The Disease Spectrum of Helicobacter Pylori : The Immunopathogenesis of Gastroduodenal Ulcer and Gastric Cancer

P1: FRD/FQU P2: FQPAugust 8, 2000 16:37 Annual Reviews AR110-18

Annu. Rev. Microbiol. 2000. 54:61540Copyright c 2000 by Annual Reviews. All rights reserved

THE DISEASE SPECTRUM OF HELICOBACTERPYLORI: The Immunopathogenesis ofGastroduodenal Ulcer and Gastric Cancer

Peter B. ErnstDepartments of Pediatrics, Microbiology and Immunology and the Sealy Center forMolecular Sciences, University of Texas Medical Branch, Galveston, Texas 77555-0366;e-mail: [email protected]

Benjamin D. GoldDivision of Pediatric Gastroenterology and Nutrition, Department of Pediatrics,Emory University School of Medicine, and Foodborne and Diarrheal Diseases Branch,Division of Bacterial and Mycotic Diseases, Centers for Disease Control and Prevention,Atlanta, Georgia 30322; e-mail: Ben [email protected]

Key Words stomach, epidemiology, mucosal immunityn Abstract Helicobacter pylori is a gram-negative bacterium that resides undermicroaerobic conditions in a neutral microenvironment between the mucus and thesuperficial epithelium of the stomach. From this site, it stimulates cytokine productionby epithelial cells that recruit and activate immune and inflammatory cells in the un-derlying lamina propria, causing chronic, active gastritis. Although epidemiologicalevidence shows that infection generally occurs in children, the inflammatory changesprogress throughout life. H. pylori has also been recognized as a pathogen that causesgastroduodenal ulcers and gastric cancer. These more severe manifestations of the in-fection usually occur later in life and in a minority of infected subjects. To interveneand protect those who might be at greatest risk of the more severe disease outcomes,it is of great interest to determine whether bacterial, host, or environmental factorscan be used to predict these events. To date, several epidemiological studies have at-tempted to define the factors affecting the transmission of H. pylori and the expressionof gastroduodenal disease caused by this infection. Many other laboratories have fo-cused on identifying bacterial factors that explain the variable expression of clinicaldisease associated with this infection. An alternative hypothesis is that microorganismsthat cause lifelong infections can ill afford to express virulence factors that directlycause disease, because the risk of losing the host is too great. Rather, we proposethat gastroduodenal disease associated with H. pylori infection is predominantly a re-sult of inappropriately regulated gastric immune responses to the infection. In thismodel, the interactions between the immune/inflammatory response, gastric physiol-ogy, and host repair mechanisms would dictate the disease outcome in response toinfection.

0066-4227/00/1001-0615$14.00 615

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CONTENTS

PATTERN OF TRANSMISSION : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 616DISEASE SPECTRUM : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 617

Gastritis : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 617Gastroduodenal Ulceration : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 618Gastric Cancer : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 619

BACTERIAL PATHOGENESIS : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 620Helicobacter Pylori: Bacterial Properties : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 621CagA and VacA and the Virulence Story : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 621Geographic Distribution of Strains/Disease : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 622Other Interpretations of Strain Variation and the Expression of

Gastroduodenal Disease : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 623IMMUNOBIOLOGY OF NATURAL INFECTION : : : : : : : : : : : : : : : : : : : : : : : : 624

Immune Evasion : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 624Interactions Between H. Pylori and the Gastric Epithelium : : : : : : : : : : : : : : : : : 624Immunopathogenesis : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 625Epithelial-Cell Injury : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 630Consequences of Epithelial Cell Damage : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 631

HOW WILL THE PATHOGENESIS OF GASTRODUODENALDISEASES BE STUDIED IN THE FUTURE? : : : : : : : : : : : : : : : : : : : : : : : : : : 632

PATTERN OF TRANSMISSION

Ever since John Snow studied the pattern of diarrheal disease during a choleraoutbreak in London and prevented further spread by removing the handle fromthe Broad Street pump in 1853, epidemiology has been a powerful approach tounderstanding the transmission of infectious diseases. The use of epidemiologicalapproaches to identify risk factors for transmission or disease pathogenesis facil-itates the design of mechanistic studies in vitro as well as the implementation oftargeted interventions to prevent infection, or at least the more severe manifes-tations of the infection. Thus, the following summarizes some of the interestingepidemiological features of Helicobacter pylori infections.

The majority of infections with H. pylori occur in children (18, 39, 81); how-ever, our understanding of the epidemiology of H. pylori transmission to chil-dren is somewhat limited. The lack of information on the prevalence of infectionis attributable to the difficulty in determining when the infection is initially ac-quired. Unlike other enteric infections, such as those caused by Escherichia coli,Salmonella spp., and Shigella spp., for which the onset of easily recognized symp-toms is invariably associated with the initial infection, acute, natural H. pyloriinfection is not known to present with specific clinical signs.

The risk factors for infection of children include familial overcrowding, endemicstatus of the organism in the country of origin, poor socioeconomic circumstances,and having a certain ethnic background. Thus, the incidence of H. pylori infectionis estimated to be between 3% and 10% of the pediatric population per year in

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H. PYLORI-ASSOCIATED GASTRIC DISEASE 617

countries with emerging economies, in contrast to wealthier countries, in whichthe rate is around 1% per year. For example, incidence rates in Bolivian childrenappear to be very high, particularly in the 2- to 4-year-old age group, with >70%of 10 year olds being infected (B Gold, unpublished observations). Conversely,the incidence of infection in children living in the southeastern United States isjust >1.2%/year, with 12%15% of 10 year olds being infected. It is importantto consider that the prevalence rates among African-Americans and Hispanicsin the United States are similar to those of people residing in developing coun-tries (106), although this may be largely attributed to their socioeconomic status(52, 72).

