Clinical Science (2006) 110, 305314 (Printed in Great Britain) doi:10.

1042/CS20050232

Immune responses to Helicobacter pylori

colonization: mechanisms and clinical outcomes
Cynthia PORTAL-CELHAY and Guillermo I. PEREZ-PEREZ

Department of Microbiology, NYU School of Medicine, VA Medical Center, 423 East 23rd Street, New York, N.Y. 10010
U.S.A., and Departments of Medicine and Microbiology, NYU School of Medicine, VA Medical Center, 423 East 23rd Street,
New York, N.Y. 10010 U.S.A.

Helicobacter pylori colonizes the stomachs of half of the worlds population and usually persists in
the gastric mucosa of human hosts for decades or life. Although most H. pylori-positive people
are asymptomatic, the presence of H. pylori is associated with increased risk for the development
of peptic ulcer disease, gastric adenocarcinoma and gastric lymphoma. The development of a sustained gastric inflammatory and immune response to infection appears to be pivotal for the development of disease. During its long co-existence with humans, H. pylori has evolved complex
strategies to maintain a mild inflammation of the gastric epithelium while limiting the extent of
immune effector activity. In this review, the nature of the host immune response to H. pylori
infection and the mechanism employed by the bacterium to evade them is considered. Understanding the mechanisms of colonization, persistence and virulence factors of the bacterium as
well as the innate and adaptive immune responses of the host are critically important for the development of new strategies to prevent the development of H. pylori-induced gastroduodenal disease.

INTRODUCTION
Helicobacter pylori is a Gram-negative microaerophilic
spiral bacterium that colonizes the gastrointestinal mucosa of its host and, despite a strong persistent humoral
and cellular immune response to H. pylori at the local and
systemic level, the organism persists for the lifetime of
its host. Virtually all people carrying H. pylori have coexisting gastric inflammation; however, only a small percentage of colonized individuals develop clinically apparent sequelae.
Chronic gastritis induced by H. pylori increases the
risk for a wide spectrum of clinical outcomes, ranging
from peptic ulcer disease (gastric and duodenal ulceration) to distal gastric adenocarcinoma and gastric mu-

cosal lymphoproliferative diseases, such as nonHodgkins lymphoma [1]. Although the factors determining the variable outcome of H. pylori infection are not
well understood, the development of a sustained gastric
inflammatory and immune response to infection appears
to be pivotal for the development of disease. Enhanced
risk may be related to differences in the expression of
specific bacterial products, to variations in the host inflammatory response to the bacteria or to specific
interactions between host and microbe [2].
We are only now beginning to understand the bacterial
and host factors that are involved in the hostpathogen
interaction during persistent colonization with H. pylori.
The answers to these questions are likely to provide
new and exciting directions for research in the fields of

Key words: colonization, gastric mucosa, Helicobacter pylori, immune response, inflammation.
Abbreviations: APC, antigen-presenting cell; CI, confidence intervals; DC, dendritic cell; HcpA, Helicobacter cysteine-rich protein
A; IFN- , interferon- ; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NF-B, nuclear factor
B; NO, nitric oxide; PAI, pathogenicity island; sIgA, secretory IgA; TLR, Toll-like receptor; TNF-, tumour necrosis factor-;
Treg, CD4+ CD25+ regulatory T-cells.
Correspondence: Dr Guillermo I. Perez-Perez (email perezg02@med.nyu.edu).


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Table 1 H. pylori proteins that may contribute to gastric colonization

Product

Gene(s)

Putative functions

Targeted host defence

Urease
Flagellae
Adhesins
Lewis antigens

ure operon
flaA , flaB , flg and flbA
babA and others
galT , futA , futB and futC

Gastric acid neutralization

Motility
Adherence to gastric epithelium
Adherence to gastric epithelium
? Molecular mimicry

Gastric acid
Gastric peristalsis
Gastric peristalsis
Gastric peristalsis
Humoral immune response

microbial pathogenesis and immunology. This review

focuses on the immune response to H. pylori colonization
and its effect on clinical outcomes.

