Advertisement

Helicobacter pylori: Immune Responses and Gastric Autoimmunity

  • Maria Kaparakis-Liaskos
  • Mario M. D’Elios
Chapter

Abstract

Helicobacter pylori infects almost half of the population worldwide. H. pylori induces the activation of a fascinating cytokine and chemokine network in the gastric mucosa. Chronic H. pylori infection represents a very interesting model of how a single bacterial infection might result in a variety of different clinical outcomes such as duodenal and gastric ulcers, gastric adenocarcinoma, autoimmune gastritis and B cell lymphoma of mucosa-associated lymphoid tissue. The type of host immune response against H. pylori, particularly the cytolytic effector functions of T cells, is crucial for the outcome of the infection. T cells are potentially able to kill a target via different mechanisms, such as perforins or Fas-Fas ligand interaction. In H. pylori-infected patients with gastric autoimmunity, cytolytic T cells that cross-recognize different epitopes of H. pylori proteins and H(+)K(+)-ATPase autoantigen infiltrate the gastric mucosa and lead to gastric atrophy via long-lasting activation of Fas ligand-mediated apoptosis and perforin-induced cytotoxicity. This chapter will focus on the innate immune responses and the role of H. pylori, T cells and cytokines in the onset of autoimmune gastritis.

Keywords

Helicobacter Autoimmunity Molecular mimicry Microbial products Immune modulation Immune suppression Innate immunity T cells Toll-like receptors 

