Pathophysiology of and immune response to Helicobacter pylori infection

INTRODUCTION — Helicobacter pylori (H. pylori) is highly adapted to the gastric environment where it lives within or beneath the gastric mucous layer (see "Bacteriology and epidemiology of Helicobacter pylori infection"). The bacterium generally does not invade gastroduodenal tissue. Instead, it renders the underlying mucosa more vulnerable to acid peptic damage by disrupting the mucous layer, liberating enzymes and toxins, and adhering to the gastric epithelium. In addition, the host immune response to H. pylori incites an inflammatory reaction which further perpetuates tissue injury.

The chronic inflammation induced by H. pylori upsets gastric acid secretory physiology to varying degrees and leads to chronic gastritis which, in most individuals is asymptomatic and does not progress (picture 1). In some cases, however, altered gastric secretion coupled with tissue injury leads to peptic ulcer disease, while in other cases, gastritis progresses to atrophy, intestinal metaplasia, and eventually gastric carcinoma or rarely, due to persistent immune stimulation of gastric lymphoid tissue, gastric lymphoma. (See "Association between Helicobacter pylori infection and duodenal ulcer" and "Acute and chronic gastritis due to Helicobacter pylori" and "Gastric intestinal metaplasia" and "Metaplastic (chronic) atrophic gastritis" and "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

As a result, the pathophysiology of H. pylori infection and its eventual clinical outcome should be viewed as a complex interaction between the host and the bacterium. This interaction is influenced by the environment and modulated by a number of largely as yet unidentified factors [1,2].

The pathophysiology of H. pylori infection as it relates to gastrointestinal disease in general will be reviewed here. The role of H. pylori in specific disease processes is discussed separately. (See "Association between Helicobacter pylori infection and duodenal ulcer" and "Acute and chronic gastritis due to Helicobacter pylori" and "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

BACTERIAL FACTORS — Tissue injury induced by H. pylori depends upon bacterial attachment and the subsequent release of enzymes and other microbial products that can cause cellular damage.

Bacterial attachment — H. pylori exclusively colonizes gastric type epithelium, which suggests specific recognition of cell type by the bacterium [3]. Electron microscopy has confirmed the presence of tight adherence of H. pylori to the gastric cell surface through formation of membrane attachment pedestals similar to those described with enteropathogenic Escherichia coli [4,5]. This process requires that bacterial adhesins recognize and specifically bind to host receptors expressed on the cell surface [3]. The attachment process may morphologically or functionally alter the epithelial cell or activate certain bacterial functions making them more toxic. At the site of adherence, bacterial membrane proteins coded by genes contained in the cag pathogenicity island (PAI) open channels in the epithelial cell membrane that enable direct contact of bacterial factors with the cytoplasm [6].

Bacterial attachment is partially mediated by a number of adhesins and outer membrane proteins. Three Hop proteins have been implicated in the pathogenesis of H. pylori infection, BabA (HopS), OipA (HopH), and SabA (HopP) [7]. BabA, the best characterized of the three adhesin proteins, mediates binding to fucosylated Lewis b (Le(b)) blood group antigens on host cells [8]. OipA may serve as an adhesin but it also promotes inflammation by increasing IL-8 expression [9]. SabA mediates binding to glycoconjugates containing sialic acid [10]. Replacement of nonsialylated Lewis antigens by sialylated Le(x) or Le(a) has been associated with H. pylori induced gastric inflammation and cancer [10,11]. Thus, the role of Lewis antigen expression in bacterial attachment is unclear. Nevertheless, the homologous structures of H. pylori lipopolysaccharide and host LewisX antigen may lead to an autoimmune response with subsequent cell injury [12,13]. H. pylori can also bind to class II MHC molecules on the surface of gastric epithelial cells and induce apoptosis [14]. In fact, binding of the organism's urease to surface class II MHC is itself sufficient to induce apoptosis [15]. H. pylori modifies its lipid A in the outer membrane by removal of phosphate groups from the 1- and 4'-positions of the lipid A backbone. The enzyme responsible for dephosphorylation of the lipid A 4'-phosphate group in H. pylori, Jhp1487 (LpxF), has been identified and mutants created to demonstrate that dephosphorylation of the lipid A domain of H. pylori LPS by LpxE and LpxF is key to its ability to colonize the mammalian host [16].