EPIDEMIOLOGY
H. pylori is the most common chronic bacterial infection
in humans [3]. Infection with H. pylori occurs worldwide,
but the prevalence varies greatly among countries and
among population groups within the same country.
H. pylori colonizes the stomachs of 50 % of the population in developed countries and approx. 80 % in the developing world. The infection is acquired by oral ingestion of the bacterium and is mainly transmitted within
families. The main source of transmission is the mother
within families [4]. Acquisition of H. pylori apparently
takes place in early childhood and is rare or does not occur
in adults. In industrialized countries, the rate of acquisition of H. pylori has decreased substantially over recent
decades. Therefore the continuous increase in prevalence
of H. pylori with age is due mostly to a cohort effect, reflecting more intense transmission at the time when members of earlier birth cohorts were children [5]. The organisms can be cultured from vomitus or diarrhoeal stools,
suggesting the potential for transmission among family
members during periods of illness [6].
The overall prevalence of H. pylori is strongly correlated with socioeconomic conditions. Factors such as
density of housing, overcrowding, number of siblings,
birth order, sharing a bed and lack of running water
have all been linked to a higher acquisition of H. pylori
infection [7].

PATHOGENESIS
Colonization of the gastric mucosa
Gastric acidity and peristalsis normally inhibit bacterial
colonization of the human stomach. However, natural
selection has provided H. pylori with several mechanisms
to elude these primary defences and establish persistent
infection, such as the ability to withstand acidic gastric
pH and motility (Table 1).
After being ingested, H. pylori has to evade the
bactericidal activity of the gastric luminal contents and

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establish intimate contact with the mucous layer. The

enzyme urease metabolizes urea to carbon dioxide and
ammonia to buffer the gastric acid. Flagella allow the
bacterium to swim across the viscous gastric mucus and
reach the more neutral pH below the mucus. Knockout
H. pylori mutants of urease or flagellar genes are defective
in gastric colonization in a gnotobiotic piglet model of
infection [8,9].
Once below the mucus, H. pylori adheres tightly to the
underlying cells. The best characterized adhesin, BabA,
is a 78 kDa outer-membrane protein that binds to the
fucosylated Lewisb blood-group antigen.
Persistent colonization depends on the ability to respond to changing environmental conditions and circumvent host defence mechanisms initiated during infection.
Rearrangement of genomic DNA allows a variety of
pathogens to adapt expression of surface antigens and
evade host immunity. H. pylori has the highest rate of
genetic recombination of any known bacterial species,
suggesting that this process confers a selective advantage
in colonization. Loughlin et al. [10] have shown that
H. pylori mutants defective for homologous recombination were spontaneously cleared from the murine
gastric mucosa, whereas the H. pylori wild-type strain
established a persistent high level of colonization.

Virulence factors
The major disease-associated genetic difference in
H. pylori isolates is the presence or absence of the cag-PAI
(pathogenicity island), a 40 kb genomic fragment containing ORFs (open reading frames) that represent 31
genes. As in other bacterial pathogens, the PAI has been
acquired by horizontal transfer of a genetic cassette.
The cag-PAI is present in 6070 % of US clinical
strains. A particular cluster of these genes encodes for
a type IV bacterial secretion system which, in addition to
playing a role in the inflammatory response, has been
shown to deliver the immunodominant CagA protein
that is encoded in the cag-PAI inside the host cells.
Once inside the gastric epithelial cell, CagA is tyrosine
phosphorylated by Src kinase activity, leading to a
growth-factor-like cellular response and cytokine production by the host cell [11]. Because of these functions,
H. pylori cagA+ strains are associated with a significantly
increased risk for severe gastritis, atrophic gastritis, peptic

