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Chen D, Wang W, Chen X, Liang N, Li J, Ding W, Zhang H, Yang Z, Zhao H, Liu Z. Plant-derived extracts or compounds for Helicobacter-associated gastritis: a systematic review of their anti-Helicobacter activity and anti-inflammatory effect in animal experiments. Chin Med 2025; 20:53. [PMID: 40264171 PMCID: PMC12013188 DOI: 10.1186/s13020-025-01093-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 03/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become common worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop. Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies of alternative natural medicines. PURPOSE This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal experiments. We intended to provide detailed preclinical-research foundation including plant and compound information, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter infection, gastritis and neoplasms for future study. METHODS The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO (CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP), the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023. Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool to evaluate the risk of bias of each study included. RESULTS Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibiting Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation. Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phenols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG. CONCLUSION Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further researches to apply these treatments in humans are needed, which will provide direction for the future development of therapeutic drugs to increase eradication rate and alleviate gastritis.
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Affiliation(s)
- Danni Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wenlai Wang
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China
| | - Xiangyun Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Ning Liang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiawang Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wei Ding
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Hongrui Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhen Yang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China.
| | - Hongxia Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China.
| | - Zhenhong Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China.
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China.
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Zhang Y, Dong Q, Tian L, Zhang S, Zuo N, Zhang S, Ding Z. Risk factors for recurrence of Helicobacter pylori infection after successful eradication in Chinese children: A prospective, nested case-control study. Helicobacter 2020; 25:e12749. [PMID: 32770644 DOI: 10.1111/hel.12749] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/24/2020] [Accepted: 07/13/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND Limited research has been published on the recurrence of Helicobacter pylori infection and risk factors in Chinese children. Our study aimed to identify risk factors for Helicobacter pylori infection recurrence after successful eradication in children. MATERIALS AND METHODS A prospective, nested case-control study was performed. A cohort of 230 children with successful eradication of Helicobacter pylori in Baoding (China) was selected from January 2018 to February 2019. A standardized questionnaire was used to obtain socioeconomic details. Eradication regimens and Helicobacter pylori antibiotic susceptibility testing results were also recorded. Interleukin-1β level, interferon-γ level, and genetic susceptibility (IFNGR1 and PTPRZ1 gene polymorphisms) were analyzed. All children were followed for 1 year. RESULTS Among 218 (94.8%) children who were successfully followed, 41 children (18.8%) had a Helicobacter pylori infection recurrence. The recurrence rate was higher in children ≤10 years old than >10 years old (22.8% vs 7.1%, P = .01). There was no significant difference between the recurrence group and the non-recurrence group in terms of types of therapy and antibiotic sensitivity (P > .05). Multivariable regression results indicated that residence in urban areas, higher household income, and having lunch at home were significantly protective against recurrence (OR 0.155, 0.408, and 0.351 respectively), whereas Helicobacter pylori infection in family members increased the risk of recurrence (OR 2.283). The levels of IL-1β and IFN-γ exhibited no significant difference between the recurrence group and the non-recurrence group. The allele frequency of G in the IFNGR1-56 site, A in the IFNGR1-600 site, and T in the IFNGR1-565 site was significantly higher in the recurrence group when compared to the non-recurrence group (P < .05). CONCLUSIONS The Helicobacter pylori infection recurrence rate is high in children in Baoding region and is closely correlated to socioeconomic factors. The IFNGR1 gene polymorphism may be an independent risk factor for Helicobacter pylori infection recurrence.
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Affiliation(s)
- Yuanda Zhang
- Department of Gastroenterology, Baoding Key Laboratory of Clinical Study on Respiratory and Digestive Diseases in Children, Baoding Children's Hospital, Baoding, China
| | - Qingwei Dong
- Department of Gastroenterology, Baoding Key Laboratory of Clinical Study on Respiratory and Digestive Diseases in Children, Baoding Children's Hospital, Baoding, China
| | - Lei Tian
- Department of Gastroenterology, Baoding Key Laboratory of Clinical Study on Respiratory and Digestive Diseases in Children, Baoding Children's Hospital, Baoding, China
| | - Shaohui Zhang
- Department of Gastroenterology, Baoding Key Laboratory of Clinical Study on Respiratory and Digestive Diseases in Children, Baoding Children's Hospital, Baoding, China
| | - Naying Zuo
- Department of Gastroenterology, Baoding Key Laboratory of Clinical Study on Respiratory and Digestive Diseases in Children, Baoding Children's Hospital, Baoding, China
| | - Sisi Zhang
- Department of Gastroenterology, Baoding Key Laboratory of Clinical Study on Respiratory and Digestive Diseases in Children, Baoding Children's Hospital, Baoding, China
| | - Zhaolu Ding
- Department of Pediatrics, Beijing United Family Hospital, Beijing, China
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Meyer TF, Morey P. A Future for a Vaccine Against the Cancer-Inducing Bacterium Helicobacter pylori? MUCOSAL VACCINES 2020:579-596. [DOI: 10.1016/b978-0-12-811924-2.00033-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Morey P, Meyer TF. The Sweeping Role of Cholesterol Depletion in the Persistence of Helicobacter pylori Infections. Curr Top Microbiol Immunol 2019; 421:209-227. [PMID: 31123891 DOI: 10.1007/978-3-030-15138-6_9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The ability of Helicobacter pylori to persist lifelong in the human gastric mucosa is a striking phenomenon. It is even more surprising since infection is typically associated with a vivid inflammatory response. Recent studies revealed the mechanism by which this pathogen inhibits the epithelial responses to IFN-γ and other central inflammatory cytokines in order to abolish an effective antimicrobial defense. The mechanism is based on the modification and depletion of cholesterol by the pathogen's cholesterol-α-glucosyltransferase. It abrogates the assembly of numerous cytokine receptors due to the reduction of lipid rafts. Particularly, the receptors for IFN-γ, IL-22, and IL-6 then fail to assemble properly and to activate JAK/STAT signaling. Consequently, cholesterol depletion prevents the release of antimicrobial peptides, including the highly effective β-defensin-3. Intriguingly, the inhibition is spatially restricted to heavily infected cells, while the surrounding epithelium continues to respond normally to cytokine stimulation, thus providing a platform of the intense inflammation typically observed in H. pylori infections. It appears that pathogen and host establish a homeostatic balance between tightly colonized and rather inflamed sites. This homeostasis is influenced by the levels of available cholesterol, which potentially exacerbate H. pylori-induced inflammation. The observed blockage of epithelial effector mechanisms by H. pylori constitutes a convincing explanation for the previous failures of T-cell-based vaccination against H. pylori, since infected epithelial cells remain inert upon stimulation by effector cytokines. Moreover, the mechanism provides a rationale for the carcinogenic action of this pathogen in that persistent infection and chronic inflammation represent a pro-carcinogenic environment. Thus, cholesterol-α-glucosyltransferase has been revealed as a central pathogenesis determinant of H. pylori.
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Affiliation(s)
- Pau Morey
- Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universidad de las Islas Baleares, Palma de Mallorca, Spain.
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
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Bagheri N, Salimzadeh L, Shirzad H. The role of T helper 1-cell response in Helicobacter pylori-infection. Microb Pathog 2018; 123:1-8. [PMID: 29936093 DOI: 10.1016/j.micpath.2018.06.033] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 06/19/2018] [Accepted: 06/21/2018] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori (H. pylori) is a human pathogen affecting over 50% of the world population. This pathogen is usually associated with chronic inflammation of the gastric mucosa that can lead to peptic ulcer disease (PUD) and gastric cancer (GC), especially in susceptible individuals. These outcomes have been attributed to the interaction of several factors, including host genetic susceptibility, local innate and adaptive immune responses, virulence factors of H. pylori, and environmental factors. T helper (Th) cell subsets and their signature cytokines especially IFN-γ, contribute to anti-bacterial response, but at the mean time sustaining chronic inflammatory responses in the site of infection. It has been acknowledged that H. pylori-infection results in a Th1-dominant response and that inflammation of the gastric mucosa depends mainly on Th1 cell responses. But, the mechanism of the role of Th1 cell responses in H. pylori-infection has not yet been clearly explained. In this review, we will focus on the role of Th1 involved in H. pylori-infection, its interaction with Th17/Treg cells and its association with the clinical consequences of the infection.