Humans appear to be the primary natural reservoir of H. pylori infection, al-though other putative sources include water (54, 61), domestic cats (50), andhouseflies (47, 85). The route of transmission of H. pylori is postulated to befecal-oral or oral-oral (77). This is supported by studies that have identifiedH. pylori DNA in dental plaque and saliva of adults and children by using thepolymerase chain reaction to amplify bacterial DNA to levels that permit detec-tion (68). The mouth may be either a reservoir for this infection or an initialsite of colonization before seeding of the stomach and colonization of the gastricepithelia.

Despite the variety of postulated reservoirs, the actual impact of each one ofthese potential environmental sources for human infection with H. pylori has notbeen determined. Thus, it is difficult to prevent infection through the manipulationof the hosts environment, given the lack of understanding of the different putativereservoirs, the mode of person-to-person transmission, and the specific pediatricpopulations at risk.

DISEASE SPECTRUM

Gastritis

The relatively recent interest in H. pylori as a human pathogen arose from theobservation by Warren & Marshall that gastritis was associated with an infectionof spiral bacteria (74). Soon after the association was made between the presenceof H. pylori in the gastric mucosa and the occurrence of antral gastritis in adults, thisrelationship was also noted in children (37). Typically, the cellular infiltrates reflectchronic inflammation, and in adults there is an additional influx of neutrophils (34).However, critics of the conclusion that H. pylori was playing a role in the gastritisargued that the bacteria were colonizing inflamed tissue rather than causing theinflammation (90). Gastritis and mucosal ulceration are less frequent findings inchildren, thereby allowing investigations of pediatric H. pylori as a cause of gastritisversus an opportunistic infection of inflamed tissue. Although the bacteria are notcommonly found on the gastric mucosae of children with secondary causes ofgastritis [e.g. eosinophilic gastroenteritis and Crohns disease (36)], H. pylori was

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618 ERNST GOLD

determined to be present in the majority of children with gastritis (37). Thisobservation implicated H. pylori as a cause of chronic antral gastritis. However,the observation that eradication of H. pylori from the gastric mucosa resolved theantral gastritis provided the most compelling evidence that H. pylori is the causeof primary gastritis in children (128).

As a consequence of persistent infection, other changes associated with gastricinflammation, including atrophy and fibrosis, can arise. In addition, it is gen-erally accepted that in some individuals, infection and gastritis are sufficient tocause an increase in gastrin and changes in gastric acid secretion, particularlymeal-stimulated acid. Other changes in epithelial cell biology associated withH. pylori-induced gastritis include an increase in epithelial-cell turnover, whichis associated with an increase in permeability across the epithelial cell barrier. Asdiscussed below, these changes could enhance the access of luminal acid and/orpepsin to underlying tissue, whereas the hyperproliferative changes might favorthe development of cancer. The key scientific issue is how bacterial factors and thehost response contribute to these changes and how these changes progress to thepoint at which more severe clinical manifestations occur.

Gastroduodenal Ulceration

One of the significant advances in our understanding of gastroduodenal diseasehas been the realization that infection with H. pylori is a significant cause ofgastroduodenal ulcers. Approximately 90%95% of duodenal ulcers and 70%75% of gastric ulcers are attributable to infection with H. pylori (24). It is nowestimated that the lifetime risk for developing peptic ulcer disease in H. pylori-infected individuals is 10% (86).

Compelling evidence that H. pylori is a cause of recurrent ulcers comes fromthe observation that the recurrence rate of duodenal ulcers is markedly reducedafter successful treatment of H. pylori infection (78, 93). Moreover, iatrogenicinfection of patients in which a natural H. pylori infection has been previouslycured by antimicrobial treatment can lead to ulcer recurrence (64). Thus, byseveral rules of evidence, H. pylori infection is accepted as a cause of ulce-ration.

Almost all peptic ulcers in children are located in the duodenum, whereas gastriculcers are extremely rare in this population (20). Similar to the findings in adults,the occurrence of duodenal ulcers in the absence of H. pylori is uncommon inchildren unless they are being administered nonsteroidal anti-inflammatory drugs(17, 83). Moreover, it has been demonstrated that duodenal ulcer disease in chil-dren does not relapse if infection with H. pylori is cleared from the gastric mucosa(20). However, given the decrease in H. pylori infection rates combined with thewidespread use of antibiotics to treat infections, there is an apparent emergenceof duodenal ulceration that appears to be independent of infection (75). Thus,there may be factors other than those associated with H. pylori infection that aresufficient to favor ulcerogenesis.

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Gastric Cancer

H. pylori was designated as a class I carcinogen by the World Health Organizationin 1994. Two distinct cancers have been associated with H. pylori infectiongastric lymphoma and adenocarcinoma (24).