Immune responses to Helicobacter pylori colonization

ulcer disease and distal gastric cancer compared with

cagA strains [12,13].
A second locus of heterogenicity is the gene vacA,
which encodes the vacuolating cytotoxin. VacA is a
secreted protein toxin that is responsible for the gastric
epithelial erosion observed in infected hosts. Despite
the fact that 100 % of H. pylori strains carry the vacA
gene, approx. 50 % of H. pylori strains produce a functional VacA protein [14]. H. pylori strains that express
vacuolating activity are more common among patients
with peptic ulcer disease and distal gastric cancer than
among infected patients with superficial gastritis alone
[15]. Although vacA is conserved among all H. pylori
strains, significant polymorphism exists. vacA alleles possess one of two types of signal region, s1 or s2, and one of
two mid-regions, m1 or m2, occurring in all possible combinations. H. pylori strains with different forms of vacA
exhibit varied phenotypes and have particular associations with gastroduodenal diseases. vacA s1/m1 strains
are most closely associated with gastric carcinoma [16].

HOST RESPONSE TO H. PYLORI

The immune response towards bacterial pathogens can
be divided into an innate and an adaptive response. The
innate response towards bacterial infection is generally
an initial non-specific process, which reacts quickly with
several bacterial molecules to signal infectious danger and
with the aim of killing the bacteria. By contrast, the adaptive immune response is delayed, antigen-specific, leads
to the activation of T-, B- and memory cells and is shaped
by the innate immune response.

Innate immunity
Recognition of bacterial molecules by the innate immune
system is mediated by TLRs (Toll-like receptors) expressed on APCs (antigen-presenting cells) such as monocytes
and DCs (dendritic cells). Bacterial contact with monocytes and other APCs leads to the secretion of proinflammatory cytokines such as TNF- (tumour necrosis
factor-), IL (interleukin)-1 and IL-8. H. pylori infection has been shown to be associated with increased levels
of these cytokines which, in turn, act as local chemoattractants, inducing granulocytic infiltration [17].
Thus far, many of the studies on innate immune responses to H. pylori in epithelial cells have focused on
TLR4, the specific pathogen-recognition molecule
(PRM) of Gram-negative LPS (lipopolysaccharide).
However, gastric epithelial cell lines were non-responsive to H. pylori LPS, even when relatively high concentrations of this endotoxin were added to the cells
[18]. Consistent with this, a TLR4-neutralizing antibody
did not block H. pylori-induced secretion of the proinflammatory cytokine IL-8 in AGS cells [19].
Two additional TLRs, TLR2 and TLR5, have been
shown to participate actively in innate immune responses

to Gram-negative bacteria through their recognition of

lipoproteins and flagellin respectively. A role for TLR2
and TLR5 signalling to H. pylori was suggested by a
study showing an increase in NF-B (nuclear factor
B) luciferase reporter activity in H. pylori-stimulated
HEK-293 cells that had been co-transfected to express
TLR2, TLR4 or TLR5. Infection of the cultures with
H. pylori induced NF-B activity in cells transfected
with TLR2 and TLR5, but not TLR4 [20]. Other groups,
however, demonstrated that flagellin-responsive epithelial cell lines do not detect native or recombinant
H. pylori flagellin, suggesting that H. pylori flagellin
evades TLR5 recognition [21].
Several studies have demonstrated that contact between H. pylori and gastric epithelial cells results in a
rapid activation of NF-B, which is followed by increased
IL-8 expression [22]. The ability of H. pylori to activate
NF-B in vitro has also been corroborated in vivo as
activated NF-B is present within gastric epithelial cells
of infected, but not uninfected, patients, which mirrors
the location of increased IL-8 protein within colonized
mucosa [23].
In addition to NF-B, MAPKs (mitogen-activated
protein kinases) have been implicated as mediators of
H. pylori-induced IL-8 expression. In vitro studies utilizing IL-8 reporter constructs have now revealed that
H. pylori-induced IL-8 gene expression is dependent upon
activation of both NF-B and AP-1 (via activation of
MAPKs), indicating that synergistic interactions between
AP-1 and NF-B within the IL-8 promoter are required
for maximal H. pylori-induced IL-8 production [24].

