Abstract
Helicobacter pylori infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, gastric carcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Recent studies have shown that apoptosis of gastric epithelial cells is increased during H. pylori infection. Apoptosis induced by microbial infections are factors implicated in the pathogenesis of H. pylori infection. The enhanced gastric epithelial cell apoptosis in H. pylori infection has been suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells via modulation of TRAIL apoptosis signaling. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, there was significantly increased CCR6+CD3+T-cell infiltration in the gastric mucosa, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These results implicate that the interaction between CCL20 and CCR6 may play a role in recruiting T cells to the sites of inflammation in the gastric mucosa during Helicobacter infection. Through these mechanisms, chemokine-mediated T lymphocyte trafficking into inflamed epithelium is initiated and the mucosal injury in Helicobacter infection is induced. This article will review the recent novel findings on the interactions of H. pylori with diverse host epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation, mucosal damage and development of MALT lymphomas.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N et al. Helicobacter pylori infection and risk of gastric carcinoma. N Engl J Med 1994; 325: 1127–1131.
Parsonnet J . Molecular mechanisms for inflammation-promoted pathogenesis of cancer – The Sixteenth International Symposium of the Sapporo Cancer Seminar. Cancer Res 1997; 57: 3620–3624.
Jones NL, Shannon PT, Cutz E, Yeger H, Sherman PM . Increase in proliferation and apoptosis of gastric epithelial cells early in the natural history of Helicobacter pylori infection. Am J Pathol 1997; 151: 1685–1703.
Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B et al. Inducible nitric oxide synthase, nitrotyrosine and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 1996; 56: 3238–3243.
Moss SF, Calam J, Agarwal B, Wang S, Holt PR . Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 1996; 38: 498–501.
Rudi J, Kuck D, Strand S, von Herbay A, Mariani SM, Krammer PH et al. Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J Clin Invest 1998; 102: 1506–1514.
Wu YY, Tsai HF, Lin WC, Chou AH, Chen HT, Yang JC et al. Helicobacter pylori enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in human gastric epithelial cells. World J Gastroenterol 2004; 10: 2334–2339.
Fan XJ, Crowe SE, Behar S, Gunasena H, Ye G, Haeberle H et al. The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage. J Exp Med 1998; 187: 1659–1669.
Jones NL, Day AS, Jennings HA, Sherman PM . Helicobacter pylori induces gastric epithelial cell apoptosis in association with increased Fas receptor expression. Infect Immun 1999; 67: 4237–4242.
Wagner S, Beil W, Westermann J, Logan RP, Bock CT, Trautwein C et al. Regulation of gastric epithelial cell growth by Helicobacter pylori: offdence for a major role of apoptosis. Gastroenterology 1997; 113: 1836–1847.
Bamford KB, Fan XJ, Crowe SE, Leary JF, Gourley WK, Luthra GK et al. Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology 1998; 114: 482–492.
D’Elios MM, Manghetti M, de Carli M, Costa F, Baldari CT, Burroni D et al. T helper 1 effector cells specific for Helicobacter pylori in gastric antrum of patients with peptic ulcer disease. J Immunol 1997; 158: 962–967.
Karttunen R, Karttunen T, Ekre HP, MacDonald TT . Interferon gamma and interleukin 4 secreting cells in the gastric antrum in Helicobacter pylori positive and negative gastritis. Gut 1995; 36: 341–345.
Lindholm C, Quiding-Jalrbrink M, Lonroth H, Hamlet A, Svennerholm AM . Local cytokine response in Helicobacter pylori-infected subjects. Infect Immun 1998; 66: 5964–5971.
Wu YY, Tsai HF, Lin WC, Hsu PI, Shun CT, Wu MS et al. Upregulation of CCL20 and recruitment of CCR6+ gastric infiltrating lymphocytes in Helicobacter pylori gastritis. Infect Immun 2007; 75: 4357–4363.
Wang J, Fan X, Lindholm C, Bennett M, O’Connoll J, Shanahan F et al. Helicobacter pylori modulates lymphoepithelial cell interactions leading to epithelial cell damage through Fas/Fas ligand interactions. Infect Immun 2000; 68: 4303–4311.
Gao LY, Kwaik YA . The modulation of host cell apoptosis by intracellular bacterial pathogens. Trends Microbiol 2000; 8: 306–313.
Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J . Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun 2001; 69: 5080–5087.
Le’Negrate G, Ricci V, Hofman V, Mograbi B, Hofman P, Rossi B . Epithelial intestinal cell apoptosis induced by Helicobacter pylori depends on expression of the cag pathogenicity island phenotype. Infect Immun 2001; 69: 5001–5009.
