The role of Th17 cytokines in H.pylori infection

描述(由申请人提供)： 对幽门螺杆菌的免疫反应在清除感染方面无效，但在大多数情况下，它成功地限制了细菌的增殖，大多数幽门螺杆菌感染者仍然没有症状。对幽门螺杆菌的T辅助细胞17应答是控制感染所必需的，但也控制炎症和免疫细胞的迁移。我们自己的研究发现，IL-17信号是宿主对幽门螺杆菌反应的重要调节因子，也是T细胞活性和效应器功能之间联系的有力候选者。IL-17调节细菌-宿主相互作用的机制尚不完全清楚。解决包括IL-17A、IL-17F和IL-22在内的T辅助17细胞因子在幽门螺杆菌感染过程中的作用特别有趣，因为幽门螺杆菌是一种持续感染，可能导致消化性溃疡和胃癌等不良后果。众所周知，IL-17可诱导上皮细胞表达趋化因子以募集中性粒细胞，但由于IL-17受体IL-17RA表达于多种细胞类型，包括上皮细胞、粒细胞和淋巴细胞，其作用更为广泛。这些特定的目的是为了阐明Th17细胞产生的细胞因子对上皮细胞和中性粒细胞反应的相对贡献，特别是在控制幽门螺杆菌感染和胃炎方面。我们将(1)研究IL-17和IL-22细胞因子在幽门螺杆菌感染过程中刺激胃上皮细胞表达抗菌物质的作用。此外，我们将(2)确定IL-22在幽门螺杆菌感染过程中控制细菌定植和维持屏障功能中的作用，以及(3)确定IL-17在幽门螺杆菌感染过程中是否对中性粒细胞的激活有直接影响。除了加深我们对幽门螺杆菌感染的了解外，这些实验还将有助于我们了解与粘膜感染和免疫介导性疾病相关的免疫病理，如银屑病、炎症性肠病和类风湿性关节炎。 公共卫生相关性： 在远东、中东和许多发展中国家，幽门螺杆菌感染的流行率高于美国。来自美国的人到世界这些地区旅行可能会在海外感染幽门螺杆菌。因此，随着退伍军人从阿富汗、伊拉克和韩国等远东国家的冲突地点返回，我们似乎可能会在美国看到许多新的幽门螺杆菌感染病例和与幽门螺杆菌相关的疾病增加。我们对幽门螺杆菌免疫反应的了解的进步将使我们更接近有效的幽门螺杆菌疫苗，从而广泛影响退伍军人的健康。此外，了解炎症细胞因子在胃粘膜对幽门螺杆菌感染的免疫应答中的作用将有助于我们更好地理解免疫介导性疾病如炎症性肠病和类风湿性关节炎的免疫病理机制。

DESCRIPTION (provided by applicant): The immune response to Helicobacter pylori is ineffective in clearing infection, but in most cases it successfully restricts bacterial proliferation, and most H. pylori-infected persons remain asymptomatic. A T helper 17 response to H. pylori is required for control of infection, but also controls inflammation and immune cell migration. Our own studies have identified IL-17 signaling as an essential regulator of the host response to H. pylori and a strong candidate for a link between T cell activity and effector functions. The mechanisms by which IL-17 regulates bacterial- host interactions are not completely understood. Addressing the role of T helper 17 cytokines, including IL-17A, IL-17F, and IL-22, during H. pylori infection is particularly interesting because H. pylori is a persistent infection which can lead to adverse outcomes including peptic ulcers and gastric cancer. It is well accepted that IL-17 induces chemokine expression in epithelial cells for the recruitment of neutrophils, but since the receptor for IL-17, IL-17RA, is expressed on many cell types, including epithelial cells, granulocytes, and lymphocytes, its effects are even more widespread. The specific aims are designed to elucidate the relative contributions of cytokines produced by Th17 cells to the epithelial cell and neutrophil response and specifically in control of H. pylori infection and gastritis. We will (1) investigate the role of IL-17 and IL-22 cytokines in stimulating gastric epithelial cell expression of antimicrobial products during H. pylori infection. Moreover, we will (2) determine the role of IL-22 in control of bacterial colonization and maintenance of barrier function during H. pylori infection, and (3) determine whether IL-17 has a direct effect on neutrophil activation during H. pylori infection. In addition to enhancing our understanding of H. pylori infection, these experiments will contribute to our understanding of the immune pathology associated with mucosal infections and immune- mediated diseases, such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis. PUBLIC HEALTH RELEVANCE: The prevalence of H. pylori infection is higher in the Far East, Middle East, and many developing countries than in the United States. Persons from the United States who travel to these parts of the world may acquire H. pylori infection while overseas. Therefore, it seems likely that we may see many new cases of H. pylori infection and an increase in H. pylori-associated illnesses in the United States as Veterans return from sites of conflict in Afghanistan, Iraq, and countries in the Far East such as Korea. Advancement in our understanding of the immune response to H. pylori will broadly impact the health of Veterans by bringing us closer to an effective H. pylori vaccine. Moreover, understanding the role of inflammatory cytokines during the immune response to H. pylori infection in the gastric mucosa should increase our understanding of the immunopathology during immune-mediated diseases such as inflammatory bowel disease and rheumatoid arthritis.