Helicobacter pylori Immune Response in Children Versus Adults

Main Article Content

Victor E. Reyes

Abstract

  1. pylori is perhaps the most prevalent human pathogen worldwide and infects almost half of the world's population. Despite the decreasing prevalence of infection overall, it is significant in developing countries. Most infections are acquired in childhood and persist for a lifetime unless treated. Children are often asymptomatic and often develop a tolerogenic immune response that includes T regulatory cells and their products, immunosuppressive cytokines, such as interleukin (IL)-10, and transforming growth factor-β (TGF-β). This contrasts to the gastric immune response seen in H. pylori-infected adults, where the response is mainly inflammatory, with predominant Th1 and Th17 cells, as well as, inflammatory cytokines, such as TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-17. Therefore, compared to adults, infected children generally have limited gastric inflammation and peptic ulcer disease. H. pylori surreptitiously subverts immune defenses to persist in the human gastric mucosa for decades. The chronic infection might result in clinically significant diseases in adults, such as peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This review compares the infection in children and adults and highlights the H. pylori virulence mechanisms responsible for the pathogenesis and immune evasion.

 

Article Details

How to Cite
REYES, Victor E.. Helicobacter pylori Immune Response in Children Versus Adults. Medical Research Archives, [S.l.], v. 10, n. 12, dec. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3370>. Date accessed: 29 jan. 2023. doi: https://doi.org/10.18103/mra.v10i12.3370.
Section
Review Articles

References

1. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: Systematic review and meta-analysis. Gastroenterology. 2017;153(0016-5085):420-429.
2. Gold BD. New approaches to Helicobacter pylori infection in children. Curr Gastroenterol Rep. 2001;3(3):235-247. doi:10.1007/S11894-001-0028-1
3. Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut. 1994;35(6):742-745. doi:10.1136/GUT.35.6.742
4. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311-1315.
5. Kotilea K, Bontems P, Touati E. Epidemiology, diagnosis and risk factors of Helicobacter pylori infection. Adv Exp Med Biol. 2019;1149:17-33. doi:10.1007/5584_2019_357/FIGURES/2
6. Kumar S, Metz DC, Ellenberg S, Kaplan DE, Goldberg DS. Risk Factors and Incidence of Gastric Cancer After Detection of Helicobacter pylori Infection: A Large Cohort Study 4. Gastroenterology. 2020;158(0016-5085):527-536.
7. Huerta-Franco MR, Banderas JW, Allsworth JE. Ethnic/racial differences in gastrointestinal symptoms and diagnosis associated with the risk of Helicobacter pylori infection in the US 10. ClinExpGastroenterol. 2018;11(1178-7023):39-49.
8. Long Parma D, Muñoz E, Ogden SM, et al. Helicobacter pylori infection in Texas hispanic and non-hispanic white men: Implications for gastric cancer risk disparities. Am J Mens Health. 2017;11(4):1039-1045. doi:10.1177/1557988317702038
9. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347(15):1175-1186. doi:10.1056/NEJMra020542 [doi];347/15/1175 [pii]
10. Mezmale L, Gonzaga Coelho L, Bordin D, Leja M. Review: Epidemiology of Helicobacter pylori. Helicobacter. 2020;25:e12734. doi:10.1111/hel.12734
11. Leja M, Grinberga I, Bilgilier C, Steininger C. Review: Epidemiology of Helicobacter pylori infection. Helicobacter. 2019;24:e12635. doi:10.1111/hel.12635
12. Mamishi S, Eshaghi H, Mahmoudi S, et al. Intrafamilial transmission of Helicobacter pylori: genotyping of faecal samples. New pub: Frontiers. 2016;73(1):38-43. doi:10.1080/09674845.2016.1150666
13. Farhadkhani M, Nikaeen M, Hassanzadeh A, Nikmanesh B. Potential transmission sources of Helicobacter pylori infection: detection of H. pylori in various environmental samples. J Environ Health Sci Eng. 2019;17(1):129. doi:10.1007/S40201-018-00333-Y
14. Karita M, Teramukai S, Matsumoto S. Risk of Helicobacter pylori transmission from drinking well water is higher than that from infected intrafamilial members in Japan. Dig Dis Sci. 2003;48(6):1062-1067. doi:10.1023/A:1023752326137
15. Castillo M, Bernabe LA, Castaneda CA, et al. Helicobacter pylori detected in tap water of peruvian patients with gastric cancer. Asian Pac J Cancer Prev. 2019;20(11):3193. doi:10.31557/APJCP.2019.20.11.3193