Odenbreit S, Püls J, Sedlmaier B, Gerland E, Fischer W, Haas R . Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 2000; 287: 1497–1500.
Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y et al. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med 2000; 191: 593–602.
Stein M, Rappuoli R, Covacci A . Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci USA 2000; 97: 1263–1268.
Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA. Science 2002; 295: 683–686.
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3: 673–682.
Griffith TS, Lynch DH . TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 1998; 10: 559–563.
Kayagaki N, Yamaguchi N, Nakayama M, Kawasaki A, Akiba H, Okumura K et al. Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol 1999; 162: 2639–2647.
Kayagaki N, Yamaguchi N, Nakayama M, Eto H, Okumura K, Yagita H . Type I interferons (IFNs) regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on human T cells: a novel mechanism for the antitumor effects of type I IFNs. J Exp Med 1999; 189: 1451–1460.
Thomas WD, Hersey P . TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 1998; 161: 2195–2200.
Nieda M, Nicol A, Koezuka Y, Kikuchi A, Lapteva N, Tanaka Y et al. TRAIL expression by activated human CD4+V alpha 24NKT cells induces in vitro and in vivo apoptosis of human acute myeloid leukemia cells. Blood 2001; 97: 2067–2074.
Kaplan MJ, Ray D, Mo RR, Yung RL, Richardson BC . TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. J Immunol 2000; 164: 2897–2904.
Dörr J, Waiczies S, Wendling U, Seeger B, Zipp F . Induction of TRAIL-mediated glioma cell death by human T cells. J Neuroimmunol 2002; 122: 117–124.
Mattapallil JJ, Dandekar S, Canfield DR, Solnick JV . A predominant Th1 type of immune response is induced early during acute Helicobacter pylori infection in rhesus macaques. Gastroenterology 2000; 118: 307–315.
D’Elios MM, Manghetti M, de Carli M, Costa F, Baldari CT, Burroni D et al. T helper 1 effector cells specific for Helicobacter pylori in gastric antrum of patients with peptic ulcer disease. J Immunol 1997; 158: 962–967.
Baggiolini M, Loetscher P . Chemokines in inflammation and immunity. Immunol Today 2000; 21: 418–420.
Butcher EC, Williams M, Youngman K, Rott L, Briskin M . Lymphocyte trafficking and regional immunity. Adv Immunol 1999; 72: 209–253.
Campbell JJ, Butcher EC . Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 2000; 12: 336–341.
Dwinell MB, Lugering N, Eckmann L, Kagnoff MF . Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology 2001; 120: 49–59.
Baggiolini M . Chemokines and leukocyte traffic. Nature 1998; 392: 565–568.
Luster AD . Chemokines: chemotactic cytokines that mediate inflammation. N Engl J Med 1998; 338: 436–445.
Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, Ponath PD et al. The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol 2000; 165: 5069–5076.
Shibahara T, Wilcox JN, Couse T, Madara JL . Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytes. Gastroenterology 2001; 120: 60–70.
Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 2000; 406: 309–314.
Campbell JJ, Haraldsen G, Pan J, Rottman J, Qin S, Ponath P et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 1999; 400: 776–780.
Eck M, Schmausser B, Scheller K, Toksoy A, Kraus M, Menzel T et al. CXC chemokines Gro(alpha)/IL-8 and IP-10/MIG in Helicobacter pylori gastritis. Clin Exp Immunol 2000; 122: 192–199.
Wen S, Felley CP, Bouzourene H, Reimers M, Michetti P, Pan-Hammarstrom Q . Inflammatory gene profiles in gastric mucosa during Helicobacter pylori infection in humans. J Immunol 2004; 172: 2595–2606.
Yamaoka Y, Kita M, Kodama T, Sawai N, Tanahashi T, Kashima K et al. Chemokines in the gastric mucosa in Helicobacter pylori infection. Gut 1998; 42: 609–617.
Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, Ait-Yahia S et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 1998; 188: 373–386.
Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K et al. Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J Biol Chem 1997; 272: 14893–14898.
Cook DN, Prosser DM, Forster R, Zhang J, Kuklin NA, Abbondanzo SJ et al. CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 2000; 12: 495–503.
Power CA, Church DJ, Meyer A, Alouani S, Proudfoot AE, Clark-Lewis I et al. Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells. J Exp Med 1997; 186: 825–835.
Greaves DR, Wang W, Dairaghi DJ, Dieu MC, Saint-Vis BD, Franz-Bacon K et al. CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3alpha and is highly expressed in human dendritic cells. J Exp Med 1997; 186: 837–844.
Liao F, Rabin RL, Smith CS, Sharma G, Nutman TB, Farber JM . CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha. J Immunol 1999; 162: 186–194.