Release of enzymes — H. pylori elaborates several enzymes that can cause cellular damage by direct or indirect mechanisms.

●Urease accounts for over 5 percent of the organism's total protein weight [17]. Urea, when hydrolyzed by bacterial urease, can form compounds such as ammonium chloride and monochloramine that can directly damage epithelial cells [18]. In addition, the urease enzyme itself is antigenic, activates the host immune system, and indirectly produces injury by stimulating inflammatory cells [18].

●Bacterial phospholipases can alter the phospholipid content of the gastric mucosal barrier, changing its surface tension, hydrophobicity, and permeability [19]. The conversion of lecithin to lysolecithin (a toxic compound) by phospholipase A2 can lead to cell injury [19], while lipolysis can disrupt the structure and integrity of gastric mucus [20].

●H. pylori produces more catalase enzyme than most other bacteria. This enzyme, an antioxidant, may protect the organism from toxic oxygen metabolites liberated by activated neutrophils and allow it to survive and proliferate in an inflamed and damaged gastric mucosa [19,21].

●Bacterial proteolytic enzyme activity can further degrade mucus. However, the importance of proteolysis remains controversial [19].

Bacterial strain differences — Functional differences exist between strains of H. pylori that may relate to virulence and tissue damage [22].

CagA and VacA — One such difference is expression of an 87 kilodalton (kd) vacuolating cytotoxin (VacA) which causes cell injury in vitro and gastric tissue damage in vivo [22-24]. All H. pylori contain the gene coding for VacA; however, only those strains that encode the cytotoxin-associated gene (cag) pathogenicity island (PAI), including cytotoxin-associated gene A (CagA), coding for a 128 to 140 kd protein (CagA), coexpress VacA [23]. VacA behaves as a passive urea transporter that is potentially capable of increasing the permeability of the gastric epithelium to urea, thereby creating a favorable environment for H. pylori infectivity [25]. Virulence of VacA appears to depend upon the function of a tyrosine phosphatase receptor in gastric epithelial cells [26]. H. pylori strains with different VacA alleles have differing toxicity [27].

CagA is not cytotoxic but is antigenic and can be detected serologically [28]. Its function is unknown but, since it is necessary for VacA expression, it may play a role in transcription, excretion, or function of the VacA cytotoxin [28]. H. pylori can translocate its CagA protein into gastric epithelial cells via a type IV secretory apparatus. There it is tyrosine phosphorylated and possibly plays a role in host cell responses [29-31].

Virulent strains of H. pylori encode cag PAI, which expresses a type IV secretion system (T4SS). This T4SS forms a syringe-like pilus structure for the injection of virulence factors such as the CagA effector protein into host target cells. This is achieved by a number of T4SS proteins, including CagI, CagL, CagY and CagA, which by itself binds the host cell integrin member β(1) followed by delivery of CagA across the host cell membrane. CagA is not cytotoxic but is antigenic and can be detected serologically [28]. A role of CagA interaction with phosphatidylserine has also been shown to be important for the injection process. After delivery, CagA becomes phosphorylated by oncogenic tyrosine kinases and mimics a host cell factor for the activation or inactivation of some specific intracellular signalling pathways [28-32].

Strains producing VacA and CagA cause more intense tissue inflammation and induce cytokine production [23,24,33]. Two other genes (picA and picB, now termed CagE) which are cotranscribed and genetically linked to cagA share homology with genes coding for toxins in other known pathogenic bacteria [23,34]. The gene product of picB (CagE) induces the release of epithelial cytokines, including interleukin-8 (IL-8) [23,34]. This effect appears to be mediated by nuclear factor kappa B, which activates transcription of IL-8 MRNA [35]. In addition, bacteria that express CagA are potent inducers of IL-8 [36,37].

The clinical significance of CagA positivity is demonstrated in two different disorders:

●Approximately 85 to 100 percent of patients with duodenal ulcers have CagA+ strains, compared to 30 to 60 percent of infected patients who do not develop ulcers [38]. Cag E positivity has also been associated with gastroduodenal disease in adults and children [39,40].

