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Xia T, Zhang Z, Xie J, Yuan H, Ren Y, Xu Y, Ning J, Li B, Wu C. Gastric mucosal CD8 +T RM cells are recruited through CXCR5-CXCL13 axis in Helicobacter pylori infected subjects. Cytokine 2025; 190:156904. [PMID: 40088523 DOI: 10.1016/j.cyto.2025.156904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/16/2025] [Accepted: 02/27/2025] [Indexed: 03/17/2025]
Abstract
Gastric mucosal CD8+ tissue-resident memory T (CD8+TRM) cells are increased in Helicobacter pylori (H. pylori) infected subjects, but the characteristics and chemotactic mechanism of CD8+TRM cells remain unknown. We demonstrated that C-X-C chemokine receptor 5 (CXCR5) was upregulated on gastric mucosal CD8+TRM cells, and gastric CXCL13 was dominantly secreted by dendritic cells and macrophages in H. pylori infected subjects. Gastric mucosal CD8+TRM cells from CagA+ H. pylori infected subjects was increased and could secrete more IFN-γ and TNF-α to engage in local immune response. The number of gastric mucosal CD8+TRM cells and the expression of CXCL13 was elevated in H. pylori infected individuals with the development of gastric diseases. In conclusion, gastric mucosal CD8+TRM cells are increased from CagA+ H. pylori infected subjects and could be recruited through CXCL13-CXCR5 axis, which mainly release IFN-γ and TNF-α in H. pylori related immune response.
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Affiliation(s)
- Tingting Xia
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zelin Zhang
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jia Xie
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Hanmei Yuan
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yayi Ren
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yue Xu
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jie Ning
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Bin Li
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Chao Wu
- Department of Laboratory Medicine, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
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2
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Bian L, Hu B, Li F, Gu Y, Hu C, Chen Y, Deng B, Fang H, Zhu X, Chen Y, Fu X, Wang T, She Q, Zhu M, Jiang Y, Dai J, Xu H, Ma H, Xu Z, Hu Z, Shen H, Ding Y, Yan C, Jin G. Single-cell eQTL mapping reveals cell-type-specific genes associated with the risk of gastric cancer. CELL GENOMICS 2025; 5:100812. [PMID: 40112817 PMCID: PMC12008807 DOI: 10.1016/j.xgen.2025.100812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 01/05/2025] [Accepted: 02/18/2025] [Indexed: 03/22/2025]
Abstract
Most expression quantitative trait locus (eQTL) analyses have been conducted in heterogeneous gastric tissues, limiting understanding of cell-type-specific regulatory mechanisms. Here, we employed a pooled multiplexing strategy to profile 399,683 gastric cells from 203 Chinese individuals using single-cell RNA sequencing (scRNA-seq). We identified 19 distinct gastric cell types and performed eQTL analyses, uncovering 8,498 independent eQTLs, with a considerable fraction (81%, 6,909/8,498) exhibiting cell-type-specific effects. Integration of these eQTLs with genome-wide association studies for gastric cancer (GC) revealed four co-localization signals in specific cell types. Genetically predicted cell-type-specific gene expression identified 15 genes associated with GC risk, including the upregulation of MUC1 exclusively in parietal cells, linked to decreased GC risk. Our findings highlight substantial heterogeneity in the genetic regulation of gene expression across gastric cell types and provide critical cell-type-specific annotations of genetic variants associated with GC risk, offering new molecular insights underlying GC.
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Affiliation(s)
- Lijun Bian
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi 214023, China
| | - Beiping Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Fengyuan Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yuanliang Gu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Caihong Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Yuheng Chen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Bin Deng
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China
| | - Haisheng Fang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xia Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Yan Chen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Xiangjin Fu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Tianpei Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Qiang She
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China
| | - Meng Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Yue Jiang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Juncheng Dai
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hongxia Ma
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhibin Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Hongbing Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China; Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yanbing Ding
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
| | - Caiwang Yan
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi 214023, China; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.
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3
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Sun M, Liu Y, Ni X, Tan R, Wang Y, Jiang Y, Ke D, Du H, Guo G, Liu K. Intranasal immunization with poly I:C and CpG ODN adjuvants enhances the protective efficacy against Helicobacter pylori infection in mice. Microbes Infect 2025; 27:105433. [PMID: 39461584 DOI: 10.1016/j.micinf.2024.105433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 10/29/2024]
Abstract
Helicobacter pylori (H. pylori) infection is a serious public health issue, and development of vaccines is a desirable preventive strategy for H. pylori. Toll-like receptor (TLR) ligands have shown potential as vaccine adjuvants that induce immune responses, but polyinosinic-polycytidylic acid (poly I:C), a nucleic acid-based TLR9 ligand, is less well studied in H. pylori vaccine research. Here, we evaluated the effects of poly I:C and CpG oligodeoxynucleotide (CpG ODN), a nucleic acid TLR3 ligand, as adjuvants in combination with the H. pylori recombinant proteins LpoB and UreA to protect against H. pylori infection. For analysis of specific immune responses, the levels of specific antibodies and splenic cytokines were measured in the immunized mice. Compared with CpG ODN, poly I:C could induce mucosal sIgA antibody responses and reduce H. pylori colonization. Additionally, the combination of poly I:C and CpG ODN caused greater immunoprotection and significantly reduced gastritis, exerting synergistic effects. Analysis of splenic cytokines revealed that poly I:C mainly triggered a mixed Th1/Th2/Th17 immune response, whereas the combination of CpG ODN and poly I:C induced a Th1/Th17 immune response. Our findings indicated that increased levels of mucosal sIgA antibodies and a robust splenic Th1/Th17 immune response were associated with reduced H. pylori colonization in vaccinated mice. This study identified a potential TLR ligand adjuvant for developing more effective H. pylori vaccines.
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Affiliation(s)
- Min Sun
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yu Liu
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiumei Ni
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Runqing Tan
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Wang
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yajun Jiang
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dingxin Ke
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Han Du
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gang Guo
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Kaiyun Liu
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
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Anthofer M, Windisch M, Haller R, Ehmann S, Wrighton S, Miller M, Schernthanner L, Kufferath I, Schauer S, Jelušić B, Kienesberger S, Zechner EL, Posselt G, Vales-Gomez M, Reyburn HT, Gorkiewicz G. Immune evasion by proteolytic shedding of natural killer group 2, member D ligands in Helicobacter pylori infection. Front Immunol 2024; 15:1282680. [PMID: 38318189 PMCID: PMC10839011 DOI: 10.3389/fimmu.2024.1282680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 01/02/2024] [Indexed: 02/07/2024] Open
Abstract
Background Helicobacter pylori (H. pylori) uses various strategies that attenuate mucosal immunity to ensure its persistence in the stomach. We recently found evidence that H. pylori might modulate the natural killer group 2, member 2 (NKG2D) system. The NKG2D receptor and its ligands are a major activation system of natural killer and cytotoxic T cells, which are important for mucosal immunity and tumor immunosurveillance. The NKG2D system allows recognition and elimination of infected and transformed cells, however viruses and cancers often subvert its activation. Here we aimed to identify a potential evasion of the NKG2D system in H. pylori infection. Methods We analyzed expression of NKG2D system genes in gastric tissues of H. pylori gastritis and gastric cancer patients, and performed cell-culture based infection experiments using H. pylori isogenic mutants and epithelial and NK cell lines. Results In biopsies of H. pylori gastritis patients, NKG2D receptor expression was reduced while NKG2D ligands accumulated in the lamina propria, suggesting NKG2D evasion. In vitro, H. pylori induced the transcription and proteolytic shedding of NKG2D ligands in stomach epithelial cells, and these effects were associated with specific H. pylori virulence factors. The H. pylori-driven release of soluble NKG2D ligands reduced the immunogenic visibility of infected cells and attenuated the cytotoxic activity of effector immune cells, specifically the anti-tumor activity of NK cells. Conclusion H. pylori manipulates the NKG2D system. This so far unrecognized strategy of immune evasion by H. pylori could potentially facilitate chronic bacterial persistence and might also promote stomach cancer development by allowing transformed cells to escape immune recognition and grow unimpeded to overt malignancy.
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Affiliation(s)
- Margit Anthofer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Markus Windisch
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Rosa Haller
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Sandra Ehmann
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Michael Miller
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Iris Kufferath
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Silvia Schauer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Barbara Jelušić
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Sabine Kienesberger
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
- Interuniversity Cooperation, BioTechMed-Graz, Graz, Austria
| | - Ellen L. Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
- Interuniversity Cooperation, BioTechMed-Graz, Graz, Austria
| | - Gernot Posselt
- Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Salzburg, Austria
| | - Mar Vales-Gomez
- Department of Immunology and Oncology, Spanish National Centre for Biotechnology, Madrid, Spain
| | - Hugh T. Reyburn
- Department of Immunology and Oncology, Spanish National Centre for Biotechnology, Madrid, Spain
| | - Gregor Gorkiewicz
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Interuniversity Cooperation, BioTechMed-Graz, Graz, Austria
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Helicobacter pylori Chronic-Stage Inflammation Undergoes Fluctuations That Are Altered in tlpA Mutants. Infect Immun 2023; 91:e0032222. [PMID: 36533917 PMCID: PMC9872690 DOI: 10.1128/iai.00322-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Helicobacter pylori colonizes half of the world's population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an 8-month mouse infection time course and comparison of the wild type (WT) and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic-stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from the wild type at some time points. tlpA mutants have equivalent total and gland colonization in late-stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to those by WT. Our results suggest the chronic inflammation setting is dynamic and may be influenced by colonization properties of early infection.
