The Keio Journal of Medicine
Online ISSN : 1880-1293
Print ISSN : 0022-9717
ISSN-L : 0022-9717
Volume 51, Issue supplement2
Displaying 1-14 of 14 articles from this issue
  • Steffen Backert, Yuri Churin, Thomas F. Meyer
    2002 Volume 51 Issue supplement2 Pages 6-14
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Helicobacter pylori is a bacterial pathogen specialised to colonise and persist the gastric mucosa and to cause severe gastroduodenal disease. A major disease-associated bacterial component is a type IV secretion system (TFSS) encoded by the cytotoxin-associated genes pathogenicity island (cagPAI). Among the multiple responses in H. pylori-infected epithelial cells, the induction of proinflammatory cytokines and chemokines, cell spreading and motility associated with the “hummingbird” phenotype appear strictly dependent on the functional transporter complex in the cagPAI. H. pylori is also capable of occasionally entering epithelial cells and manipulates the host immune system for immune evasion. Attached bacteria actively translocate the CagA protein into epithelial cells by a TFSS-dependent process and translocated CagA undergoes tyrosine phosphorylation in the carboxy terminal EPIYA sequence repeat motif (Y-972) by kinases of the Src family. Furthermore, we have identified a novel TFSS in H. pylori involved in horizontal DNA-transfer. Host cell signalling events and cellular phenotypes provoked by the cagPAI, the investigation of mechanisms related to gastric cancer as well as the development of a Salmonella based live recombinant vaccine are in the focus of additional departmental activities.
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  • Teruko Nakazawa
    2002 Volume 51 Issue supplement2 Pages 15-19
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Helicobacter pylori bacterium is characterized by its strong urease activity. Our studies on the role of H. pylori urease revealed; (i) it is essential for colonization, (ii) exogenous urea is required for acid resistance, (iii) the bacteria have the ability to move toward urea and sodium bicarbonate, (iv) urea hydrolysis accelerates chemotactic locomotion, and (v) decay of urease mRNA to accomplish the active center is pH-regulated; i.e., the mRNA is stabilized and destabilized under acidic and neutral conditions, respectively. Based on the above results, I propose the growth cycle of H. pylori in gastric mucous layer. H. pylori bacteria proliferate on the epithelial cell surface by utilizing nutrients derived from degraded cells. Proliferated bacteria leave the cell surface to pH-variable region where they encounter strong acid. Urease is activated with simultaneous opening of Urel channel so that urea is hydrolyzed to neutralize acid. Chemotaxis of H. pylori toward urea and sodium bicarbonate that are abundant on the cell surface is accelerated by urea hydrolysis so that the bacteria go back to the cell surface for the next round of proliferation. This growth cycle may allow the bacteria to infect persistently in the stomach.
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  • Toshiya Hirayama
    2002 Volume 51 Issue supplement2 Pages 20-23
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Helicobacter pylori is the leading bacterial cause of food-borne illness worldwide and plays a major role in the development of chronic gastritis, peptic ulcer, and gastric cancer. Strains isolated from patients contain the cagA gene (cytotoxin-associated gene A) and produce the vacuolating cytotoxin VacA. VacA binding to specific high-affinity cell surface receptors was shown by using indirect immunofluorescence and flow cytometry; high-affinity toxin binding was necessary for cell intoxication. A 250-kDa receptor protein tyrosine phosphatase (RPTP) β served as a receptor for VacA on AZ-521 cells. The overexpression of RPTP β conferred VacA sensitivity on BHK-21 cells transfected with the RPTP β cDNA, consistent with RPTP β acting as a receptor for VacA. Increased binding of acid- or alkali-activated VacA to RPTP β may alter its activity and possibly accelerate or inhibit dephosphorylation of tyrosine on cytosolic proteins. Understanding the pathological responses of wild type and RPTP β-deficient animal models may well provide valuable information regarding the mechanism of VacA toxicity.
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  • Shigeru Kamiya, Takako Osaki, Haruhiko Taguchi, Hiroyuki Yamaguchi
    2002 Volume 51 Issue supplement2 Pages 24-25
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The reactive epitope of heat shock protein 60 (HSP60) of Helicobacter pylori to its monoclonal antibody (H9) was determined, and its synthesized peptide designated pH9 was used for ELISA. The patients with H. pylori infection had significantly lower titers of pH9 antibody than did uninfected patients. In C57BL/6 mice immunized intraperitoneally with the pH9 peptide with Freund's complete adjuvant (FCA), the number of H. pylori organisms colonizing the stomach was significantly lower than that in mice immunized with FCA only. These results suggest that HSP60 of H. pylori is effective in protection against H. pylori infection and might be a good candidate as a vaccine component.