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Affiliation(s)
- Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Loghman Salimzadeh
- Department of Microbiology and Immunology Programme, National University of Singapore, Singapore
| | - Hedayatollah Shirzad
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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WATANABE T, ASANO N, KUDO M, STROBER W. Nucleotide-binding oligomerization domain 1 and gastrointestinal disorders. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2017; 93:578-599. [PMID: 29021509 PMCID: PMC5743859 DOI: 10.2183/pjab.93.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 05/31/2017] [Indexed: 05/08/2023]
Abstract
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular sensor that detects small peptides derived from the cell wall component of intestinal microflora. NOD1 is expressed in both non-hematopoietic cells such as epithelial cells and hematopoietic cells such as antigen-presenting cells. Detection of its ligand by NOD1 leads to innate immune responses through activation of nuclear factor kappa B and type I interferon as well as induction of autophagy. Innate immune responses through NOD1 activation play an indispensable role both in host defense against microbial infection and in the development of gastrointestinal disorders. Of particular importance, NOD1-mediated innate immune responses are associated with mucosal host defenses against Helicobacter pylori (H. pylori) infection of the stomach and with the development of pancreatitis. In this review, we discuss the molecular mechanisms by which NOD1 activation leads to the development of H. pylori-related gastric diseases and pancreatitis.
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Affiliation(s)
- Tomohiro WATANABE
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, U.S.A.
| | - Naoki ASANO
- Division of Gastroenterology and Hepatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masatoshi KUDO
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Warren STROBER
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, U.S.A.
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Sohn YA, Hwang SA, Lee SY, Hwang IY, Kim SW, Kim SY, Moon A, Lee YS, Kim YH, Kang KJ, Jeong CS. Protective Effect of Liriodendrin Isolated from Kalopanax pictus against Gastric Injury. Biomol Ther (Seoul) 2015; 23:53-9. [PMID: 25593644 PMCID: PMC4286750 DOI: 10.4062/biomolther.2014.103] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 10/07/2014] [Accepted: 10/30/2014] [Indexed: 01/12/2023] Open
Abstract
In this study, we investigated the inhibitory activities on gastritis and gastric ulcer using liriodendrin which is a constituent isolated from Kalopanax pictus. To elucidate its abilities to prevent gastric injury, we measured the quantity of prostaglandin E2 (PGE2) as the protective factor, and we assessed inhibition of activities related to excessive gastric acid be notorious for aggressive factor and inhibition of Helicobacter pylori (H. pylori) colonization known as a cause of chronic gastritis, gastric ulcer, and gastric cancer. Liriodendrin exhibited higher PGE2 level than rebamipide used as a positive control group at the dose of 500 μM. It was also exhibited acid-neutralizing capacity (10.3%) and H+/K+-ATPase inhibition of 42.6% (500 μM). In pylorus-ligated rats, liriodendrin showed lower volume of gastric juice (4.38 ± 2.14 ml), slightly higher pH (1.53 ± 0.41), and smaller total acid output (0.47 ± 0.3 mEq/4 hrs) than the control group. Furthermore liriodendrin inhibited colonization of H. pylori effectively. In vivo test, liriodendrin significantly inhibited both of HCl/EtOH-induced gastritis (46.9 %) and indomethacin-induced gastric ulcer (46.1%). From these results, we suggest that liriodendrin could be utilized for the treatment and/or protection of gastritis and gastric ulcer.
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Affiliation(s)
- Yoon Ah Sohn
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - Seon A Hwang
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - Sun Yi Lee
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - In Young Hwang
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - Sun Whoe Kim
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - So Yeon Kim
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - Aree Moon
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - Yong Soo Lee
- College of Pharmacy, Duksung Women's University, Seoul 132-714
| | - Young Ho Kim
- College of Pharmacy, Choongnam University, Daejeon 305-764
| | - Keum Jee Kang
- Department of food and nutrition, Duksung Women's University, Seoul 132-714, Republic of Korea
| | - Choon Sik Jeong
- College of Pharmacy, Duksung Women's University, Seoul 132-714
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Rudnicka K, Włodarczyk M, Moran AP, Rechciński T, Miszczyk E, Matusiak A, Szczęsna E, Walencka M, Rudnicka W, Chmiela M. Helicobacter pylori antigens as potential modulators of lymphocytes' cytotoxic activity. Microbiol Immunol 2012; 56:62-75. [PMID: 22040089 DOI: 10.1111/j.1348-0421.2011.00399.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori (H.p) colonizes human gastric mucosa and causes gastric and duodenal ulcer disease or gastric cancer. Various H.p compounds may modulate the host immune response in regards to tolerance of the infection or disease development. The aim of this study was to determine whether H.p lipopolysaccharide (LPS) and glycine acid extract antigens (GE) or E. coli LPS influence the cytotoxic activity of peripheral blood lymphocytes from H.p infected - H.p (+) or uninfected - H.p (-) individuals, in the presence or absence of exogenous interleukin (IL)12. Individual H.p status was defined by the urea breath test. Lymphocytes, stimulated or not with H.p, and control antigens, with or without IL-12, were used as effector cells and epithelial HeLa cells as targets. The cytotoxicity of lymphocytes was expressed as the percentage of dead target cells unable to reduce tetrazolium salt. The supernatants from HeLa/lymphocyte cultures were used for detection of the cellular cytotoxicity markers granzyme B and caspase 8. The natural cytotoxic activity of lymphocytes from H.p (+) was less than that of H.p (-) donors. This may have been due to fewer natural killer cells of CD3(-) CD56(+) Nkp46(+) phenotype in H.p (+) in comparison to H.p (-) subjects. H.p GE and standard E. coli LPS enhanced the cytotoxicity of lymphocytes towards target cells whereas H.p LPS downregulated this activity. The decrease in lymphocyte cytotoxicity in response to H.p LPS correlated with a lack of IL-2 and IL-12 production, inhibition of interferon-γ production, and low IL-10 secretion by mononuclear leukocytes. IL-12 significantly enhanced the natural as well as H.p LPS and H.p GE driven cytotoxic capacity of lymphocytes. In conclusion, H.p LPS may negatively modulate natural cytotoxic activity and cytokine secretion by immunocompetent cells and thus be involved in the maintenance of infection and development of gastric pathologies.
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Affiliation(s)
- Karolina Rudnicka
- Department of Immunology and Infectious Biology, University of Łódź, Banacha 12/16, 90-237, Łódź, Poland
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Kido M, Watanabe N, Aoki N, Iwamoto S, Nishiura H, Maruoka R, Ikeda A, Azuma T, Chiba T. Dual roles of CagA protein in Helicobacterpylori-induced chronic gastritis in mice. Biochem Biophys Res Commun 2011; 412:266-72. [PMID: 21820415 DOI: 10.1016/j.bbrc.2011.07.081] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 07/20/2011] [Indexed: 01/09/2023]
Abstract
Cytotoxin-associated gene A (CagA) acts directly on gastric epithelial cells. However, the roles of CagA in host adaptive immunity against Helicobacter pylori (H. pylori) infection are not fully understood. In this study, to investigate the roles of CagA in the development of H. pylori-induced chronic gastritis, we used an adoptive-transfer model in which spleen cells from C57BL/6 mice with or without H. pylori infection were transferred into RAG2(-/-) mice, with gastric colonization of either CagA(+) H. pylori or CagA(-) H. pylori. Colonization of CagA(+) H. pylori but not CagA(-) H. pylori in the host gastric mucosa induced severe chronic gastritis in RAG2(-/-) mice transferred with spleen cells from H. pylori-uninfected mice. In addition, when CagA(+) H. pylori-primed spleen cells were transferred into RAG2(-/-) mice, CD4(+) T cell infiltration in the host gastric mucosa were observed only in RAG2(-/-) mice infected with CagA(+) H. pylori but not CagA(-) H. pylori, suggesting that colonization of CagA(+) H. pylori in the host gastric mucosa is essential for the migration of H. pylori-primed CD4(+) T cells. On the other hand, transfer of CagA(-) H. pylori-primed spleen cells into CagA(+) H. pylori-infected RAG2(-/-) mice induced more severe chronic gastritis with less Foxp3(+) regulatory T-cell infiltration as compared to transfer of CagA(+) H. pylori-primed spleen cells. In conclusion, CagA in the stomach plays an important role in the migration of H. pylori-primed CD4(+) T cells in the gastric mucosa, whereas CagA-dependent T-cell priming induces regulatory T-cell differentiation, suggesting dual roles for CagA in the pathophysiology of H. pylori-induced chronic gastritis.