Izadpanah A, Dwinell MB, Eckmann L, Varki NM, Kagnoff MF . Regulated MIP-3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am J Physiol Gastrointest Liver Physiol 2001; 280: G710–G719.
Tanaka Y, Imai T, Baba M, Ishikawa I, Uehira M, Nomiyama H et al. Selective expression of liver and activation-regulated chemokine (LARC) in intestinal epithelium in mice and humans. Eur J Immunol 1999; 29: 633–642.
Nishi T, Okazaki K, Kawasaki K, Fukui T, Tamaki H, Matsuura M et al. Involvement of myeloid dendritic cells in the development of gastric secondary lymphoid follicles in Helicobacter pylori-infected neonatally thymectomized BALB/c mice. Infect Immun 2003; 71: 2153–2162.
Tomimori K, Uema E, Teruya H, Ishikawa C, Okudaira T, Senba M et al. Helicobacter pylori induces CCL20 expression. Infect Immun 2007; 75: 5223–5232.
Yoshida A, Isomoto H, Hisatsune J, Nakayama M, Nakashima Y, Matsushim K et al. Enhanced expression of CCL20 in human Helicobacter pylori-associated gastritis. Clin Immunol 2009; 130: 290–297.
Peek RM Jr, Blaser MJ . Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2002; 2: 28–37.
Hussell T, Isaacson PG, Crabtree JE, Spencer J . The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 1993; 342: 571–574.
Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993; 342: 575–577.
Eck M, Schmausser B, Haas R, Greiner A, Czub S, Müller-Hermelink HK . MALT-type lymphoma of the stomach is associated with Helicobacter pylori strains expressing the CagA protein. Gastroenterology 1997; 112: 1482–1486.
Peng H, Ranaldi R, Diss TC, Isaacson PG, Bearzi I, Pan L . High frequency of CagA+Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas. J Pathol 1998; 185: 409–412.
Fan XJ, Chua A, Shahi CN, McDevitt J, Keeling PW, Kelleher D . Gastric T lymphocyte response to Helicobacter pylori in patients with H. pyloricolonisation. Gut 1994; 35: 1379–1384.
Greiner A, Knörr C, Qin Y, Sebald W, Schimpl A, Banchereau J et al. Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. Am J Pathol 1997; 150: 1583–1593.
Hussell T, Isaacson PG, Crabtree JE, Spencer J . Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol 1996; 178: 122–127.
Segal ED, Cha J, Lo J, Falkow S, Tompkins LS . Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci USA 1999; 96: 14559–14564.
Selbach M, Moese S, Hauck CR, Meyer TF, Backert S . Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem 2002; 277: 6775–6778.
Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A . c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 2002; 43: 971–980.
Poppe M, Feller SM, Römer G, Wessler S . Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility. Oncogene 2007; 26: 3462–3472.
Zhu Y, Wang C, Huang J, Ge Z, Dong Q, Zhong X et al. The Helicobacter pylori virulence factor CagA promotes Erk1/2-mediated Bad phosphorylation in lymphocytes: a mechanism of CagA-inhibited lymphocyte apoptosis. Cell Microbiol 2007; 9: 952–961.
Umehara S, Higashi H, Ohnishi N, Asaka M, Hatakeyama M . Effects of Helicobacter pylori CagA protein on the growth and survival of B lymphocytes, the origin of MALT lymphoma. Oncogene 2003; 22: 8337–8342.
Acknowledgements
This work was supported by grants from the National Health Research Institute (NHRI-EX95-9532SI), National Science Council, Taiwan (NSC90-2314B-075B003 and NSC91-2320B-002) and China Medical University (CMU96-266, CMU97-299).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tsai, HF., Hsu, PN. Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology. Cell Mol Immunol 7, 255–259 (2010). https://doi.org/10.1038/cmi.2010.2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cmi.2010.2
Keywords
This article is cited by
-
Relationship between Helicobacter pylori infection and white matter lesions in patients with migraine
BMC Neurology (2022)
-
Dysregulated Expression of Apoptosis-Associated Genes and MicroRNAs and Their Involvement in Gastric Carcinogenesis
Journal of Gastrointestinal Cancer (2021)
-
Clinicopathological and molecular characteristics of synchronous gastric adenocarcinoma and gastrointestinal stromal tumors
Scientific Reports (2017)
-
A Comprehensive Review on Pharmacotherapeutics of Three Phytochemicals, Curcumin, Quercetin, and Allicin, in the Treatment of Gastric Cancer
Journal of Gastrointestinal Cancer (2017)
-
Importance of the C-terminal histidine residues of Helicobacter pylori GroES for Toll-like receptor 4 binding and interleukin-8 cytokine production
Scientific Reports (2016)