16. Zabala Torrres B, Lucero Y, Lagomarcino AJ, et al. Review: Prevalence and dynamics of Helicobacter pylori infection during childhood. Helicobacter. 2017;22(5):e12399. doi:10.1111/HEL.12399
17. Yuan C, Adeloye D, Luk TT, et al. The global prevalence of and factors associated with Helicobacter pylori infection in children: a systematic review and meta-analysis. Lancet Child Adolesc Health. 2022;6(3):185-194. doi:10.1016/S2352-4642(21)00400-4
18. Opekun AR, Gilger MA, Denyes SM, et al. Helicobacter pylori infection in children of Texas. J Pediatr Gastroenterol Nutr. 2000;31(4):405-410. doi:10.1097/00005176-200010000-00014
19. Wizla-Derambure N, Michaud L, Ategbo S, et al. Familial and community environmental risk factors for Helicobacter pylori infection in children and adolescents. J Pediatr Gastroenterol Nutr. 2001;33(1):58-63. doi:10.1097/00005176-200107000-00010
20. Okuda M, Lin Y, Kikuchi S. Helicobacter pylori Infection in children and adolescents. Adv Exp Med Biol. 2019;1149:107-120. doi:10.1007/5584_2019_361/TABLES/7
21. Chen Y, Blaser MJ. Helicobacter pylori Colonization is inversely associated with childhood asthma. J Infect Dis. 2008;198(4):553-560. doi:10.1086/590158
22. Fouda EM, Kamel TB, Nabih ES, Abdelazem AA. Helicobacter pylori seropositivity protects against childhood asthma and inversely correlates to its clinical and functional severity. Allergol Immunopathol (Madr). 2018;46(1):76-81. doi:10.1016/J.ALLER.2017.03.004
23. Serrano C, Wright SW, Bimczok D, et al. Downregulated Th17 responses are associated with reduced gastritis in Helicobacter pylori-infected children. Mucosal Immunol. 2013;6(5):950-959. doi:mi2012133 [pii];10.1038/mi.2012.133 [doi]
24. Harris PR, Wright SW, Serrano C, et al. Helicobacter pylori gastritis in Children Is associated with a regulatory T-cell response. Gastroenterology. 2008;134(2):491-499. doi:10.1053/J.GASTRO.2007.11.006
25. Arnold IC, Lee JY, Amieva MR, et al. Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology. 2011;140(1):199-209. doi:S0016-5085(10)00956-X [pii];10.1053/j.gastro.2010.06.047 [doi]
26. Waksman G. From conjugation to T4S systems in gram-negative bacteria: a mechanistic biology perspective. EMBO Rep. 2019;20(2):e47012. doi:10.15252/EMBR.201847012
27. Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci U S A. 2000;97(3):1263-1268. http://www.ncbi.nlm.nih.gov/pubmed/10655519
28. Naito M, Yamazaki T, Tsutsumi R, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology. 2006;130(4):1181-1190. doi:S0016-5085(05)02591-6 [pii];10.1053/j.gastro.2005.12.038 [doi]


29. Mueller D, Tegtmeyer N, Brandt S, et al. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest. 2012;122(4):1553-1566. doi:10.1172/JCI61143
30. Ohnishi N, Yuasa H, Tanaka S, et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A. 2008;105(3):1003-1008. http://www.ncbi.nlm.nih.gov/pubmed/18192401
31. Lina TT, Alzahrani S, House J, et al. Helicobacter pylori cag pathogenicity island’s role in B7-H1 induction and immune evasion. PLoS One. 2015;10(3). doi:10.1371/journal.pone.0121841
32. Lina TT, Pinchuk IV, House J, et al. CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection. Journal of Immunology. 2013;191(7). doi:10.4049/jimmunol.1300524
33. Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996;12:697-715. doi:10.1146/ANNUREV.CELLBIO.12.1.697
34. Telford JL, Ghiara P, Dell’Orco M, et al. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med. 1994;179(5):1653-1658. doi:10.1084/JEM.179.5.1653
35. Voss BJ, Gaddy JA, McDonald WH, Cover TL. Analysis of surface-exposed outer membrane proteins in Helicobacter pylori. J Bacteriol. 2014;196(13):2455-2471. doi:10.1128/JB.01768-14
36. Atherton JC, Cao P, Peek RM, Tummuru MKR, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem. 1995;270(30):17771-17777. doi:10.1074/JBC.270.30.17771
37. Rhead JL, Letley DP, Mohammadi M, et al. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133(3):926-936. doi:10.1053/J.GASTRO.2007.06.056
38. Cover TL. Helicobacter pylori diversity and gastric cancer risk. mBio. 2016;7(1). doi:10.1128/MBIO.01869-15
39. Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol. 2005;3(4):320-332. http://www.ncbi.nlm.nih.gov/pubmed/15759043
40. Papini E, de Bernard M, Milia E, et al. Cellular vacuoles induced by Helicobacter pylori originate from late endosomal compartments. Proc Natl Acad Sci U S A. 1994;91(21):9720-9724.