Lymphoma B-cell lymphomas, or maltomas, are a recognized complication ofH. pylori infection. Although most gastric tissues infected with H. pylori displaylymphoid aggregates that are enriched with B cells, lymphomas are distinct in theirtendency to invade the epithelial-cell compartment. Recent studies have suggestedthat the expansion of B-cell lymphomas is primarily driven by T-cellderivedcytokines (31, 55) and is reversed by clearance of the H. pylori infection from thehost (9). These observations raise questions regarding the accurate diagnosis ofB-cell lymphomas; specifically, when does a B-cell response become classified asa lymphoma? Although some investigators have used oligoclonality of the B-cellresponse as an indicator of malignancy, chronic infection by a microbe displayinga relatively homogeneous array of immunogens may select for oligoclonality. Thiswould be particularly true in an environment that usually has a paucity of B cells inthe absence of infection. Thus, more specific markers to verify cases of malignantlymphoma would help in understanding this relatively rare, but potentially serious,complication.

Adenocarcinoma Gastric adenocarcinoma is the fourteenth most commonly oc-curring cancer and is expected to become the eighth as the worlds populationages (24). Gastric cancer is more common in nations with emerging economiesand among economically disadvantaged people in the industrialized world (21).In many countries of Latin America and Asia, gastric adenocarcinoma remainsthe most common malignancy among men and the second most common amongwomen. Incidence rates are 80/100,000 population in regions of Colombia andJapan. By contrast, gastric cancer afflicts


620 ERNST GOLD

from Japan, a high-risk country, to regions of lower risk, such as the United States,only moderately decreased their cancer risk, even if they immigrated at a young age(i.e. first generation) (48). Second-generation immigrants, however, were foundto acquire a gastric cancer risk much closer to that of the population of their newcountry. Similar results have been reported in other studies (76, 98). It is also worthnoting that short-term studies that document reversal of preneoplastic conditionsby anti-H. pylori therapy lend support to the association of H. pylori and cancer(111). Moreover, in an animal model, chronic infection with H. pylori has beenshown to increase the rate of gastric cancer (117).

Support for H. pylori as a cause of cancer, however, will be accomplished onlywhen a mechanistic understanding of the pathogenesis of gastric cancer is obtainedand when controlled trials demonstrate that elimination or prevention of infectionprevents malignancy. Correa and colleagues have described a progression, begin-ning with an infection by H. pylori, leading to gastritis, gastric atrophy, intestinalmetaplasia, dysplasia, and finally malignant transformation (21, 22, 23). In thismodel, Correa proposed that the malignant transformation is caused by the persis-tent oxidative stress attributable to the inflammatory response that occurs duringthe gastritis. Ames and colleagues have predicted the role for oxidative stress inthe pathogenesis of cancer in general as well as in H. pylori-associated gastritis(2). The most likely mechanism includes oxidative DNA damage that eventuallyescapes repair within the host cell. In addition, oxidative stress regulates the ex-pression of several genes that govern epithelial cell-turnover, which is consistentwith the increased rate of malignancy associated with other forms of chronic in-flammatory disease in the digestive tract, including celiac disease and ulcerativecolitis.

Although H. pylori infection is associated with gastric cancer, it should bepointed out that many people who develop gastric cancer are not infected. Thus,other environmental or host factors are important both as etiologies and as dis-ease modifiers. In addition, it is difficult to link infection with cancer whendecades intervene between the time of infection and the manifestation of the can-cer. Although the most conclusive evidence of a role for H. pylori will comefrom prospective studies in which cancer rates in infected and uninfected humansubjects are compared, the ethics of leaving patients infected with a declaredcarcinogen may make these studies difficult to complete. Such studies will beimportant because they will determine whether it is preferable to prevent irre-versible damage and the development of gastric cancer by treating the infection inchildren.

BACTERIAL PATHOGENESIS

Although infection with H. pylori is a significant cause of duodenal ulcers, thereis a significant lack of understanding of the mechanism by which these bacteriacause disease. Clearly, gastric acid is important. Inhibition of acid secretion can

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greatly enhance ulcer healing, even if the recurrence rate is high. Perhaps the morechallenging question is: What does H. pylori do that allows acid to cause an ulcer?One can consider two viewsfirst, that H. pylori, or the host response to infectionby this organism, causes sufficient epithelial cell damage that luminal acid canaccess the tissue and create an ulcer; and second, that infection impairs healing,and curing of the infection simply allows effective healing to proceed.

Because gastroduodenal diseases can be attributed to infection with H. pylori, itis natural to assume that pathogenicity will be defined by bacterial factors. Falkowrecently discussed properties of pathogenicity (40). First, infection by the microbemust cause disease. The basis for this is linked to the ability to breach host cellbarriers. This process is facilitated by the ability of the organism to avoid, subvert,or otherwise circumvent the hosts immune response, thus leading to tissue damageand, eventually, disease. It is important to remember that the host response is anessential element, not just for protection but for pathogenicity. Moreover, manybacteria cause severe disease quite rapidly while others, like H. pylori, do soover decades. Thus, the presence and/or potency of virulence factors must varywidely. We suggest that bacteria causing chronic infections have evolved to favorcolonization and persistence, while tending to lose virulence factors that causesignificant disease directly.

Helicobacter Pylori : Bacterial Properties

Two primary morphological shapes, bacillary and coccoid, have been describedfor this organism (19). Although the bacillary form is clearly the predominant,viable form of H. pylori, the coccoid morphology is easily observed in cultureas well as in some patients (19). The biological relevance of each morphologicalform is not clearly understood, although it is believed that the bacillary form isthe virulent morphology, whereas the coccoid form is either nonviable or pro-tects the organism during dormancy. The bacillary forms are highly motile withmultiple unipolar flagella. H. pylori produces many enzymes that facilitate colo-nization; these include catalase, phospholipase, thioredoxin reductase, and urease(24, 35, 118, 120). It is the urease that allows this organism to metabolize urea tohelp neutralize luminal acid during colonization.