Abbreviations

AIG

Autoimmune gastritis

AP

Activating protein-1

ATPase

Adenosine triphosphatase

CagA

Cytotoxin-associated protein

cagPAI

cag pathogenicity island

E. coli

Escherichia coli

EAIG

Experimental autoimmune gastritis

FasL

Fas ligand

GlcNAc-MurNAc

N-Acetyl glucosamine-N-acetyl muramic acid

H. pylori

Helicobacter pylori

HBD

Human beta-defensin

HLA

Human leukocyte antigen

HP0175

Secreted peptidyl prolyl cis, trans-isomerase of H. pylori

HP-NAP

H. pylori neutrophil-activating protein

IFN

Interferon

IL

Interleukin

IRF

IFN regulatory factor

IRFs

Interferon regulatory factors

ISGs

Interferon-stimulated genes

LPS

Lipopolysaccharide

MALT

Mucosal-associated lymphoid tissue

MAMP

Microbe-associated molecular pattern

MAPK

Mitogen-activated protein kinase

MCP

Monocyte chemotactic protein

mDAP

Meso-diaminopimelate

MMP

Matrix metalloproteinase

NF-κB

Nuclear factor transcription beta

NLR

Nod-like receptor

NOD

Nucleotide-binding oligomerization domain

OMVs

Outer membrane vesicles

PA

Pernicious anaemia

PgdA

Peptidoglycan deacetylase

PRR

Pathogen recognition receptor

RIG

Retinoic acid-inducible gene

TCR

T cell receptor

Th

T helper

TILs

Tumour-infiltrating lymphocytes

TLR

Toll-like receptor

TNF

Tumour necrosis factor

VacA

Vacuolating cytotoxin A

References

  1. 1.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    O’Neill LA. The interleukin-1 receptor/toll-like receptor superfamily: 10 years of progress. Immunol Rev. 2008;226:10–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Schmausser B, Andrulis M, Endrich S, Lee SK, Josenhans C, Muller-Hermelink HK, et al. Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol. 2004;136:521–6.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ishihara S, Rumi MA, Kadowaki Y, Ortega-Cava CF, Yuki T, Yoshino N, et al. Essential role of MD-2 in TLR4-dependent signaling during helicobacter pylori-associated gastritis. J Immunol. 2004;173:1406–16.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999;11:443–51.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chaouche-Drider N, Kaparakis M, Karrar A, Fernandez MI, Carneiro LA, Viala J, et al. A commensal helicobacter sp. of the rodent intestinal flora activates TLR2 and NOD1 responses in epithelial cells. PLoS One. 2009;4:e5396.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lepper PM, Triantafilou M, Schumann C, Schneider EM, Triantafilou K. Lipopolysaccharides from Helicobacter pylori can act as antagonists for toll-like receptor 4. Cell Microbiol. 2005;7:519–28.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Smith MF Jr, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K, et al. Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J Biol Chem. 2003;278:32552–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Mandell L, Moran AP, Cocchiarella A, Houghton J, Taylor N, Fox JG, et al. Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4. Infect Immun. 2004;72:6446–54.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Torok AM, Bouton AH, Goldberg JB. Helicobacter pylori induces interleukin-8 secretion by toll-like receptor 2- and toll-like receptor 5-dependent and -independent pathways. Infect Immun. 2005;73:1523–31.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A, Benagiano M, et al. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. J Clin Invest. 2006;116:1092–101.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Takenaka R, Yokota K, Ayada K, Mizuno M, Zhao Y, Fujinami Y, et al. Helicobacter pylori heat-shock protein 60 induces inflammatory responses through the toll-like receptor-triggered pathway in cultured human gastric epithelial cells. Microbiology. 2004;150:3913–22.CrossRefPubMedGoogle Scholar
  14. 14.
    Ferrero RL, Thiberge JM, Kansau I, Wuscher N, Huerre M, Labigne A. The GroES homolog of Helicobacter pylori confers protective immunity against mucosal infection in mice. Proc Natl Acad Sci U S A. 1995;92:6499–503.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Macchia G, Massone A, Burroni D, Covacci A, Censini S, Rappuoli R. The Hsp60 protein of Helicobacter pylori: structure and immune response in patients with gastroduodenal diseases. Mol Microbiol. 1993;9:645–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Suerbaum S, Thiberge JM, Kansau I, Ferrero RL, Labigne A. Helicobacter pylori hspA-hspB heat-shock gene cluster: nucleotide sequence, expression, putative function and immunogenicity. Mol Microbiol. 1994;14:959–74.CrossRefPubMedGoogle Scholar
  17. 17.
    Gobert AP, Bambou JC, Werts C, Balloy V, Chignard M, Moran AP, et al. Helicobacter pylori heat shock protein 60 mediates interleukin-6 production by macrophages via a toll-like receptor (TLR)-2-, TLR-4-, and myeloid differentiation factor 88-independent mechanism. J Biol Chem. 2004;279:245–50.CrossRefPubMedGoogle Scholar
  18. 18.
    Rad R, Ballhorn W, Voland P, Eisenacher K, Mages J, Rad L, et al. Extra- and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology. 2009;136(7):2247–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Obonyo M, Sabet M, Cole SP, Ebmeyer J, Uematsu S, Akira S, et al. Deficiencies of myeloid differentiation factor 88, toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori. Infect Immun. 2007;75:2408–14.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Maeda S, Akanuma M, Mitsuno Y, Hirata Y, Ogura K, Yoshida H, et al. Distinct mechanism of Helicobacter pylori-mediated NF-kappa B activation between gastric cancer cells and monocytic cells. J Biol Chem. 2001;276:44856–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature. 2001;410:1099–103.CrossRefPubMedGoogle Scholar
  22. 22.
    Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM Jr. Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis. 2004;189:1914–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee SK, Stack A, Katzowitsch E, Aizawa SI, Suerbaum S, Josenhans C. Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Microbes Infect. 2003;5:1345–56.CrossRefPubMedGoogle Scholar
  24. 24.
    Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, et al. Evasion of toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A. 2005;102:9247–52.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, et al. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol. 2004;34:2541–50.CrossRefPubMedGoogle Scholar