41. Molinari M, Galii C, Norais N, et al. Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers. Journal of Biological Chemistry. 1997;272(40):25339-25344.
42. Molinari M, Salio M, Galli C, et al. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin vacA. J Exp Med. 1998;187(1):135-140.
43. Yahiro K, Satoh M, Nakano M, et al. Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. J Biol Chem. 2012;287(37):31104-31115. doi:10.1074/JBC.M112.387498
44. Galmiche A, Rassow J. Targeting of Helicobacter pylori VacA to mitochondria. Gut Microbes. 2010;1(6):392. doi:10.4161/GMIC.1.6.13894
45. Yamasaki E, Wada A, Kumatori A, et al. Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J Biol Chem. 2006;281(16):11250-11259. doi:10.1074/JBC.M509404200
46. Papini E, Satin B, Norais N, et al. Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J Clin Invest. 1998;102(4):813-820. http://www.ncbi.nlm.nih.gov/pubmed/9710450
47. Cover TL, Krishna US, Israel DA, Peek Jr. RM. Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res. 2003;63(5):951-957. http://www.ncbi.nlm.nih.gov/pubmed/12615708
48. Radin JN, González-Rivera C, Ivie SE, McClain MS, Cover TL. Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect Immun. 2011;79(7):2535-2543. doi:10.1128/IAI.01370-10
49. Sundrud MS, Torres VJ, Unutmaz D, Cover TL. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci U S A. 2004;101(20):7727-7732. http://www.ncbi.nlm.nih.gov/pubmed/15128946
50. Bauerfeind P, Garner R, Dunn BE, Mobley HLT. Synthesis and activity of Helicobacter pylori urease and catalase at low pH. Gut. 1997;40(1):25. doi:10.1136/GUT.40.1.25
51. Karita M, Tsuda M, Nakazawa T. Essential role of urease in vitro and in vivo Helicobacter pylori colonization study using a wild-type and isogenic urease mutant strain. J Clin Gastroenterol. 1995;21 Suppl 1:S160-3. http://www.ncbi.nlm.nih.gov/pubmed/8775011
52. Tsuda M, Karita M, Morshed MG, Okita K, Nakazawa T. A urease-negative mutant of Helicobacter pylori constructed by allelic exchange mutagenesis lacks the ability to colonize the nude mouse stomach. Infect Immun. 1994;62(8):3586-3589.
53. Tsuda M, Karita M, Mizote T, Morshed MG, Okita K, Nakazawa T. Essential role of Helicobacter pylori urease in gastric colonization: definite proof using a urease-negative mutant constructed by gene replacement. Eur J Gastroenterol Hepatol. 1994;6 Suppl 1:S49-S52. http://www.ncbi.nlm.nih.gov/pubmed/7735935
54. Hu LT, Mobley HLT. Purification and N-terminal analysis of urease from Helicobacter pylori. Infect Immun. 1990;58(4):992-998. doi:10.1128/IAI.58.4.992-998.1990
55. Phadnis SH, Parlow MH, Levy M, et al. Surface localization of Helicobacter pylori urease and a heat shock protein homolog requires bacterial autolysis. Infect Immun. 1996;64(3):905-912. http://www.ncbi.nlm.nih.gov/pubmed/8641799
56. Dunn BE, Vakil NB, Schneider BG, et al. Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies. Infect Immun. 1997;65(4):1181-1188.