CagA and VacA and the Virulence Story

Bacteria commonly use one or more of three basic mechanisms, called virulencedeterminants, to produce disease in the host: adhesion, invasion, and toxin elab-oration. Although urease and flagella may be necessary for colonization, otherstudies have tried to identify virulence factors produced by H. pylori that actuallycause gastroduodenal disease. H. pylori infection is essentially limited to the lu-men, under the mucus layer and adjacent to the epithelium, allowing the organismto cause damage to the gastric mucosa.

One of the earliest signs that H. pylori is particularly capable of inflicting epithe-lial cell damage came from Leunk and colleagues (65), who described the ability

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622 ERNST GOLD

of H. pylori to induce vacuolization in the membrane of epithelial cells. Subse-quently, a vacuolating toxin, VacA, was purified, characterized, cloned, and usedto study the pathogenesis of these vacuoles (7, 25, 109). Similarly, the cytotoxin-associated gene cagA was identified. Although the cagA gene does not actuallyencode the vacuolating toxin, it is often coexpressed with vacA.

Several studies have examined the association of these genes with the moresevere disease manifestations of H. pylori infection. CagA has been associatedwith both duodenal ulcers and gastric cancer (14, 49). Similarly, the vacA locus hasundergone extensive scrutiny. VacA is capable of causing epithelial cell damage andis sufficient to cause gastritis in mice (109). Atherton and colleagues have suggestedthat virulence and clinical outcome are associated with strains of H. pylori thathave a particular pattern of nucleotides in the vacA gene (7). Their studies indicatedthat strains of H. pylori with vacA signal sequence type s1a were associated withenhanced gastric inflammation and duodenal ulceration. However, the genotype ofstrains based on these genes varies widely among different geographic regions anddoes not always associate with disease (126). Clearly, the fact that many subjectswithout significant disease also have strains bearing these genotypes makes itdifficult to ascribe disease to any putative virulence factor.

Geographic Distribution of Strains/Disease

Using the cagA and vacA genotypes, investigators have pursued the association ofvirulence factors and gastroduodenal disease. This led to the description of type Iand type II strains, defined by the presence or absence of both the cagA and vacAgenes, respectively (123). The type I strains, which express both factors, havebeen implicated as a predictor of a more adverse disease outcome. Upon furtherdissection, it became evident that these tools would not significantly help identifyindividuals at greater risk of peptic ulcers or gastric cancer. To begin with, strainsexpressing CagA constitute 70%95% of all isolates, depending on the study andthe geographic location of the subjects. Because peptic ulceration affects10% ofall infected subjects and gastric cancer occurs in



that the overwhelming majority of individuals infected with high-risk strains iden-tified to date do not suffer the more severe clinical consequences (see Figure 1).Thus, no single entity or array of genes has yet been identified that can serve as amarker for predicting the development of gastric disease. This could be attributedto the role of other factors that govern disease expression. In particular, changesin gastric physiology (45) and the host immune/inflammatory response (38a) havebeen implicated in the pathogenesis of gastric disease.

Other Interpretations of Strain Variation andthe Expression of Gastroduodenal Disease

Although population studies have identified interesting associations of disease withbacterial genes or gene products, they have provided little definitive evidence ofa particular bacterial product that may cause disease. Because peptic ulcerationand gastric cancer associated with the infection usually occur decades after theinitial infection, it is less likely that a bacterial factor per se causes the disease.However, the infection stimulates a host response. The association between cagPAI-bearing strains and inflammation as well as disease leads to the hypothesisthat the host response is responsible for expression of disease. Thus, the vagariesof these responses across a population, combined with other disease modifiers,become the focus for a discussion of the pathogenesis of gastroduodenal disease.

Figure 1 The context of Cag and the disease spectrum associated with Helicobacter pylori in-fection. The clinical presentations associated with H. pylori infection, including gastroduodenalulcers and gastric cancer, are the tip of the iceberg that constitutes the entire H. pylori carrierpopulation. Of all infected individuals, 10% would be expected to develop these more severeclinical manifestations. Although the CagC strains are associated with an increased risk of devel-oping duodenal ulcer or gastric cancer, some disease is observed in subjects infected with Cagstrains. Moreover, the vast majority individuals who do not develop ulcers or cancer also carryCagC strains. Thus, the presence of strains bearing the cag PAI or the other putative bacterialfactors that are associated with disease does not adequately predict why some individuals developdisease and others do not.

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624 ERNST GOLD

IMMUNOBIOLOGY OF NATURAL INFECTION

Immune Evasion

One of the tenets of pathogenicity as described by Falkow is the ability of apathogen to circumvent the host defense mechanisms (40). Little direct evidencefor this process has been described in the context of H. pylori infection. It hasbeen suggested that the bacterium may adapt its immunogenicity by acquiringthe ability to express antigens that mimic host antigens. For example, the Lewisantigen phenotype of H. pylori has been reported to mirror that of the host (121).In this case, it is possible that these antigens activate local T cells that secreteanti-inflammatory cytokines that could attenuate the host response via a bystandereffect. That is, a small population of T cells that confer tolerance may be activatedand impair the immune reactivity of other T cells around them (95). However,this has not been substantiated by cytokine analysis, because it appears that mostof the cytokines present in the gastric mucosa during infection are inflammatoryrather than anti-inflammatory (38a). This situation in itself may favor chronicinfection because the predominant T-helper 1 cell (Th1) response observed duringinfection is unlikely to be effective against a pathogen within the lumen. Indeed,a Th1 response is far more likely to have adverse effects on the host and actuallycontribute to gastroduodenal disease.

