Immunology of Helicobacter pylori: Insights Into the Failure of the Immune Response and Perspectives on Vaccine Studies
2007; Elsevier BV; Volume: 133; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2007.05.008
ISSN1528-0012
AutoresKeith T. Wilson, Jean E. Crabtree,
Tópico(s)Galectins and Cancer Biology
ResumoHelicobacter pylori infects the stomach of half of the human population worldwide and causes chronic active gastritis, which can lead to peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The host immune response to the infection is ineffective, because the bacterium persists and the inflammation continues for decades. Bacterial activation of epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils leads to a T helper cell 1 type of adaptive response, but this remains inadequate. The host inflammatory response has a key functional role in disrupting acid homeostasis, which impacts directly on the colonization patterns of H pylori and thus the extent of gastritis. Many potential mechanisms for the failure of the host response have been postulated, and these include apoptosis of epithelial cells and macrophages, inadequate effector functions of macrophages and dendritic cells, VacA inhibition of T-cell function, and suppressive effects of regulatory T cells. Because of the extent of the disease burden, many strategies for prophylactic or therapeutic vaccines have been investigated. The goal of enhancing the host’s ability to generate protective immunity has met with some success in animal models, but the efficacy of potential vaccines in humans remains to be demonstrated. Aspects of H pylori immunopathogenesis are reviewed and perspectives on the failure of the host immune response are discussed. Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease. Helicobacter pylori infects the stomach of half of the human population worldwide and causes chronic active gastritis, which can lead to peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The host immune response to the infection is ineffective, because the bacterium persists and the inflammation continues for decades. Bacterial activation of epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils leads to a T helper cell 1 type of adaptive response, but this remains inadequate. The host inflammatory response has a key functional role in disrupting acid homeostasis, which impacts directly on the colonization patterns of H pylori and thus the extent of gastritis. Many potential mechanisms for the failure of the host response have been postulated, and these include apoptosis of epithelial cells and macrophages, inadequate effector functions of macrophages and dendritic cells, VacA inhibition of T-cell function, and suppressive effects of regulatory T cells. Because of the extent of the disease burden, many strategies for prophylactic or therapeutic vaccines have been investigated. The goal of enhancing the host’s ability to generate protective immunity has met with some success in animal models, but the efficacy of potential vaccines in humans remains to be demonstrated. Aspects of H pylori immunopathogenesis are reviewed and perspectives on the failure of the host immune response are discussed. Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease. In many diseases, including those resulting from chronic infections, dysregulation of the immune system is a hallmark. In the case of Helicobacter pylori, the sine qua non of the infection is the presence of chronic active gastritis, characterized by both chronic (lymphocytic) and active (neutrophilic) forms of inflammation.1Goodwin C.S. Armstrong J.A. Marshall B.J. Campylobacter pyloridis, gastritis, and peptic ulceration.J Clin Pathol. 1986; 39: 353-365Google Scholar, 2Marshall B.J. Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Google Scholar The fact that the bacterium remains in the stomach at a high density despite the host response indicates that, by definition, the immune response is ineffective. Furthermore, the presence of inflammation for many years also supports the notion that the immune response is dysregulated. Studies over the last 2 decades have led to numerous discoveries about the pathogenesis of H pylori infection and have identified key bacterial virulence factors contributing to varied clinical outcomes. In this review we will focus on mechanisms of immune dysfunction that have been implicated in the ability of H pylori to persist for decades in the human stomach, the effect of infection on gastric physiology, and the efforts to modulate the immune response with vaccine strategies.General Overview of ImmunityInnate ImmunityAs a framework for discussion, innate immunity generally refers to responses that do not require previous exposure to the immune stimulus. There have been tremendous advances in this field over the last decade, including the elucidation of the toll-like receptors (TLRs) that are activated by recognition of pathogen-associated molecular patterns.3Akira S. Takeda K. Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity.Nat Immunol. 2001; 2: 675-680Google Scholar The innate immune system represents the “first line of defense” in the response to pathogens. Nonspecific activation by various stimuli from microorganisms can lead to important antimicrobial effects, but can also result in inflammation and injury because of release of inflammatory mediators such as cytokines, reactive oxygen species, and nitric oxide (NO). We will discuss these concepts in the setting of H pylori infection, with a focus on postulated defects in the response, and the mechanisms underlying induction of apoptosis and attenuation of antimicrobial NO production by macrophages.Adaptive ImmunityThe adaptive immune response is considered the predetermined response to a previously identified immunologic stimulus. Thus, the response is specific to a particular pathogen and involves immunologic memory. However, the lines between adaptive and innate immunity are frequently blurred by the close interactions between pathways, such that stimulation of antigen presenting macrophages and dendritic cells (DCs) leads to activation and recruitment of lymphocytes, and the development of T-helper (Th) cell-specific responses.Classically, differentiation of Th cells4Abbas A.K. Murphy K.M. Sher A. Functional diversity of helper T lymphocytes.Nature. 1996; 383: 787-793Google Scholar involves clonal expansion that is caused by engagement of the T-cell receptor.5Murphy K.M. Reiner S.L. The lineage decisions of helper T cells.Nat Rev Immunol. 2002; 2: 933-944Google Scholar Th cells can differentiate to 2 major functional classes, namely Th1 cells, which produce a set of cytokines that include interferon (IFN)-γ and interleukin (IL)-2, and Th2 cells, which produce cytokines such as IL-4, IL-5, IL-10, and IL-13.6Farrar J.D. Asnagli H. Murphy K.M. T helper subset development: roles of instruction, selection, and transcription.J Clin Invest. 2002; 109: 431-435Google Scholar Th1 cells generate cell-mediated immunity, which is important in protection against intracellular parasites such as the protozoa Leishmania and Toxoplasma gondii, whereas Th2 response is associated with humoral immunity and protection against intestinal helminths.5Murphy K.M. Reiner S.L. The lineage decisions of helper T cells.Nat Rev Immunol. 2002; 2: 933-944Google Scholar The concept of Th1/Th2 polarization is an important part of our approach to understanding mucosal immunity and inflammation (reviewed in Neurath et al7Neurath M.F. Finotto S. Glimcher L.H. The role of Th1/Th2 polarization in mucosal immunity.Nat Med. 2002; 8: 567-573Google Scholar).In the case of H pylori infection of the gastric mucosa, the resulting gastritis is driven by a variety of bacterial factors that stimulate epithelial cell, macrophage, and DC activation, as well as a Th1 predominant lymphocyte response. Colonization of H pylori can be abrogated by immunization with bacterial components such as urease,8Panchal P.C. Forman J.S. Blumberg D.R. Wilson K.T. Helicobacter pylori infection: pathogenesis.Curr Opin Gastroenterol. 