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.
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