Another possibility is that a natural infection with H. pylori selectively inhibitsantigen-specific responses. Recent studies showed that H. pylori has the abilityto induce death of T cells through Fas-FasL interactions (J Wang, P Ernst, un-published data). It is interesting that the induction of apoptosis was restricted toH. pylori bearing the cag PAI and was not observed with cag PAI-deficient strainsor Campylobacter jejuni, suggesting that it is a specific mechanism of immune eva-sion. Because cag PAI strains predominate in humans, it is possible that this abilityto induce apoptosis of T cells confers a selective advantage that complements othermechanisms favoring the persistent growth and survival of these strains.

Interactions Between H. Pylori and the Gastric Epithelium

The overwhelming majority of the antigenic mass of H. pylori resides in the lumen.Therefore, the interaction between H. pylori and the epithelium provides a key focalpoint for examination of the induction of the host response. H. pylori can bind togastric epithelial cells via numerous receptors. One potential interaction is throughthe bacterial BabA protein interacting with Lewis B-like molecules on the host cell(56). However, to date, the only host cell receptor that has been shown be capableof signal transduction is the class II major histocompatibility complex (MHC)molecule. As a consequence of binding these molecules on the apical surface,gastric epithelial cells begin the process of cell death by apoptosis (41). It shouldbe noted that the evidence to date suggests that strains with or without the cag PAIcan bind comparably and induce apoptosis of gastric epithelial cells (116).

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Because H. pylori does not have a strong tendency to invade the host, theepithelial cells must initiate the host response. Bodger & Crabtree (15) were thefirst to show that interleukin-8 (IL-8) is produced by the gastric epithelium, bothin vitro and in vivo. Other studies linked infection with strains bearing CagA toincreased production of IL-8, epithelial neutrophil-activating peptide-78 (ENA),and the chemokine regulated on activation, normal T cell expressed, and secreted(RANTES) by epithelial cells (26, 29, 102). A more careful examination of thecagA gene showed that it is linked to a pathogenicity island, the cag PAI. The cagPAI contains 31 genes, including several that encode a type IV secretory engine(24). Within this region, the cagE gene is a required element for the induction ofIL-8 (110). It has recently been reported that the type IV secretory engine encodedby genes within the cag PAI permits the transfer of bacterial proteins into the hostcell (84, 107). To date, CagA has been identified as one bacterial protein that istransferred and phosphorylated in the host cell (Figure 2, see color insert). Perhapsother bacterial products are similarly transported into the host cell, where they havean impact on signal transduction pathways and modify the host response, includingthe initial burst of chemokine production that recruits and activates immune cells,thereby contributing to the gastritis.

Immunopathogenesis

As mentioned above, most infected people carry strains of H. pylori expressing thecag PAI. The dominance of these strains suggests that they may have a selectiveadvantage, perhaps achieved by avoiding a protective immune response. Althoughthese strains may avoid a protective response, they are still capable of inducinggreater levels of inflammation in the gastric mucosa than strains lacking the cag PAI(89, 124, 125). Thus, it is possible that any association between strains bearing thecag PAI and disease is governed by the variation in the host response to infectionin general and these strains in particular.

There are several examples that illustrate the principle that the host immune/in-flammatory response is necessary for the manifestation of disease caused by infec-tion. For example, it is well recognized that some infections trigger autoimmunedisease; the microorganism is the trigger and the host response is the bullet thatleads to the actual disease. Others have shown that infection with Clostridiumdifficile causes enteritis, but administration of antibodies recognizing adhesionmolecules on immune or inflammatory cells prevents the manifestation of diar-rhea (60). Even the prototypic microbial virulence factor, cholera toxin, cannotexert its pathogenic effect in an animal with an immunodeficiency (62). For exam-ple, infection of mice deficient in stem cell factor or its receptor does not inducefluid accumulation in the intestinal lumen after administration of cholera toxin.Thus, the host response must often be considered an essential element of microbialpathogenicity.

If the host response contributes to pathogenicity, then it is possible to extendthe notion such that it can actually define pathogenicity. The digestive tract is

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626 ERNST GOLD

colonized with an extensive flora including 200300 different species of bacteria.In fact, the normal intestinal immune response is designed to limit its reactivity toantigenic stimuli that persist in the lumen. However, several experimental modelshave shown that disruption of the delicate balance in immune regulation allowsthe otherwise innocuous luminal flora to become extremely dangerous (91). Withthe advent of genetic engineering in animal models, it readily became apparentthat targeted manipulations of the immune system resulted in colitis. For example,deletion of the gene encoding IL-2, IL-10, the T-cell receptor chain, class II MHCmolecules, or transforming growth factor resulted in the spontaneous develop-ment of colitis in these animal models (63, 79, 108). Subsequently, it was shownthat Th1 responses were over-represented in these animals. From these findings,it was predicted that manipulation of genes encoding receptors for these cytokinesor disruption of signaling mechanisms that favored Th1 development would alsolead to colitis (105, 122). In most of the models tested, disease has been completelyprevented by housing the animals under germ-free conditions. Therefore, colitis inanimals housed in conventional conditions was not caused by the introduction ofa new pathogen; rather, the altered immune response rendered some element of thenormal flora pathogenic. In essence, the host response defined the pathogenicityof the organisms. The same model can be applied to H. pylori.