Adaptive immunity
Cellular response
Adaptive immune responses towards H. pylori infection
have also been identified. H. pylori causes continuous
gastric inflammation in virtually all infected people. This
inflammatory response initially consists of neutrophils,
followed by lymphocytes (T- and B-cells), plasma cells
and macrophages, along with varying degrees of epithelial
cell degeneration and injury [25].
Since H. pylori rarely, if ever, invades the gastric
mucosa, the host response is triggered primarily by the
attachment of bacteria to epithelial cells. The organism
produces a number of antigenic substances, including
HSP (heat-shock protein), urease and LPS, all of which
can be taken up and processed by lamina propia macrophages and activate T-cells [26]. Cellular disruption, especially adjacent to epithelial tight junctions, undoubtedly
enhances antigen presentation to the lamina propia and
facilitates immune stimulation. The net result is increased
production of inflammatory cytokines such as IL-1, IL-6,
TNF- and, most notably, IL-8 [27,28].
Chronic active gastritis is associated with an increased
CD4/CD8 T-cell ratio within the gastric mucosa, due

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largely to the accumulation of CD4+ T-helper lymphocytes in the lamina propia. H. pylori infection results
in a Th1-predominant host immune response in the
gastric mucosa, characterized by the induction of IFN (interferon- ) and IFN- -related genes. A Th1-predominant immune response is associated with elevated
levels of the pro-inflammatory cytokines IL-12, IL-18
and TNF- [11]. The severity of gastritis associated
with H. pylori infection was correlated with mucosal
expression of the TNF- subunit CD68 and IFN- [29].
A more robust mucosal Th1 response has also been
associated with progression to atrophic gastritis and gastric cancer, as supported by animal models [30].
The host genetic background contributes to the immune and inflammatory response to H. pylori infection.
The IL-1B gene encodes the expression of IL-1, a potent
pro-inflammatory cytokine and powerful inhibitor of
gastric acid secretion that plays a major role in initiating
and amplifying the inflammatory response to H. pylori
infection [31]. A polymorphic allele with T instead of
C at position 511 of the regulatory region of the
IL-1B gene (IL-1B 511 T) is associated with increased IL-1 production [32]. IL-1RN encodes the
IL-1-receptor antagonist, an anti-inflammatory cytokine
that competitively binds to IL-1 receptors and thereby
modulates the potentially damaging effects of IL-1 [33].
The IL-1RN gene has a penta-allelic 86 bp variable number tandem repeat in intron 2, of which allele 2 (IL1RN 2) is associated with a wide range of chronic inflammatory and autoimmune conditions and enhanced
IL-1 secretion. Hwang et al. [34] have shown that, in
H. pylori-infected Japanese subjects, individuals who
carried an IL-1B gene polymorphism (IL-1B 511T/T)
or those carrying the IL-1RN 2 allele had higher mucosal
IL-1 levels than non-carriers. These studies demonstrate
that host genetic polymorphisms in inflammatory
response genes can influence the nature and extent of
H. pylori-mediated gastritis and thereby disease expression.

Humoral response
Individuals colonized with H. pylori elicit a strong specific systemic and local antibody response to the infection.
Tosi and Czinn [35] reported that binding of IgG to
H. pylori promoted phagocytosis and killing in vitro
by polymorphonuclear leucocytes. H. pylori strains are
susceptible to complement and activate it either via the
classical pathway, even in the absence of specific antibodies, or by the alternative pathway [36,37]. Despite this
vigorous immune response, H. pylori is not eradicated
unless an infected individual is treated with a combination of antibiotics, and lifelong chronic infection
usually develops. These observations suggest that gastric
mucus may be a protective niche in which H. pylori
exist and are relatively inaccessible to specific antibodies
or their effector functions. The ineffective humoral res
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ponse generated towards H. pylori and its components