57. Eaves-Pyles TD, Reyes VE. H-pylori urease and urease UreA induces proinflammatory responses in gastric epithelial cells. Mol Biol Cell. 2001;12:327A-328A.
58. Beswick EJ, Bland D, Das S, Suarez G, Sierra J, Reyes VE. Helicobacter pylori urease binds to CD74 and stimulates gastric epithelial cell responses associated with pathogenesis. Gastroenterology. 2004;126(4):A401-A401.
59. Fan X, Gunasena H, Cheng Z, et al. Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. Journal of Immunology. 2000;165(4). doi:10.4049/jimmunol.165.4.1918
60. Fan XJ, Gunasena H, Gonzales M, et al. Class II MHC molecules on gastric epithelial cells act as receptors for Helicobacter pylori urease and signal apoptosis of the epithelium. FASEB Journal. 1998;12(5).
61. Beswick EJJ, Pinchuk IV v, Minch K, et al. The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NFĸB activation and interleukin-8 production. Infect Immun. 2006;74(2):1148-1155. doi:10.1128/IAI.74.2.1148-1155.2006
62. Uberti AF, Olivera-Severo D, Wassermann GE, et al. Pro-inflammatory properties and neutrophil activation by Helicobacter pylori urease. Toxicon. 2013;69:240-249. doi:10.1016/J.TOXICON.2013.02.009
63. Olivera-Severo D, Uberti AF, Marques MS, et al. A new role for Helicobacter pylori urease: Contributions to angiogenesis. Front Microbiol. 2017;8(SEP):1883. doi:10.3389/FMICB.2017.01883/BIBTEX
64. Valenzuela-Valderrama M, Cerda-Opazo P, Backert S, et al. The Helicobacter pylori urease virulence factor is required for the induction of hypoxia-induced factor-1α in gastric cells. Cancers (Basel). 2019;11(6):799. doi:10.3390/CANCERS11060799
65. Canales J, Valenzuela M, Bravo J, et al. Helicobacter pylori induced phosphatidylinositol-3-OH kinase/mTOR activation increases hypoxia inducible factor-1α to promote loss of cyclin D1 and G0/G1 cell cycle arrest in human gastric cells. Front Cell Infect Microbiol. 2017;7(MAR):92. doi:10.3389/FCIMB.2017.00092/BIBTEX
66. Walsh D, McCarthy J, O’Driscoll C, Melgar S. Pattern recognition receptors—Molecular orchestrators of inflammation in inflammatory bowel disease. Cytokine Growth Factor Rev. 2013;24(2):91-104. doi:10.1016/J.CYTOGFR.2012.09.003
67. Moran AP. The role of endotoxin in infection: Helicobacter pylori and campylobacter Jejuni. Subcell Biochem. 2010;53:209-240. doi:10.1007/978-90-481-9078-2_10
68. Moran AP. Molecular structure, biosynthesis, and pathogenic roles of lipopolysaccharides. Helicobacter pylori. Published online April 9, 2014:81-95. doi:10.1128/9781555818005.CH8
69. Andersen-Nissen E, Smith KD, Strobe KL, et al. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A. 2005;102(26):9247-9252. doi:10.1073/PNAS.0502040102
70. Ramarao N, Meyer TF. Helicobacter pylori resists phagocytosis by macrophages: quantitative assessment by confocal microscopy and fluorescence-activated cell sorting. Infect Immun. 2001;69(4):2604-2611. doi:10.1128/IAI.69.4.2604-2611.2001
71. Allen LA, Schlesinger LS, Kang B. Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J Exp Med. 2000;191(1):115-128. http://www.ncbi.nlm.nih.gov/pubmed/10620610
72. Rittig MG, Shaw B, Letley DP, Thomas RJ, Argent RH, Atherton JC. Helicobacter pylori-induced homotypic phagosome fusion in human monocytes is independent of the bacterial vacA and cag status. Cell Microbiol. 2003;5(12):887-899. doi:10.1046/J.1462-5822.2003.00328.X
73. Spiegelhalder C, Gerstenecker B, Kersten A, Schiltz E, Kist M. Purification of Helicobacter pylori superoxide dismutase and cloning and sequencing of the gene. Infect Immun. 1993;61(12):5315-5325. doi:10.1128/IAI.61.12.5315-5325.1993