●CagA strains are associated with a higher frequency of precancerous lesions and gastric cancer [41]. The risk of malignancy may be related to specific amino acid sequences (EPIYA) in the CagA protein [42]. (See "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

Other virulence factors — In addition to CagA, several other H. pylori virulence factors have been described [43-49]. The strength of these associations has not been well defined in large populations.

●"Induced by contact with epithelium" (iceA) has been associated with peptic ulcers [43,46,47].

●"Blood group antigen-binding adhesin" (babA2) has been associated with duodenal ulcers and gastric cancer [48].

●"Outer inflammatory protein" (oipA) has been associated with duodenal ulcers [49].

Many of the virulence factors described above can coexist in the same H. pylori strains, making it unclear as to which factors might be most important. In addition, as noted above, expression of CagA is associated with both gastric cancer and duodenal ulcer, yet these two disorders rarely, if ever, coexist thereby minimizing the significance of this "virulence factor" in understanding disease pathogenesis.

One study suggested that the oipA status may be a better predictor of H. pylori virulence than any of the other previously described virulence factors. The study included 247 H. pylori infected patients (86 with gastritis, 86 with a duodenal ulcer, and 75 with gastric carcinoma) in whom H. pylori isolates were tested for the other H. pylori virulence factors discussed above. On multivariate analysis, only oipA status remained an independent predictor of H. pylori density, mucosal inflammation, and high mucosal IL-8 levels. However, the actual biological significance of these observations is unknown. Adaptation to gastric conditions is enabled by phase variation of genes encoding outer membrane proteins [50,51].

INFLAMMATORY RESPONSE — Although H. pylori is a noninvasive organism, it stimulates a robust inflammatory and immune response [52,53]. A variety of factors may contribute to these changes, which are described below. Bacterial colonization, persistence and virulence, and resulting innate and adaptive host immune responses are all important in the pathogenesis of H. pylori related disease [7,54,55].

●The organism produces a number of antigenic substances, including heat shock protein, urease, and lipopolysaccharide, all of which can be taken up and processed by lamina propria macrophages and activate T-cells [53,56]. Cellular disruption, especially adjacent to epithelial tight junctions, undoubtedly enhances antigen presentation to the lamina propria and facilitates immune stimulation. The net result is increased production of inflammatory cytokines such as IL-1, IL-6, tumor necrosis factor-alpha (TNF-alpha), and most notably, IL-8 [36,52,57,58]. (See 'Interleukin-8 and other cytokines' below.)

●A B cell response to H. pylori (with production of IgG and IgA antibodies) occurs locally in the gastroduodenal mucosa and systemically. The role of local antibodies in producing tissue injury or modulating inflammation in H. pylori infection remains controversial [52,53]. Prolonged stimulation of gastric B cells by activated T cells can lead to MALT lymphoma in rare cases. (See "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

T cells are also activated during infection and their cytokines boost bacterial binding (by inducing class II MHC). While T cells are recruited to the infected gastric mucosa, they appear to be hyporesponsive. B7-H1 (programmed death-1 ligand 1), a member of B7 family of proteins associated with T cell inhibition, appears to be involved in the suppression of T cell proliferation and IL-2 synthesis during H. pylori infection, and thus may contribute to its chronicity [59].

Different T helper cell subsets can be distinguished by characteristic profiles of cytokine secretion. Th1 cells promote cell-mediated immune responses through elaboration of TNF-alpha and IFN gamma. Th2 cells produce Il-4, IL-10 and TGF beta. It appears that during H. pylori infection the T-cell immunity is inappropriately skewed toward a Th1 response that promotes epithelial cell inflammatory cytokine production (IL-8 stimulated by IFN gamma and TNF-alpha) and directly impacts epithelial apoptosis [60,61].

●H. pylori infection induces a marked increase in the flux of leukocytes and in the appearance of platelet and leukocyte-platelet aggregates in gastric venules in a murine model [62]. Circulating platelet aggregates and activated platelets were also detected in patients infected with H. pylori, suggesting that platelet activation and aggregation contribute to the associated microvascular dysfunction and inflammatory cell recruitment. Platelet aggregation mediated by an H. pylori interaction with von Willebrand factor is speculated to contribute to infection related ulcer disease but also possibly non-GI manifestations of infection such as cardiovascular disease and idiopathic thrombocytopenia [63,64].