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Affiliation(s)
- Masahiro Kido
- Department of Gastroenterology and Hepatology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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Mimura T, Yoshida M, Nishiumi S, Tanaka H, Nobutani K, Takenaka M, Suleiman YB, Yamamoto K, Ota H, Takahashi S, Matsui H, Nakamura M, Miki I, Azuma T. IFN-γ plays an essential role in the pathogenesis of gastric lymphoid follicles formation caused by Helicobacter suis infection. ACTA ACUST UNITED AC 2011; 63:25-34. [PMID: 21631601 DOI: 10.1111/j.1574-695x.2011.00823.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In this study, we aimed to assess the role of helper T cells in the development of gastric lymphoid follicles induced by Helicobacter suis infection. C57BL/6J mice were orally inoculated with H. suis. Six weeks after infection, gastric lymphoid follicles were observed in the gastric mucosa by hematoxylin and eosin staining, and the number of follicles was increased throughout the infection period. An immunohistological examination showed that the lymphoid follicles were composed of B cells, CD4-positive helper T cells, and dendritic cells (DC). It was also revealed that the mRNA expression level of interferon-γ (IFN-γ) in the gastric mucosa was significantly increased at 12 weeks after infection. No gastric lymphoid follicles were detected in IFN-γ-deficient mice that had been infected with H. suis at 12 weeks after infection, although the development of lymphoid follicles in IL-4-deficient mice infected with H. suis was similar to that seen in the wild-type mice. In conclusion, IFN-γ, a Th1 cytokine, is deeply involved in the pathogenesis of gastric lymphoid follicles induced by H. suis infection, and it is suggested that CD4-positive T cells and DC aid in the expansion of gastric lymphoid follicles.
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Affiliation(s)
- Takuya Mimura
- Department of Internal Medicine, Division of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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Watanabe T, Asano N, Kitani A, Fuss IJ, Chiba T, Strober W. Activation of type I IFN signaling by NOD1 mediates mucosal host defense against Helicobacter pylori infection. Gut Microbes 2011; 2:61-65. [PMID: 21637021 PMCID: PMC3225799 DOI: 10.4161/gmic.2.1.15162] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2011] [Revised: 02/15/2011] [Accepted: 02/15/2011] [Indexed: 02/03/2023] Open
Abstract
Infection of gastric epithelial cells with Helicobacter pylori (H. pylori) induces a complex array of host protective immune responses. The best known are the adaptive T helper type 1 and type 17 responses that are induced in the gastric lamina propria by antigen-presenting cells via presentation of H. pylori antigens to CD4(+) T cells. Recently, it has become apparent that innate immune responses are also induced by H.pylori infection, both in epithelial cells and in underlying antigen-presenting cells. One important component of these innate responses involves the activity of NOD1, an intra-cellular sensor of peptides derived from the peptidoglycan component of the bacterial cell wall. In this review, we discuss our recent work showing that the signaling pathway utilized by NOD1 results in the generation of type I interferon and that this cytokine mediates both chemokine and cytokine responses that regulate the severity of gastric H. pylori infection.
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Affiliation(s)
- Tomohiro Watanabe
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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Watanabe T, Asano N, Kitani A, Fuss IJ, Chiba T, Strober W. NOD1-Mediated Mucosal Host Defense against Helicobacter pylori. Int J Inflam 2010; 2010:476482. [PMID: 21152124 PMCID: PMC2989736 DOI: 10.4061/2010/476482] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Accepted: 06/11/2010] [Indexed: 01/02/2023] Open
Abstract
Infection of the stomach with Helicobacter pylori is an important risk factor for gastritis, peptic ulcer, and gastric carcinoma. Although it has been well established that persistent colonization by H. pylori is associated with adaptive Th1 responses, the innate immune responses leading to these Th1 responses are poorly defined. Recent studies have shown that the activation of nucleotide-binding oligomerization domain 1 (NOD1) in gastric epithelial cells plays an important role in innate immune responses against H. pylori. The detection of H. pylori-derived ligands by cytosolic NOD1 induces several host defense factors, including antimicrobial peptides, cytokines, and chemokines. In this paper, we review the molecular mechanisms by which NOD1 contributes to mucosal host defense against H. pylori infection of the stomach.
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Affiliation(s)
- Tomohiro Watanabe
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC Room 5W3940, 10 Center Drive, Bethesda, MD 20892, USA
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Naoki Asano
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC Room 5W3940, 10 Center Drive, Bethesda, MD 20892, USA
| | - Atsushi Kitani
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC Room 5W3940, 10 Center Drive, Bethesda, MD 20892, USA
| | - Ivan J. Fuss
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC Room 5W3940, 10 Center Drive, Bethesda, MD 20892, USA
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC Room 5W3940, 10 Center Drive, Bethesda, MD 20892, USA
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13
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Watanabe T, Asano N, Fichtner-Feigl S, Gorelick PL, Tsuji Y, Matsumoto Y, Chiba T, Fuss IJ, Kitani A, Strober W. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest 2010; 120:1645-1662. [PMID: 20389019 PMCID: PMC2860924 DOI: 10.1172/jci39481] [Citation(s) in RCA: 187] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Accepted: 02/03/2010] [Indexed: 12/16/2022] Open
Abstract
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-beta production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-beta or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.
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Affiliation(s)
- Tomohiro Watanabe
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Naoki Asano
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Stefan Fichtner-Feigl
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Peter L. Gorelick
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Yoshihisa Tsuji
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Yuko Matsumoto
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Tsutomu Chiba
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Ivan J. Fuss
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Atsushi Kitani
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, National Cancer Institute — Frederick, Science Applications International Corporation, Frederick, Maryland, USA
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14
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Tanaka H, Yoshida M, Nishiumi S, Ohnishi N, Kobayashi K, Yamamoto K, Fujita T, Hatakeyama M, Azuma T. The CagA protein of Helicobacter pylori suppresses the functions of dendritic cell in mice. Arch Biochem Biophys 2010; 498:35-42. [PMID: 20363211 DOI: 10.1016/j.abb.2010.03.021] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2010] [Revised: 03/29/2010] [Accepted: 03/30/2010] [Indexed: 02/06/2023]
Abstract
CagA protein is the most assessed effecter molecule of Helicobacter pylori. In this report, we demonstrate how CagA protein regulates the functions of dendritic cells (DC) against H. pylori infection. In addition, we found that CagA protein was tyrosine-phosphorylated in DC. The responses to cagA-positive H. pylori in DC were reduced in comparison to those induced by cagA-negative H. pylori. CagA-overexpressing DC also exhibited a decline in the responses against LPS stimulation and the differentiation of CD4(+) T cells toward Th1 type cells compared to wild type DC. In addition, the level of phosphorylated IRF3 decreased in CagA-overexpressing DC stimulated with LPS, indicating that activated SHP-2 suppressed the enzymatic activity of TBK1 and consequently IRF3 phosphorylation. These data suggest that CagA protein negatively regulates the functions of DC via CagA phosphorylation and that cagA-positive H. pylori strains suppress host immune responses resulting in their chronic colonization of the stomach.