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Shimamura M, Kamijo SI, Illarionov P. C-type lectin Mincle-dependent and -independent activation of invariant NKT cells by exposure to Helicobacter pylori α-cholesteryl glucosides. FEBS J 2023; 290:134-147. [PMID: 35920835 DOI: 10.1111/febs.16588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 07/01/2022] [Accepted: 08/03/2022] [Indexed: 01/14/2023]
Abstract
Helicobacter pylori extracts cholesterol from the host and converts it to its glycosides. We found that cholesteryl 6'-O-acyl α-glucoside (ChAcαG) produced by H. pylori is recognised by both invariant Vα14+ NKT (iNKT) cells and a C-type lectin receptor Mincle (Clec4e). However, it is unclear how these duplicated recognitions cooperate and contribute to host defence against H. pylori. Among T cell populations in the liver, iNKT cells predominantly expressed the T cell activation marker CD69 just after stimulation with ChAcαG. The production of IFN-γ and IL-4 was strictly dependent on both CD1d and Jα18 expressions, indicating the necessity of iNKT cell activation for the initiation of immune responses. Production of IFN-γ by iNKT cells was markedly reduced by the Mincle deficiency on antigen-presenting cells (APCs), while IL-4 production was not significantly influenced. IL-2 production by iNKT cell hybridomas was also diminished by the Mincle deficiency upon stimulation with APCs previously loaded with ChAcαG. Here, the immune responses of iNKT cell hybridomas stimulated with wild-type APCs were reduced by the addition of anti-IL-12 blocking antibody to the level stimulated with Mincle-deficient APCs. Collectively, these results suggest that iNKT cells can be activated with the cholesteryl glycosides via a Mincle-dependent, IL-12 signal-dependent pathway and a Mincle-independent, invariant TCR signal-dominant pathway. iNKT cells activated via the Mincle-dependent pathway produce IFN-γ-dominant cytokines; hence, they may contribute to enhancing proinflammatory responses against H. pylori infection.
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Affiliation(s)
- Michio Shimamura
- Tsukuba Research Center for Interdisciplinary Materials Science, University of Tsukuba, Japan.,Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.,School of Science and Technology, Meiji University, Kawasaki, Japan
| | - Shin-Ichi Kamijo
- Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.,LifeWill Corporation, Tokyo, Japan
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Muacevic A, Adler JR, Hirabata A, Tanaka T, Otsuka F, Okada H. Increased CCR4+ and Decreased Central Memory CD4+ T Lymphocytes in the Background Gastric Mucosa of Patients Developing Gastric Cancer After Helicobacter pylori Eradication: An Exploratory Study. Cureus 2022; 14:e31713. [PMID: 36569708 PMCID: PMC9768248 DOI: 10.7759/cureus.31713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2022] [Indexed: 11/22/2022] Open
Abstract
The composition of lymphocytes in the gastric mucosa following the eradication of Helicobacter pylori (H. pylori) in patients with and without gastric cancer has not been compared. This study performed a single spot analysis of gastric mucosal lymphocytes after H. pylori eradication in patients with (n = 13) and without (n = 20) gastric cancer. Our comprehensive analysis of lymphocyte composition in the gastric mucosa revealed that: i) the proportion of CD8+/CD3+ cells was relatively higher in the peri-tumor mucosa than in the background mucosa; ii) the proportion of CCR4+/CD3+ cells was higher, and the ratio of CD62L+/CD3+CD4+ cells was relatively lower in the gastric mucosa of cancer patients than in non-cancer patients; and iii) the proportion of CD45RA-CD62L+/CD3+CD4+ cells, namely, the central memory CD4+ T-cell fraction, was lower in the gastric mucosa of cancer patients than in non-cancer patients. Although the exact mechanism of the altered proportions of CCR4+/CD3+ and central memory CD4+ cells in the gastric mucosa of patients with cancer is unknown, focusing on lymphocytes in the gastric mucosa might help improve our understanding of gastric cancer development after H. pylori eradication.
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8
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Ginger Extract Modulates the Production of Chemokines CCL17, CCL20, CCL22, and CXCL10 and the Gene Expression of Their Receptors in Peripheral Blood Mononuclear Cells from Peptic Ulcer Patients Infected with Helicobacter pylori. Jundishapur J Nat Pharm Prod 2021. [DOI: 10.5812/jjnpp.100824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: The imbalanced expression of chemokines plays critical role in the development of Helicobacter pylori-mediated complications. Objectives: Our aim was to determine ginger extract (GE) effects on the expression of chemokines CCL17, CCL20, CCL22, and CXCL10, as well as CCR4, CCR6, and CXCR3 receptors by peripheral blood mononuclear cells (PBMCs) from H. pylori -infected patients with peptic ulcer (PU). Methods: Peripheral blood mononuclear cells were obtained from 20 patients with H. pylori-associated PU, 20 H. pylori-infected asymptomatic subjects (HAS), and 20 non-infected healthy subjects (NHS). The PBMCs were stimulated by 10 µg/mL of H. pylori-derived crude extract (HPCE) in the presence of 0, 10, 20, and 30 µg/mL of GE. After 36 hours, the supernatant and the RNA extracted from the cells were tested for chemokine concentration and chemokine receptor expression using ELISA and real-time PCR techniques, respectively. Results: In PU patients, treating HPCE-stimulated PBMCs with 10, 20, or 30 µg/mL GE reduced the production of CXCL10 (1.47, 1.5, and 1.53 folds, respectively, P < 0.001 for all), CCL20 (1.44, 1.62, and 1.65 folds, respectively, P < 0.003), and treatment with 30 µg/mL GE increased CCL17 (1.28-fold, P < 0.001) and CCL22 (1.59-fold, P < 0.001) production compared with untreated HPCE-stimulated PBMCs. In PU patients, the HPCE-stimulated PBMCs treated with 10, 20, or 30 µg/mL GE expressed lower levels of CXCR3 (1.9, 3, and 3.5 folds, respectively, P < 0.001) and CCR6 (2.3, 2.7, and 2.8 folds, respectively, P < 0.002) while treating with 10 µg/mL GE upregulated CCR4 (1.7 fold, P = 0.003) compared with untreated HPCE-stimulated PBMCs. Conclusions: Ginger extract modulated the expression of chemokines and their receptors in the PBMCs derived from H. pylori-infected PU patients. The therapeutic potentials of ginger for treating HP-related complications need to be further explored.
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Xie W, Zhao W, Zou Z, Kong L, Yang L. Oral multivalent epitope vaccine, based on UreB, HpaA, CAT, and LTB, for prevention and treatment of Helicobacter pylori infection in C57BL / 6 mice. Helicobacter 2021; 26:e12807. [PMID: 33847026 DOI: 10.1111/hel.12807] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/19/2021] [Accepted: 03/26/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND As the resistance of Helicobacter pylori to traditional triple therapy is gradually revealed, an increasing number of people are focusing on vaccine treatments for H. pylori infection. Epitope vaccines are a promising strategy for the treatment of H. pylori infection, and multivalent vaccines will be more effective than monovalent vaccines. MATERIALS AND METHODS In this study, we designed a multivalent vaccine named LHUC, which consists of the adjuvant LTB as well as three Th cell epitopes (HpaA154-171 , UreB237-251, and UreB546-561 ) and five B-cell epitopes (UreB349-363 , UreB327-334 , CAT394-405 , CAT387-397, and HpaA132-141 ) from UreB, HpaA, and catalase. In BALB/c mice, the specificity and immunogenicity of the fusion peptide LHUC and the neutralization of H. pylori urease and catalase by the specific IgG elicited by LHUC were evaluated. The preventive and therapeutic effects of LHUC were evaluated in C57BL/6 mice infected with H. pylori. RESULTS The results showed that compared with LTB and PBS, LHUC induced specific IgG and IgA antibody production in mice, and IgG antibodies significantly inhibited the H. pylori urease and catalase activities in vitro. Additionally, by detecting the levels of IFN-γ, IL-4, and IL-17 in lymphocyte supernatants, we proved that LHUC could activate Th1, Th2, and Th17 mixed T-cell immune responses in vivo. Finally, a C57BL/6 mouse model of gastric infection with H. pylori was established. The results showed that compared with the effects of LTB and PBS, the prevention and treatment effects of oral inoculation with LHUC significantly inhibited bacterial colonization. CONCLUSIONS In conclusion, LHUC, a multivalent vaccine based on multiple H. pylori antigens, is a promising and safe vaccine that can effectively reduce the colonization of H. pylori in the stomach.
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Affiliation(s)
- Wenwei Xie
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Wenfeng Zhao
- Department of Biochemistry, China Pharmaceutical university, Nanjing, China
| | - Ziling Zou
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Lingyi Kong
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
| | - Lei Yang
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China
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Structure, metabolism and biological functions of steryl glycosides in mammals. Biochem J 2021; 477:4243-4261. [PMID: 33186452 PMCID: PMC7666875 DOI: 10.1042/bcj20200532] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/09/2020] [Accepted: 10/21/2020] [Indexed: 12/20/2022]
Abstract
Steryl glycosides (SGs) are sterols glycosylated at their 3β-hydroxy group. They are widely distributed in plants, algae, and fungi, but are relatively rare in bacteria and animals. Glycosylation of sterols, resulting in important components of the cell membrane SGs, alters their biophysical properties and confers resistance against stress by freezing or heat shock to cells. Besides, many biological functions in animals have been suggested from the observations of SG administration. Recently, cholesteryl glucosides synthesized via the transglycosidation by glucocerebrosidases (GBAs) were found in the central nervous system of animals. Identification of patients with congenital mutations in GBA genes or availability of respective animal models will enable investigation of the function of such endogenously synthesized cholesteryl glycosides by genetic approaches. In addition, mechanisms of the host immune responses against pathogenic bacterial SGs have partially been resolved. This review is focused on the biological functions of SGs in mammals taking into consideration their therapeutic applications in the future.