may actually contribute to pathogenesis. Some of the
monoclonal antibodies directed against H. pylori crossreact with gastric epithelium of both mice and humans
and delivery of these antibodies alone to mice can induce
gastritis [2].
Clyne et al. [38] have shown that human serum from
both infected and non-infected subjects exerted a bactericidal effect on H. pylori. Furthermore heat inactivation abolished the killing effect of the serum samples on
the organism, strongly suggesting that it was complement
mediated. Later it was reported that bovine normal serum
and serum from immunized cows is highly bactericidal
for H. pylori. This bactericidal effect is destroyed by
heating to 56 C for 30 min and restored by the addition
of fetal calf serum as a source of complement, indicating
that the bactericidal effect is probably dependent on an
antibodycomplement system. However, the bactericidal
activity did not correlate with titres of specific antibody
or with IgG concentrations [39]. In the study by Clyne
et al. [38], serum samples from infected subjects killed the
organism more effectively than serum from non-infected
individuals, indicating that some of this effect is mediated
by the classical pathway.
Sampling of gastric secretions from H. pylori-infected
individuals also reveals an active mucosal antibody response, primarily of the IgA isotype. This response is
consistent with the predominance of sIgA (secretory IgA)
in the gastric secretions of healthy individuals. sIgA anti(H. pylori) antibodies are also found in saliva and breast
milk [11].
Thomas et al. [40] have reported that children in
Gambia who were breastfed by mothers that had high
titres of specific anti-(H. pylori) sIgA in their milk were
protected from infection for a longer period than children
whose mothers had lower anti-(H. pylori) antibody titres.
It was postulated that specific antibodies in human milk
passed from mother to child during breast feeding are
protective against infection by H. pylori; however, most
children were infected by 12 months of age. Other studies
have questioned the role of breast feeding as protective
factor in H. pylori acquisition. The relationship between
infection and childhood home environment has been
evaluated in German [41], Japanese [42] and Italian [43]
populations. No association was seen between H. pylori
seropositivity and a history of breast feeding in any of the
three studies.
Studies have shown that sIgA can interfere with the
ability of some enteric pathogens to establish infection
[44,45]. Others have shown that sIgA can inhibit bacterial
adherence [46]. However, Clyne et al. [38] have shown
that the systemic antibody response and the sIgA response against H. pylori do not inhibit the organism from
adhering to gastric cells in vitro. This may explain why
chronic infection develops in infected subjects despite a
vigorous immune response.

Immune responses to Helicobacter pylori colonization

IMMUNOMODULATION BY H. PYLORI
To maintain prolonged colonization of the human gastric
mucosa, H. pylori must avoid both innate and adaptive
immune responses.
Following infection with H. pylori, DCs phagocytose
bacterial proteins and express peptides on their surface,
together with MHC and co-stimulatory molecules. This
presentation of antigens effectively leads to the activation
of CD4+ T-cells that react towards these antigens and
trigger the immune response. Naive CD4 T-cells can
differentiate upon activation into either Th1 or Th2 cells,
which differ in the type of cytokines that they produce
and therefore in their function. The factors that determine whether a proliferating CD4 T-cell in vivo will differentiate into a Th1 or a Th2 cell are not fully understood.
The cytokines elicited by infectious agents (principally
IFN- , IL-2 and IL-4), the co-stimulators used to drive
the response and the nature of the peptideMHC ligand
all have an effect [47].
The consequences of inducing Th1 versus Th2 cells
are profound: the selective production of Th1 cells leads
to cell-mediated immunity and the production of opsonizing antibody classes (predominantly IgG), whereas the
production of predominantly Th2 cells provides humoral
immunity, especially IgM, IgA and IgE.
Most intracellular bacteria induce Th1 responses,
whereas extracellular pathogens stimulate Th2-type responses. Based on the fact that H. pylori is non-invasive
and that infection is accompanied by an exuberant humoral response, one might predict that a Th2 response
would be predominant within H. pylori-colonized gastric
mucosa. Paradoxically, the majority of H. pylori antigenspecific T-cell clones isolated from infected gastric
mucosa produce higher levels of IFN- than IL-4, which
is reflective of a Th1-type response [48]. H. pylori also
stimulates production of IL-12 in vitro, a cytokine
that promotes Th1 differentiation. These findings raise
the hypothesis that an aberrant host response (Th1)
to an organism predicted to induce secretory immune
responses (Th2) may influence and perpetuate gastric
inflammation. Animal models of H. pylori-induced gastritis have supported these conclusions [49]. Furthermore,
a bacterial factor contributing to the initiation of Th1
polarization of H. pylori-specific immune response was
recently characterized. Deml et al. [50] identified HcpA
(Helicobacter cysteine-rich protein A) as a novel proinflammatory and Th1-promoting protein. Using splenic
cells of H. pylori-negative naive mice, the authors found
that HcpA induces a substantial secretion of pro-inflammatory (IL-6 and TNF-) and Th1-promoting cytokines
(IL-12 and IFN- ), but no significant release of IL-2 and
the Th2-promoting cytokines IL-4 and IL-5.
A major mechanism for self/non-self discrimination by
the immune system and establishment of self-tolerance
is the clonal deletion of self-reactive T- and B-cells ex-