B-Cell Responses The B-cell response has been examined to understand a clas-sical potential autoimmune component of a disease. It is interesting that there iscompelling evidence that the B-cell response to H. pylori contributes to an au-toimmune component of gastritis. The first suggestion that H. pylori might causea bona fide autoimmune response was based on evidence that monoclonal anti-bodies directed against H. pylori recognize an epitope on the gastric epithelium ofmice and humans [reviewed by Appelmelk et al (4)]. Moreover, administration ofthese antibodies to mice resulted in gastritis and caused mild erosions (82). Morerecently, it has been shown that antibodies to H. pylori lipopolysaccharide cross-react with antigens on epithelial cells (5). In humans, it appears that there is anantibody response to the HC-KCATPase in the gastric parietal cell that is driven byH. pylori infection. However, no cross-reactivity between H. pylori and the HC-KCATPase has yet been identified (4). Other studies have shown that immunoglobu-lin M (IgM) antibodies produced by immortalized B cells obtained from the gas-tric mucosa recognize the gastric epithelium (114). Additional evidence suggeststhat B cells within a maltoma express a repertoire that recognizes a determinantshared by both IgA and IgM (46). Thus, antibodies within the gastric mucosa mayrecognize epithelial cells or act as a rheumatoid factor. This could lead to immunecomplex-mediated disease that directly damages the epithelium. This hypothesisis supported by the observation that activated complement is found adjacent to thegastric epithelium during infection (11).

Therefore, inappropriate B-cell responses in a subset of infected subjects willdrastically affect the outcome. A response to parietal cells could lead to atrophy

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and achlorhydria, whereas a more general response, to epithelial cells or throughthe production of rheumatoid factor, could increase the gastritis and epithelial celldamage (see Figure 3).

T-Cell Responses For the mucosal tissues, the host response discriminates be-tween pathogens and commensal flora within the lumen, which is achieved by anapparent inhibition of immune responses to enteric commensal organisms that ismediated through T cells. However, in certain individuals, an inappropriate T-cellresponse to commensal flora may occur. Thus, a failure of the immune responseto flora that persist in the lumen, such as H. pylori, may lead to tissue damageon a scale equivalent to that seen in classical autoimmune diseases. This model issupported by the reports, described above, of the development of colitis in mice

Figure 3 Immunological changes during infection with Helicobacter pylori. In response to in-fection, gastric epithelial cells produce chemokines [interleukin-8 (IL-8), ENA-78] that can recruitand activate neutrophils. In addition, the numbers of both T and B cells in the lamina propriaincrease. The presence of Th1 cells and interferon (IFN- ) production leads to immunophysiolog-ical interactions that directly promote tissue damage. For example, IFN- alters epithelial barrierfunction in intestinal cell lines (71). Other cytokines, including tumor necrosis factor- (TNF-),can collaborate with IFN- to alter epithelial cell IL-8 gene expression (127). Activated T cellscan increase the expression of Fas on epithelial cells and induce cell death via Fas-FasL interaction.T-cell cytokines also increase B-cell responses, including the induction of IgG antibodies that canactivate complement (C0) and contribute to epithelial damage through immune complex-mediatedmechanisms.

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628 ERNST GOLD

after the ablation of the gene coding for IL-10, a cytokine that selects for Th2responses (63). This disease appears to be driven by luminal bacteria, becauseanimals maintained in an environment free of commensal flora do not developcolitis (100a, 104).

Studies have identified H. pylori antigen-specific T-cell clones in infected pa-tients (32). Most of the T cells associated with infection are of the Th1 type (8, 32,33, 59, 67, 104; see Table 1). Moreover, both IL-12 (51) and Th1 response (32)levels have been reported to be higher in subjects with duodenal ulceration. This is

TABLE 1 Characterization of Th1 and Th2 cellsa

Property Th1 Th2

CytokinesIFN- CCC TNF- CCC C=TNF- CCC IL-2 CCC CIL-4 CCCIL-5 CCCIL-6 CCIL-10 C= CCCIL-13 C= CCC

ImmunityCellular immunity CCC Delayed hypersensitivity

CytotoxicityDelayed CCC C=

hypersensitivityPhagocytosis CC CIgG C CCCIgA CCCIgE CCC

Clinical relevance Immunity to Immunity to nematodes,viruses, tumors, mucosal immunityintracellular bacteria

Autoimmune diseases AllergiesPredominant in gastric

mucosa

aTh1 and Th2 cells are characterized primarily by their cytokine profiles. After exposure to IL-12 and IL-18,Th1 cells are selected and produce IFN- , TNF-, and IL-2, which can combine to increase cell-mediatedimmunity. They also can increase the level of complement-fixing IgG and enhance phagocytosis of opsonizedbacteria. However, Th2 cells have a decided advantage in the induction of mucosal immune responses, includingthe production of IgA. Either subset can also contribute to disease. For example, Th2 cells are implicated in thepathogenesis of allergies, and Th1 cells contribute to immune-mediated epithelial damage in the stomach (97).