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Affiliation(s)
- Hiroshi Tanaka
- Department of Internal Medicine, Kobe University, Chu-o-ku, Hyogo, Japan
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15
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Chiba T, Marusawa H, Seno H, Watanabe N. H. pyloriInfection – The Route from Inflammation to Cancer. BACTERIAL VIRULENCE 2010:31-41. [DOI: 10.1002/9783527629664.ch3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Helicobacter pylori promotes the production of thymic stromal lymphopoietin by gastric epithelial cells and induces dendritic cell-mediated inflammatory Th2 responses. Infect Immun 2009; 78:108-14. [PMID: 19841072 DOI: 10.1128/iai.00762-09] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Helicobacter pylori colonizes the stomach and induces strong, specific local and systemic humoral and cell-mediated immunity, resulting in the development of chronic gastritis in humans. Although H. pylori-induced chronic atrophic gastritis is characterized by marked infiltration of T helper type 1 (Th1) cytokine-producing CD4(+) T cells, almost all of the inflamed gastric mucosae also contain focal lymphoid aggregates with germinal centers. In addition, typical H. pylori-induced chronic gastritis in children, called follicular gastritis, is characterized by B-cell follicle formation in the gastric mucosa. The aim of this study was to examine whether thymic stromal lymphopoietin (TSLP), an epithelial-cell-derived cytokine inducing a dendritic cell (DC)-mediated inflammatory Th2 response, is involved in Th2 responses triggering B-cell activation in H. pylori-induced gastritis. Here, we show that H. pylori triggered human gastric epithelial cells to produce TSLP, together with the DC-attracting chemokine MIP-3alpha and the B-cell-activating factor BAFF. After DCs were incubated with supernatants from H. pylori-infected epithelial cells, the conditioned cells expressed high levels of costimulatory molecules, such as CD80, and triggered naïve CD4(+) T cells to produce high levels of the Th2 cytokines interleukin-4 and interleukin-13 and of the inflammatory cytokines tumor necrosis factor alpha and gamma interferon. In contrast, after incubation of the supernatants with the neutralizing antibodies to TSLP, the conditioned DCs did not prime T cells to produce high levels of Th2 cytokines. These results, together with the finding that TSLP was expressed by the epithelial cells of human follicular gastritis, suggest that H. pylori can directly trigger epithelial cells to produce TSLP. It also suggests that TSLP-mediated DC activation may be involved in Th2 responses triggering B-cell activation in H. pylori-induced gastritis.
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Abstract
Helicobacter pylori (H. pylori) infection plays a crucial role in the development of gastric cancer. There are two major pathways for the development of gastric cancer by H. pylori infection: the indirect action of H. pylori on gastric epithelial cells through inflammation, and the direct action of the bacteria on epithelial cells through the induction of protein modulation and gene mutation. Both pathways work together to promote gastric carcinogenesis.
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18
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Wang SK, Zhu HF, He BS, Zhang ZY, Chen ZT, Wang ZZ, Wu GL. CagA+ H pylori infection is associated with polarization of T helper cell immune responses in gastric carcinogenesis. World J Gastroenterol 2007; 13:2923-31. [PMID: 17589941 PMCID: PMC4171143 DOI: 10.3748/wjg.v13.i21.2923] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To characterize the immune responses including local and systemic immunity induced by infection with H pylori, especially with CagA+ H pylori strains and the underlying immunopathogenesis.
METHODS: A total of 711 patients with different gastric lesions were recruited to determine the presence of H pylori infection and cytotoxin associated protein A (CagA), the presence of T helper (Th) cells and regulatory T (Treg) cells in peripheral blood mononuclear cells (PBMCs), expression of plasma cytokines, and RNA and protein expression of IFN-γ and IL-4 in gastric biopsies and PBMCs were determined by rapid urease test, urea [14C] breath test, immunoblotting test, flow cytometry , real time RT-PCR and immunohistochemistry.
RESULTS: Of the patients, 629 (88.47%) were infected with H pylori; 506 (71.16%) with CagA+ and 123 (17.30%) with CagA- strains. Among patients infected with CagA+ H pylori strains, Th1-mediated cellular immunity was associated with earlier stages of gastric carcinogenesis, while Th2-mediated humoral immunity dominated the advanced stages and was negatively associated with an abundance of Treg cells. However, there was no such tendency in Th1/Th2 polarization in patients infected with CagA- H pylori strains and those without H pylori infection.
CONCLUSION: Polarization of Th cell immune responses occurs in patients with CagA+ H pylori infection, which is associated with the stage and severity of gastric pathology during the progression of gastric carcinogenesis. This finding provides further evidence for a causal role of CagA+ H pylori infection in the immunopathogenesis of gastric cancer.
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Affiliation(s)
- Shu-Kui Wang
- Department of Pathogen Biology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu Province, China
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19
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Goll R, Gruber F, Olsen T, Cui G, Raschpichler G, Buset M, Asfeldt AM, Husebekk A, Florholmen J. Helicobacter pylori stimulates a mixed adaptive immune response with a strong T-regulatory component in human gastric mucosa. Helicobacter 2007; 12:185-92. [PMID: 17492997 DOI: 10.1111/j.1523-5378.2007.00495.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Host factors play an important role in the pathophysiology of Helicobacter pylori infection and development of gastritis and related disease. The established opinion is that the T-cell-mediated immune response to H. pylori infection is of Th1 type. Our earlier immune cell phenotype studies indicate a mixed Th1-Th2 profile of the effector cells. Therefore, an extensive adaptive and regulatory cytokine gene expression profile was conducted by quantitative real-time polymerase chain reaction (qPCR). MATERIALS AND METHODS Biopsies from gastric mucosa of 91 patients diagnosed as H. pylori negative, H. pylori positive with gastritis, or H. pylori positive with peptic ulcer were obtained by endoscopy. Gene expressions of nine cytokines and CagA status were measured by qPCR. RESULTS All cytokine genes showed higher expression levels in the presence of H. pylori when compared to H. pylori-negative samples (fold increase: IL8: x 11.2; IL12A: x 2.4; TNF-alpha: x 5.2; IFN-gamma: x 4.3; IL4: x 3.6; IL6: x 14.7; and IL10: x 6.7). Patients infected with CagA-positive strains had higher expression of IL1-beta and IL18 compared to patients infected with CagA-negative strains (x 1.6 for IL1-beta and x 2.0 for IL18). Patients with duodenal ulcer had a lower antral Th1/Th2 ratio than other H. pylori-positive patients. CONCLUSIONS The cytokine profile of H. pylori-infected gastric mucosa shows a mixed Th1-Th2 profile. Furthermore, a high IL10 expression may indicate that also regulatory T cells play a role in the chronic phase of H. pylori infection.
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Affiliation(s)
- Rasmus Goll
- Institute of Clinical Medicine, Medical Faculty, University of Tromsø, Norway.