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  • Masanori Hatakeyama
    2002 Volume 51 Issue supplement2 Pages 26-32
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Helicobacter pylori (H. pylori) is estimated to infect about half of the world population. It causes gastric diseases ranging from gastritis to cancer and has been classified as a class I carcinogen by WHO. However, little is known about the molecular mechanisms by which H. pylori induces pathogenesis. CagA is the product of the cagA gene carried among virulent H. pylori strains and is associated with severe clinical outcomes, most notably gastric carcinoma. CagA is injected from the attached H. pylori into gastric epithelial cells and undergoes tyrosine phosphorylation. We found that wild-type, but not phosphorylation-resistant CagA, is capable of inducing a growth factor-like morphological change, termed the hummingbird phenotype, in cells. Furthermore, CagA specifically binds the SH2-containing protein tyrosine phosphatase SHP-2 in a tyrosine phosphorylation-dependent manner and stimulates phosphatase activity. Disruption of the CagA-SHP-2 complex abolishes the CagA-dependent morphological change. Conversely, constitutively active SHP-2 is capable of inducing a CagA-like morphological change when it is plasma membrane-targeted. Our results show that CagA perturbs cellular functions by deregulating SHP-2 phosphatase after translocation from H. pylori into gastric epithelial cells. Given the positive regulatory roles of SHP-2 in both cell proliferation and cell movement, the CagA-SHP-2 interaction may play an important role in the oncogenic transformation that is a hallmark of cagA+ H. pylori infection.
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  • Barry Marshall
    2002 Volume 51 Issue supplement2 Pages 33-37
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    The discovery of Helicobacter pylori, by Warren and Marshall in 1982, was preceded by nearly 100 years of inconspicuous publications relating to spiral bacteria, achlorhydria, gastritis, gastric urease, and antimicrobial therapy for ulcers. Japanese investigators, notably Kasai and Kobayashi, should be acknowledged for their pioneering work showing that spiral bacteria could infect many animals, could cause haemorrhagic erosions, and would be effectively cured with various antimicrobials.
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  • Tadayoshi Takemoto
    2002 Volume 51 Issue supplement2 Pages 38-39
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
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  • Hidekazu Suzuki, Tatsuhiro Masaoka, Masaharu Miyazawa, Masayuki Suzuki ...
    2002 Volume 51 Issue supplement2 Pages 40-44
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Since Marshall's discovery before 20 years, Helicobacter pylori (H. pylori) infection is reportedly to be associated with a variety of clinical outcomes including peptic ulcer disease and gastric cancer. The first step of the H. pylori colonization might be its adhesion to the surface epithelial cells, which evokes gastric inflammatory events initiated by neutrophil recruitment from the microcirculation. Mongolian gerbil is one of the suitable animal models for H. pylori infection, which exerts gastric ulcer and cancer with its bacterial infection. In H. pylori-colonized gerbils, extensive levels of microvascular leukocyte adhesion and migration into the parenchymal side and significant levels of inflammatory cell infiltration are encountered. Bacterial urease not only neutralizes gastric luminal acid, but also plays as an adhesion factor to the surface epithelium. Recently, such an adhesion to the epithelium is reported to be important for bacterial type IV secretory system, which intermediates Cag A injection into the epithelial cells. Then, multiple chemokine and cytokine networks are activated and mucosal inflammatory lesion formation would be completed. In the long-term colonization of H. pylori, gastric mucosal cell turnover would be modified due to persistent inflammation and then such deregulation of cell turnover might link to the precancerous lesion formation.
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  • Norimasa Yoshida, Toshikazu Yoshikawa
    2002 Volume 51 Issue supplement2 Pages 45-50
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drugs (NSAIDs) are two major causes of gastric ulceration, but relation between H. pylori infection and use of these drugs in gastric mucosal injury is controversial. Neutrophils have been implicated in the pathogenesis of gastric mucosal damage induced by H. pylori or NSAIDs. H. pylori itself and H. pylori extract induce neutrophil activation, such as superoxide production, expression of adhesion molecule (CD11b/CD18) and transendothelial migration, capillary plugging. Several clinical and experimental studies demonstrated that the degree of H. pylori-induced gastric mucosal injury was closely correlated with the extents of H. pylori infection and of neutrophil infiltration, suggesting implication in extravascular neutrophils for H. pylori-induced gastric mucosal injury. On the other hand, aspirin promotes neutrophil-endothelial adhesive interactions via increasing CD11b/CD18, but not neutrophil migration to extravascular space. In addition, our recent in vivo study suggests that neutrophils adhering to the blood vessels, but not neutrophils migrating to the interstitium, are implicated in aspirin-induced gastric mucosal injury. Recently, we found that administration of aspirin to gerbils three weeks after H. pylori inoculation produced severe gastric mucosal injury via marked infiltration of neutrophils. In this animal model, pretreatment with anti-neutrophil serum, elastase inhibitor or scavengers of reactive oxygen species remarkably inhibited gastric mucosal injury. These results suggest that H. pylori infection potentiates aspirin-induced gastric mucosal injury by mechanisms that include accumulation of activated neutrophils.
