Tolerance Rather Than Immunity Protects From Helicobacter pylori-Induced Gastric Preneoplasia

作者：Arnold Isabelle C; Lee Josephine Y; Amieva Manuel R; Roers Axel; Flavell Richard A; Sparwasser Tim; Mueller Anne

来源：Gastroenterology, 2011, 140(1): 199-+.

DOI：10.1053/j.gastro.2010.06.047

• Helicobacter pylori
• Gastric Cancer
• Neonatal Tolerance
• Regulatory T Cells

BACKGROUND & AIMS: 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-beta 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.

• 出版日期2011-1