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consistent with the model in which Th1 cells promote epithelial cell death throughan increase in H. pylori binding and the induction of apoptosis (41). Additionalintercellular interactions between epithelial cells and T cells mediated by Fas-Fasligand interactions may also contribute to apoptosis of epithelial cells (57, 99).More-recent studies have also suggested that gastric T cells can mediate epithelialcell death directly through Fas-FasL interactions (116a).

The evidence that the number of Th1 cells may be increased relative to thatof Th2 cells during H. pylori infection suggests that a marked skewing of thisresponse may lead to disease as observed in the pathogenesis of more-classicalautoimmune diseases (66). These observations imply that the difference in gas-tric disease associated with H. pylori infection may be partially attributed to themagnitude of the host response and the balance of pro- and anti-inflammatorycytokines that are regulated by Th cells. This notion is consistent with the factthat strains associated with a higher frequency of peptic ulceration or cancer arealso known to induce inflammatory responses of a higher magnitude (28, 89, 125).Additional evidence that an eberrant immune response contributes to gastric dis-ease is found in the study by El-Omar et al showing that polymorphisms in theIL-1 gene are associated with an increased risk of gastric cancer (37a). Thus,the host response to the infection may indeed largely control the outcome ofinfection.

Innate Inflammatory Responses In addition to the inflammation caused by au-toreactive lymphocytes, tissue damage can be caused by activated neutrophils,macrophages, or even mast cells. A monocyte and macrophage response canbe seen in infected gastric mucosa, particularly in children, whereas in adults,polymorphonuclear cells are also present in the inflammatory infiltrate (6, 119).The presence of cells from both the acute and chronic aspects of the inflamma-tory response can be explained by the stimulation of neutrophil chemokines byother cytokines produced by mononuclear cells (127). A classic example is IL-8. Throughout most of the infection with H. pylori in adults, IL-8 levels can bedetected in the gastric mucosa, particularly in the epithelial cell layer (27), and theIL-8 response by the gastric epithelium is boosted by the Th1-derived cytokines -interferon (IFN- and tumor necrosis factor alpha (TNF-) (127). This chemokineis particularly specific for neutrophils and likely accounts for the active compo-nent that is mixed with the infiltrate associated with chronic gastritis. The lack ofneutrophils in the gastric mucosae of children may be attributed to differences inchemokine production that reflect the duration of infection; however, this postulateremains to be directly examined.

Using activated neutrophils as an example, one can easily imagine the damagethey can cause. For example, neutrophils can migrate across the epithelium and inso doing disrupt epithelial-cell permeability (69). In addition, secretion of medi-ators such as histamine (30), proteases (115), adenosine (70), or H2O2 (10) fromneutrophils or mast cells can also modify the barrier and/or ion transport function

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630 ERNST GOLD

of epithelial cells. Oxidative metabolites from neutrophils can also induce cellulardamage, including apoptosis and DNA injury (23). Thus, the longer the period ofexposure of a tissue to activated immune/inflammatory cells and mediators, themore cellular damage may accumulate.

If mucosal ulceration is in part caused by an autoimmune response, it should benoted that apparently there is very little immunological memory because cure ofthe infection effectively prevents recurrence of peptic ulcers. However, peripheral-blood T cells from seropositive and seronegative donors can respond to stimula-tion with water-extractable H. pylori proteins (101). This suggests either that sero-negative donors have cleared an infection and retain T-cell memory or that theseproteins cross-react with other antigens to which the host is sensitized. However,there is no protective immunity in gastric tissue, as reinfection can occur. Theseobservations are not inconsistent with the concept that at least some autoreactiveT and B cells are activated during H. pylori infection, because the immunologi-cal memory of mucosal lymphocytes appears to be very short-lived. Indeed, mostof the increase in T and B cells observed in the gastric mucosa is reversed afterantibiotic treatment. In addition, the self-antigen may be present only during in-fection. For example, epithelial cells may express surface antigens in response tothe stress of infection and the inflammatory milieu. Likewise, the loss of gastricB cells after treatment may permit rheumatoid factor to wane, and the absence ofH. pylori itself may remove a luminal antigen to which the host has never es-tablished an immunological equilibrium. In contrast, any effect of H. pylori onclassical autoimmune gastritis-targeting specific antigens present in the parietalcell may be more long lasting (4).

Epithelial-Cell Injury

Moss and colleagues found that apoptotic cells were rare in uninfected gastrictissue samples, constituting a mean of 2.9% of epithelial cells, located in the mostsuperficial aspect of the gastric glands (80). In infected tissues, apoptotic cellswere located throughout the depth of the gastric glands and increased in meannumber (16.8%), a value that fell to 3.1% after H. pylori eradication. This re-port was substantiated by Jones et al, who confirmed the occurrence of increasedepithelial-cell apoptosis in gastric biopsy specimens from H. pylori-infected pa-tients, which decreased after successful eradication therapy (58). The frequencyof epithelial-cell apoptosis was found to be significantly lower in other forms ofgastritis or noninflamed mucosa in this study. Another report also describes in-creased apoptosis of epithelial cells, in the neck region of the gastric glands of H.pylori-infected subjects, that decreased after eradication therapy (73). The pres-ence of apoptotic epithelial cells suggests that the epithelial barrier may be com-promised. This could contribute to an increased permeability and a breakdownin the cytoprotective mechanisms that guard the epithelium against damage byluminal acid and pepsin.