  27. 27.
    Gantier MP, Irving AT, Kaparakis-Liaskos M, Xu D, Evans VA, Cameron PU, et al. Genetic modulation of TLR8 response following bacterial phagocytosis. Hum Mutat. 2010;31:1069–79.CrossRefPubMedGoogle Scholar
  28. 28.
    Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4(7):702.CrossRefPubMedGoogle Scholar
  29. 29.
    Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300:1584–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5:1166–74.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Allison CC, Kufer TA, Kremmer E, Kaparakis M, Ferrero RL. Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J Immunol. 2009;183:8099–109.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Watanabe T, Asano N, Fichtner-Feigl S, Gorelick PL, Tsuji Y, Matsumoto Y, et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest. 2010;120:1645–62.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Boughan PK, Argent RH, Body-Malapel M, Park JH, Ewings KE, Bowie AG, et al. Nucleotide-binding oligomerization domain-1 and epidermal growth factor receptor: critical regulators of beta-defensins during Helicobacter pylori infection. J Biol Chem. 2006;281:11637–48.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Grubman A, Kaparakis M, Viala J, Allison C, Badea L, Karrar A, et al. The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides. Cell Microbiol. 2010;12:626–39.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Allison CC, Ferrand J, McLeod L, Hassan M, Kaparakis-Liaskos M, Grubman A, et al. Nucleotide oligomerization domain 1 enhances IFN-gamma signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. J Immunol. 2013;190:3706–15.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Suarez G, Romero-Gallo J, Piazuelo MB, Wang G, Maier RJ, Forsberg LS, et al. Modification of Helicobacter pylori peptidoglycan enhances NOD1 activation and promotes cancer of the stomach. Cancer Res. 2015;75:1749–59.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kim BJ, Kim JY, Hwang ES, Kim JG. Nucleotide binding oligomerization domain 1 is an essential signal transducer in human epithelial cells infected with Helicobacter pylori that induces the transepithelial migration of neutrophils. Gut Liver. 2015;9:358–69.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Kaparakis M, Turnbull L, Carneiro L, Firth S, Coleman HA, Parkington HC, et al. Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cell Microbiol. 2010;12:372–85.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kaparakis-Liaskos M, Ferrero RL. Immune modulation by bacterial outer membrane vesicles. Nat Rev Immunol. 2015;15:375–87.CrossRefPubMedGoogle Scholar
  40. 40.
    Irving AT, Mimuro H, Kufer TA, Lo C, Wheeler R, Turner LJ, et al. The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe. 2014;15:623–35.CrossRefPubMedGoogle Scholar
  41. 41.
    Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004;117:561–74.CrossRefPubMedGoogle Scholar
  42. 42.
    Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481:278–86.CrossRefPubMedGoogle Scholar
  43. 43.
    Hitzler I, Sayi A, Kohler E, Engler DB, Koch KN, Hardt WD, et al. Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1beta and IL-18. J Immunol. 2012;188:3594–602.CrossRefPubMedGoogle Scholar
  44. 44.
    Semper RP, Mejias-Luque R, Gross C, Anderl F, Muller A, Vieth M, et al. Helicobacter pylori-induced IL-1beta secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island. J Immunol. 2014;193:3566–76.CrossRefPubMedGoogle Scholar
  45. 45.
    Kim DJ, Park JH, Franchi L, Backert S, Nunez G. The cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL-1beta production in Helicobacter pylori infected dendritic cells. Eur J Immunol. 2013;43:2650–8.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Perez-Figueroa E, Torres J, Sanchez-Zauco N, Contreras-Ramos A, Alvarez-Arellano L, Maldonado-Bernal C. Activation of NLRP3 inflammasome in human neutrophils by Helicobacter pylori infection. Innate Immun. 2016;22:103–12.CrossRefPubMedGoogle Scholar
  47. 47.
    Li X, Liu S, Luo J, Liu A, Tang S, Liu S, et al. Helicobacter pylori induces IL-1beta and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway. Pathog Dis. 2015;73:ftu024.CrossRefPubMedGoogle Scholar
  48. 48.
    Kameoka S, Kameyama T, Hayashi T, Sato S, Ohnishi N, Hayashi T, et al. Helicobacter pylori induces IL-1beta protein through the inflammasome activation in differentiated macrophagic cells. Biomed Res. 2016;37:21–7.CrossRefPubMedGoogle Scholar
  49. 49.
    McGuckin MA, Linden SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol. 2011;9:265–78.CrossRefPubMedGoogle Scholar
  50. 50.
    Ng GZ, Menheniott TR, Every AL, Stent A, Judd LM, Chionh YT, et al. The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome. Gut. 2016;65:1087–99.CrossRefPubMedGoogle Scholar
  51. 51.
    Sorrentino D, Faller G, DeVita S, Avellini C, Labombarda A, Ferraccioli G, et al. Helicobacter pylori associated antigastric autoantibodies: role in Sjogren’s syndrome gastritis. Helicobacter. 2004;9:46–53.CrossRefPubMedGoogle Scholar
  52. 52.
    Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, et al. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med. 1998;187:135–40.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, et al. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med. 2003;198:1887–97.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Sawalha AH, Schmid WR, Binder SR, Bacino DK, Harley JB. Association between systemic lupus erythematosus and Helicobacter pylori seronegativity. J Rheumatol. 2004;31:1546–50.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Rigante D, Esposito S. Infections and systemic lupus erythematosus: binding or sparring partners? Int J Mol Sci. 2015;16:17331–43.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Doaty S, Agrawal H, Bauer E, Furst DE. Infection and lupus: which causes which? Curr Rheumatol Rep. 2016;18:13.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.La Trobe UniversityMelbourneAustralia
  2. 2.University of FlorenceFlorenceItaly

Personalised recommendations