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20
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Seno H, Satoh K, Tsuji S, Shiratsuchi T, Harada Y, Hamajima N, Sugano K, Kawano S, Chiba T. Novel interleukin-4 and interleukin-1 receptor antagonist gene variations associated with non-cardia gastric cancer in Japan: comprehensive analysis of 207 polymorphisms of 11 cytokine genes. J Gastroenterol Hepatol 2007; 22:729-37. [PMID: 17444864 DOI: 10.1111/j.1440-1746.2007.04934.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Helicobacter pylori (H. pylori)-induced chronic atrophic gastritis is a high-risk factor for gastric cancer. Immune responses to H. pylori are involved in gastric mucosal inflammation, and might affect clinical outcome, including the development of gastric cancer. The present study examines the significance of gene polymorphisms of various cytokines in the development of gastric cancer following H. pylori infection. METHODS One hundred Japanese non-cardia gastric cancer patients and 93 dyspeptic patients as controls were enrolled in the study (age range 50-75 years). All patients were positive for H. pylori. Genomic DNA was extracted from peripheral whole blood leukocytes, and we comprehensively analyzed 207 single nucleotide polymorphisms (SNP) in 11 cytokine genes; interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (RN), IL-4, IL-4R, IL-8, IL-10, IL-12, TNF-alpha, TNF-beta, and IFN-gamma, using either invader assay (163 SNP), direct sequencing (22 SNP), or PCR-restriction fragment length polymorphism (22 SNP). RESULTS Among the 207 SNP examined, the IL-4 gene diplotypes (984 and 2983 AA/GA) had a significant negative association with gastric cancer development (odds ratio =0.3, 95% confidence interval =0.1-0.9). When we adopted the dyspeptic patients over 66 years of age as the controls, the IL-1RN gene diplotypes (-1102 and 6110 CG/GA) also had a significant negative association (odds ratio =0.2, 95% confidence interval =0.1-0.7). CONCLUSION A comprehensive analysis of 207 SNP of 11 cytokine genes revealed that variations in IL-4 and IL-1RN genes are negatively associated with the risk of developing gastric cancer following H. pylori infection. Distinct host cytokine responses in the gastric mucosa might have a role in H. pylori-induced carcinogenesis.
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Affiliation(s)
- Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Robinson K, Argent RH, Atherton JC. The inflammatory and immune response to Helicobacter pylori infection. Best Pract Res Clin Gastroenterol 2007; 21:237-59. [PMID: 17382275 DOI: 10.1016/j.bpg.2007.01.001] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Lifelong Helicobacter pylori infection and its associated gastric inflammation underlie peptic ulceration and gastric carcinogenesis. The immune and inflammatory responses to H. pylori are doubly responsible: gastric inflammation is the main mediator of pathology, and the immune and inflammatory response is ineffective, allowing lifelong bacterial persistence. However, despite inducing gastric inflammation, most infections do not cause disease, and bacterial, host and environmental factors determine individual disease risk. Although H. pylori avoids many innate immune receptors, specific virulence factors (including those encoded on the cag pathogenicity island) stimulate innate immunity to increase gastric inflammation and increase disease risk. An acquired T helper 1 response upregulates local immune effectors. The extent to which environmental factors (including parasite infection), host factors and H. pylori itself influence T-helper differentiation and regulatory T-cell responses remains controversial. Finally, effective vaccines have still not been developed: a better understanding of the immune response to H. pylori may help.
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Affiliation(s)
- Karen Robinson
- Wolfson Digestive Diseases Centre, University of Nottingham, C Floor, South Block, Queen's Medical Centre Campus, Nottingham University Hospital NHS Trust, Nottingham NG7 2UH, UK.
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22
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Wex T, Treiber G, Venerito M, Leodolter A, Peitz U, Kuester D, Hritz I, Krueger S, Roessner A, Malfertheiner P. Helicobacter pylori-induced downregulation of the secretory leukocyte protease inhibitor (SLPI) in gastric epithelial cell lines and its functional relevance for H. pylori-mediated diseases. Biol Chem 2006; 387:893-901. [PMID: 16913839 DOI: 10.1515/bc.2006.113] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The secretory leukocyte protease inhibitor (SLPI) exerts antiproteolytic activity towards serine proteases, as well as anti-microbial and anti-inflammatory effects. To investigate its role in H. pylori-mediated diseases, SLPI expression was analyzed by RT-PCR, ELISA and immunohistochemistry in clinical samples and gastric tumor cell lines. Determination of the mucosal SLPI levels in 126 patients confirmed the previously reported downregulation of SLPI in H. pylori-infected patients. The lower SLPI levels in antral biopsies of H. pylori-positive subjects were associated with a 30-fold increase (p<0.01) in neutrophil elastase activity, and a significant negative correlation was demonstrated for both parameters (R=-0.63, p=0.0002). Eradication of the bacterium in a long-term study (5-7 years) led to a recovery of mucosal SLPI expression. In vitro experiments using four gastric tumor cell lines (AGS, MKN-28, MKN-45, NCI-N87) generally confirmed the clinical findings. While the co-incubation of these cell lines with H. pylori resulted in lower or unchanged SLPI protein levels, the corresponding SLPI mRNA amounts were upregulated by up to five-fold (p=0.006) in all cell lines. Taken together, these results indicate that the reduction in antral SLPI levels in H. pylori-infected subjects has a functional relevance for gastric mucosa and the H. pylori-induced decrease in SLPI is primarily regulated at the posttranslational level.
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Affiliation(s)
- Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, D-39120 Magdeburg, Germany.
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23
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Vorobjova T, Ren Z, Dunkley M, Clancy R, Maaroos HI, Labotkin R, Kull K, Uibo R. Response of IgG1 and IgG2 subclasses to Helicobacter pylori in subjects with chronic inflammation of the gastric mucosa, atrophy and gastric cancer in a country with high Helicobacter pylori infection prevalence. APMIS 2006; 114:372-380. [PMID: 16725014 DOI: 10.1111/j.1600-0463.2006.apm_392.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Polarized immune response to Helicobacter pylori and induction of chronic inflammation may increase the risk of gastric atrophy and adenocarcinoma. We studied the association of the response of IgG1 and IgG2 antibodies to H. pylori with grade of gastric chronic inflammation and atrophy in a population with a high prevalence of H. pylori, and compared these data with the data obtained from the study of gastric cancer patients, as well as with the data for CagA positivity. Altogether, 114 persons from two adult population samples from Estonia and 45 consecutive gastric cancer patients were studied. All patients were positive for the H. pylori antibody determined by ELISA. Adenocarcinoma was classified histologically according to the Laurén's system. The response of the IgG subclasses to H. pylori (acid glycine-extracted whole cell proteins) was determined by ELISA and the results were compared with the ELISA results for the recombinant fragment of the CagA protein. Helicobacter pylori IgG level was lower in atrophic gastritis compared with nonatrophic gastritis (chronic inflammation) (p=0.001). In the group of cancer patients, the response of IgG and IgG1 was lower compared with both gastritis groups (p=0.01 and p=0.0002 for IgG, and p=0.001 and p=0.0005 for IgG1). IgG2 was lower for gastric cancer localized in the corpus (p=0.03). In conclusion, atrophic gastritis and gastric cancer were associated with a significant decline in IgG and IgG1 response to H. pylori compared with nonatrophic gastritis. Higher value of CagA antibodies was seen in gastric cancer and in gastric atrophy compared with nonatrophic gastritis; in gastric cancer patients, IgG1 response to H. pylori was correlated with CagA status.
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Affiliation(s)
- Tamara Vorobjova
- Centre of Molecular and Clinical Medicine, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia.
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Chiba T, Seno H, Marusawa H, Wakatsuki Y, Okazaki K. Host factors are important in determining clinical outcomes of Helicobacter pylori infection. J Gastroenterol 2006; 41:1-9. [PMID: 16501851 DOI: 10.1007/s00535-005-1743-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2005] [Accepted: 12/21/2005] [Indexed: 02/04/2023]
Affiliation(s)
- Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kawahara-cho 54, Shogoin, Sakyo, Kyoto, 606-8507, Japan
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25
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Ernst PB, Peura DA, Crowe SE. The translation of Helicobacter pylori basic research to patient care. Gastroenterology 2006; 130:188-206; quiz 212-3. [PMID: 16401482 DOI: 10.1053/j.gastro.2005.06.032] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2005] [Accepted: 06/09/2005] [Indexed: 12/14/2022]
Abstract
In 1984, Barry Marshall and Robin Warren proposed a role for bacterial infections in the pathogenesis of gastroduodenal disease, which triggered an avalanche of research intended to prove or disprove their theory. The result has been a series of advances that have enhanced our understanding of these diseases and completely modernized the clinical approach to their management. In just over 20 years, many aspects of the immunopathogenesis of these diseases have been dissected at the molecular level, with key pathogenic mechanisms being validated by the identification of genes that are associated with the development of gastric cancer. There has been particular emphasis on understanding the molecular structures associated with Helicobacter pylori and their role in modifying the host responses. Gastric immune and inflammatory responses have emerged as key elements in the pathogenesis of gastritis and epithelial cell damage. This review summarizes important findings emanating from basic research primarily related to the immunopathogenesis of H pylori that have advanced the practice of medicine or our understanding of gastroduodenal disease.