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11
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Crowley E, Hussey S. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:275-292.e12. [DOI: 10.1016/b978-0-323-67293-1.00027-x] [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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12
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Jafarzadeh A, Nemati M, Jafarzadeh S. The important role played by chemokines influence the clinical outcome of Helicobacter pylori infection. Life Sci 2019; 231:116688. [PMID: 31348950 DOI: 10.1016/j.lfs.2019.116688] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 06/30/2019] [Accepted: 07/22/2019] [Indexed: 02/07/2023]
Abstract
The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Maryam Nemati
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Jafarzadeh
- Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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13
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Fung C, Tan S, Nakajima M, Skoog EC, Camarillo-Guerrero LF, Klein JA, Lawley TD, Solnick JV, Fukami T, Amieva MR. High-resolution mapping reveals that microniches in the gastric glands control Helicobacter pylori colonization of the stomach. PLoS Biol 2019; 17:e3000231. [PMID: 31048876 PMCID: PMC6497225 DOI: 10.1371/journal.pbio.3000231] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 03/29/2019] [Indexed: 12/22/2022] Open
Abstract
Lifelong infection of the gastric mucosa by Helicobacter pylori can lead to peptic ulcers and gastric cancer. However, how the bacteria maintain chronic colonization in the face of constant mucus and epithelial cell turnover in the stomach is unclear. Here, we present a new model of how H. pylori establish and persist in stomach, which involves the colonization of a specialized microenvironment, or microniche, deep in the gastric glands. Using quantitative three-dimensional (3D) confocal microscopy and passive CLARITY technique (PACT), which renders tissues optically transparent, we analyzed intact stomachs from mice infected with a mixture of isogenic, fluorescent H. pylori strains with unprecedented spatial resolution. We discovered that a small number of bacterial founders initially establish colonies deep in the gastric glands and then expand to colonize adjacent glands, forming clonal population islands that persist over time. Gland-associated populations do not intermix with free-swimming bacteria in the surface mucus, and they compete for space and prevent newcomers from establishing in the stomach. Furthermore, bacterial mutants deficient in gland colonization are outcompeted by wild-type (WT) bacteria. Finally, we found that host factors such as the age at infection and T-cell responses control bacterial density within the glands. Collectively, our results demonstrate that microniches in the gastric glands house a persistent H. pylori reservoir, which we propose replenishes the more transient bacterial populations in the superficial mucosa.
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Affiliation(s)
- Connie Fung
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Shumin Tan
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Mifuyu Nakajima
- Department of Biology, Stanford University, Stanford, California, United States of America
| | - Emma C Skoog
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California, United States of America
| | | | - Jessica A Klein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America
| | - Trevor D Lawley
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Jay V Solnick
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California, United States of America
- Department of Medicine, University of California, Davis School of Medicine, Davis, California, United States of America
- Department of Microbiology and Immunology, University of California, Davis School of Medicine, Davis, California, United States of America
| | - Tadashi Fukami
- Department of Biology, Stanford University, Stanford, California, United States of America
| | - Manuel R Amieva
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America
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Wang J, Yao Y, Zhang Q, Li S, Tang L. Inflammatory responses induced by Helicobacter pylori on the carcinogenesis of gastric epithelial GES‑1 cells. Int J Oncol 2019; 54:2200-2210. [PMID: 31081048 DOI: 10.3892/ijo.2019.4775] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 01/01/2019] [Indexed: 11/06/2022] Open
Abstract
Helicobacter pylori (HP) is a pathogenic bacterium associated with chronic gastritis, gastric ulcer and gastric cancer. In the present study, the primary carcinogenesis process of normal gastric epithelial cells (GES‑1) infected with HP was investigated. It was determined that infected gastric mucosal epithelial GES‑1 cells secreted increased interleukin‑8 (IL‑8) and IL‑23, and exhibited enhanced expression of inducible nitric oxide synthase and cyclooxygenase‑2, inducing inflammatory reactions and resulting in apoptosis. The bacterial infection significantly increased the expression of carcinogenesis‑associated genes, including p16, c‑Myc, p53 and p21, as well as the expression of cell surface signaling molecules cluster of differentiation 44 (CD44) and CD54 in GES‑1 cells or tissues of patients with gastritis and gastric cancer in vitro or in vivo. Simultaneously, the migration and invasion abilities of normal gastric epithelial GES‑1 cells were increased following HP infection. These observations demonstrated that the inflammatory response of HP infection could cause normal gastric epithelial cells to undergo significant cancerous reactions, indicating that HP is a risk factor for gastric cancer.
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Affiliation(s)
- Jianjun Wang
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Yongliang Yao
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Qinghui Zhang
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Shasha Li
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Lijun Tang
- Molecular Biology Research Center, School of Life Science, Central South University, Changsha, Hunan 410078, P.R. China
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Vinagre RMDF, Vinagre IDF, Vilar-E-Silva A, Fecury AA, Martins LC. HELICOBACTER PYLORI INFECTION AND IMMUNE PROFILE OF PATIENTS WITH DIFFERENT GASTRODUODENAL DISEASES. ARQUIVOS DE GASTROENTEROLOGIA 2018; 55:122-127. [PMID: 30043859 DOI: 10.1590/s0004-2803.201800000-21] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 01/09/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND The association between infection with Helicobacter pylori and different gastroduodenal diseases is related to bacterial, host and environmental factors. Studies have demonstrated an association between the genetic diversity of H. pylori, especially in the vacA and cagA genes, and the development of digestive diseases such as peptic ulcer and gastric cancer. In addition, the nature of the host inflammatory response may explain these different manifestations of infection caused by this microorganism. In this respect, host factors that regulate the immune and inflammatory responses involving the functional interaction of H. pylori infection with different components of the immune system, particularly T cells, in gastroduodenal diseases still need further investigation. OBJECTIVE To characterize the immune response, including immunity induced by infection with H. pylori, especially virulent strains (vacA alleles and cagA gene), by analyzing the cytokine profile and T-cell population present in gastroduodenal diseases in a Brazilian population. METHODS In a prospective study, gastric biopsies were collected from 554 patients with different gastroduodenal diseases for histological analysis and for the determination of bacterial genotype and cytokine production (IL-4, IL-10, IFN-γ and IL-12) by ELISA. RESULTS The predominant genotype of the H. pylori strains isolated from the patients studied was s1m1cagA+, which was more common among patients with gastric ulcer, duodenal ulcer and gastric cancer. A significant association was observed between the s1m1cagA+ genotype and a higher degree of inflammation, higher neutrophil activity and the development of intestinal metaplasia. The gastric concentrations of IFN-γ and IL-12 were significantly higher in patients infected with H. pylori than in uninfected individuals. Higher levels of these cytokines were detected in patients with gastric ulcer and cancer, while the levels of IL-4 and IL-10 in the gastric mucosa were lower in these patients. In addition, IFN-γ and IL-12 concentrations in gastric biopsies were higher in patients infected with the virulent s1m1cagA+ genotype. In contrast, IL-4 and IL-10 levels were higher in tissue infected with s2m2cagA in gastric biopsies. CONCLUSION Our study shows that the interaction between the type of infectious strain and the Th1 immune response can influence and perpetuate gastric inflammation, and thus contributes to the development of the different clinical manifestations of H. pylori infection.
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Affiliation(s)
| | | | - Adenielson Vilar-E-Silva
- Universidade Federal do Pará, Laboratório de Patologia Clínica de Doenças Tropicais, Belém, PA, Brasil
| | - Amanda Alves Fecury
- Universidade Federal do Pará, Laboratório de Patologia Clínica de Doenças Tropicais, Belém, PA, Brasil
| | - Luisa Caricio Martins
- Universidade Federal do Pará, Laboratório de Patologia Clínica de Doenças Tropicais, Belém, PA, Brasil
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Bravo D, Hoare A, Soto C, Valenzuela MA, Quest AFG. Helicobacter pylori in human health and disease: Mechanisms for local gastric and systemic effects. World J Gastroenterol 2018; 24:3071-3089. [PMID: 30065554 PMCID: PMC6064966 DOI: 10.3748/wjg.v24.i28.3071] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/17/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is present in roughly 50% of the human population worldwide and infection levels reach over 70% in developing countries. The infection has classically been associated with different gastro-intestinal diseases, but also with extra gastric diseases. Despite such associations, the bacterium frequently persists in the human host without inducing disease, and it has been suggested that H. pylori may also play a beneficial role in health. To understand how H. pylori can produce such diverse effects in the human host, several studies have focused on understanding the local and systemic effects triggered by this bacterium. One of the main mechanisms by which H. pylori is thought to damage the host is by inducing local and systemic inflammation. However, more recently, studies are beginning to focus on the effects of H. pylori and its metabolism on the gastric and intestinal microbiome. The objective of this review is to discuss how H. pylori has co-evolved with humans, how H. pylori presence is associated with positive and negative effects in human health and how inflammation and/or changes in the microbiome are associated with the observed outcomes.
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Affiliation(s)
- Denisse Bravo
- Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile
| | - Anilei Hoare
- Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile
| | - Cristopher Soto
- Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile
| | - Manuel A Valenzuela
- Advanced Center for Chronic Diseases, Institute for Health-Related Research and Innovation, Faculty of Health Sciences, Universidad Central de Chile, Santiago 8380447, Chile
| | - Andrew FG Quest
- Advanced Center for Chronic Diseases, Center for Studies on Exercise, Metabolism and Cancer, Biomedical Science Institute, Faculty of Medicine, Universidad de Chile, Santiago 8380447, Chile
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Attenuation of Helicobacter pylori-induced gastric inflammation by prior cag- strain (AM1) infection in C57BL/6 mice. Gut Pathog 2017; 9:14. [PMID: 28286572 PMCID: PMC5343599 DOI: 10.1186/s13099-017-0161-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 02/28/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Helicobacter pylori, colonize in stomach of ~50% of the world population. cag pathogenicity Island of H. pylori is one of the important virulent factors that attributed to gastric inflammation. Coinfection with H. pylori strain with different genetic makeup alters the degree of pathogenicity and susceptibility towards antibiotics. The present study investigates host immunomodulatory effects of H. pylori infection by both cag+ strain (SS1) and cag- strain (AM1). C57BL/6 mice were infected with AM1 or SS1 strain as well as AM1 followed by SS1 (AM1/SS1) and vice versa. RESULTS Mice infected with AM1/SS1 strain exhibited less gastric inflammation and reduced proMMP9 and proMMP3 activities in gastric tissues as compared to SS1/SS1 and SS1/AM1 infected groups. The expression of both MMP9 and MMP3 followed similar trend like activity in infected tissues. Both Th1 and Th17 responses were induced by SS1 strain more profoundly than AM1 strain infection which induced solely Th1 response in spleen and gastric tissues. Moreover, IFN-γ, TNF-α, IL-1β and IL-12 were significantly downregulated in mice spleen and gastric tissues infected by AM1/SS1 compared to SS1/SS1 but not with SS1/AM1 coinfection. Surprisingly, IL-17 level was dampened significantly in AM1/SS1 compared to SS1/AM1 coinfected groups. Furthermore, number of Foxp3+ T-regulatory (Treg) cells and immunosuppressive cytokines like IL-10 and TGF-β were reduced in AM1/SS1 compared to SS1/SS1 and SS1/AM1 coinfected mice gastric tissues. CONCLUSIONS These data suggested that prior H. pylori cag- strain infection attenuated the severity of gastric pathology induced by subsequent cag+ strain in C57BL/6 mice. Prior AM1 infection induced Th1 cytokine IFN-γ, which reduced the Th17 response induced by subsequent SS1 infection. The reduced gastritis in AM1/SS1-infected mice might also be due to enrichment of AM1- primed Treg cells in the gastric compartment which inhibit Th1 and Th17 responses to subsequent SS1 infection. In summary, prior infection by non-virulent H. pylori strain (AM1) causes reduction of subsequent virulent strain (SS1) infection by regulation of inflammatory cytokines and MMPs expression.
