Risk factors for gastric disease in pediatric H. pylori

描述（申请人提供）：幽门螺杆菌（Hp）是慢性活动性胃炎、原发性十二指肠溃疡的主要病因，与胃癌密切相关。全世界大多数Hp感染是在儿童期获得的。为什么有些个体会出现症状性疾病尚不清楚，直到最近，还没有研究严格评估儿童Hp菌株和/或宿主因素在疾病结局中的作用。在过去5年的NIH资助下，来自亚特兰大、克利夫兰和迈阿密的486名儿童被纳入研究；184例（38%）感染hp。种族（非裔美国人）和年轻年龄，以及表达cagA和vacas1b的Hp菌株，被证明是食道和胃疾病的危险因素；这表明与感染hp的成人不同的疾病模式。使用更新的悉尼系统，我们展示了儿童的组织病理学谱，其中包括萎缩性胃炎伴肠化生的新观察结果。竞争更新的总体假设：Hp感染儿童的疾病表现受特定宿主因素（即种族、免疫表型）、环境暴露和感染Hp菌株的特定毒力因素的影响。具体目的：1)使用明确定义的病例和对照，进一步表征导致症状性儿童感染的特定宿主因素和环境暴露，强调在特定年龄、性别和人口阶层中进行有针对性的登记，以促进发现以前未达到的显著差异，并对2个已建立的特定队列进行随访，以确定免疫反应自然史。2)利用基因阵列技术进行Hp全基因组评估和与儿童Hp菌株相关的特定毒力决定因素的细菌基因表达。3)进一步描述Hp感染儿童的宿主免疫和粘膜反应。在我们建立的三个高、中、低检出率临床中心的hp感染症状内窥镜检查病例将与年龄匹配的hp感染无症状和未感染症状对照进行比较。增加了两个地理和人口统计学上不同的中心，为患者队列提供了额外的地理和主题代表性。更新的Sydney系统将用于评估特定年龄、性别和人口阶层的新入组病例的胃组织病理学严重程度和表型，并对过去5年建立的两个“新颖”队列进行随访；A)萎缩性胃炎；b)食道和胃疾病组，能够对两种不同疾病范式的hp感染儿童的自然史进行全面、多元的评估。利用分子方法（多重[MP]-PCR， RT-PCR）和外周血单个核细胞（PBMCS）的微量ELISPOT测定，将确定Th1， Th2， Th3或平衡Th1/Th2反应，以进一步表征hp感染儿童的免疫反应表型。我们建议通过多变量方法进一步研究我们之前的工作，从而更好地了解人类Hp感染的胃十二指肠疾病后遗症和整体病理生物学。

DESCRIPTION (provided by applicant): Helicobacter pylori (Hp) is a major cause of chronic-active gastritis, primary duodenal ulcers and strongly linked to gastric cancer. Most Hp infections worldwide are acquired in childhood. Why some individuals develop symptomatic disease is unclear and, until recently, no studies critically evaluated the role of pediatric Hp strains and/or host factors in disease outcomes. Over the past 5 years of NIH funding, 486 children from Atlanta, Cleveland, and Miami were enrolled; 184 (38%) were Hp-infected. Race (African American) and younger age, in conjunction with Hp strains expressing cagA and vacAs1 B, were shown to be risk factors for both esophageal and gastric disease; suggesting a different disease paradigm from Hp-infected adults. Using the Updated Sydney system, we demonstrated a histopathologic spectrum in children, which included novel observations of atrophic gastritis with intestinal metaplasia. Overall hypothesis for competitive renewal: disease manifestations in Hp-infected children are influenced by specific host factors (i.e., race, immune phenotype), environmental exposures, and specific virulence factors of infecting Hp strains. Specific aims: 1) Using well defined cases and controls, further characterize specific host factors and environmental exposures contributing to symptomatic childhood infection emphasizing targeted enrollment in specific age, gender and demographic strata to facilitate detection of significant differences not attained previously and follow up of 2 established specific cohorts to ascertain immune response natural history. 2) Utilize gene-array technology for whole Hp genome assessment and bacterial gene expression of specific virulence determinants associated with pediatric Hp strains. 3) Further, characterize the host immunologic and mucosal response in Hp infected children. Hp-infected symptomatic endoscopy cases at our established three clinical centers of high, moderate and low tip prevalence will be compared with age-matched Hp-infected asymptomatic and uninfected symptomatic controls. Two geographically and demographically distinct centers have been added to provide additional geographic and subject representativeness to the patient cohort. The Updated Sydney system will be employed to assess gastric histopathology severity and phenotype in newly enrolled cases in specific age, gender and demographic strata and follow-up of the two "novel" cohorts established in the past 5 years; a) atrophic gastritis; b) esophageal and gastric disease group enabling a comprehensive, multivariate evaluation of the natural history of Hp-infected children in two distinct disease paradigms. Using molecular methods (multiplex [MP]-PCR, RT-PCR) and a micro ELISPOT assay on peripheral blood mononuclear cells (PBMCS), Th1, Th2, Th3 or balanced Th1/Th2 response will be determined to further characterize the Hp-infected child's immune response phenotype. We propose to further our previous work with critically lacking studies from a multivariate approach leading to a better understanding of the gastroduodenal disease sequelae and overall pathobiology of Hp infection in humans.