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As discussed above, cytokines from Th1 cells can enhance death of gastricepithelial cells through apoptosis (41, 116). One explanation for the augmenta-tion of apoptosis by IFN- is the increase in the expression of receptors forH. pylori. For example, class II MHC molecules have been identified as re-ceptors capable of binding H. pylori (41). Because IFN- can increase theexpression of class II MHC molecules, T cells producing this cytokine may in-crease the bacterial load as well as facilitate the delivery of additional hits byH. pylori.

These processes mediating epithelial cell death may be important in regulat-ing cell death and eliminating malignant cells, but they could also induce breaksin the epithelial barrier that create erosions that lead to ulcers (71). Because im-mune responses are so variable within the population, the manifestation of diseasewould be restricted by as-yet-unidentified factors regulating the gastric immuneand inflammatory response (see Figure 3).

Consequences of Epithelial Cell Damage

The increased apoptosis observed in the gastric epithelium during infection withH. pylori can be interpreted in two ways. Epithelial-cell death may lead to acompensatory increase in epithelial-cell proliferation as part of the healing andrepair process. Alternatively, part of the increase in apoptosis may be a response toepithelial-cell proliferation. The existing data are insufficient to resolve the circularargument of which event leads to the other. However, it is safe to speculate thatthe increase in epithelial-cell turnover can lead to altered function and possiblyerrors in epithelial-cell restitution (23).

As described above, infection and the ensuing inflammatory response can in-duce a significant amount of damage to the gastric epithelium. The functionalchanges in barrier function increase permeability to luminal contents (16, 30, 92,113). This increase in gastric epithelial permeability not only increases the accessof acid to underlying tissue but may also facilitate the transport of immunogenicproteins into the lamina propria (30). Another consequence of an increase in ep-ithelial cell turnover is the eventual failure of proper repair and the infiltration ofthe mucosa with fibrotic tissue and/or replacement of the epithelium with poorlydifferentiated cells. Indeed, atrophy of glandular tissue, with or without fibrosis,is a common finding associated with chronic infection. In addition, the chronic in-flammatory process and the persistent stimulation of epithelial-cell restitution mayalso be factors contributing to the development of intestinal metaplasia. Althoughthe mechanisms that regulate these processes are poorly defined, the associationof these morphological changes in the sequential progression to gastric adenocar-cinoma (21, 23) illustrates their importance.

One of the important triggers for the loss of control of epithelial-cell prolif-eration or apoptosis is the introduction of mutations into key genes as a con-sequence of oxidative damage. For example, many gastric-cancer cell lines have

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mutations in the p53 gene, which encodes a protein that limits cell growth(Figure 4, see color insert). The oxidative environment in the gastric mucosa isaltered by a decrease in antioxidants, such as vitamin C in gastric juice (96, 100,103), and an increase in oxidative stress inflicted by the inflammatory cells. Neu-trophils and macrophages generate reactive oxygen or reactive nitrogen speciesthat are capable of inducing oxidative injury to DNA (23). Thus, persistent expo-sure to the inflammatory process increases the amount of DNA damage. Shouldthis damage occur in a key gene in the stem cells, then a clone of cells withabnormal growth regulation can be perpetuated and hasten the development ofcancer. It is important that both the neutrophil infiltrate (3, 42, 44) and localascorbic acid levels (96, 103) return to normal after curing of H. pyloriinfection, which again supports the idea that treatment may reduce the risk ofcancer.

HOW WILL THE PATHOGENESIS OFGASTRODUODENAL DISEASES BESTUDIED IN THE FUTURE?

Many exciting advances have been made since H. pylori became recognized asa significant human pathogen. In particular, advances in molecular bacteriology,including the complete determination of the H. pylori genome, have providedtools with which to gain an understanding of the pathogenesis of disease. How-ever, relatively less attention has focused on the role of the host response and theimmunophysiological reactions in the pathogenesis of H. pylori infection and aspredictors of disease. This is, in part, caused by the complex nature of the responseand the enormity of the human genome, which is only just beginning to be under-stood. Presumably, with the advent of new techniques in genomics, advances willbe accelerated.

The animal models in hand do not provide the ideal means to study pathogen-esis, because ulceration and cancer are relatively difficult to observe. Therefore,additional improvement in these models along with validation of key observa-tions in humans will be essential. The complexity of studies in humans, includingthe significant differences in disease manifestation among different regions of theglobe, will also complicate interpretation of new findings.

Future studies will continue to delve into the role of bacterial factors in thepathogenesis of gastroduodenal disease. Although the bacterial infection doesprovide the stimulus, defining the pathogenesis of disease without consideringthe role of the host response will leave huge voids in our understanding thatwill limit our ability to develop effective screening tests, therapies, or meansof preventing infection, such as vaccines. Ideally, scientists will be encouragedto continue their studies characterizing the differential host response in subjectsdisplaying the various manifestations of infection.

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ACKNOWLEDGMENTS

This work was supported by grants from the National Institutes of Health (DK50669, DK 51577, DK53708, and CHD 35741).

Visit the Annual Reviews home page at www.AnnualReviews.org

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Documents

The Disease Spectrum of Helicobacter Pylori : The Immunopathogenesis of Gastroduodenal Ulcer and Gastric Cancer