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Semper RP, Gerhard M. The Lost Friend: H. pylori. BIRKHÄUSER ADVANCES IN INFECTIOUS DISEASES 2017:69-97. [DOI: 10.1007/978-3-319-69968-4_5] [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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19
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Barrozo RM, Hansen LM, Lam AM, Skoog EC, Martin ME, Cai LP, Lin Y, Latoscha A, Suerbaum S, Canfield DR, Solnick JV. CagY Is an Immune-Sensitive Regulator of the Helicobacter pylori Type IV Secretion System. Gastroenterology 2016; 151:1164-1175.e3. [PMID: 27569724 PMCID: PMC5124400 DOI: 10.1053/j.gastro.2016.08.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/08/2016] [Accepted: 08/17/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Peptic ulcer disease and gastric cancer are caused most often by Helicobacter pylori strains that harbor the cag pathogenicity island, which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host cells. cagY is an essential gene in the T4SS and has an unusual DNA repeat structure that predicts in-frame insertions and deletions. These cagY recombination events typically lead to a reduction in T4SS function in mouse and primate models. We examined the role of the immune response in cagY-dependent modulation of T4SS function. METHODS H pylori T4SS function was assessed by measuring CagA translocation and the capacity to induce interleukin (IL)8 in gastric epithelial cells. cagY recombination was determined by changes in polymerase chain reaction restriction fragment-length polymorphisms. T4SS function and cagY in H pylori from C57BL/6 mice were compared with strains recovered from Rag1-/- mice, T- and B-cell-deficient mice, mice with deletion of the interferon gamma receptor (IFNGR) or IL10, and Rag1-/- mice that received adoptive transfer of control or Ifng-/- CD4+ T cells. To assess relevance to human beings, T4SS function and cagY recombination were assessed in strains obtained sequentially from a patient after 7.4 years of infection. RESULTS H pylori infection of T-cell-deficient and Ifngr1-/- mice, and transfer of CD4+ T cells to Rag1-/- mice, showed that cagY-mediated loss of T4SS function requires a T-helper 1-mediated immune response. Loss of T4SS function and cagY recombination were more pronounced in Il10-/- mice, and in control mice infected with H pylori that expressed a more inflammatory form of cagY. Complementation analysis of H pylori strains isolated from a patient over time showed changes in T4SS function that were dependent on recombination in cagY. CONCLUSIONS Analysis of H pylori strains from mice and from a chronically infected patient showed that CagY functions as an immune-sensitive regulator of T4SS function. We propose that this is a bacterial adaptation to maximize persistent infection and transmission to a new host under conditions of a robust inflammatory response.
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Affiliation(s)
- Roberto M Barrozo
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Lori M Hansen
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Anna M Lam
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Emma C Skoog
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Miriam E Martin
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Lucy P Cai
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Yong Lin
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Andreas Latoscha
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Sebastian Suerbaum
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; Deutsches Zentrum für Infektionsforschung, German Center for Infection Research, Hannover-Braunschweig Partner Site, Hannover, Germany
| | - Don R Canfield
- California National Primate Research Center, University of California, Davis School of Medicine, Davis, California
| | - Jay V Solnick
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California; California National Primate Research Center, University of California, Davis School of Medicine, Davis, California; Department of Medicine, University of California, Davis School of Medicine, Davis, California; Department of Microbiology and Immunology, University of California, Davis School of Medicine, Davis, California.
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Sukri A, Hanafiah A, Kosai NR, Mohamed Taher M, Mohamed Rose I. Surface Antigen Profiling of Helicobacter pylori-Infected and -Uninfected Gastric Cancer Cells Using Antibody Microarray. Helicobacter 2016; 21:417-27. [PMID: 26807555 DOI: 10.1111/hel.12295] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Comprehensive immunophenotyping cluster of differentiation (CD) antigens in gastric adenocarcinoma, specifically between Helicobacter pylori-infected and -uninfected gastric cancer patients by using DotScan(™) antibody microarray has not been conducted. Current immunophenotyping techniques include flow cytometry and immunohistochemistry are limited to the use of few antibodies for parallel examination. We used DotScan(™) antibody microarray consisting 144 CD antibodies to determine the distribution of CD antigens in gastric adenocarcinoma cells and to elucidate the effect of H. pylori infection toward CD antigen expression in gastric cancer. METHODS Mixed leukocytes population derived from gastric adenocarcinoma patients were immunophenotyped using DotScan(™) antibody microarray. AGS cells were infected with H. pylori strains and cells were captured on DotScan(™) slides. RESULTS Cluster of differentiation antigens involved in perpetuating the tolerance of immune cells to tumor cells was upregulated in gastric adenocarcinoma cells compared to normal cells. CD279 which is essential in T cells apoptosis was found to be upregulated in normal cells. Remarkably, H. pylori-infected gastric cancer patients exhibited upregulated expression of CD27 that important in maintenance of T cells. Infection of cagA+ H. pylori with AGS cells increased CD antigens expression which involved in cancer stem cell while cagA- H. pylori polarized AGS cells to express immune-regulatory CD antigens. Increased CD antigens expression in AGS cells infected with cagA+ H. pylori were also detected in H. pylori-infected gastric cancer patients. CONCLUSION This study suggests the tolerance of immune system toward tumor cells in gastric cancer and distinct mechanisms of immune responses exploited by different H. pylori strains.
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Affiliation(s)
- Asif Sukri
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Mustafa Mohamed Taher
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
| | - Isa Mohamed Rose
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia
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21
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Kronsteiner B, Bassaganya-Riera J, Philipson C, Viladomiu M, Carbo A, Abedi V, Hontecillas R. Systems-wide analyses of mucosal immune responses to Helicobacter pylori at the interface between pathogenicity and symbiosis. Gut Microbes 2016; 7:3-21. [PMID: 26939848 PMCID: PMC4856448 DOI: 10.1080/19490976.2015.1116673] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/29/2015] [Accepted: 10/31/2015] [Indexed: 02/08/2023] Open
Abstract
Helicobacter pylori is the dominant member of the gastric microbiota in over half of the human population of which 5-15% develop gastritis or gastric malignancies. Immune responses to H. pylori are characterized by mixed T helper cell, cytotoxic T cell and NK cell responses. The presence of Tregs is essential for the control of gastritis and together with regulatory CX3CR1+ mononuclear phagocytes and immune-evasion strategies they enable life-long persistence of H. pylori. This H. pylori-induced regulatory environment might contribute to its cross-protective effect in inflammatory bowel disease and obesity. Here we review host-microbe interactions, the development of pro- and anti-inflammatory immune responses and how the latter contribute to H. pylori's role as beneficial member of the gut microbiota. Furthermore, we present the integration of existing and new data into a computational/mathematical model and its use for the investigation of immunological mechanisms underlying initiation, progression and outcomes of H. pylori infection.
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Affiliation(s)
- Barbara Kronsteiner
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | - Josep Bassaganya-Riera
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | | | - Monica Viladomiu
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | | | - Vida Abedi
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
| | - Raquel Hontecillas
- Nutritional Immunology and Molecular Medicine Laboratory and Center for Modeling Immunity to Enteric Pathogens; Virginia Bioinformatics Institute; Virginia Tech; Blacksburg, VA, USA
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22
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Immunodominant epitope-specific Th1 but not Th17 responses mediate protection against Helicobacter pylori infection following UreB vaccination of BALB/c mice. Sci Rep 2015; 5:14793. [PMID: 26434384 PMCID: PMC4593181 DOI: 10.1038/srep14793] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 09/09/2015] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) infects more than half of the world’s population, causing chronic gastritis, peptic ulcers and gastric cancer. Urease B subunit (UreB), a conserved protein of H. pylori, is capable of inducing specific CD4+ T-cell responses and provides protection against this infection. Previous studies have confirmed the effectiveness of rUreB subunit vaccines in generating CD4+ T-cell-mediated protection, but less is known regarding the roles of different subtypes of T-cell immunity, such as Th1, Th2 and Th17, particularly the immunodominant epitopes inducing specific CD4+ T-cell responses, in vaccine-mediated protection. In this study, we demonstrated that the vaccination of BALB/c mice with rUreB resulted in significant antigen-specific Th1 and Th17 immune responses. Importantly, two novel Th epitopes, UreB317–329 and UreB409–421, which are recognized by a major population of CD4+ T cells, were identified in immunized mice. Our results demonstrated that two novel epitopes can simultaneously induce Th1 and Th17 immune responses; however, only the epitope vaccine-induced CD4+ T-cells secreting IFN-γ mediated the protection against H. pylori; cells secreting IL-17A did not. Taken together, our results suggest that two novel immunodominant epitopes can induce Th1 and Th17 immune responses, but only the induced Th1 lymphocytes mediate protection against H. pylori.