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Affiliation(s)
- Peter B Ernst
- Digestive Health Center of Excellence, Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia 22908-0708, USA.
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Itoh T, Seno H, Kita T, Chiba T, Wakatsuki Y. Th response to Helicobacter pylori differs between patients with gastric ulcer and duodenal ulcer. Scand J Gastroenterol 2005; 40:641-7. [PMID: 16036523 DOI: 10.1080/00365520510015520] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Helicobacter pylori (H. pylori) infection induces both gastric (GU) and duodenal ulcers (DU). We examined whether host immunological response to H. pylori determines different disease outcomes. MATERIAL AND METHODS Thirty-two GU and 28 DU patients infected with H. pylori, and 24 dyspeptic patients without infection were enrolled. The constituents of cellular infiltrates in biopsies from each patient were determined and lymphokines secreted by stimulated T cells were measured. Serum concentrations of IgG subclasses specific to H. pylori were measured. RESULTS Low pepsinogen I and high pepsinogen II levels were observed in GU patients, while a high pepsinogen I level was found in DU patients. T cells predominate over other cell types in both GU and DU patients. GU patients had a higher number of T cells (p < 0.01) and lower plasma cells (p < 0.05) than those in DU patients. T cells from GU patients produced greater amounts of IFN-gamma and less IL-4 than those in DU patients (p < 0.01). GU patients had a higher serum level of IgG2 specific to H. pylori than that in DU patients (p < 0.01). CONCLUSIONS Th response by gastric T cells in GU patient was more polarized to Th1 as compared with that in DU patients, suggesting that a distinct immune response to H. pylori induces different disease outcomes.
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Affiliation(s)
- Toshiyuki Itoh
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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27
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Lu AP, Zhang SS, Zha QL, Ju DH, Wu H, Jia HW, Xiao C, Li S, Jian H. Correlation between CD4, CD8 cell infiltration in gastric mucosa, Helicobacter pylori infection and symptoms in patients with chronic gastritis. World J Gastroenterol 2005; 11:2486-90. [PMID: 15832423 PMCID: PMC4305640 DOI: 10.3748/wjg.v11.i16.2486] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the correlation between CD4, CD8 cell infiltration in gastric mucosa, Helicobacter pylori (H pylori) infection and symptoms or the assemblage of symptoms in cases with chronic gastritis.
METHODS: Biopsy samples at the gastric antrum were obtained from 62 patients with chronic gastritis. CD4 and CD8 cell infiltration was evaluated by immunohistochemical assays on frozen sections of the biopsy samples. Fifteen symptoms referring to digestion-related activity and non-digestion related activity were observed. The correlation between lymphocyte infiltration and each symptom or symptom assemblage was analyzed by logistic regression and K-mean cluster methods.
RESULTS: CD4 cell infiltrations in gastric mucosa were much more in patients with H pylori infection, while CD8 cell infiltrations were similar in patients with or without H pylori infection. Logistic regression analysis showed that the symptoms including heavy feeling in head or body (t = 2.563), and thirst (t = 2.478) were significantly related with CD4 cell infiltration in gastric mucosa (P<0.05), and cool limbs with aversion to cold were related with CD8 cell infiltration (t = 2.872, P<0.05). Further analysis showed that non-digestive related symptom assemblage could increase the predicted percentage of CD4 and CD8 cell infiltration in gastric mucosa, including lower CD4 infiltration by 12.5%, higher CD8 infiltration by 33.3%, and also non-H pylori infection by 23.6%. K-means cluster analysis of all symptoms and CD4 and CD8 cell infiltration in gastric mucosa showed a similar tendency to increase the predicted percentage of CD4, CD8 cell infiltration and H pylori infection.
CONCLUSION: Based on correlation between the gastric mucosa lymphocyte infiltration, H pylori infection and clinical symptoms, symptoms or symptomatic assemblages play an important role in making further classification of chronic gastritis, which might help find a more specific therapy for chronic gastritis.
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Affiliation(s)
- Ai-Ping Lu
- Institute of Basic Theory, China Academy of Traditional Chinese Medicine, Dongzhimen, Beijing 100700, China.
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28
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Ren Z, Borody T, Pang G, Dunkley M, Clancy R, Xia HHX, Chu KM, Wong J, Wong BCY. Evaluation of anti-Helicobacter pylori IgG2 antibody for the diagnosis of Helicobacter pylori infection in western and Chinese populations. Aliment Pharmacol Ther 2005; 21:83-89. [PMID: 15644049 DOI: 10.1111/j.1365-2036.2004.02293.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The performance of commercial Helicobacter pylori diagnostic kits developed for particular geographic regions has often been found to be of poor diagnostic value when applied to other regions, possibly because of infections being caused by different H. pylori strains in different regions. AIM To evaluate the performance of an IgG2 anti-H. pylori enzyme-linked immunoassay test (Helirad Alert) for detection of H. pylori infection in both Australian and Hong Kong (Chinese) subjects. METHODS Serum samples were tested for H. pylori specific IgG2 and IgG antibodies by enzyme-linked immunoassay kits using identical antigen preparation in 168 Australian and 160 Hong Kong (Chinese) subjects diagnosed with dyspepsia. RESULTS Using a cut-off value determined by analysis of H. pylori-negative Australian samples, the sensitivity, specificity and accuracy of the IgG2 assay were 77.8, 97.4 and 91.1%, respectively, for the Australian samples and 96.3, 83.8 and 90% for Hong Kong samples. For the IgG assay, sensitivity, specificity and accuracy were 87.0, 99.1 and 95.2% for Australian samples and 97.5, 75 and 86.3% for Hong Kong samples respectively. Receiver-operating characteristic analysis showed better discrimination of H. pylori status when the IgG2 assay was applied to Hong Kong samples, while the IgG assay was better in the Australian samples. CONCLUSION These data demonstrate that the Helirad Alert enzyme-linked immunoassay could provide a reliable method for screening H. pylori infection in both western and Chinese populations.
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Affiliation(s)
- Z Ren
- VRI BioMedical Limited, Newcastle Unit, Newcastle, NSW, Australia.
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29
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Goll R, Husebekk A, Isaksen V, Kauric G, Hansen T, Florholmen J. Increased Frequency of Antral CD4+ T and CD19+ B Cells in Patients with Helicobacter pylori-Related Peptic Ulcer Disease. Scand J Immunol 2005; 61:92-7. [PMID: 15644128 DOI: 10.1111/j.0300-9475.2005.01537.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Only a fraction of Helicobacter pylori (HP)-infected individuals develop clinical disease. Recent research indicates that immunological mechanisms may be important for understanding the pathophysiology of HP infection. Differences in the individual cellular immune response may reflect the clinical diversity. The aim of the present study was to investigate the cellular immune response against HP in three clinically well-defined patient groups: HP-positive peptic ulcer, HP-positive and HP-negative gastritis. Biopsies from gastric mucosa were processed for analysis by flow cytometry and histology. The number of T lymphocytes (CD3+) was significantly higher in HP-positive peptic ulcer (13.8%) than in HP-positive nonulcer gastritis (6.3%). A nonsignificant increase for B lymphocytes (CD19+) was noted as well. Furthermore, a significant difference was seen in mucosal CD4/CD8 ratio between HP ulcer (2.4) and nonulcer HP gastritis (1.0) patients. Thus, B cells (CD19+) and T-helper cells (CD4+) were dominant in gastric mucosa from peptic ulcer patients, and cytotoxic T cells (CD8+) were relatively dominant in gastric mucosa from nonulcer patients. In conclusion, distinct differences in the T-cell subset distribution of mucosal lymphocytes were detected in patients with HP infection, strongly correlated with the presence or absence of peptic ulcer.