posed to self-antigens during development in the thymus [51]. The deletion mechanism is not complete, however, and potentially hazardous self-reactive lymphocytes
are present in the periphery of normal individuals. It has
become increasingly evident that active suppression of
self-reactive T-cells by regulatory T-cells takes place in
the periphery of normal individuals avoiding the onset
of harmful autoimmunity. Three phenotypically distinct
subsets of suppressor-regulatory T-cell have been described based on one or more surface-marker antigens
and/or cytokine-production profiles: the natural
CD4+ CD25+ regulatory T-cells (Treg) [52], the IL-10secreting Tr1 cells [53] and the TGF- (transforming
growth factor-)-secreting Th3 cells [54], which functionally both in vitro and in vivo have been shown to
suppress the proliferation and cytokine secretion of effector T-cells.
The recognition of an important role for regulatory T-cells in the suppression of pathogen-induced inflammatory responses has just started to emerge. Recent
evidence suggests that the activation of regulatory
T-cells, including both Treg and Tr1 cells, might result
in decreased pathological responses and prolonged persistence of infection as a mechanism for the maintenance
of pathogen-specific immunological memory [55].
Treg seem to play a role in modulating inflammation in
H. pylori infection. A recent study [56] has demonstrated
that infection of athymic nu/nu mice with H. pylori resulted in considerably lower colonization in mice reconstituted previously with lymph node cells depleted of
Treg compared with those reconstituted with control
cells. In another study, Lundgren et al. [57] observed that
memory T-cell responses were increased upon specific
antigen stimulation of peripheral blood lymphocytes
taken from H. pylori-infected subjects when the cell
population was depleted of Treg. These studies indicate
that Treg may reduce immunopathology in H. pylori
gastritis, possibly by reducing activation of IFN- producing CD4+ T-cells, but at the expense of a higher
H. pylori bacterial load.

EVASION OF IMMUNE RESPONSE BY

H. PYLORI (Figure 1)
Evasion of innate response
NO (nitric oxide) is a key component of the innate
immune system and an effective antimicrobial agent [58].
Gobert et al. [59] have shown that H. pylori prevents
NO production by host cells by producing the enzyme
arginase. This enzyme is encoded by the gene rocF, and
competes with NOS2 (NO synthase 2) for the substrate
l-arginine and converts it into urea and l-ornithine,
rather than NO. Mutation of rocF results in efficient killing of the bacteria in an NO-dependent manner, whereas
wild-type bacteria survive under these conditions.

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Figure 1 H. pylori pathogenesis and the inflammatory response

H. pylori resides in the gastric lumen and colonizes the gastric epithelium using urease. Binding of H. pylori to epithelial cells and injection of CagA results in the
production of IL-8 and other chemokines, and activation of the innate and adaptive immune systems. To evade the immune response, H. pylori has evolved mechanisms
to reduce recognition by immune sensors, down-regulate activation of immune cells and escape immune effectors. PMN, polymorphonuclear cells.
Furthermore, the rocF mutant is mildly attenuated in its
ability to colonize mice.
It has been shown that, during H. pylori infection,
bacteria can survive intracellularly within macrophages
by interfering with lysosomal proteins, similar to Mycobacterium tuberculosis [60]. Therefore, although there
is an innate response to the bacteria, it is not effective
enough to eliminate the infection. In one study, Allen
et al. [61] have shown a delayed uptake of bacteria into
macrophages followed by the formation of megasomes as
a result of phagosome fusion. These megasomes protect
intracellular bacteria from efficient killing. Furthermore,
using human blood monocytes and polymorphonuclear
cells, Ramarao et al. [62] have shown that H. pylori can
actively block its own uptake, as well as the uptake of cocultured bacteria of other species and latex beads. Both of
these phenotypes depended on the presence of Cag-PAI.
Bacterial LPSs are classic mediators of inflammation,
because of their activation of phagocytic cells, endothelial
and epithelial cells and lymphocytes [63]. However, despite a general conservation of LPS structure, large differences in their pro-inflammatory activity have been noted.
When compared with LPS from Enterobacteriaceae,
H. pylori LPS is 1000-fold less active and only weakly
activates macrophages [64]. Therefore it has been sug
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gested that there is selective pressure in H. pylori cells