2003; 19: 4-10PubMed Google Scholar indicating activation of the adaptive response, but urease is also a major inducer of innate responses in monocytes and macrophages, stimulating cytokine and NO generation.9Mai U.E. Perez-Perez G.I. Allen J.B. Wahl S.M. Blaser M.J. Smith P.D. Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa.J Exp Med. 1992; 175: 517-525Google Scholar, 10Mai U.E. Perez-Perez G.I. Wahl L.M. Wahl S.M. Blaser M.J. Smith P.D. Soluble surface proteins from Helicobacter pylori activate monocytes/macrophages by lipopolysaccharide-independent mechanism.J Clin Invest. 1991; 87: 894-900Google Scholar, 11Gobert A.P. Mersey B.D. Cheng Y. Blumberg D.R. Newton J.C. Wilson K.T. Cutting edge: urease release by Helicobacter pylori stimulates macrophage inducible nitric oxide synthase.J Immunol. 2002; 168: 6002-6006Google Scholar Thus, distinguishing whether the response of a particular cell type represents purely an innate, or adaptive response, is difficult and the recognition that cells such as B cells can respond to H pylori directly, or via the interaction of activated T cells, illustrates the complexity of the immune response.Consequences of Immune Evasion—Examples of Other Chronic InfectionsA common theme in many diseases has long been recognized to be persistence of viral, bacterial, or parasitic infection, with the resulting tissue damage deriving largely from the inflammatory host response that can predispose to neoplastic transformation. In addition to H pylori, prototypical examples of microbial colonization of mucosal surfaces or epithelial cells leading to such consequences include human papilloma virus and cervical cancer; Hepatitis C and B viruses leading to hepatocellular carcinoma; Epstein-Barr Virus and nasopharyngeal carcinoma; and the parasitic digenean helminths Opisthorchis viverrini and cholangiocarcinoma, and Schistosoma haematobium and bladder carcinoma.12Moss S.F. Blaser M.J. Mechanisms of disease: inflammation and the origins of cancer.Nat Clin Pract Oncol. 2005; 2: 90-97Google Scholar, 13Herrera L.A. Benitez-Bribiesca L. Mohar A. Ostrosky-Wegman P. Role of infectious diseases in human carcinogenesis.Environ Mol Mutagen. 2005; 45: 284-303Google Scholar The mechanisms of immune evasion of pathogens has been the subject of recent reviews for infections such as Leishmania,14Peters N. Sacks D. Immune privilege in sites of chronic infection: Leishmania and regulatory T cells.Immunol Rev. 2006; 213: 159-179Google Scholar human papillomaviruses,15Kanodia S. Fahey L.M. Kast W.M. Mechanisms used by human papillomaviruses to escape the host immune response.Curr Cancer Drug Targets. 2007; 7: 79-89Google Scholar Hepatitis C virus,15Kanodia S. Fahey L.M. Kast W.M. Mechanisms used by human papillomaviruses to escape the host immune response.Curr Cancer Drug Targets. 2007; 7: 79-89Google Scholar and Mycobacterium tuberculosis.16Bhatt K. Salgame P. Host innate immune response to Mycobacterium tuberculosis.J Clin Immunol. 2007; Google Scholar As our understanding of innate and adaptive immunity continues to evolve, insights are developing about the host defense mechanisms needed for the clearance of infections. It is recognized that stimulation of different TLRs by microbial products results in innate immune responses as well as development of adaptive immunity through antigen-specific pathways.17Akira S. Takeda K. Toll-like receptor signalling.Nat Rev Immunol. 2004; 4: 499-511Google Scholar One example is the demonstration that skin infection with Staphylococcus aureus requires both myeloid differentiation factor 88 and IL-1 receptor-mediated signaling by resident skin cells to recruit sufficient neutrophils to contain the infection.17Akira S. Takeda K. Toll-like receptor signalling.Nat Rev Immunol. 2004; 4: 499-511Google Scholar In this review, we will discuss potential mechanisms for the failure of the immune response to H pylori.The Immune Response to H pyloriH pylori induces both humoral and cellular immune responses. Both local and systemic antibody responses have been demonstrated that include IgA, IgM, and IgG istotypes.18Crabtree J.E. Taylor J.D. Wyatt J.I. Heatley R.V. Shallcross T.M. Tompkins D.S. Rathbone B.J. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology.Lancet. 1991; 338: 332-335Google Scholar, 19Rathbone B.J. Wyatt J.I. Worsley B.W. Shires S.E. Trejdosiewicz L.K. Heatley R.V. Losowsky M.S. Systemic and local antibody responses to gastric Campylobacter pyloridis in non-ulcer dyspepsia.Gut. 1986; 27: 642-647Google Scholar, 20Wyatt J.I. Rathbone B.J. Heatley R.V. Local immune response to gastric Campylobacter in non-ulcer dyspepsia.J Clin Pathol. 1986; 39: 863-870Google Scholar Early studies in mouse models demonstrated that immunization with H pylori antigens could produce protective immunity.21Marchetti M. Arico B. Burroni D. Figura N. Rappuoli R. Ghiara P. Development of a mouse model of Helicobacter pylori infection that mimics human disease.Science. 1995; 267: 1655-1658Google Scholar It was recognized early on that H pylori causes an inflammatory reaction with both polymorphonuclear and mononuclear cells,1Goodwin C.S. Armstrong J.A. Marshall B.J. Campylobacter pyloridis, gastritis, and peptic ulceration.J Clin Pathol. 1986; 39: 353-365Google Scholar, 2Marshall B.J. Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Google Scholar and that gastric mucosa of infected patients has increased levels of pro-inflammatory cytokines such as IL-1β, tumor necrosis factor alpha (TNF-α), IL-8, and IL-6.22Crabtree J.E. Shallcross T.M. Heatley R.V. Wyatt J.I. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis.Gut. 1991; 32: 1473-1477Google Scholar, 23Crabtree J.E. Peichl P. Wyatt J.I. Stachl U. Lindley I.J. Gastric interleukin-8 and IgA IL-8 autoantibodies in Helicobacter pylori infection.Scand J Immunol. 1993; 37: 65-70Google Scholar As H pylori research has evolved over the last 2 decades, bacterial factors involved in disease pathogenesis have been intensively investigated. Major virulence factors include the cytotoxin-associated gene pathogenicity island (cag PAI), which encodes a type IV bacterial secretion system that injects bacterial products into gastric epithelial cells resulting in signaling events leading to increased inflammation and neoplastic risk8Panchal P.C. Forman J.S. Blumberg D.R. Wilson K.T. Helicobacter pylori infection: pathogenesis.Curr Opin Gastroenterol. 2003; 19: 4-10PubMed Google Scholar, 12Moss S.F. Blaser M.J. Mechanisms of disease: inflammation and the origins of cancer.Nat Clin Pract Oncol. 2005; 2: 90-97Google Scholar, 24Peek Jr, R.M. Crabtree J.E. Helicobacter infection and gastric neoplasia.J Pathol. 2006; 208: 233-248Google Scholar, 25Naumann M. Crabtree J.E. Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis.Trends Microbiol. 2004; 12: 29-36Google Scholar and vacuolating toxin A (VacA), which is also strongly associated with cellular damage and inflammation.8Panchal P.C. Forman J.S. Blumberg D.R. Wilson K.T. Helicobacter pylori infection: pathogenesis.Curr Opin Gastroenterol. 2003; 19: 4-10PubMed Google Scholar, 12Moss S.F. Blaser M.J. Mechanisms of disease: inflammation and the origins of cancer.Nat Clin Pract Oncol. 2005; 2: 90-97Google Scholar, 24Peek Jr, R.M. Crabtree J.E. Helicobacter infection and gastric neoplasia.J Pathol. 2006; 208: 233-248Google Scholar The bacterial factors involved in H pylori pathogenesis will be discussed in detail in the next review article in this series by Emad El-Omar and Manuel Amieva.Although H pylori proteins had been demonstrated in the lamina propria of the stomach,9Mai U.E. Perez-Perez G.I. Allen J.B. Wahl S.M. Blaser M.J. Smith P.D. Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa.J Exp Med. 1992; 175: 517-525Google ScholarH pylori has generally been considered to be a noninvasive pathogen residing primarily in the extracellular mucus layer. However, several studies have demonstrated the ability of H pylori to invade gastric epithelial cells both in vitro26Amieva M.R. Salama N.R. Tompkins L.S. Falkow S. Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells.Cell Microbiol. 