●Not all H. pylori infected individuals develop clinical disease. Host genetics are important in determining the physiologic and clinical response to infection [65]. Host polymorphism of IL-1 beta (and possibly IL-10) appears to determine the degree of inflammatory response to infection, resulting alteration in acid secretion (hyper or hypo secretion), and risk for subsequent gastric cancer [66,67]. One series of meta-analyses investigated genes coding for the interleukin (IL) proteins (IL1B, IL1RN, IL8, and IL10) and for TNF-alpha. Gastric cancers were stratified by histologic subtype and anatomic subsite, by H. pylori infection status, by geographic location (Asian or non-Asian study population), and by a quantitative index of study quality. Results consistently supported increased cancer risk for IL1RN2 carriers; the increased risk was specific to non-Asian populations and was seen for intestinal and diffuse cancers, distal cancers, and, to a lesser extent, cardia cancers. In Asian populations, reduced risk was observed in association with IL1B-31C carrier status. These results indicate the importance of stratification by anatomic site, histologic type, H. pylori infection, and country of origin. Study quality considerations, both laboratory and epidemiologic, can also affect results and may explain, in part, the variability in results published to date [68].

Interleukin-8 and other cytokines — Research has centered on epithelial IL-8 production induced by different strains of H. pylori [36,69]. IL-8 is a potent chemotactic factor, activates neutrophils, and recruits acute inflammatory cells into the mucosa. H. pylori appears to activate transcription factor NF-kB (nuclear factor kappa B), which in turn increases IL-8 production [35,70]. NF-kB also regulates the expression of additional inflammatory response genes, and may play a role in the mucosal epithelial response to other bacterial infections in addition to H. pylori.

Bacteria that express CagA and VacA are more potent inducers of IL-8; however, the gene primarily responsible for IL-8 induction is picB (now renamed CagE), which is located upstream of the CagA gene [34]. CagA/VacA-positive strains are also more often found in patients with clinical manifestations of H. pylori infection, indirectly suggesting that IL-8 may play an important pathophysiologic role in gastroduodenal disease.

TNF-alpha can also augment IL-8 production by the inflamed mucosa. Following successful eradication of H. pylori, mucosal levels of mRNA for both TNF-alpha and IL-8 are reduced in parallel with the decline in local inflammation [71].

H. pylori infection increases IL-17 in the gastric mucosa of humans and experimental animals. IL-17 induces the secretion of IL-8 by activating the ERK 1/2 MAP kinase pathway. IL-23 is also increased in patients with H. pylori related gastritis and regulates IL-17 secretion via the STAT3 pathway. The early events in the immune response of immunized and challenged mice include the recruitment of T cells and the production of IL-17. Neutrophil attracting chemokines are released, and the bacterial load is considerably reduced [72]. IL-17 plays a dual role in infection and vaccination. In infection, T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL-17, thereby favoring bacterial persistence. Immunization produces Helicobacter-specific memory T-helper cells that can possibly alter the ratio between T-helper 17 and Treg responses so that the IL-17-driven inflammatory reaction can overcome the Treg response leading to bacterial clearance [72].

Virulent H. pylori strains that specifically activate signaling in epithelial cells via the innate immune molecule, nucleotide oligomerization domain 1 (NOD1), are more frequently associated with IFN-gamma-dependent inflammation and with severe clinical outcomes (ie, gastric cancer and peptic ulceration). H. pylori activation of the NOD1 pathway causes enhanced proinflammatory signaling in epithelial cells in response to IFN-gamma stimulation through the direct effects of H. pylori on two components of the IFN-gamma signaling pathway, STAT1 and IFN regulatory factor 1 (IRF1) [73].

Survival of H. pylori — H. pylori itself is in part able to survive this inflammatory onslaught by producing the enzyme, catalase. This enzyme neutralizes the damaging reactive oxygen metabolites liberated by neutrophils [19]. With time, the host appears to downregulate the acute inflammatory response, making it easier for the organism to persist and proliferate [74].