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  • Atsushi Takagi, Ryuzo Deguchi, Kenji Kobayashi, Takeshi Miwa
    2002 Volume 51 Issue supplement2 Pages 51-52
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    To determine the role of host genetic factors in Helicobacter pylori infection, we examined the relation between gastroduodenal diseases and IL-1B polymorphisms in patients with H. pylori infection. In addition, we also compared gastric mucosal cytokine levels in those patients. We confirmed the findings that the IL-1B-31 C-to-T base transition was inverted in association with the -511 T-to-C base transition. There was no relation regarding to IL-1B polymorphisms and clinical outcomes. The gastric mucosal IL-1B level of the body of the stomach but not the antrum was significantly different among IL-1B genotypes. Furthermore, the IL-8 levels in the body were also higher in IL-1B-511C/C/ IL-1B-31TT than H. pylori negative patients. These findings suggested that IL-1B polymorphisms enhance not only IL-1-B production but also IL-8 production in the gastric body and may play an important role in the development of atrophic gastritis.
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  • Kenneth E.L. McColl, Emad El-Omar
    2002 Volume 51 Issue supplement2 Pages 53-56
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    H. pylori is now recognised to be an important co-factor in the aetiology of non-cardia gastric cancer of both the diffuse and intestinal histological type. The latter type develops via a complex multistage and multifactorial process. The fist stage involves progression from superficial gastritis to atrophic pangastritis with intestinal metaplasia and associated hypochlorhydria. This gastric phenotype may then progress to dysplasia and cancer. Many co-factors are involved in this progression including the strain of H. pylori, host genetic factors, such as interleukin-1 polymorphisms and gender, plus environmental factors such as smoking and diet. Intestinal colonisation with helminthic infection may retard the progression by altering the immune and inflammatory response to H. pylori and colonisation of the achlorhydric stomach with nitrosating bacteria may promote progression to cancer. H. pylori appears to be an obligatory co-factor in the aetiology of most gastric cancers. Consequently, prevention of the infection or its eradication in early life should reduce the incidence of this common and usually fatal tumour.
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  • Toshiro Sugiyama, Masahiro Asaka
    2002 Volume 51 Issue supplement2 Pages 57-62
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
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  • Naomi Uemura, Shiro Okamoto, Soichiro Yamamoto
    2002 Volume 51 Issue supplement2 Pages 63-68
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    BACKGROUND: Recently, many study have shown that Helicobacter pylori infection is crucial in development of atrophic gastritis, which is closely associated with gastric cancer. We conducted a long-term endoscopic prospective follow-up study to investigate the development of gastric cancer in H. pylori-positive and -negative patients. METHODS: 1603 patients who underwent endoscopy and were assessed as to the presence of H. pylori infection by histology, rapid urease test and serologic test between April 1990 and March 1993 were entered. We prospectively studied 1246 subjects with and 280 subjects without H. pylori infection for a mean follow-up of 7.8 years (range 1-10.6 years). RESULTS: Gastric cancer of both the intestinal and diffuse type developed in 36 (2.9%) infected patients but in none of the uninfected patients during follow-up. There was an increased risk for gastric cancer in infected patients with severe gastric atrophy and corpus predominant gastritis and intestinal metaplasia. Gastric cancer was detected in 21 (4.7%) of the patients with non ulcer dyspepsia, in 10 (3.4%) of those with gastric ulcer and in 5 (2.2%) of those with gastric hyperplastic polyp, at enrollment. No gastric cancer was detected in duodenal ulcer patients. CONCLUSION: These results suggest that the development of both types of gastric cancer is caused by H. pylori-associated gastritis, and the risk for development of gastric cancer in H. pylori-negative subjects is extremely low. Subjects having H. pylori-positive gastric mucosa with severe atrophy and/or corpus gastritis may be at particularly high risk for gastric cancer.
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  • Toshio Fujioka, Kazunari Murakami, Masaaki Kodama, Jiro Kagawa, Tadayo ...
    2002 Volume 51 Issue supplement2 Pages 69-73
    Published: 2002
    Released on J-STAGE: March 27, 2009
    JOURNAL FREE ACCESS
    Many epidemiological studies have shown a strong association between chronic Helicobacter pylori infection and subsequent development of gastric carcinoma in humans. To confirm this link more clearly, it is necessary to use this bacterium in experimental studies to develop gastric carcinoma in suitable experimental animals. Persistent H. pylori infection has recently been achieved in the Japanese Monkeys and Mongolian gerbil models, with results demonstrating that the sequential histopathological changes in the gastric mucosa are closely mimic the gastric mucosal changes caused by H. pylori infection in humans. Gastric mucosa infected with H. pylori exhibited significantly higher gastritis score, reduction in glandular height, increase in the number of Ki-67 positive cells and over expression of p53 protein and p53 gene mutation in the Japanese Monkey Model. In the Mongolian gerbil model, H. pylori infection enhances gastric carcinogenesis in combination with known carcinogens such as MNU and MNNG, and also demonstrated that H. pylori infection alone can result in the development of gastric carcinoma. However, diagnostic criteria of gastric carcinoma in animal models remain in the great discussion. These important results provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of H. pylori infection and assist the planning of eradication therapy to prevent gastric carcinoma.
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