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Helicobacter pylori Infection Status Correlates with Serum Parameter Levels Responding to Multi-organ Functions. Dig Dis Sci 2015; 60:1748-54. [PMID: 25599961 DOI: 10.1007/s10620-015-3522-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 01/03/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Epidemiological studies have demonstrated the relationship between Helicobacter pylori infection and gastric and extra-gastric diseases. Therefore, H. pylori infection might be a "systemic" disease. AIM To investigate the relationship between H. pylori infection status and serum parameter levels responding to multi-organ functions. METHODS A total of 2,044 subjects were selected, including 1,249 males and 795 females with ages ranging from 16 to 86 years. Relevant parameters including blood lipids, complete blood count, tumor markers, indexes of stomach, kidney, liver, thyroid, and immune system function, H.pylori IgG antibody levels, and (14)C-UBT were collected. RESULTS Serum pepsinogen (PG)I, PGII, and gastrin (G)17 levels were decreased in chronic long-term, past, and acute short-term infection patients compared with uninfected controls. However, the serum PGI/II ratio increased gradually. Serum white blood cell levels gradually decreased in past, chronic long-term, and acute short-term infection patients compared with uninfected controls. The same trend was also observed for CD4(+) T cell levels. In addition, LDL levels were higher in chronic long-term infection, HDL levels were lower in past infection, and ALP and CEA levels were higher in acute short-term infection compared with the uninfected group. CONCLUSIONS Helicobacter pylori infection correlated with increased PGI, PGII, G17, WBC, and CD4(+) T cell levels, and decreased PGI/II ratio. In chronic long-term or past infection, H. pylori infection was associated with higher LDL or lower HDL levels. In acute short-term infection, H. pylori infection correlated with higher ALP and CEA levels. H. pylori infection correlated with serum parameter levels responding to multi-organ functions.
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Robinson K. Helicobacter pylori-Mediated Protection against Extra-Gastric Immune and Inflammatory Disorders: The Evidence and Controversies. Diseases 2015; 3:34-55. [PMID: 28943607 PMCID: PMC5548235 DOI: 10.3390/diseases3020034] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 03/03/2015] [Accepted: 03/05/2015] [Indexed: 12/11/2022] Open
Abstract
A large number of studies link H. pylori infection with a reduced risk of developing extra-gastric conditions such as allergy, asthma, inflammatory bowel disease, coeliac disease and multiple sclerosis. The strength of the evidence for these protective associations is quite variable, and published studies often do not agree. This review article discusses some of the reasons for these discrepancies, and the difficulties faced when designing studies. Examples of some protective disease associations are described in detail, where the evidence is most abundant and thought to be more reliable. The most convincing of these are supported by published mechanistic data, for example with animal models, or incidence of disease exacerbation in humans following H. pylori eradication. Although controversial, this field is very important as the prevalence of H. pylori is decreasing throughout the world whilst many chronic diseases are becoming more common. These trends are likely to continue in the future, therefore it is important that we fully understand if and how H. pylori confers protection.
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Affiliation(s)
- Karen Robinson
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
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Cook KW, Crooks J, Hussain K, O'Brien K, Braitch M, Kareem H, Constantinescu CS, Robinson K, Gran B. Helicobacter pylori infection reduces disease severity in an experimental model of multiple sclerosis. Front Microbiol 2015; 6:52. [PMID: 25762984 PMCID: PMC4327743 DOI: 10.3389/fmicb.2015.00052] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 01/15/2015] [Indexed: 12/19/2022] Open
Abstract
Recent research has demonstrated that infection with the bacterial pathogen Helicobacter pylori is less common amongst patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). We aimed to compare the prevalence of H. pylori amongst MS patients and healthy controls, and also investigated the impact of this infection on an animal model for MS, experimental autoimmune encephalomyelitis (EAE). The H. pylori status of 71 MS patients and 42 healthy controls was determined by serology. Groups of C57BL/6 mice were infected with H. pylori, or given diluent alone as a placebo, prior to inducing EAE. Clinical scores were assessed for all mice, and spleens and spinal cord tissue were harvested. CD4+ T cell subsets were quantified by flow cytometry, and T cell proliferation assays were performed. In MS patients the seroprevalence of H. pylori was half that of healthy controls (p = 0.018). Over three independent experiments, prior H. pylori infection had a moderate effect in reducing the severity of EAE (p = 0.012). In line with this, the antigen-specific T cell proliferative responses of infected animals were significantly reduced (p = 0.001), and there was a fourfold reduction in the number of CD4+ cells in the CNS. CD4+ populations in both the CNS and the spleens of infected mice also contained greatly reduced proportions of IFNγ+, IL-17+, T-bet+, and RORγt+ cells, but the proportions of Foxp3+ cells were equivalent. There were no differences in the frequency of splenic CD4+cells expressing markers of apoptosis between infected and uninfected animals. H. pylori was less prevalent amongst MS patients. In mice, the infection exerted some protection against EAE, inhibiting both Th1 and Th17 responses. This could not be explained by the presence of increased numbers of Foxp3+ regulatory T cells, or T cell apoptosis. This is the first direct experimental evidence showing that H. pylori may provide protection against inflammatory demyelination in the CNS.
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Affiliation(s)
- Katherine W Cook
- Nottingham Digestive Diseases Biomedical Research Unit, Centre for Biomolecular Sciences, University of Nottingham School of Medicine Nottingham, UK
| | - James Crooks
- Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine Nottingham, UK
| | - Khiyam Hussain
- Nottingham Digestive Diseases Biomedical Research Unit, Centre for Biomolecular Sciences, University of Nottingham School of Medicine Nottingham, UK
| | - Kate O'Brien
- Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine Nottingham, UK
| | - Manjit Braitch
- Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine Nottingham, UK
| | - Huner Kareem
- Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine Nottingham, UK
| | - Cris S Constantinescu
- Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine Nottingham, UK
| | - Karen Robinson
- Nottingham Digestive Diseases Biomedical Research Unit, Centre for Biomolecular Sciences, University of Nottingham School of Medicine Nottingham, UK
| | - Bruno Gran
- Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine Nottingham, UK
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Milani M, Sharifi Y, Rahmati-Yamchi M, Somi MH, Akbarzadeh A. Immunology and vaccines and nanovaccines for Helicobacter pylori infection. Expert Rev Vaccines 2015; 14:833-40. [PMID: 25645086 DOI: 10.1586/14760584.2015.1008460] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Helicobacter pylori infection is very common worldwide and is an important cause of gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma. Since the eradication requires treatment with multidrug regimens, prevention of primary infection by a suitable vaccine is attractive. Developing vaccines on the spot when and where an infection is breaking out might be possible, thanks to engineered nanoparticles. In this review, the nature of the host immune response to H. pylori infection is considered. We explain recent candidate vaccines and prophylactic or therapeutic immunization strategies for use against H. pylori. We also describe identification of different types of immune responses that may be related to protection against H. pylori infection. Thus, it seems that there is still a strong need to clarify the main protective immune response against H. pylori.
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Affiliation(s)
- Morteza Milani
- Liver and Gastrointestinal disease research center, Tabriz University of Medical Sciences, Tabriz, Iran
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Cook KW, Letley DP, Ingram RJM, Staples E, Skjoldmose H, Atherton JC, Robinson K. CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa. Gut 2014; 63:1550-9. [PMID: 24436142 PMCID: PMC4173663 DOI: 10.1136/gutjnl-2013-306253] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Helicobacter pylori-induced peptic ulceration is less likely to occur in patients with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs into the gastric mucosa is therefore important. OBJECTIVE To identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses. DESIGN Gastric biopsy samples and peripheral blood were donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified gastric biopsy chemokine concentrations. Flow cytometry was used to characterise homing receptors on CD4(+)CD25(hi) Tregs. H pylori wild-type and isogenic mutants were used to investigate the signalling mechanisms behind CCL20 and IL-8 induction in gastric epithelial cell lines. Transwell assays were used to quantify Treg migration towards chemokines in vitro. RESULTS CCL20, CXCL1-3 and IL-8 concentrations were significantly increased in gastric biopsy samples from H pylori-infected patients. CCR6 (CCL20 receptor), CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) were expressed by a higher proportion of peripheral blood Tregs in infected patients. Most gastric Tregs expressed these receptors. H pylori induced CCL20 production by gastric epithelial cells via cag pathogenicity island (cagPAI)-dependent NF-κB signalling. Foxp3(+), but not Foxp3(-), CD4 cells from infected mice migrated towards recombinant CCL20 in vitro. CONCLUSIONS As well as increasing Treg numbers, H pylori infection induces a change in their characteristics. Expression of CCR6, CXCR1 and CXCR2 probably enables their migration towards CCL20 and IL-8 in the infected gastric mucosa. Such qualitative changes may also explain how H pylori protects against some extragastric inflammatory disorders.
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Affiliation(s)
- Katherine W Cook
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Darren P Letley
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Richard J M Ingram
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Emily Staples
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Helle Skjoldmose
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
| | - John C Atherton
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
| | - Karen Robinson
- Nottingham Digestive Diseases Biomedical Research Unit, School of Medicine, The University of Nottingham, Nottingham, UK
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Th1 and Th17 responses to Helicobacter pylori in Bangladeshi infants, children and adults. PLoS One 2014; 9:e93943. [PMID: 24714675 PMCID: PMC3979705 DOI: 10.1371/journal.pone.0093943] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 03/10/2014] [Indexed: 12/12/2022] Open
Abstract
Both Th1 and Th17 cells are important components of the immune response to Helicobacter pylori (Hp) in adults, but less is known about T cell responses to Hp during early childhood, when the infection is often acquired. We investigated Th1 and Th17 type responses to Hp in adults, children and infants in Bangladesh, where Hp is highly endemic. IL-17 and IFN-γ mRNA levels in gastric biopsies from Hp-infected Bangladeshi adults were analyzed and compared to levels in infected and uninfected Swedish controls. Since biopsies could not be collected from infants and children, cytokine responses in Bangladeshi infants (6-12 months), children (3-5 years) and adults (>19 years) were instead compared by stimulating peripheral blood mononuclear cells (PBMCs) with a Hp membrane preparation (MP) and analyzing culture supernatants by ELISA and cytometric bead array. We found significantly higher expression of IL-17 and IFN-γ mRNA in gastric mucosa of Hp-infected Bangladeshi and Swedish adults compared to uninfected Swedish controls. PBMCs from all age groups produced IL-17 and IFN-γ after MP stimulation, but little Th2 cytokines. IL-17 and IFN-γ were primarily produced by CD4+ T cells, since CD4+ T cell depleted PBMCs produced reduced amounts of these cytokines. Infant cells produced significantly more IL-17, but similar levels of IFN-γ, compared to adult cells after MP stimulation. In contrast, polyclonal stimulation induced lower levels IL-17 and IFN-γ in infant compared to adult PBMCs and CD4+ T cells. The strong IL-17 production in infants after MP stimulation was paralleled by significantly higher production of the IL-17 promoting cytokine IL-1β from infant compared to adult PBMCs and monocytes. In conclusion, these results show that T cells can produce high levels of IL-17 and IFN-γ in response to Hp from an early age and indicate a potential role for IL-1β in promoting Th17 responses to Hp during infancy.
