Skip to main content
Log in

Apoptosis of Gastric Lymphocytes in Helicobacter pylori-Infected Rhesus Macaques

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

In vitro studies suggest that H. pylori induces apoptosis in gastric epithelial cells and perhaps in gastric lymphocytes as well. However, the early effects of H. pylori infection on lymphocyte apoptosis have not been examined in experimental animal models, nor have studies been performed using markers specific for T cells and T-cell subsets. Gastric T-cell apoptosis and Fas ligand expression were examined by flow cytometry after experimental infection of rhesus macaques with H. pylori. Infection induced transient apoptosis of gastric CD4+ and CD8+ T-cells, which began as soon as three days after inoculation and declined to baseline within eight weeks. Fas ligand expression showed a similar transient induction, suggesting that it mediates gastric T-cell apoptosis. We propose that transient, Fas-mediated apoptosis in gastric lymphocytes is a compensatory response to the initial T-cell inflammatory response after acute H. pylori infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Dunn BE, Cohen H, Blaser, MJ: Helicobacter pylori. Clin Microbiol Rev 10:720-741, 1997

    Google Scholar 

  2. Yamaoka Y, Kikuchi S, el-Zimaity HM, Gutierrez O, Osato MS, Graham DY: Importance ofHelicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production. Gastroenterology 123:414-424, 2002

    Google Scholar 

  3. Gerhard M, Lehn N, Neumayer N, Borén T, Rad R, Schepp W, Miehlke S, Classen M, Prinz C: Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci USA 96:12778-12783, 1999

    Google Scholar 

  4. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF, Jr, Rabkin CS: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398-402, 2000

    Google Scholar 

  5. Moss SF, Calam J, Agarwal B, Wang S, Holt PR: Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 38:498-501, 1996

    Google Scholar 

  6. Shirin H, Sordillo EM, Oh SH, Yamamoto H, Delohery T, Weinstein IB, Moss SF: Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial cells. Cancer Res 59: 2277-2281, 1999

    Google Scholar 

  7. Jones NL, Day AS, Jennings HA, Sherman PM: Helicobacter pylori induces gastric epithelial cell apoptosis in association with increased Fas receptor expression. Infect Immun 67:4237-4242, 1999

    Google Scholar 

  8. Wagner S, Beil W, Westermann J, Logan RP, Bock CT, Trautwein C, Bleck JS, Manns MP: Regulation of gastric epithelial cell growth by Helicobacter pylori: evidence for a major role of apoptosis. Gastroenterol 113:1836-1847, 1997

    Google Scholar 

  9. Fan X, Gunasena H, Cheng Z, Espejo R, Crowe SE, Ernst PB, Reyes VE: Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J Immunol 165:1918-1924, 2000

    Google Scholar 

  10. 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 69:5080-5087, 2001

    Google Scholar 

  11. 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 69:5001-5009, 2001

    Google Scholar 

  12. Houghton J, Macera-Bloch LS, Harrison L, Kim KH, Korah RM: Tumor necrosis factor alpha and interleukin 1beta up-regulate gastric mucosal Fas antigen expression in Helicobacter pylori infection. Infect Immun 68:1189-1195, 2000

    Google Scholar 

  13. Igarashi M, Kitada Y, Yoshiyama H, Takagi A, Miwa T, Koga Y: Ammonia as an accelerator of tumor necrosis factor alpha-induced apoptosis of gastric epithelial cells in Helicobacter pylori infection. Infect Immun 69:816-821, 2001

    Google Scholar 

  14. 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 151:1695-1703, 1997

    Google Scholar 

  15. Kohda K, Tanaka K, Aiba Y, Yasuda M, Miwa T, Koga Y: Role of apoptosis induced by Helicobacter pylori infection in the development of duodenal ulcer. Gut 44:456-462, 1999

    Google Scholar 

  16. Peek RM, Jr, Moss SF, Tham KT, Perez-Perez GI, Wang S, Miller GG, Atherton JC, Holt PR, Blaser MJ: Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst 89:863-868, 1997