to minimize pro-inflammatory activities to permit longterm colonization, since enhanced inflammation, leading
to atrophic gastritis, would lead to a loss of niche.
Finally, it has been recently demonstrated [65] that
members of the and Proteobacteria, including
H. pylori, possess flagellin molecules that cannot be
recognized by TLR5. Their unique flagellin sequences
contain amino acid differences in the TLR5 recognition
site that permit TLR5 evasion, as well as compensatory
mutations that preserve bacterial motility. These results
suggest that TLR5 evasion is critical for the survival of
H. pylori at mucosal sites.

Evasion of adaptive response

H. pylori has evolved to subvert not only the innate, but
also the adaptive immune response. It has been shown
that H. pylori specifically can block antigen-dependent
proliferation of T-cells. This effect is mediated by the
virulence factor VacA, which acts as an immunomodulator by interfering with the IL-2 signalling pathway in
T-cells by blocking Ca2+ mobilization and the activity of
the Ca2+ /calmodulin-dependent phosphatase calcineurin
[66]. Another possible function of VacA in subverting
the adaptive immune response is its ability to interfere

Immune responses to Helicobacter pylori colonization

Figure 2 H. pylori -induced diseases in humans

H. pylori is acquired in early childhood, and it may take decades to lead to symptomatic disease. The clinical course is highly variable and depends on bacterial and
host factors. High acid outputs predispose patients to duodenal ulcers, whereas lower acid outputs are associated with gastric atrophy and cancer.
with antigen presentation mediated by MHC class II
[67]. A recent study [68] strongly supports the possibility
that VacA is immunosuppressive, but the mechanism described involves a direct action on T-cells rather than
APCs. The authors [68] show that the toxin inhibits the
activation and proliferation of T-cells.
Several findings indicate that a strong inflammatory
reaction is necessary for the elimination of H. pylori and,
at least in animal models, it seems to be actively repressed
by the bacterium: an increased inflammatory reaction, as
seen in IL-10 knockout mice, is associated with clearance
of H. pylori from the stomach within 8 days of the
infection [69]. Similarly, increased inflammation due to
deletion of the gene encoding PHOX (NADPH oxidase)
results in a marked reduction in bacterial numbers [70].
Genomic DNA recombination has been shown to be
critical for mediating persistence of H. pylori through
the induction of ineffective immune responses. Robinson
et al. [71] found that the H. pylori wild-type strain and
the ruvC mutant (which encodes a Holliday junction
resolvase) elicited oppositely polarized Th2 cell responses
that correlated with persistence and clearance respectively. Temporary colonization by the ruvC mutant conferred significant protection against subsequent challenge
with the wild-type strain.