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Pacifico L, Osborn JF, Tromba V, Romaggioli S, Bascetta S, Chiesa C. Helicobacter pylori infection and extragastric disorders in children: a critical update. World J Gastroenterol 2014; 20:1379-401. [PMID: 24587617 PMCID: PMC3925850 DOI: 10.3748/wjg.v20.i6.1379] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 11/10/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a highly prevalent, serious and chronic infection that has been associated causally with a diverse spectrum of extragastric disorders including iron deficiency anemia, chronic idiopathic thrombocytopenic purpura, growth retardation, and diabetes mellitus. The inverse relation of H. pylori prevalence and the increase in allergies, as reported from epidemiological studies, has stimulated research for elucidating potential underlying pathophysiological mechanisms. Although H. pylori is most frequently acquired during childhood in both developed and developing countries, clinicians are less familiar with the pediatric literature in the field. A better understanding of the H. pylori disease spectrum in childhood should lead to clearer recommendations about testing for and treating H. pylori infection in children who are more likely to develop clinical sequelae. A further clinical challenge is whether the progressive decrease of H. pylori in the last decades, abetted by modern clinical practices, may have other health consequences.
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Harris PR, Smythies LE, Smith PD, Perez-Perez GI. Role of childhood infection in the sequelae of H. pylori disease. Gut Microbes 2013; 4:426-38. [PMID: 24275060 PMCID: PMC3928156 DOI: 10.4161/gmic.26943] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The persistence of Helicobacter pylori infection plays a fundamental role in the development of H. pylori-associated complications. Since the majority of infected persons acquire the bacteria during early childhood, an examination of the immunobiology of H. pylori infection in children compared with that of adults may help identify host factors that contribute to persistent infection. Therefore, we begin our review of the role of persistence in H. pylori disease with an assessment of the clinical features of H. pylori infection in children. We next review the bacterial factors that promote colonization and evasion of host defense mechanisms. We then focus our attention on the early host immunological factors that promote persistence of the infection and its complications in humans and mouse models. We also highlight topics in which further research is needed. An examination of how immunological factors cause divergent manifestations of H. pylori infection in children compared with adults may provide new insight for therapeutic modification or prevention of persistent H. pylori infection and its complications.
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Affiliation(s)
- Paul R Harris
- Division of Pediatrics; Unit of Gastroenterology and Nutrition; School of Medicine; Pontificia Universidad Catolica de Chile; Santiago, Chile
| | - Lesley E Smythies
- Departments of Medicine and Microbiology; University of Alabama at Birmingham; Birmingham, AL USA
| | - Phillip D Smith
- Departments of Medicine and Microbiology; University of Alabama at Birmingham; Birmingham, AL USA,VA Medical Center; Birmingham, AL USA
| | - Guillermo I Perez-Perez
- Departments of Medicine and Microbiology; Langone Medical Center; New York University School of Medicine; New York, NY USA,Correspondence to: Guillermo I Perez-Perez,
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Stein M, Ruggiero P, Rappuoli R, Bagnoli F. Helicobacter pylori CagA: From Pathogenic Mechanisms to Its Use as an Anti-Cancer Vaccine. Front Immunol 2013; 4:328. [PMID: 24133496 PMCID: PMC3796731 DOI: 10.3389/fimmu.2013.00328] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/25/2013] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa of more than 50% of the human population, causing chronic inflammation, which however is largely asymptomatic. Nevertheless, H. pylori-infected subjects can develop chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Chronic exposure to the pathogen and its ability to induce epithelial to mesenchymal transition (EMT) through the injection of cytotoxin-associated gene A into gastric epithelial cells may be key triggers of carcinogenesis. By deregulating cell-cell and cell-matrix interactions as well as DNA methylation, histone modifications, expression of micro RNAs, and resistance to apoptosis, EMT can actively contribute to early stages of the cancer formation. Host response to the infection significantly contributes to disease development and the concomitance of particular genotypes of both pathogen and host may turn into the most severe outcomes. T regulatory cells (Treg) have been recently demonstrated to play an important role in H. pylori-related disease development and at the same time the Treg-induced tolerance has been proposed as a possible mechanism that leads to less severe disease. Efficacy of antibiotic therapies of H. pylori infection has significantly dropped. Unfortunately, no vaccine against H. pylori is currently licensed, and protective immunity mechanisms against H. pylori are only partially understood. In spite of promising results obtained in animal models of infection with a number of vaccine candidates, few clinical trials have been conducted so far and with no satisfactory outcomes. However, prophylactic vaccination may be the only means to efficiently prevent H. pylori-associated cancers.
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Affiliation(s)
- Markus Stein
- Albany College of Pharmacy and Health Sciences, Albany, NY, USA
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Carbo A, Bassaganya-Riera J, Pedragosa M, Viladomiu M, Marathe M, Eubank S, Wendelsdorf K, Bisset K, Hoops S, Deng X, Alam M, Kronsteiner B, Mei Y, Hontecillas R. Predictive computational modeling of the mucosal immune responses during Helicobacter pylori infection. PLoS One 2013; 8:e73365. [PMID: 24039925 PMCID: PMC3764126 DOI: 10.1371/journal.pone.0073365] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
T helper (Th) cells play a major role in the immune response and pathology at the gastric mucosa during Helicobacter pylori infection. There is a limited mechanistic understanding regarding the contributions of CD4+ T cell subsets to gastritis development during H. pylori colonization. We used two computational approaches: ordinary differential equation (ODE)-based and agent-based modeling (ABM) to study the mechanisms underlying cellular immune responses to H. pylori and how CD4+ T cell subsets influenced initiation, progression and outcome of disease. To calibrate the model, in vivo experimentation was performed by infecting C57BL/6 mice intragastrically with H. pylori and assaying immune cell subsets in the stomach and gastric lymph nodes (GLN) on days 0, 7, 14, 30 and 60 post-infection. Our computational model reproduced the dynamics of effector and regulatory pathways in the gastric lamina propria (LP) in silico. Simulation results show the induction of a Th17 response and a dominant Th1 response, together with a regulatory response characterized by high levels of mucosal Treg) cells. We also investigated the potential role of peroxisome proliferator-activated receptor γ (PPARγ) activation on the modulation of host responses to H. pylori by using loss-of-function approaches. Specifically, in silico results showed a predominance of Th1 and Th17 cells in the stomach of the cell-specific PPARγ knockout system when compared to the wild-type simulation. Spatio-temporal, object-oriented ABM approaches suggested similar dynamics in induction of host responses showing analogous T cell distributions to ODE modeling and facilitated tracking lesion formation. In addition, sensitivity analysis predicted a crucial contribution of Th1 and Th17 effector responses as mediators of histopathological changes in the gastric mucosa during chronic stages of infection, which were experimentally validated in mice. These integrated immunoinformatics approaches characterized the induction of mucosal effector and regulatory pathways controlled by PPARγ during H. pylori infection affecting disease outcomes.
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Affiliation(s)
- Adria Carbo
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Josep Bassaganya-Riera
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Mireia Pedragosa
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Monica Viladomiu
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Madhav Marathe
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Network Dynamics and Simulation Science Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Stephen Eubank
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Network Dynamics and Simulation Science Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Katherine Wendelsdorf
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Network Dynamics and Simulation Science Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Keith Bisset
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Network Dynamics and Simulation Science Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Stefan Hoops
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Xinwei Deng
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Department of Statistics, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Maksudul Alam
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Network Dynamics and Simulation Science Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Barbara Kronsteiner
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Yongguo Mei
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
| | - Raquel Hontecillas
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- Center for Modeling Immunity to Enteric Pathogens Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America
- * E-mail:
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Karimi A, Fakhimi-Derakhshan K, Imanzadeh F, Rezaei M, Cavoshzadeh Z, Maham S. Helicobacter pylori infection and pediatric asthma. IRANIAN JOURNAL OF MICROBIOLOGY 2013; 5:132-5. [PMID: 23825730 PMCID: PMC3696848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
OBJECTIVE Childhood infectious diseases are one of the most known environmental pathogenic causes of childhood asthma. The high prevalence of both Helicobacter pylori infection and asthma in our country prompted us to assess anyprobable association between them in childhood. METHODS This cross-sectional study recruited 196 children aged 6 to 12 years old comprising 98 asthmatic (case group) and 98 healthy (control group) individuals. Urea breath test was performed for all of the children and H. pylori infection was compared between the two groups according to the urea breath test results. RESULTS Urea breath test was positive in 18 asthmatic (18.36) and 23 (23.36) healthy subjects but was not significantly different between the case and controls (p = 0.380). Further analysis in the asthmatic group revealed association of H. pylori infection withage (p < 0.001) and duration of asthma (p = 0.010). However, no significant correlation was found between sex, severity of asthma, controled asthma or abnormal pulmonary function tests with H. pylori infection (p= 0.804, 0.512, 0.854 and 0.292, respectively). CONCLUSION Given the results of the study, H. pylori infection was not significantly different between asthmatic and healthy children. In asthmatic patients, there was no significant association between H. pylori infection and sex, severity of disease, control status of disease and normal or abnormal pulmonary function tests. H. Pylori infection had a significant association with increasing age and duration of asthma.