2002; 4: 677-690Google Scholar and in vivo in the stomach of humans and monkeys,27Semino-Mora C. Doi S.Q. Marty A. Simko V. Carlstedt I. Dubois A. Intracellular and interstitial expression of Helicobacter pylori virulence genes in gastric precancerous intestinal metaplasia and adenocarcinoma.J Infect Dis. 2003; 187: 1165-1177Google Scholar as well as in mice with atrophic gastritis.28Oh J.D. Karam S.M. Gordon J.I. Intracellular Helicobacter pylori in gastric epithelial progenitors.Proc Natl Acad Sci U S A. 2005; 102: 5186-5191Google Scholar Recently, the bacteria have also been shown to be bound to erythrocytes within the microvessels of the lamina propria.29Aspholm M. Olfat F.O. Norden J. Sonden B. Lundberg C. Sjostrom R. Altraja S. Odenbreit S. Haas R. Wadstrom T. Engstrand L. Semino-Mora C. Liu H. Dubois A. Teneberg S. Arnqvist A. Boren T. SabA is the H pylori hemagglutinin and is polymorphic in binding to sialylated glycans.PLoS Pathog. 2006; 2: e110Google Scholar Furthermore, it has now been shown by transmission electron microscopy and immunogold detection that H pylori are in direct contact with immune cells of the lamina propria in the majority of cases of gastritis and gastric cancer.30Necchi V. Candusso M.E. Tava F. Luinetti O. Ventura U. Fiocca R. Ricci V. Solcia E. Intracellular, intercellular, and stromal invasion of gastric mucosa, preneoplastic lesions, and cancer by Helicobacter pylori.Gastroenterology. 2007; 132: 1009-1023Abstract Full Text Full Text PDF Scopus (186) Google Scholar These studies provide additional relevance for numerous important studies of the host immune cell responses to H pylori, many of which have been accomplished through the use of reductionist in vitro and ex vivo approaches. A schematic overview of cellular pathways implicated in the response to H pylori is illustrated in Figure 1. We will discuss the host response by major cell types.MacrophagesMacrophages are essential as innate responders to H pylori-derived products and signals from epithelial cells in direct contact with the bacterium on the surface of the mucosa. Monocytes and macrophages are important coordinators of immune response to pathogens, and in the case of H pylori are likely activators, along with DCs, of adaptive immunity by producing factors such as IL-1231Haeberle H.A. Kubin M. Bamford K.B. Garofalo R. Graham D.Y. El-Zaatari F. Karttunen R. Crowe S.E. Reyes V.E. Ernst P.B. Differential stimulation of interleukin-12 (IL-12) and IL-10 by live and killed Helicobacter pylori in vitro and association of IL-12 production with gamma interferon-producing T cells in the human gastric mucosa.Infect Immun. 1997; 65: 4229-4235Google Scholar, 32Meyer F. Wilson K.T. James S.P. Modulation of innate cytokine responses by products of Helicobacter pylori.Infect Immun. 2000; 68: 6265-6272Google Scholar, 33Meyer F. Ramanujam K.S. Gobert A.P. James S.P. Wilson K.T. Cutting edge: cyclooxygenase-2 activation suppresses Th1 polarization in response to Helicobacter pylori.J Immunol. 2003; 171: 3913-3917Crossref Scopus (48) Google Scholar that stimulate Th1 cells resulting in production of cytokines such as IFN-γ.31Haeberle H.A. Kubin M. Bamford K.B. Garofalo R. Graham D.Y. El-Zaatari F. Karttunen R. Crowe S.E. Reyes V.E. Ernst P.B. Differential stimulation of interleukin-12 (IL-12) and IL-10 by live and killed Helicobacter pylori in vitro and association of IL-12 production with gamma interferon-producing T cells in the human gastric mucosa.Infect Immun. 1997; 65: 4229-4235Google Scholar, 32Meyer F. Wilson K.T. James S.P. Modulation of innate cytokine responses by products of Helicobacter pylori.Infect Immun. 2000; 68: 6265-6272Google Scholar, 33Meyer F. Ramanujam K.S. Gobert A.P. James S.P. Wilson K.T. Cutting edge: cyclooxygenase-2 activation suppresses Th1 polarization in response to Helicobacter pylori.J Immunol. 2003; 171: 3913-3917Crossref Scopus (48) Google Scholar Recently, it has been reported that the neutrophil-activating protein (NAP) of H pylori contributes to Th1 polarization by stimulating both IL-12 and IL-23 secretion from neutrophils and monocytes.34Amedei A. Cappon A. Codolo G. Cabrelle A. Polenghi A. Benagiano M. Tasca E. Azzurri A. D’Elios M.M. Del Prete G. de Bernard M. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses.J Clin Invest. 2006; 116: 1092-1101Google Scholar Importantly, IL-12 production in the gastric mucosa is linked to the development of peptic ulcers in infection with cagA-positive H pylori strains, most likely because of the stimulation of the Th1 response.35Hida N. Shimoyama Jr, T. Neville P. Dixon M.F. Axon A.T. Shimoyama Sr, T. Crabtree J.E. Increased expression of IL-10 and IL-12 (p40) mRNA in Helicobacter pylori infected gastric mucosa: relation to bacterial cag status and peptic ulceration.J Clin Pathol. 1999; 52: 658-664Google Scholar Macrophages are also involved in the amplification of the inflammatory response by production of cytokines such as IL-1, TNF-α, and IL-6.10Mai U.E. Perez-Perez G.I. Wahl L.M. Wahl S.M. Blaser M.J. Smith P.D. Soluble surface proteins from Helicobacter pylori activate monocytes/macrophages by lipopolysaccharide-independent mechanism.J Clin Invest. 1991; 87: 894-900Google Scholar, 36Gobert A.P. Bambou J.C. Werts C. Balloy V. Chignard M. Moran A.P. Ferrero R.L. 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: 245-250Google Scholar, 37Harris P.R. Ernst P.B. Kawabata S. Kiyono H. Graham M.F. Smith P.D. Recombinant Helicobacter pylori urease activates primary mucosal macrophages.J Infect Dis. 1998; 178: 1516-1520PubMed Google Scholar The IL-6 activation has been linked to activation of TLR4, MAP kinase, and NF-κB signaling events.38Pathak S.K. Basu S. Bhattacharyya A. Pathak S. Banerjee A. Basu J. Kundu M. TLR4-dependent NF-kappaB activation and mitogen- and stress-activated protein kinase 1-triggered phosphorylation events are central to Helicobacter pylori peptidyl prolyl cis-, trans-isomerase (HP0175)-mediated induction of IL-6 release from macrophages.J Immunol. 2006; 177: 7950-7958Crossref Scopus (84) Google ScholarImportantly, macrophages are also effector cells. One such pathway that has been well explored is the generation of NO derived from the enzyme inducible NO synthase (iNOS, NOS2), which has been shown to be up-regulated by H pylori in macrophages in vitro11Gobert A.P. Mersey B.D. Cheng Y. Blumberg D.R. Newton J.C. Wilson K.T. Cutting edge: urease release by Helicobacter pylori stimulates macrophage inducible nitric oxide synthase.J Immunol. 2002; 168: 6002-6006Google Scholar, 39Wilson K.T. Ramanujam K.S. Mobley H.L.T. Musselman R.F. James S.P. Meltzer S.J. Helicobacter pylori stimulates inducible nitric oxide synthase expression and activity in a murine macrophage cell line.Gastroenterology. 1996; 111: 1524-1533Google Scholar, 40Gobert A.P. McGee D.J. Akhtar M. Mendz G.L. Newton J.C. Cheng Y. Mobley H.L. Wilson K.T. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival.Proc Natl Acad Sci U S A. 2001; 98: 13844-13849Google Scholar, 41Bussiere F.I. Chaturvedi R. Cheng Y. Gobert A.P. Asim M. Blumberg D.R. Xu H. Kim P.Y. Hacker A. Casero Jr, R.A. Wilson K.T. Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation.J Biol Chem. 2005; 280: 2409-2412Google Scholar and in vivo.42Mannick E.E. Bravo L.E. Zarama G. Realpe J.L. Zhang X.J. Ruiz B. Fontham E.T. Mera R. Miller M.J. Correa P. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants.Cancer Res. 1996; 56: 3238-3243Google Scholar, 43Fu S. Ramanujam K.S. Wong A. Fantry G.T. Drachenberg C.B. James S.P. Meltzer S.J. Wilson K.T. Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis.Gastroenterology. 1999; 116: 1319-1329Google Scholar Events involved in the host iNOS response to H pylori are illustrated in Figure 2. Coculture studies demonstrate that H pylori can be killed by macrophages even when the bacteria are physically separated from these effector cells by a filter support, and that this antimicrobial defense is NO dependent.40Gobert A.P. McGee D.J. Akhtar M. Mendz G.L. Newton J.C. Cheng Y. Mobley H.L. Wilson K.T. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival.Proc Natl Acad Sci U S A. 2001; 98: 13844-13849Google Scholar, 41Bussiere F.I. Chaturvedi R. Cheng Y. Gobert A.P. Asim M. Blumberg D.R. Xu H. Kim P.Y. Hacker A. Casero Jr, R.A. Wilson K.T. Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation.J Biol Chem. 2005; 280: 2409-2412Google Scholar The discovery that the arginase enzyme possessed by H pylori encoded by the gene rocF can compete sufficiently with the eukaryotic macrophage for the iNOS substrate L-arginine (L-Arg) led to the demonstration that H pylori arginase enhances the survival of the bacterium through this mechanism.40Gobert A.P. McGee D.J. Akhtar M. Mendz G.L. Newton J.C. Cheng Y. Mobley H.L. Wilson K.T. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival.Proc Natl Acad Sci U S A. 2001; 98: 13844-13849Google Scholar The evolution of the bacterial arginase enzyme likely derived from its ability to generate urea from L-Arg, which is then utilized by urease to synthesize ammonia that is required to neutralize the gastric luminal HCl. However, the reduction of macrophage NO generation is an added bonus for the bacterium that enhances its immune evasion. Another mechanism by which H pylori can escape the macrophage response is by glucosylation of cholesterol; a mutant strain of H pylori that could not process cholesterol had increased susceptibility to phagocytosis by macrophages and could not colonize the mouse stomach.44Wunder C. Churin Y. Winau F. et al.Cholesterol glucosylation promotes immune evasion by Helicobacter pylori.Nat Med. 2006; 12: 1030-1038Google ScholarFigure 2Pathways involved in the regulation of macrophage iNOS synthesis and NO production in response to H pylori, and proposed pathogenic role of the generation of the polyamine spermine by the induction of arginase and ODC that results in inhibition of iNOS protein translation.11Gobert A.P. Mersey B.D. Cheng Y. Blumberg D.R. Newton J.C. Wilson K.T. Cutting edge: urease release by Helicobacter pylori stimulates macrophage inducible nitric oxide synthase.J Immunol. 2002; 168: 6002-6006Google Scholar, 39Wilson K.T. Ramanujam K.S. Mobley H.L.T. Musselman R.F. James S.P. Meltzer S.J. Helicobacter pylori stimulates inducible nitric oxide synthase expression and activity in a murine macrophage cell line.Gastroenterology. 1996; 111: 1524-1533Google Scholar, 40Gobert A.P. McGee D.J. Akhtar M. Mendz G.L. Newton J.C. Cheng Y. Mobley H.L. Wilson K.T. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival.Proc Natl Acad Sci U S A. 2001; 98: 13844-13849Google Scholar, 41Bussiere F.I. Chaturvedi R. Cheng Y. Gobert A.P. Asim M. Blumberg D.R. Xu H. Kim P.Y. Hacker A. Casero Jr, R.A. Wilson K.T. Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation.J Biol Chem. 2005; 280: 2409-2412Google Scholar, 48Chaturvedi R. Asim M. Lewis N.D. Bussiere F.I. Wilson K.T. Arginine availability is critical to the innate immune response to Helicobacter pylori by regulation of iNOS translation.Nitric Oxide. 2006; 14: A8Google Scholar CAT2, cationic amino acid transporter 2.View Large Image Figure ViewerDownload Hi-res image Download (PPT)H pylori also induces an alternative pathway of L-Arg metabolism in macrophages that is pathogenic in multiple respects (Figure 2). Exposure of macrophages to H pylori products results in up-regulation of the enzyme arginase II,45Gobert A.P. Cheng Y. Wang J.Y. Boucher J.L. Iyer R.K. Cederbaum S.D. Casero Jr, R.A. Newton J.C. Wilson K.T. Helicobacter pylori induces macrophage apoptosis by activation of arginase II.J Immunol. 2002; 168: 4692-4700Google Scholar which produces L-ornithine in addition to urea. This arginase induction potentially has at least 3 pathogenic roles. First, it amplifies the effect of the bacterial arginase by also depleting substrate availability for iNOS. Second, it has a central role in causing apoptosis of macrophages, which derives from the metabolism of its product, L-ornithine, into polyamines.45Gobert A.P. Cheng Y. Wang J.Y. Boucher J.L. Iyer R.K. Cederbaum S.D. Casero Jr, R.A. Newton J.C. Wilson K.T. Helicobacter pylori i
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