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Affiliation(s)
- R Goll
- Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
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30
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Campbell DI, Pearce MS, Parker L, Thomas JE. IgG subclass responses in childhood Helicobacter pylori duodenal ulcer: evidence of T-helper cell type 2 responses. Helicobacter 2004; 9:289-92. [PMID: 15270742 DOI: 10.1111/j.1083-4389.2004.00234.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Duodenal ulcer in adults chronically infected with Helicobacter pylori is associated with a polarized T-helper cell type 1 (Th1) mucosal immune response, with a predominantly immunoglobulin G2 (IgG2) systemic specific response. It has been suggested that children colonized by H. pylori also produce a mucosal Th1 response, but there are few studies that have measured IgG subclass responses in children with duodenal ulcer. MATERIALS AND METHODS Seven children with endoscopically proven duodenal ulcer and H. pylori infection and 18 children with biopsy proven H. pylori infection but no duodenal ulcer had relative concentrations of IgG subclass responses (IgGsc) against H. pylori antigens measured by ELISA. Eighteen IgG seropositive adults acted as controls. The range of antigens recognised by IgG1 and IgG2 subclass responses were investigated by Western blots. RESULTS There were no differences in mean IgGsc responses between children with or without duodenal ulcer. Adults produced an IgG2 predominant response. Western blots showed no qualitative differences in antigens recognised by IgG1 or IgG2. CONCLUSION Children with duodenal ulcer, in contrast to adults, produce an IgGsc response consistent with a mucosal Th2 response to H. pylori regardless of the presence of duodenal ulceration. This suggests that disease causation amongst children with H. pylori associated duodenal ulceration may not be dependant upon a mucosal Th1 biased response.
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Affiliation(s)
- David I Campbell
- Paediatric and Life Course Epidemiology Research Group, School of Clinical and Medical Sciences (Child Health), University of Newcastle-upon-Tyne, Royal Victoria Infirmary, UK.
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31
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Yamori M, Yoshida M, Watanabe T, Shirai Y, Iizuka T, Kita T, Wakatsuki Y. Antigenic activation of Th1 cells in the gastric mucosa enhances dysregulated apoptosis and turnover of the epithelial cells. Biochem Biophys Res Commun 2004; 316:1015-21. [PMID: 15044086 DOI: 10.1016/j.bbrc.2004.02.145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2004] [Indexed: 11/26/2022]
Abstract
Colonization of Helicobacter pylori in the stomach leads to chronic gastritis with massive infiltration by Th1 cells. To assess a role played by those T cells in the remodeling of gastric epithelium, we activated gastric T cells utilizing mice with CD4 T cells bearing transgenic TCR with or without deficiency in either IL-4 or IFN-gamma or IL-12. Mice developed gastritis upon injection of an antigen into gastric mucosa. While neutrophil infiltration occurred even with a control antigen, infiltration by transgenic T cells was dependent on the specific antigen. The numbers of epithelial cells undergoing apoptosis and regeneration were increased in the mice with infiltrating T cells producing IFN-gamma and the alignment of those cells in the glands was markedly dysregulated. In contrast, mice deficient in Th1 response showed no increase in cell division and apoptosis of epithelial cells. Thus, Th1 type T cells infiltrating into gastric mucosa play an independent role in controlling turnover of epithelial cells.
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Affiliation(s)
- Masashi Yamori
- Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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32
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Dzierzanowska-Fangrat K, Raeiszadeh M, Dzierzanowska D, Gladkowska-Dura M, Celinska-Cedro D, Crabtree JE. IgG subclass response to Helicobacter pylori and CagA antigens in children. Clin Exp Immunol 2004; 134:442-6. [PMID: 14632749 PMCID: PMC1808885 DOI: 10.1111/j.1365-2249.2003.02304.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Specific serum IgG subclass antibodies against Helicobacter pylori antigens and recombinant CagA were analysed in 75 symptomatic children with histologically confirmed H. pylori infection. H. pylori stimulated an IgG1 predominant response, and IgG3 titres showed a positive association with peptic ulcer disease, chronicity of antral inflammation and density of H. pylori colonization. Two methods used for assessing serum IgG CagA antibody status, i.e. Western blotting and enzyme-linked immunosorbent assay (ELISA), were concordant. CagA stimulated an IgG1 and IgG3 predominant humoral response. Total CagA IgG titres were higher in children with active and more severe chronic antral inflammation. These findings suggest that in children the systemic humoral immune response to H. pylori infection may reflect gastroduodenal pathology.
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33
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Itoh T, Yoshida M, Chiba T, Kita T, Wakatsuki Y. A coordinated cytotoxic effect of IFN-gamma and cross-reactive antibodies in the pathogenesis of Helicobacter pylori gastritis. Helicobacter 2003; 8:268-78. [PMID: 12950599 DOI: 10.1046/j.1523-5378.2003.00154.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection is associated with chronic infiltration into the stomach by T cells and plasma cells producing IFN-gamma and antibodies of various specificities, respectively. It is unknown whether these lymphocyte-products may play coordinated roles in the gastric pathology of this infection. AIMS To know how IFN-gamma may relate to anti-H. pylori antibodies in their roles in pathogenesis, we determined the isotype subclass of those antibodies as well as their cross-reactivity and cytotoxicity to gastric epithelium. METHODS AND RESULTS We infected BALB/c mice with H. pylori (SS1, Sydney Strain 1) and generated monoclonal antibodies, which were comprised of 240 independent clones secreting immunoglobulin and included 80 clones reactive to SS1. Ninety percent of the SS1-reactive clones had IgG2a isotype. Two clones, 2B10 and 1A9, were cross reactive to cell surface antigens in H. pylori and to antigens of 28 KDa and 42 KDa, respectively, which were present on the cell surface of and shared by both mouse and human gastric epithelial cells. The antigens recognized by these monoclonal antibodies localized a distinctive area in the gastric glands. In the presence of complement, 2B10 showed cytotoxicity to gastric epithelial cells. The effect was dose dependant and augmented by IFN-gamma. Finally, administration of 2B10 to mice with SS1 infection aggravated gastritis by increasing cellular infiltration. CONCLUSION IFN-gamma by gastric T cells may participate in pathogenesis of the H. pylori infected stomach by directing an isotype-switch of anti-H. pylori antibodies to complement-binding subclass and by augmenting cytotoxic activity of a certain autoantibody. This may explain a host-dependent diversity in gastric pathology of the patients with H. pylori infection.
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Affiliation(s)
- Toshiyuki Itoh
- Department of Clinical Bio-regulatory Science, Kyoto University Graduate School of Medicine, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto city 606-8507, Japan
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34
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Kim JM, Kim JS, Jung HC, Song IS, Kim CY. Up-regulation of inducible nitric oxide synthase and nitric oxide in Helicobacter pylori-infected human gastric epithelial cells: possible role of interferon-gamma in polarized nitric oxide secretion. Helicobacter 2002; 7:116-28. [PMID: 11966872 DOI: 10.1046/j.1083-4389.2002.00068.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Nitric oxide (NO) generated by nitric oxide synthase (NOS) is known to be an important modulator of the mucosal inflammatory response. In this study, we questioned whether Helicobacter pylori infection could up-regulate the epithelial cell inducible NOS (iNOS) gene expression and whether NO production could show polarity that can be regulated by immune mediators. MATERIALS AND METHODS Human gastric epithelial cell lines were infected with H. pylori, and the iNOS mRNA expression was assessed by quantitative RT-PCR. NO production was assayed by determining nitrite/nitrate levels in culture supernatants. To determine the polarity of NO secretion by the H. pylori-infected epithelial cells, Caco-2 cells were cultured as polarized monolayers in transwell chambers, and NO production was measured. RESULTS iNOS mRNA levels were significantly up-regulated in the cells infected with H. pylori, and expression of iNOS protein was confirmed by Western blot analysis. Increased NO production in the gastric epithelial cells was seen as early as 18 hours postinfection, and reached maximal levels by 24 hours postinfection. The specific MAP kinase inhibitors decreased H. pylori-induced iNOS and NO up-regulation. After H. pylori infection of polarized epithelial cells, NO was released predominantly into the apical compartment, and IL-8 was released predominantly into basolateral compartment. The addition of IFN-gamma to H. pylori-infected polarized epithelial cells showed a synergistically higher apical and basolateral NO release. CONCLUSION These results suggest that apical NO production mediated by MAP kinase in H. pylori-infected gastric epithelial cells may influence the bacteria and basolateral production of NO and IL-8 may play a role in the tissue inflammation.