74. Ramarao N, Gray-Owen SD, Meyer TF. Helicobacter pylori induces but survives the extracellular release of oxygen radicals from professional phagocytes using its catalase activity. Mol Microbiol. 2000;38(1):103-113. doi:10.1046/J.1365-2958.2000.02114.X
75. Schmausser B, Josenhans C, Endrich S, et al. Downregulation of CXCR1 and CXCR2 expression on human neutrophils by Helicobacter pylori: a new pathomechanism in H. pylori infection? Infect Immun. 2004;72(12):6773. doi:10.1128/IAI.72.12.6773-6779.2004
76. Lewis ND, Asim M, Barry DP, et al. Arginase II restricts host defense to Helicobacter pylori by attenuating inducible nitric oxide synthase translation in macrophages. J Immunol. 2010;184(5):2572-2582. doi:10.4049/JIMMUNOL.0902436
77. Gobert AP, McGee DJ, Akhtar M, et al. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: A strategy for bacterial survival. Proc Natl Acad Sci U S A. 2001;98(24):13844-13849. doi:10.1073/PNAS.241443798/ASSET/701906C4-F840-4EF5-82AA-809BDEBC3CD7/ASSETS/GRAPHIC/PQ2414437003.JPEG
78. Oertli M, Sundquist M, Hitzler I, et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J Clin Invest. 2012;122(3):1085-1096. doi:10.1172/JCI61029
79. Manojlovic N, Babic D, Filipovic-Ljeskovic I, Pilcevic D. Anti Helicobacter pylori IgG and IgA response in patients with gastric cancer and chronic gastritis. Hepatogastroenterology. 2008;55(82-83):807-813.
80. Yamaji Y, Mitsushima T, Ikuma H, et al. Weak response of helicobacter pylori antibody is high risk for gastric cancer: a cross-sectional study of 10,234 endoscoped Japanese. Scand J Gastroenterol. 2002;37(2):148-153. doi:10.1080/003655202753416795
81. Bamford KB, Fan XJ, Crowe SE, et al. Lymphocytes during infection with Helicobacter pylori have a helper 1 (Th1) phenotype. Gastro. 1998;114:1-12.
82. D’Elios MM, Manghetti M, de Carli M, et al. T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease. J Immunol. 1997;158(2):962-967.
83. Amedei A, Cappon A, Codolo G, et al. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. J Clin Invest. Published online 2006. http://www.ncbi.nlm.nih.gov/pubmed/16543949
84. Bagheri N, Salimzadeh L, Shirzad H. The role of T helper 1-cell response in Helicobacter pylori-infection. Microb Pathog. 2018;123:1-8. doi:10.1016/J.MICPATH.2018.06.033
85. Osaki LH, Bockerstett KA, Wong CF, et al. Interferon-γ directly induces gastric epithelial cell death and is required for progression to metaplasia. J Pathol. 2019;247(4):513. doi:10.1002/PATH.5214
86. Obonyo M, Guiney DG, Harwood J, Fierer J, Cole SP. Role of gamma interferon in Helicobacter pylori induction of inflammatory mediators during murine infection. Infect Immun. 2002;70(6):3295. doi:10.1128/IAI.70.6.3295-3299.2002
87. Serelli-Lee V, Ling KL, Ho C, et al. Persistent Helicobacter pylori specific Th17 responses in patients with past H. pylori infection are associated with elevated gastric mucosal IL-1beta. PLoS One. 2012;7(6):e39199. doi:10.1371/journal.pone.0039199 [doi];PONE-D-12-01375 [pii]
88. Lundgren A, Suri-Payer E, Enarsson K, Svennerholm AM, Lundin BS. Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals. Infect Immun. 2003;71(4):1755-1762. http://www.ncbi.nlm.nih.gov/pubmed/12654789
89. Lundgren A, Stromberg E, Sjoling A, et al. Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients. Infect Immun. 2005;73(1):523-531. http://www.ncbi.nlm.nih.gov/pubmed/15618192
90. Enarsson K, Lundgren A, Kindlund B, et al. Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma. Clin Immunol. Published online 2006. http://www.ncbi.nlm.nih.gov/pubmed/16934529
91. Rodríguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Immunol. 2016;185(3):281-291. doi:10.1111/CEI.12804