ANTIBODY RESPONSE — Most infected individuals systemically produce specific antibodies to a variety of H. pylori antigens. The antibody response changes as infection progresses from an acute to a chronic stage [75].

●Detection of IgM antibodies is an insensitive indicator of acute infection and generally is not clinically useful, even in children [76].

●IgA and IgG antibodies are produced in response to infection, remain present as long as infection is active, and quantitatively decrease after infection is cured [77].

●Antibodies to CagA protein are detectable in gastric tissue and serum and permit the identification of infection with presumably more virulent organisms [78].

The role of local antibodies in the immunopathogenesis of gastroduodenal mucosal injury is unclear [52]. Virtually all infected persons have a specific gastric mucosal IgA and IgG response. IgA antibodies may modulate mucosal injury by inhibiting antigen uptake, disrupting bacterial adherence and motility, and neutralizing various toxins. IgG presumably augments inflammatory injury by activating complement and facilitating neutrophil activation.

An antibody response may also be seen against autoantigens, including IL-8 [79], antral epithelium [80,81], and homologous host and bacterial epitopes (eg, LewisX, lipopolysaccharide, and heat shock protein) [52]. The immunoglobulin specificity of MALT lymphoma may be for such autoantigens [82].

VACCINATION — While the mucosal immune response to H. pylori leads to tissue injury, it is also key to vaccination strategies [72,83,84]. One could question if effective vaccination is possible since the organism can successfully evade the immune response to natural infection [85]. Nevertheless, preliminary studies suggest that preventive vaccination may be feasible. Immunization with crude sonicates of bacteria [86,87] and recombinant subunits of urease [88,89] and catalase [90] protect animals from H. pylori exposure. Human vaccines have undergone [89,91] and continue to undergo clinical testing [92]. In a randomized phase 3 vaccine trial, 4464 H. pylori uninfected children (ages 6 to 15 years) were assigned to a three-dose oral recombinant H. pylori vaccine or placebo [93]. The vaccine contained fusion proteins composed of the B subunits of H. pylori urease and heat-labile toxin of Escherichia coli. At one year, the incidence of H. pylori infection was significantly lower in the vaccine group as compared with placebo (0.7 versus 2.4 events per 100 person-years), with a vaccine efficacy of 72 percent (95% CI 48.2-85.6). Among patients who completed extended follow-up, H. pylori acquisition continued to be lower in vaccinated as compared with unvaccinated children, but protection levels were lower in the second and third year (vaccine efficacy 55 [95% CI 0.9-81.0] and 56 [95% CI -24.7-86.2] percent, respectively). There were no serious adverse events related to the vaccine. Additional studies with long-term follow-up are needed to validate these results.

Studies on vaccination have expanded to the area of therapeutic immunization [85,94]. A therapeutic vaccine could boost the natural immune response and facilitate spontaneous bacterial eradication or enhance the effectiveness of antibiotic regimens. A successful therapeutic vaccine would obviate the widespread use of antibiotics and minimize the development of antibiotic-resistant H. pylori organisms. Unfortunately, the promise of vaccines has not been met after more than two decades of research. A renewed or expanded commitment to exploit advances in our understanding of the host immune response to H. pylori is necessary for the advancement of an H. pylori vaccine [95].

SUMMARY AND RECOMMENDATIONS

●The pathophysiology of H. pylori infection and its eventual clinical outcome should be viewed as a complex interaction between the host and the bacterium. This interaction is influenced by the environment and modulated by a number of largely as yet unidentified factors.

●Tissue injury induced by H. pylori depends upon bacterial attachment and the subsequent release of enzymes and other microbial products that can cause cellular damage. (See 'Bacterial factors' above.)

●Functional differences exist between strains of H. pylori that may relate to virulence and tissue damage. However, many of the virulence factors can coexist in the same H. pylori strains, making it unclear as to which factors might be most important. (See 'Bacterial strain differences' above.)

●Although H. pylori is a noninvasive organism, it stimulates a robust inflammatory and immune response. Bacterial colonization, persistence and virulence, and resulting innate and adaptive host immune responses are all important in the pathogenesis of H. pylori related disease. (See 'Inflammatory response' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sheila E Crowe, MD, FRCPC, FACP, FACG, AGAF, who contributed to an earlier version of this topic review.