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Affiliation(s)
- Abdullah Karimi
- Pediatric Infections Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Salama NR, Hartung ML, Müller A. Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol 2013; 11:385-99. [PMID: 23652324 DOI: 10.1038/nrmicro3016] [Citation(s) in RCA: 465] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The bacterial pathogen Helicobacter pylori has co-evolved with humans and colonizes approximately 50% of the human population, but only causes overt gastric disease in a subset of infected hosts. In this Review, we discuss the pathogenesis of H. pylori and the mechanisms it uses to promote persistent colonization of the gastric mucosa, with a focus on recent insights into the role of the virulence factors vacuolating cytotoxin (VacA), cytotoxin-associated gene A (CagA) and CagL. We also describe the immunobiology of H. pylori infection and highlight how this bacterium manipulates the innate and adaptive immune systems of the host to promote its own persistence.
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Affiliation(s)
- Nina R Salama
- Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, Washington 981091024, USA.
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Shimamura M. Immunological Functions of Steryl Glycosides. Arch Immunol Ther Exp (Warsz) 2012; 60:351-9. [DOI: 10.1007/s00005-012-0190-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 08/08/2012] [Indexed: 12/12/2022]
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Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients. Appl Microbiol Biotechnol 2012; 96:211-20. [PMID: 22526791 PMCID: PMC3433674 DOI: 10.1007/s00253-012-4034-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 03/16/2012] [Accepted: 03/16/2012] [Indexed: 02/08/2023]
Abstract
The current study was to investigate the interaction between Helicobacter pylori and human dendritic cells (DCs). Whether impaired DC function can influence the outcome of H. pylori infections. Human monocyte-derived DCs (MDDCs) from five gastric cancer patients and nine healthy controls were stimulated with H. pylori. Maturation markers of MDDC were examined by flow cytometry. IL-10 and TNF-α released by MDDCs and IL-17 produced by T cells were measured by ELISA. Regulatory signaling pathways of IL-10 were examined by ELISA, western blotting, and chromatin immunoprecipitation assay. The results showed that as compared with healthy individuals, the maturation marker CD40 in MDDCs, IL-17A expression from T cells, and IL-10 expression from MDDCs were significantly lower in gastric cancer patients. Blocking DC-SIGN, TLR2, and TLR4 could reverse H. pylori-associated IL-10 production. Activation of the p38 MAPK and NF-kB signaling pathways concomitant with decreased tri-methylated H3K9 and increased acetylated H3 accounted for the effect of H. pylori on IL-10 expression. Furthermore, upregulated IL-10 expression was significantly suppressed in H. pylori-pulsed MDDCs by histone acetyltransferase and methyltransferase inhibitors. Taken together, impaired DC function contributes to the less effective innate and adaptive immune responses against H. pylori seen in gastric cancer patients. H. pylori can regulate IL-10 production through Toll-like and DC-SIGN receptors, activates p-p38 MAPK signaling and the transcription factors NF-kB, and modulates histone modification.
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Flach CF, Mozer M, Sundquist M, Holmgren J, Raghavan S. Mucosal vaccination increases local chemokine production attracting immune cells to the stomach mucosa of Helicobacter pylori infected mice. Vaccine 2012; 30:1636-43. [DOI: 10.1016/j.vaccine.2011.12.111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 12/07/2011] [Accepted: 12/22/2011] [Indexed: 10/14/2022]
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41
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Hu S, Xie Y, Zhou N, Jin L, Tan Y, Liu D, Gong Y, Liu L, Liu J, Liu W, Chen Y, Zhang Y, Lv N. Expression of T-cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (Tim-1 and Tim-3) in Helicobacter pylori infection. Helicobacter 2011; 16:373-81. [PMID: 21923683 DOI: 10.1111/j.1523-5378.2011.00855.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Th immune response plays an important role in Helicobacter pylori (H. pylori) infection. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim in H. pylori infection remains unclear. MATERIALS AND METHODS (1) Lymphocytes isolated from the spleen of BALB/c mice were co-cultured with different concentrations of viable H. pylori. Alternatively, mice were challenged by viable H. pylori to set up the H. pylori infection model. (2) The expression of Tim-1 and Tim-3 on mRNA level in lymphocytes or spleen of mice was determined by RT-PCR. The percentage of Tim-3-positive cells was determined by flow cytometric analysis. The production of cytokine in supernatants was measured by standard sandwich cytokine ELISA. RESULTS (1) Co-culture: At 12 hours, there was markedly decreased production of Tim-1 and increased production of Tim-3 in lymphocytes co-cultured with H. pylori compared with normal control. The change of Th2 cytokine had the similar tendency as that of Tim-1 expression; alternatively, the change of Th1 cytokine had the similar tendency as that of Tim-3 expression. (2) INFECTION: Tim-1 expression was declined in infected mice compared with control group; in the contrast, Tim-3 expression was increased. Furthermore, the expression of Tim-1 and Tim-3 mRNA in spleen was significantly positively correlated with the level of Th2 and Th1 cytokine in gastric homogenized supernatant, respectively. CONCLUSION H. pylori could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1-biased immune response. The expression of Tim-1 and Tim-3 could reflect Th2 and Th1 immune response, respectively, which provide evidence for the prevention and treatment of H. pylori infection and correlation diseases through regulation of Tim-1 and Tim-3.
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Affiliation(s)
- Sijun Hu
- Institute of Digestive Diseases, the First Affiliated Hospital of Nanchang University, China
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Wu YY, Chen JH, Kao JT, Liu KC, Lai CH, Wang YM, Hsieh CT, Tzen JTC, Hsu PN. Expression of CD25(high) regulatory T cells and PD-1 in gastric infiltrating CD4(+) T lymphocytes in patients with Helicobacter pylori infection. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2011; 18:1198-1201. [PMID: 21562113 PMCID: PMC3147316 DOI: 10.1128/cvi.00422-10] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 04/28/2011] [Indexed: 01/30/2023]
Abstract
We observed by flow cytometry that the frequency of both gastric infiltrating Tregs and PD-1-positive CD4 T cells is correlated with the density of Helicobacter pylori, suggesting that cellular immunity against this pathogen is inhibited.
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Affiliation(s)
- Yi-Ying Wu
- Department of Medical Laboratory Science and Biotechnology, China Medical University and Hospital, No. 91 Hsueh-Shih Rd., Taichung 404, Taiwan.
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Lindgren Å, Yun CH, Sjöling Å, Berggren C, Sun JB, Jonsson E, Holmgren J, Svennerholm AM, Lundin SB. Impaired IFN-γ production after stimulation with bacterial components by natural killer cells from gastric cancer patients. Exp Cell Res 2011; 317:849-58. [PMID: 21255568 DOI: 10.1016/j.yexcr.2011.01.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Revised: 12/30/2010] [Accepted: 01/03/2011] [Indexed: 12/13/2022]
Abstract
Gastric adenocarcinoma is a major health problem world-wide, as this is the second most common cause of cancer death in the world. It has been estimated that infection by Helicobacter pylori cause at least half of the gastric cancers. Previously, we have demonstrated that H. pylori antigens directly activate NK cells to secrete IFN-γ. There is also a marked synergistic effect in NK cells stimulated with bacterial lysate and low levels of IL-12, a cytokine which is produced by macrophages and dendritic cells in the H. pylori-infected stomach. The present study was designed to investigate whether NK cells from gastric cancer patients display an altered ability to respond to components from H. pylori and other bacteria. The results show that NK cells from peripheral blood of gastric cancer patients have a severely suppressed ability to produce IFN-γ after stimulation with H. pylori lysate and the synthetic bacterial lipoprotein FSL-1. Furthermore, the synergistic effect of IL-12 and lysate is absent in gastric cancer patients, unless the concentration of IL-12 is increased 10-fold. We also demonstrate that there is a similar lack of IFN-γ production from NK cells isolated from the gastric mucosa of cancer patients. In addition, we propose that the observed suppression is due to tumour-derived TGF-β and that increased expression of the transcription factor GATA-3 may be responsible for the TGF-β induced suppression.
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Affiliation(s)
- Åsa Lindgren
- Institute of Biomedicine, Department of Microbiology and Immunology, and Mucosal Immunobiology and Vaccine Institute for Strategic Research, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden.
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Hussey S, Jones NL. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2011:293-308.e10. [DOI: 10.1016/b978-1-4377-0774-8.10028-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zhang JY, Liu T, Guo H, Liu XF, Zhuang Y, Yu S, Chen L, Wu C, Zhao Z, Tang B, Luo P, Mao XH, Guo G, Shi Y, Zou QM. Induction of a Th17 cell response by Helicobacter pylori Urease subunit B. Immunobiology 2010; 216:803-10. [PMID: 21269729 DOI: 10.1016/j.imbio.2010.12.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Revised: 12/14/2010] [Accepted: 12/19/2010] [Indexed: 02/05/2023]
Abstract
Th17 cells represent a novel subset of CD4(+) T cells, which is associated with Helicobacter pylori infection. In the present study, we investigated the potential role of Urease subunit B (UreB) in the induction of Th17 cell response. Co-cultured splenic lymphocytes from H. pylori-infected mice with the recombinant UreB (rUreB) elevated IL-17 secretion and caused an increase in the number of Th17 cells. The expression of IL-6 and IL-23 p19 was significantly increased in rUreB-stimulated macrophages. Whole cell protein (WCP) of UreB-deficient strain (UreB(-) strain) induced less Th17 cell responses than that of wild-type strain. In addition, subcutaneous and intranasal immunization of rUreB elicited antigen-specific Th17 cell responses. Intranasal immunization of rUreB reduced H. pylori colonization in the stomach, which was closely related with the increased rUreB-specific Th17 cell responses. These results suggest that UreB is an important protein which is able to elicit Th17 cell responses against H. pylori both in vivo and in vitro.