92. Beswick EJ, Pinchuk I v, Earley RB, Schmitt DA, Reyes VE. The role of gastric epithelial cell-derived TGF-β in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun. 2011;79(7):2737-2745. doi:IAI.01146-10 [pii];10.1128/IAI.01146-10 [doi]
93. Beswick EJ, Pinchuk IV, Earley RB, Schmitt DA, Reyes VE. Role of gastric epithelial cell-derived transforming growth factor β in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun. 2011;79(7). doi:10.1128/IAI.01146-10
94. Ziegler SF. FOXP3: of mice and nen. Annu Rev Immunol. Published online 2005. DOI: 10.1146/annurev.immunol.24.021605.090547
95. Katoh H, Zheng P, Liu Y. FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun. 2013;41:72-78. doi:10.1016/J.JAUT.2012.12.004
96. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (1979). 2003;299(5609):1057-1061. doi:10.1126/science.1079490 [doi];1079490 [pii]
97. Fan XJ, Chua A, Shahi CN, Mcdevitt J, Keeling PWN, Kelleher D. Gastric T lymphocyte responses to Helicobacter pylori in patients with H-pylori colonisation. Gut. 1994;35:1379-1384.
98. Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A. Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. Int Immunol. 2018;30(8):357-373. doi:10.1093/INTIMM/DXY043
99. Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE. Expression of B7-H1 on gastric epithelial cells: Its potential role in regulating T cells during Helicobacter pylori infection. Journal of Immunology. 2006;176(5). doi:10.4049/jimmunol.176.5.3000
100. Beswick EJJ, Pinchuk IV v, Das S, Powell DWW, Reyes VEE. B7-H1 Expression on gastric epithelial cells after Helicobacter pylori exposure promotes the development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun. 2007;75(9):4334-4341. doi:10.1128/IAI.00553-07
101. Raghavan S, Fredriksson M, Svennerholm AM, Holmgren J, Suri-Payer E. Absence of CD4+CD25+ regulatory T cells is associated with a loss of regulation leading to increased pathology in Helicobacter pylori-infected mice. Clin Exp Immunol. 2003;132(3):393-400. doi:10.1046/J.1365-2249.2003.02177.X
102. Zhuang Y, Shi Y, Liu XF, et al. Helicobacter pylori-infected macrophages induce Th17 cell differentiation. Immunobiology. 2011;216(1-2):200-207. doi:10.1016/J.IMBIO.2010.05.005
103. Horvath DJ, Washington MK, Algood HMS. IL-23 Contributes to control of chronic Helicobacter Pylori infection and the development of T helper responses in a mouse model. Front Immunol. 2012;3(MAR). doi:10.3389/FIMMU.2012.00056
104. Mus AMC, Cornelissen F, Asmawidjaja PS, et al. Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22, but not interleukin-21, in autoimmune experimental arthritis. Arthritis Rheum. 2010;62(4):1043-1050. doi:10.1002/ART.27336
105. Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol. 2008;181(9):5948. doi:10.4049/JIMMUNOL.181.9.5948
106. Zhang JY, Liu T, Guo H, et al. Induction of a Th17 cell response by Helicobacter pylori urease subunit B. Immunobiology. 2011;216(7):803-810. doi:10.1016/J.IMBIO.2010.12.006
107. Bedoya SK, Lam B, Lau K, Larkin J. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013;2013:986789. doi:10.1155/2013/986789
108. Jäger A, Kuchroo VK. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand J Immunol. 2010;72(3):173-184. doi:10.1111/J.1365-3083.2010.02432.X
109. Pinchuk I v., Morris KT, Nofchissey RA, et al. Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment. PLoS One. 2013;8(1). doi:10.1371/JOURNAL.PONE.0053798
110. Dixon BREA, Hossain R, Patel R v., Scott Algood HM. Th17 Cells in Helicobacter pylori Infection: a Dichotomy of Help and Harm. Infect Immun. 2019;87(11). doi:10.1128/IAI.00363-19
111. Flach CF, Östberg AK, Nilsson AT, Malefyt RDW, Raghavan S. Proinflammatory cytokine gene expression in the stomach correlates with vaccine-induced protection against Helicobacter pylori infection in mice: an important role for interleukin-17 during the effector phase. Infect Immun. 2011;79(2):879-886. doi:10.1128/IAI.00756-10