    Google Scholar 

  17. Rudi J, Kuck D, Strand S, von Herbay A, Mariani SM, Krammer PH, Galle PR, Stremmel W: Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J Clin Invest 102:1506-1514, 1998

    Google Scholar 

  18. Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ET, Mera R, Miller MJ, Correa P: Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 56:3238-3243, 1996

    Google Scholar 

  19. Hirasawa R, Tatsuta M, Iishi H, Yano H, Baba M, Uedo N, Sakai N: Increase in apoptosis and decrease in ornithine decarboxylase activity of the gastric mucosa in patients with atrophic gastritis and gastric ulcer after successful eradication of Helicobacter pylori. Am J Gastroenterol 94:2398-2402, 1999

    Google Scholar 

  20. Rokkas T, Ladas S, Liatsos C, Petridou E, Papatheodorou G, Theocharis S, Karameris A, Raptis S: Relationship of Helicobacter pylori CagA status to gastric cell proliferation and apoptosis. Dig Dis Sci 44:487-493, 1999

    Google Scholar 

  21. Kim JS, Kim JM, Jung HC, Song IS, Kim CY: Inihibition of apoptosis in human neutrophils by Helicobacter pylori water-soluble surface proteins. Scand J Gastroenterol 36:589-600, 2001

    Google Scholar 

  22. Hofman V, Ricci V, Mograbi B, Brest P, Luciano F, Boquet P, Rossi B, Auberger P, Hofman P: Helicobacter pylori lipolysaccharide hinders polymorphonuclear leucocyte apoptosis. Lab Invest 81:375-384, 2001

    Google Scholar 

  23. Betten AB, Bylund J, Cristophe T, Boulay F, Romero A, Hellstrand K, Dahlgren C: A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunctino and apoptosis. J Clin Invest 108:1221-1228, 2001

    Google Scholar 

  24. Wang J, Brooks EG, Bamford KB, Denning TL, Pappo J, Ernst PB: Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion. J Immunol 167:926-934, 2001

    Google Scholar 

  25. Wang J, Fan X, Lindholm C, Bennett M, O'Connoll J, Shanahan F, Brooks EG, Reyes VE, Ernst PB: Helicobacter pylori modulates lymphoepithelial cell interactions leading to epithelial cell damage through Fas/Fas ligand interactions. Infect Immun 68:4303-4311, 2000

    Google Scholar 

  26. Lembo A, Caradonna L, Magrone T, Mastronardi ML, Caccavo D, Jirillo E, Amati L: Helicobacter pylori organisms induce expression of activation and apoptotic surface markers on human lymphocytes and AGS cells: a cytofluorimetric evaluation. Immunopharmacol Immunotoxicol 24:567-582, 2002

    Google Scholar 

  27. Houghton J, Korah RM, Condon MR, Kim KH: Apoptosis in Helicobacter pylori-associated gastric and duodenal ulcer disease is meditaed via the Fas antigen pathway. Dig Dis Sci 44:465-478, 1999

    Google Scholar 

  28. Koyama S: Apoptotic depletion of infiltrating mucosal lymphocytes associated with Fas ligand expresion by Helicobacter pylori-infected gasric mucosal epithelium: human glandular stomach as a site of immune privilege. Dig Dis Sci 45:773-780, 2000

    Google Scholar 

  29. Dubois A, Fiala N, Weichbrod RH, Ward GS, Nix M, Mehlman P, Taub DM, Perez-Perez GI, Blaser MJ: Seroepizootiology of Helicobacter pylori gastric infection in nonhuman primates housed in social environments. J Clin Microbiol 33:1492-1495, 1995

    Google Scholar 

  30. Dubois A, Fiala N, Heman-Ackah LM, Drazek ES, Tarnawski A, Fishbein WN, Perez-Perez GI, Blaser MJ: Natural gastric infection with Helicobacter pylori in monkeys: A model for spiral bacteria infection in humans. Gastroenterology 106:1405-1417, 1994

    Google Scholar 

  31. Solnick JV, Canfield DR, Yang S, Parsonnet J: The rhesus monkey (Macaca mulatta) model of Helicobacter pylori: noninvasive detection and derivation of specific pathogen free monkeys. Lab Anim Sci 49:197-201, 1999

