Pinchuk, Iryna V; Earley, Rachel B et al. (2011) Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun 79:2737-45
Beswick, Ellen J; Reyes, Victor E (2009) CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World J Gastroenterol 15:2855-61
Beswick, Ellen J; Reyes, Victor E (2008) Macrophage migration inhibitory factor and interleukin-8 produced by gastric epithelial cells during Helicobacter pylori exposure induce expression and activation of the epidermal growth factor receptor. Infect Immun 76:3233-40
Lu, Hong; Wu, Jeng Yih; Beswick, Ellen J et al. (2007) Functional and intracellular signaling differences associated with the Helicobacter pylori AlpAB adhesin from Western and East Asian strains. J Biol Chem 282:6242-54
Minohara, Yutaka; Boyd, David K; Hawkins, Hal K et al. (2007) The effect of the cag pathogenicity island on binding of Helicobacter pylori to gastric epithelial cells and the subsequent induction of apoptosis. Helicobacter 12:583-90
Beswick, Ellen J; Pinchuk, Irina V; Das, Soumita et al. (2007) Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 75:4334-41
Ding, Song-Ze; Minohara, Yutaka; Fan, Xue Jun et al. (2007) Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells. Infect Immun 75:4030-9
Bland, David A; Suarez, Giovanni; Beswick, Ellen J et al. (2006) H pylori receptor MHC class II contributes to the dynamic gastric epithelial apoptotic response. World J Gastroenterol 12:4689-93
Suarez, Giovanni; Reyes, Victor E; Beswick, Ellen J (2006) Immune response to H. pylori. World J Gastroenterol 12:5593-8
Beswick, Ellen J; Pinchuk, Irina V; Minch, Kyle et al. (2006) The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production. Infect Immun 74:1148-55

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