112. Velin D, Favre L, Bernasconi E, et al. Interleukin-17 is a critical mediator of vaccine-induced reduction of Helicobacter infection in the mouse model. Gastroenterology. 2009;136(7). doi:10.1053/J.GASTRO.2009.02.077
113. Zhou F, Qiu LX, Cheng L, et al. Associations of genotypes and haplotypes of IL-17 with risk of gastric cancer in an eastern Chinese population. Oncotarget. 2016;7(50):82384. doi:10.18632/ONCOTARGET.11616
114. Saldinger PF, Porta N, Launois P, et al. Immunization of BALB/c mice with Helicobacter urease B induces a T helper 2 response absent in Helicobacter infection. Gastroenterology. 1998;115(4):891-897. doi:10.1016/S0016-5085(98)70261-6
115. Garhart CA, Nedrud JG, Heinzel FP, Sigmund NE, Czinn SJ. Vaccine-induced protection against Helicobacter pylori in mice lacking both antibodies and interleukin-4. Infect Immun. 2003;71(6):3628. doi:10.1128/IAI.71.6.3628-3633.2003
116. Sanaii A, Shirzad H, Haghighian M, et al. Role of Th22 cells in Helicobacter pylori-related gastritis and peptic ulcer diseases. Mol Biol Rep. 2019;46(6):5703-5712. doi:10.1007/S11033-019-05004-1
117. Ohtani N, Ohtani H, Nakayama T, et al. Infiltration of CD8+ T cells containing RANTES/CCL5+ cytoplasmic granules in actively inflammatory lesions of human chronic gastritis. Laboratory Investigation 2004 84:3. 2004;84(3):368-375. doi:10.1038/labinvest.3700039
118. Quiding-Järbrink M, Lundin BS, Lönroth H, Svennerholm AM. CD4+ and CD8+ T cell responses in Helicobacter pylori-infected individuals. Clin Exp Immunol. 2001;123(1):81. doi:10.1046/J.1365-2249.2001.01427.X
119. Huang Y, Wang QL, Cheng DD, Xu WT, Lu NH. Adhesion and invasion of gastric mucosa epithelial cells by Helicobacter pylori. Front Cell Infect Microbiol. 2016;6(NOV):159. doi:10.3389/FCIMB.2016.00159
120. Allen LAH, Schlesinger LS, Kang B. Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J Exp Med. 2000;191(1):115-127. doi:10.1084/JEM.191.1.115
121. Ramarao N, Gray-Owen SD, Backert S, Meyer TF. Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol Microbiol. 2000;37(6):1389-1404. doi:10.1046/J.1365-2958.2000.02089.X
122. Zheng PY, Jones NL. Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol. 2003;5(1):25-40. http://www.ncbi.nlm.nih.gov/pubmed/12542468
123. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science (1979). 2003;301(5636):1099-1102. http://www.ncbi.nlm.nih.gov/pubmed/12934009
124. 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 . The Journal of Immunology. 2001;167(2):926-934. doi:10.4049/JIMMUNOL.167.2.926
125. Ganten TM, Aravena E, Sykora J, et al. Helicobacter pylori-induced apoptosis in T cells is mediated by the mitochondrial pathway independent of death receptors. Eur J Clin Invest. 2007;37(2):117-125. doi:10.1111/J.1365-2362.2007.01761.X
126. Boanca G, Sand A, Barycki JJ. Uncoupling the enzymatic and autoprocessing activities of Helicobacter pylori gamma-glutamyltranspeptidase. J Biol Chem. 2006;281(28):19029-19037. doi:10.1074/JBC.M603381200
127. Schmees C, Prinz C, Treptau T, et al. Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase. Gastroenterology. 2007;132(5):1820-1833. doi:S0016-5085(07)00388-5 [pii];10.1053/j.gastro.2007.02.031 [doi]
128. Zabaleta J, McGee DJ, Zea AH, et al. Helicobacter pylori arginase inhibits T cell proliferation and reduces the expression of the TCR zeta-chain (CD3zeta). J Immunol. 2004;173(1):586-593. doi:10.4049/JIMMUNOL.173.1.586
129. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4 [see comments]. Science (1979). 1995;270:985-988.
130. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-548. doi:10.1146/annurev.immunol.23.021704.115611 [doi]
131. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation [Review]. Annu Rev Immunol. 1996;14:233-258.
132. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1(5):405-413.
133. Nowak EC, Lines JL, Varn FS, et al. Immunoregulatory functions of VISTA. ImmunolRev. 2017;276(0105-2896 (Linking)):66-79.
134. Brandt CS, Baratin M, Yi EC, et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med. 2009;206(7):1495-1503. doi:jem.20090681 [pii];10.1084/jem.20090681 [doi]
135. Zhao R, Chinai JM, Buhl S, et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc Natl Acad Sci U S A. 2013;110(24):9879-9884. doi:10.1073/PNAS.1303524110
136. Mager DL, Hunter DG, Schertzer M, Freeman JD. Endogenous retroviruses provide the primary polyadenylation signal for two new human genes (HHLA2 and HHLA3). Genomics. 1999;59(3):255-263. doi:10.1006/GENO.1999.5877
137. Boussiotis VA, Gribben JG, Freeman GJ, Nadler LM. Blockade of the CD28 co-stimulatory pathway: A means to induce tolerance. Curr Opin Immunol. 1994;6:797-807.
138. Freeman GJ, Boussiotis VA, Anumanthan A, et al. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity. 1995;2:523-532.
139. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. http://www.ncbi.nlm.nih.gov/pubmed/11224527
140. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015-3029. doi:jem.20090847 [pii];10.1084/jem.20090847 [doi]
141. Nandi D, Pathak S, Verma T, et al. T cell costimulation, checkpoint inhibitors and anti-tumor therapy. J Biosci. 2020;45(1):1-36. doi:10.1007/S12038-020-0020-2/FIGURES/11
142. Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 2013;34(11):556-563. doi:S1471-4906(13)00110-5 [pii];10.1016/j.it.2013.07.003 [doi]
143. Reyes VE, Peniche AG. Helicobacter pylori deregulates T and B cell signaling to trigger immune evasion. Vol 421.; 2019. doi:10.1007/978-3-030-15138-6_10
144. Lina TT, Alzahrani S, Gonzalez J, Pinchuk IV, Beswick EJ, Reyes VE. Immune evasion strategies used by Helicobacter pylori. World J Gastroenterol. 2014;20(36). doi:10.3748/wjg.v20.i36.12753
145. Amarnath S, Mangus CW, Wang JC, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med. 2011;3(111):111ra120. doi:3/111/111ra120 [pii];10.1126/scitranslmed.3003130 [doi]
146. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A. 2003;100(9):5336-5341. http://www.ncbi.nlm.nih.gov/pubmed/12697896
147. Sharma MD, Hou DY, Baban B, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity. 2010;33(6):942-954. doi:S1074-7613(10)00452-8 [pii];10.1016/j.immuni.2010.11.022 [doi]
148. Baban B, Chandler PR, Sharma MD, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009;183(4):2475-2483. doi:jimmunol.0900986 [pii];10.4049/jimmunol.0900986 [doi]
149. Lina TT, Gonzalez J, Pinchuk I v, Beswick EJ, Reyes VE. Helicobacter pylori elicits B7-H3 expression on gastric epithelial cells: implications in local T cell regulation and subset development during infection. Clin Oncol Res. 2019;2(5):1-12. https://www.sciencerepository.org/articles/helicobacter-pylori-elicits-b7-h3-expression-on-gastric-epithelial-cells-implications-in-local-t-cell-regulation-and-subset-development-durin_COR-2019-5-105.pdf
150. Fung C, Tan S, Nakajima M, et al. High-resolution mapping reveals that microniches in the gastric glands control Helicobacter pylori colonization of the stomach. PLoS Biol. 2019;17(5):e3000231. doi:10.1371/JOURNAL.PBIO.3000231


151. Anderson WF, Rabkin CS, Turner N, Fraumeni JF, Rosenberg PS, Camargo MC. The changing face of noncardia gastric cancer incidence among US non-hispanic whites. JNCI: Journal of the National Cancer Institute. 2018;110(6):608-615. doi:10.1093/JNCI/DJX262