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.
Showing the most recent 10 out of 32 publications
