Gastric infiltrating T cells in immunopathogenesis of Helicobacter gastritis

• Main Authors: Yi-Ying Wu, 吳怡瑩
• Other Authors: 許秉寧
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/71669716424234275473

博士 === 國立臺灣大學 === 免疫學研究所 === 94 === H. pylori, a common pathogen of human, is the leading cause of chronic gastritis and peptic ulcer diseases. Recent studies have shown that apoptosis of gastric epithelial cells is increased during H. pylori infection. The enhanced gastric epithelial cell apoptosis in H. pylori infection has been suggested to play an important role in the pathogenesis of chronic gastritis, peptic ulcer and gastric neoplasia. H. pylori infection could induce gastric mucosa damage by increasing gastric epithelial cell apoptosis through interaction with infiltrating T cells. These findings suggest a role for immune-mediated apoptosis of gastric epithelial cells during H. pylori infection. To investigate role and mechanisms of gastric infiltrating lymphocytes in immune-mediated gastric epithelium damage during H. pylori infection, we first investigate role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of TNF superfamily molecule with apoptosis-inducing activity and could serve as an effector molecule for T cells, in inducing apoptosis in human gastric epithelial cells and to assess the expression of TRAIL on the surface of infiltrating T-cells in H pylori-infected gastric mucosa. Our results demonstrated that H. pylori could sensitize human gastric epithelial cells, confer susceptibility to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H pylori was dependent upon direct cell contact of viable bacteria, but not the virulent factors, CagA and VacA of H pylori. Further studies demonstrated that infiltrating T-cells in gastric mucosa expressed TRAIL on their surfaces. Our results indicate that H. pylori could modulate host cell apoptosis and confer sensitivity to death receptor-induced apoptosis. Modulation of host cell sensitivity to apoptosis by bacterial interaction adds a new dimension to the immunopathogenesis of H pylori infection. In order to understand the mechanisms of induction of inflammatory response and recruitment of infiltrating lymphocytes into gastric mucosa during H. pylori infection, we then investigate the expression of chemokine receptors in gastric infiltrating lymphocytes and the upregulation of chemokines in inflamed gastric tissues, and to further define role of chemokine/chemokine receptor interaction in recruitment of gastric infiltrating lymphocytes during H. pylori infection. The gastric infiltrating lymphocytes express Th1 chemokine receptors CXCR3, CCR5 and CXCR6 but not Th2 chemokine receptor CCR3. In addition, the gastric T cells express significant high level of CCR6. Recent studies have demonstrated that CCR6, the specificβ -chemokine receptor for CCL20 (MIP-3α), is selected expressed on some memory T cells and may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation. We further investigate CCR6 and its ligand CCL20 in inducing gastric inflammation during H. pylori infection. Our results indicated that expression of chemokine, CCL20 was markedly increased in inflamed gastric tissues, and the production of CCL20 was upregulated in response to H. pylori when stimulated by proinflammatory cytokines IL-1β and TNF-α. Moreover, the gastric infiltrating T cells isolated from gastritis tissues migrated toward recombinant CCL20 in a dose dependent manner in chemotaxis assay. Our results imply that interaction between CCL20/CCR6 may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation. Taken together, our study indicates that during H. pylori infection, it could sensitize gastric epithelial cells to TRAIL-mediated apoptosis, via interaction with TRAIL from gastric infiltrating T cells subsequently induced by interaction between chemokine receptor /chemokine, in particular, CCR6/CCL20 in inflamed gastric tissues induced by H. pylori, leading to gastric mucosa damage. Our study suggests a role of CCR6/CCL20 in the immunopathogenesis of H pylori infection.