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Affiliation(s)
- Jung Mogg Kim
- Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul 133-791, Korea
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35
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Uchida K, Okazaki K, Debrecceni A, Nishi T, Iwano H, Inai M, Uose S, Nakase H, Ohana M, Oshima C, Matsushima Y, Kawanami C, Hiai H, Masuda T, Chiba T. Analysis of cytokines in the early development of gastric secondary lymphoid follicles in Helicobacter pylori-infected BALB/c mice with neonatal thymectomy. Infect Immun 2001; 69:6749-54. [PMID: 11598047 PMCID: PMC100052 DOI: 10.1128/iai.69.11.6749-6754.2001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Immunological interaction between the host and Helicobacter pylori seems to play a critical role in follicular formation in gastric mucosa. We reported H. pylori-induced follicular gastritis model using neonatally thymectomized mice. In this study, we investigated the involvement of various cytokines in this model. BALB/c mice were thymectomized on the third day after birth (nTx). At 6 weeks old, these mice were orally infected with H. pylori. Histological studies showed that follicular formation occurred from 8 weeks after the infection and that most of the infiltrating lymphocytes were CD4(+) and B cells. Neutrophils increased transiently at 1 week after the infection. Gamma interferon, interleukin-7 (IL-7), and IL-7 receptor were expressed in the stomach of the nTx mice irrespective of the infection. In contrast, expressions of the tumor necrosis factor alpha, IL-4 and lymphotoxin-alpha genes were remarkably upregulated by the infection. Our findings suggest that follicular formation may require cooperative involvement of a Th2-type immune response, tumor necrosis factor alpha and lymphotoxin-alpha in addition to the Th1-type immune response in H. pylori-induced gastritis in nTx mice.
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Affiliation(s)
- K Uchida
- Department of Gastroenterology and Endoscopic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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36
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Amjad M, Kazmi SU, Qureshi SM, Reza-ul Karim M. Inhibitory effect of IL-4 on the production of IL-1 beta and TNF-alpha by gastric mononuclear cells of Helicobacter pylori infected patients. Ir J Med Sci 2001; 170:112-6. [PMID: 11491045 DOI: 10.1007/bf03168822] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The mechanisms by which Helicobacter pylori damages host tissues are complex and unclear. AIMS To determine the effect interleukin (IL)-4 and interferon-gamma (IFN-gamma) on the production of proinflammatory cytokines by the gastric mononuclear cells of H. pylori infected patients was determined. METHODS The effect of IL-4 and IFN-gamma on the production of proinflammatory cytokines by the gastric mononuclear cells of H. pylori infected patients was determined. RESULTS IL-4 markedly reduced the production of IL-1 beta and tumour necrosis factor-a (TNF-alpha) by the gastric mononuclear cells of H. pylori infected patients (P < 0.01). Enzyme-linked immunospot (ELISPOT) assay indicated a decrease in IL-4 producing cells (P < 0.05) and an increase in IFN-gamma secreting cells (P < 0.01). CONCLUSIONS The increased level of proinflammatory cytokines may be due to hyposecretion of IL-4 in H. pylori infected patients. T helper type 1 (Th1) immune response with increased IFN-gamma also contributes to the inflammation of the gastric mucosa.
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Affiliation(s)
- M Amjad
- Department of Microbiology, University of Karachi, Karachi, Pakistan
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37
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Meyer F, Wilson KT, James SP. Modulation of innate cytokine responses by products of Helicobacter pylori. Infect Immun 2000; 68:6265-72. [PMID: 11035734 PMCID: PMC97708 DOI: 10.1128/iai.68.11.6265-6272.2000] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The gastric inflammatory and immune response in Helicobacter pylori infection may be due to the effect of different H. pylori products on innate immune mechanisms. The aim of this study was to determine whether bacterial components could modulate cytokine production in vitro and thus contribute to Th1 polarization of the gastric immune response observed in vivo. The effect of H. pylori recombinant urease, bacterial lysate, intact bacteria, and bacterial DNA on proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) from H. pylori-negative donors was examined as a model for innate cytokine responses. Each of the different H. pylori preparations induced gamma interferon (IFN-gamma) and interleukin-12p40 (IL-12p40), but not IL-2 or IL-5, production, and all but H. pylori DNA stimulated release of IL-10. Addition of anti-IL-12 antibody to cultures partially inhibited IFN-gamma production. In addition, each bacterial product inhibited mitogen-stimulated IL-2 production by PBMCs and Jurkat T cells. The inhibitory effect of bacterial products on IL-2 production correlated with inhibition of mitogen-stimulated lymphocyte proliferation, although urease inhibited IL-2 production without inhibiting proliferation, suggesting that inhibition of IL-2 production alone is not sufficient to inhibit lymphocyte proliferation. The results of these studies demonstrate that Th1 polarization of the gastric immune response may be due in part to the direct effects of multiple different H. pylori components that enhance IFN-gamma and IL-12 production while inhibiting both IL-2 production and cell proliferation that may be necessary for Th2 responses.
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Affiliation(s)
- F Meyer
- Division of Gastroenterology, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA
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38
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Shirai Y, Wakatsuki Y, Kusumoto T, Nakata M, Yoshida M, Usui T, Iizuka T, Kita T. Induction and maintenance of immune effector cells in the gastric tissue of mice orally immunized to Helicobacter pylori requires salivary glands. Gastroenterology 2000; 118:749-59. [PMID: 10734026 DOI: 10.1016/s0016-5085(00)70144-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Helicobactor pylori mostly colonizes the gastric mucus that contains salivary antibodies. We studied the role of saliva in the induction and maintenance of gastric immunity conferred by oral vaccination against H. pylori. METHODS C57BL/6 mice underwent a sialoadenectomy before and after intragastric immunization using whole-cell sonicates of H. pylori and cholera toxin as an adjuvant. At 1 and 6 months after oral inoculation, we assessed the density of the H. pylori colonizing the stomach, specific antibodies in gastric secretion and sera, and the constituents of cellular infiltrates in the tissue. RESULTS A sialoadenectomy before, but not after, immunization abrogated protection by the vaccination at 1 month after inoculation. Protected mice had more neutrophils, plasma cells, and lymphocytes, but fewer eosinophils, in the gastric tissue than nonprotected mice. Protected mice had a greater increase of immunoglobulin (Ig) G1 specific to H. pylori than IgG2a in sera. At 6 months after inoculation, oral immunization was less effective in mice who had a sialoadenectomy than in control immunized mice. The antibody titers in both gastric secretion and in sera did not correlate with the density of bacteria colonizing the stomach. CONCLUSIONS It is suggested that, in intragastric immunization against H. pylori, saliva is necessary for both the induction and maintenance of optimal immunity in the stomach. Effective immunity was associated with an increased number of neutrophils and lymphocytes in gastric tissue.
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Affiliation(s)
- Y Shirai
- Department of Clinical Bioregulatory Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
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