CLINICAL OUTCOMES
Everyone who carries H. pylori in their stomach develops
a cellular infiltrate in their gastric mucosa, termed chronic

gastritis (Figure 2). In most patients (80 %), H. pylori

does not cause clinical symptoms and the infection can
persist for a lifetime without further problems. A proportion (1020 %) of infected patients will develop gastric
hyperacidity and peptic ulcers, but can be cured by antibiotic treatment. However a small percentage (0.1 4 %)
of infected patients will develop distal gastric adenocarcinoma, depending on the circumstances of the infection and the individual immune response towards the
bacterium.
Although the factors determining this variable outcome are not well understood, the development of a
sustained gastric inflammatory and immune response to
infection appears to be pivotal for the development of
disease [72]. Mucosal T-cells in infected individuals are
polarized towards the production of IFN- , rather than
IL-4 or IL-5, indicating a strong bias towards a Th1-type
response [48].
Bacterial determinants of virulence are considered critical for initiating close interactions with host epithelial
cells and inducing mucosal inflammation. H. pylori
strains containing the cag-PAI are associated with more
severe antral inflammation, higher mucosal levels of IL1 and IL-8 [73], peptic ulceration [74] and increased acid
secretion [75].
Other virulence-independent factors, such as the duration and density of infection, may also influence the outcome, but have been studied less well. Surveys of the early
phases of infection (in children) are few, but indicate that a
pro-inflammatory response and Th1-type cytokines were

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detected in response to infection [76,77]. In contrast with

adults, in whom neutrophilic infiltrates predominate,
children develop a predominantly mononuclear infiltrate
and have a higher degree of lymphoid follicular hyperplasia. The mechanisms underlying the differences in
histopathology and disease pattern between children and
adults and the early and late stages of infection are still
not well understood.
Recent studies have begun to shed light on specific
host genetic determinants of risk for H. pylori-associated
disease outcomes. Polymorphisms that increase the IL-1
response to H. pylori are associated with an increased risk
of developing hypochlorhydria, gastric atrophy and adenocarcinoma [78,79]. In a large population-based casecontrol study of gastrointestinal carriers, El Omar
et al. [80] recently demonstrated that pro-inflammatory
genotypes of TNF- and IL-10 were each associated with
more than doubling the risk of noncardia gastric cancer
and that carriage of multiple pro-inflammatory polymorphisms conferred even greater risks.
When the influence of CagA and VacA status on histological changes was analysed in subjects stratified according to IL-1B and IL-RN polymorphisms, it appeared that
more severe gastric abnormalities correlated both with
high-risk polymorphisms (IL-1B 511T and IL-RN 2
alleles) and virulence factors (cagA + /vacAs1+).
In vacAs1/IL-1B 511T patients and cagA-positive/
IL1RN 2/ 2, the odds ratios for gastric carcinoma were
87 [95 % CI (confidence intervals), 11679] and 23 respectively (95 % CI, 7.072) [81].

CONCLUSIONS
H. pylori continues to be one of the most common bacterial infections in humans, colonizing the stomach and
persisting for the hosts lifetime. Although the human
host mounts a vigorous innate and adaptive immune response against the bacterium, H. pylori escapes and evades
host responses by a variety of mechanisms, leading to
persistent colonization and chronic active inflammation.
An intriguing characteristic of H. pylori-induced gastritis
is its capacity to persist for decades without causing
serious damage in most cases. In its long association with
humans, H. pylori has established a fine balance between
establishing a comfortable niche and avoiding the immune
consequences of its colonization. Clinical complications
of H. pylori colonization, such as peptic ulcer disease and
gastric cancer, are therefore likely to represent imbalances
in gastric homoeostasis that are disadvantageous for both
microbe and host, particularly if death of the host ensues.
Considerable efforts have focused on delineating the
precise mechanisms by which H. pylori colonization
leads to gastric inflammation. It is likely that the
polarized Th1 responses and the inflammatory cytokines
induced by H. pylori gene products play major roles

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2006 The Biochemical Society

in the gastric epithelial inflammation associated with

H. pylori disease. Genetic or environmentally influenced
variability in the propensity to mount these types of inflammatory responses may, at least in part, help to explain
the different outcomes of H. pylori-induced disease in
different individuals.

ACKNOWLEDGMENTS
This study was supported by RO3 CA099512-01A1 from
the National Cancer Institute (National Institutes of
Health), by the NYU School of Medicine Institute for
Urban and Global Health, and by grant 02816-9 from the
Thrasher Research Fund.

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Received 28 July 2005/15 September 2005; accepted 10 October 2005

Published on the Internet 10 February 2006, doi:10.1042/CS20050232


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