title: Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia.
abstract: OBJECTIVE
  Chronic infection with the bacterial pathogen Helicobacter pylori causes gastric disorders, ranging from chronic gastritis to gastric adenocarcinoma. Only a subset of infected persons will develop overt disease; most remains asymptomatic despite lifelong colonization. This study aims to elucidate the differential susceptibility to H pylori that is found both across and within populations.
  
  
  METHODS
  We have established a C57BL/6 mouse model of H pylori infection with a strain that is capable of delivering the virulence factor cytotoxin-associated gene A (CagA) into host cells through the activity of a Cag-pathogenicity island-encoded type IV secretion system.
  
  
  RESULTS
  Mice infected at 5-6 weeks of age with CagA(+)H pylori rapidly develop gastritis, gastric atrophy, epithelial hyperplasia, and metaplasia in a type IV secretion system-dependent manner. In contrast, mice infected during the neonatal period with the same strain are protected from preneoplastic lesions. Their protection results from the development of H pylori-specific peripheral immunologic tolerance, which requires transforming growth factor-β signaling and is mediated by long-lived, inducible regulatory T cells, and which controls the local CD4(+) T-cell responses that trigger premalignant transformation. Tolerance to H pylori develops in the neonatal period because of a biased ratio of T-regulatory to T-effector cells and is favored by prolonged low-dose exposure to antigen.
  
  
  CONCLUSIONS
  Using a novel CagA(+)H pylori infection model, we report here that the development of tolerance to H pylori protects from gastric cancer precursor lesions. The age at initial infection may thus account for the differential susceptibility of infected persons to H pylori-associated disease manifestations.
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Arnold
authors.forename: Josephine Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Amieva
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D000818:Animals; D058947:Bacterial Secretion Systems / Q000276:immunology; D005260:Female; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology; D005757:Gastritis, Atrophic / Q000382:microbiology / Q000473:pathology; D044404:Genomic Islands / Q000276:immunology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000276:immunology*; D006965:Hyperplasia / Q000276:immunology / Q000382:microbiology; D007108:Immune Tolerance; D008297:Male; D008679:Metaplasia / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000276:immunology / Q000382:microbiology*; D013272:Stomach Diseases / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000382:microbiology
chemical_list: D058947:Bacterial Secretion Systems