    Google Scholar 

  32. Mattapallil JJ, Dandekar S, Canfield DR, Solnick JV: A predominant Th-1 type of immune response is induced early during acuteHelicobacter pylori infection in the rhesus monkey. Gastroenterology 118:307-315, 2000

    Google Scholar 

  33. Dubois A, Berg DE, Incecik ET, Fiala N, Heman-Ackah LM, Perez-Perez GI, Blaser MJ: Transient and persistent experimental infection of nonhuman primates with Helicobacter pylori: implications for human disease. Infect Immun 64:2885-2891, 1996

    Google Scholar 

  34. Solnick JV, Schauer DB: Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases. Clin Microbiol Rev 14:59-97, 2001

    Google Scholar 

  35. Covacci A, Falkow S, Berg DE, Rappuoli R: Did the inheritance of a pathogenicity island modify the virulence of Helicobacter pylori? Trends Microbiol 5:205-208, 1997

    Google Scholar 

  36. Telford JL, Ghiara P, Dell'Orco M, Comanducci M, Burroni D, Bugnoli M, Tecce MF, Censini S, Covacci A, Xiang Z, Papini E, Montecucco C, Parente L, Rappuoli R: Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med 179:1653-1658, 1994

    Google Scholar 

  37. Solnick JV, Hansen LM, Canfield DR, Parsonnet J: Determination of the infectious dose of Helicobacter pylori during primary and secondary infection in rhesus monkeys (Macaca mulatta). Infect Immun 69:6887-6892, 2001

    Google Scholar 

  38. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK: Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325:1127-1136, 1991

    Google Scholar 

  39. Ferrero RL, Thiberge JM, Huerre M, Labigne A: Immune responses of specific-pathogen-free mice to chronic Helicobacter pylori (strain SS1) infection. Infection and Immunity 66:1349-1355, 1998

    Google Scholar 

  40. Atherton JC, Tham KT, Peek RM, Cover TL, Jr, Blaser MJ: Density of Helicobacter pylori infection in vivo as assessed by quantitative culture and histology. J Infect Dis 174:552-556, 1996

    Google Scholar 

  41. He Q, Wang JP, Osato M, Lachman LB: Real-time quantitative PCR for detection of Helicobacter pylori. J Clin Microbiol 40:3720-3728, 2002

    Google Scholar 

  42. Houghton JM, Bloch LM, Goldstein M, Von Hagen S, Korah RM: In vivo disruption of the fas pathway abrogates gastric growth alterations secondary to Helicobacter infection. J Infect Dis 182:856-864, 2000

    Google Scholar 

  43. Peek RM, Jr, Wirth HP, Moss SF, Yang M, Abdalla AM, Tham KT, Zhang T, Tang LH, Modlin IM, Blaser MJ: Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology 118:48-59, 2000

    Google Scholar 

  44. Frazier BA, Pfeifer JD, Russell DG, Falk P, Olsén AN, Hammar M, Westblom TU, Normark SJ: Paracrystalline inclusions of a novel ferritin containing nonheme iron, produced by the human gastric pathogen Helicobacter pylori: evidence for a third class of ferritins. J Bacteriol 175:966-972, 1993

    Google Scholar 

  45. Bechi P, Balzi M, Becciolini A, Maugeri A, Raggi CC, Amorosi A, Dei R: Helicobacter pylori and cell proliferation of the gastric mucosa: possible implications for gastric carcinogenesis. Am J Gastroenterol 91:271-276, 1996

    Google Scholar 

  46. Blaser MJ, Kirschner D: Dynamics of Helicobacter pylori colonization in relation to the host response. Proc Natl Acad Sci USA 96:8359-8364, 1999

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dandekar, S., Reay, E., Taylor, J.M. et al. Apoptosis of Gastric Lymphocytes in Helicobacter pylori-Infected Rhesus Macaques. Dig Dis Sci 48, 1073–1080 (2003). https://doi.org/10.1023/A:1023756427046

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1023756427046

Navigation