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Affiliation(s)
- Jin-Yu Zhang
- Department of Clinical Microbiology and Immunology, College of Medical Laboratory, The Third Military Medical University, Chongqing, PR China
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Suzuki A, Kobayashi M, Matsuda K, Matsumoto T, Kawakubo M, Kumazawa S, Koide N, Miyagawa S, Ota H. Induction of high endothelial venule-like vessels expressing GlcNAc6ST-1-mediated L-selectin ligand carbohydrate and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in a mouse model of "Candidatus Helicobacter heilmannii"-induced gastritis and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Helicobacter 2010; 15:538-48. [PMID: 21073611 DOI: 10.1111/j.1523-5378.2010.00801.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND "Candidatus Helicobacter heilmannii" induce chronic gastritis, which eventually leads to gastric B-cell type mucosa-associated lymphoid tissue (MALT) lymphoma. This study was performed using an animal model of infection with "Candidatus Helicobacter heilmannii" to elucidate how this chronic inflammation is induced or maintained. MATERIALS AND METHODS BALB/c mice were infected with the "Candidatus Helicobacter heilmannii" isolate SH4. The animals were examined at 8, 26, 54, and 83 weeks after the infection. The stomach of the animals was resected and immunostained for peripheral lymph node addressin (PNAd) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1), "Candidatus Helicobacter heilmannii," and CD45R/B220. An in vitro binding assay with L- and E-selectin·IgM chimeric proteins was performed. Real-time polymerase chain reaction was used to evaluate transcripts of N-acetylglucosamine-6-O-sulfotransferases (GlcNAc6STs), which direct the expression of the PNAd and MAdCAM-1. RESULTS Chronic gastritis developed in the infected animals, and its severity increased with the duration of the infection. B-cell type MALT lymphoma developed in some animals at 54 and 83 weeks after infection. PNAd- and MAdCAM-1-expressing high endothelial venule (HEV)-like vessels were induced in infected animals which developed chronic gastritis and MALT lymphoma. The number of HEV-like vessels increased as chronic inflammation progressed. The induced HEV-like vessels were bound by L- and E-selectin·IgM chimeric protein. mRNA expressions of GlcNAc6ST-1 and MAdCAM-1 increased in the infected animals. CONCLUSIONS HEV-like vessels expressing GlcNAc6ST-1-mediated L-selectin ligand carbohydrate and MAdCAM-1 may play a crucial role in the pathogenesis of "Candidatus Helicobacter heilmannii"-induced chronic gastritis and MALT lymphoma.
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MESH Headings
- Animals
- Antigens, Surface/genetics
- Antigens, Surface/immunology
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/immunology
- Disease Models, Animal
- Endothelial Cells/immunology
- Female
- Gastric Mucosa/immunology
- Gastric Mucosa/microbiology
- Gastritis/etiology
- Gastritis/genetics
- Gastritis/immunology
- Gastritis/microbiology
- Gene Expression
- Helicobacter Infections/complications
- Helicobacter Infections/immunology
- Helicobacter Infections/microbiology
- Helicobacter heilmannii/immunology
- Helicobacter heilmannii/physiology
- Humans
- L-Selectin/immunology
- Lymphoma, B-Cell, Marginal Zone/etiology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/microbiology
- Membrane Proteins/genetics
- Membrane Proteins/immunology
- Mice
- Mice, Inbred BALB C
- Mucoproteins
- Sulfotransferases/genetics
- Sulfotransferases/immunology
- Carbohydrate Sulfotransferases
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Affiliation(s)
- Akira Suzuki
- Department of Surgery, Shinshu University Hospital, Matsumoto, Japan
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Pacifico L, Anania C, Osborn JF, Ferraro F, Chiesa C. Consequences of Helicobacter pylori infection in children. World J Gastroenterol 2010; 16:5181-94. [PMID: 21049552 PMCID: PMC2975089 DOI: 10.3748/wjg.v16.i41.5181] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Revised: 06/21/2010] [Accepted: 06/28/2010] [Indexed: 02/06/2023] Open
Abstract
Although evidence is emerging that the prevalence of Helicobacter pylori (H. pylori) is declining in all age groups, the understanding of its disease spectrum continues to evolve. If untreated, H. pylori infection is lifelong. Although H. pylori typically colonizes the human stomach for many decades without adverse consequences, children infected with H. pylori can manifest gastrointestinal diseases. Controversy persists regarding testing (and treating) for H. pylori infection in children with recurrent abdominal pain, chronic idiopathic thrombocytopenia, and poor growth. There is evidence of the role of H. pylori in childhood iron deficiency anemia, but the results are not conclusive. The possibility of an inverse relationship between H. pylori and gastroesophageal reflux disease, as well as childhood asthma, remains a controversial question. A better understanding of the H. pylori disease spectrum in childhood should lead to clearer recommendations about testing for and treating H. pylori infection in children who are more likely to develop clinical sequelae.
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Perez-Perez GI, Maw AM, Feingold-Link L, Gunn J, Bowers AL, Minano C, Rautelin H, Kosunen TU, Blaser MJ. Longitudinal analysis of serological responses of adults to Helicobacter pylori antigens. J Infect Dis 2010; 202:916-23. [PMID: 20698790 PMCID: PMC2924458 DOI: 10.1086/655660] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Because Helicobacter pylori persist for decades in the human stomach, the aim of this study was to examine the long-term course of H. pylori-specific serum immunoglobulin G (IgG) responses with respect to subclass and antigenic target. We studied paired serum samples obtained in 1973 and in 1994 in Vammala, Finland, from 64 healthy H. pylori-positive adults and from other healthy control subjects. H. pylori serum immunoglobulin A, IgG, and IgG subclass responses were determined by antigen-specific enzyme-linked immunosorbent assays. H. pylori-specific IgG1 and IgG4 subtype responses from 47 subjects were similar in 1973 and 1994, but not when compared with unrelated persons. H. pylori-specific IgG1:IgG4 ratios among the participants varied >1000-fold; however, 57 (89.1%) of 64 subjects had an IgG1:IgG4 ratio >1.0, consistent with a predominant IgG1 (Th1) response. Furthermore, ratios in individual hosts were stable over the 21-year period (r = 0.56; P < .001). The immune response to heat shock protein HspA was unchanged in 49 (77%) of the 64 subjects tested; of the 15 whose serostatus changed, all seroconverted and were significantly younger than those whose status did not change. These findings indicate that H. pylori-specific antibody responses are host-specific with IgG1:IgG4 ratios stable over 21 years, IgG1 responses predominating, and HspA seroconversion with aging.
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Affiliation(s)
- Guillermo I Perez-Perez
- Department of Medicine, New York University Langone Medical Center, New York, New York, USA.
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Zhuang Y, Shi Y, Liu XF, Zhang JY, Liu T, Fan X, Luo J, Wu C, Yu S, Chen L, Luo P, Guo G, Liu Z, Tang B, Mao XH, Guo Y, Zou QM. Helicobacter pylori-infected macrophages induce Th17 cell differentiation. Immunobiology 2010; 216:200-7. [PMID: 21112468 DOI: 10.1016/j.imbio.2010.05.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 04/08/2010] [Accepted: 05/08/2010] [Indexed: 12/16/2022]
Abstract
Th17 cells represent a novel subset of CD4(+) T cells, which is associated with chronic inflammation. The present study evaluated Th17 cell responses to Helicobacter pylori infection in mouse model and CD4(+) T cell differentiation in response to H. pylori-infected macrophages. Th17 cells were observed in the H. pylori-infected gastric tissue. Co-culture of CD4(+) T cells with H. pylori-infected macrophages elevated IL-17 and IFN-γ secretion, up-regulated retinoid-related orphan receptor gamma t (RORγt) and T box expressed in T cells (T-bet) expression and increased the numbers of Th17 and Th1 cells. The expression of CD40, CD80, and CD86 and the secretion of IL-6, TGF-β1, IL-23, and CCL20 were significantly increased in H. pylori-stimulated macrophages. NF-κB pathway participated in the production of IL-6, IL-23, and CCL20 from macrophages in response to H. pylori, and inhibition of NF-κB pathway of macrophages resulted in less Th17 cell differentiation. Taken together, these results suggest that H. pylori induces Th17 cell differentiation via infected macrophages.
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Affiliation(s)
- Yuan Zhuang
- Department of Clinical Microbiology and Immunology, College of Medical Laboratory Science, Third Military Medical University, Chongqing 400038, PR China
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Helicobacter pylori stimulates dendritic cells to induce interleukin-17 expression from CD4+ T lymphocytes. Infect Immun 2009; 78:845-53. [PMID: 19917709 DOI: 10.1128/iai.00524-09] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori is a human gastroduodenal pathogen that leads to active chronic inflammation characterized by T-cell responses biased toward a Th1 phenotype. It has been accepted that H. pylori infection induces a Th17 response. At mucosal sites, dendritic cells (DCs) have the capacity to induce effector T cells. Here, we evaluate the role of DCs in the H. pylori-induced interleukin-17 (IL-17) response. Immunohistochemistry and immunofluorescence were performed on human gastric mucosal biopsy samples and showed that myeloid DCs in H. pylori-infected patients colocalized with IL-23- and that IL-17-producing lymphocytes were present in H. pylori-infected antral biopsy samples. In parallel, human monocyte-derived DCs stimulated in vitro with live H. pylori cells produced significant levels of IL-23 in the absence of IL-12 release. The subsequent incubation of H. pylori-infected DCs with autologous CD4(+) T cells led to gamma interferon (IFN-gamma) and IL-17 expression. The inhibition of IL-1 and, to a lesser extent, IL-23 inhibited IL-17 production by T cells. Finally, isogenic H. pylori mutant strains not expressing major virulence factors were less effective in inducing IL-1 and IL-23 release by DCs and IL-17 release by T cells than parental strains. Altogether, we can conclude that DCs are potent inducers of IL-23/IL-17 expression following H. pylori stimulation. IL-1/IL-23 as well as H. pylori virulence factors seem to play an important role in mediating this response.
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