Chapter 39Host Inflammatory Response to Infection

Wang J, Blanchard TG, Ernst PB.

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Much has been written about the host and microbial factors that have an impact on the pathogenesis of gastroduodenal disease associated with Helicobacter pylori infection. One remarkable feature of the infection is that it persists throughout the life of the host in the face of a significant inflammatory response. Thus, the species has found a niche in which it can thrive despite obvious host responses that have the potential to confer antimicrobial effects. In effect, H. pylori has "domesticated its host" (44). The relative ability of H. pylori to circumvent the various host defense mechanisms tends to be ignored. Many of the hypotheses explaining the persistence of an infection with H. pylori are difficult to prove, thereby relegating discussions on the subject to an exercise in arm waving. Nonetheless, the topic has direct implications for our understanding of the immunobiology of H. pylori and the development of strategies to modify the host response artificially in order to improve human health.

Normally, there are several layers of innate and adaptive responses that contribute to the protection of the host. This complementation is essential because total reliance on an individual factor jeopardizes the survival of a species as a single mutation may prove to be lethal. This review will consider some of the challenges from the various layers of the host response to which H. pylori must adapt in order to survive in the gastric niche. The outcome of a persistent infection interacting with a chronic inflammatory response will be discussed in the context of the survival of the organism and the impact this may have on the host.

The Interactions between H. pylori and the Host Regulate Colonization and Pathogenicity

To guarantee the survival of the species, bacteria must evolve to ensure continued carriage and viability so that they may be disseminated into other hosts (44). Microbial factors are important in facilitating colonization and in allowing the infection to localize in a specific niche. Subsequently, these infectious agents are described as being commensals or pathogens based on the interactions among the host, a microbe, and environmental factors. Falkow has stated that avoiding the immune response is an important property contributing to pathogenicity (24). This is particularly relevant for H. pylori since it is not a highly infectious organism and humans appear to be the major reservoir. Clearly, if H. pylori did not evade host responses in order to create a chronic infection in humans, transmission and survival of the species would be compromised. However, as discussed below, the pervading immune response that permits persistent infection also has the ability to contribute to gastroduodenal disease.

Accommodation to Innate Mechanisms Protecting the Stomach

An infection introduced into the digestive tract must immediately deal with antimicrobial factors that exist in the mucous secretions of the oral cavity and stomach. Saliva has been shown to possess antiviral and antibacterial activity (50, 74). In fact, some studies have suggested that saliva may also have a protective activity against H. pylori (69). Unfortunately, antimicrobial activity in saliva is too poorly defined to speculate how H. pylori may cope with it. Suffice it to say that the transit time through the oral cavity is so brief that the greater challenge to H. pylori is probably found in the gastric microenvironment.

The mucus overlaying the gastric epithelium provides an "antiseptic paint" containing antibodies and antimicrobial factors such as lactoferrin and lysozyme that protect mucosal tissues. To help circumvent this barrier, H. pylori expresses molecules that are mucolytic. This property, along with the presence of flagella, allows H. pylori to penetrate the mucous layer and become situated adjacent to the epithelial cells.

The nonspecific protective molecules such as lactoferrin, lysozyme, and defensins found within mucosal secretions are receiving an increasing amount of attention in research laboratories (59, 60, 62). Recent reports demonstrating the presence of these soluble innate defense factors in the H. pylori-infected gastric mucosa imply that H. pylori may also possess mechanisms to evade their antimicrobial effects. However, to date, our understanding of the expression, function, and interaction of these molecules with H. pylori in the stomach is limited. Again, this ignorance makes it difficult to appreciate how H. pylori can cope with this particular antimicrobial barrier.

While the mucous barrier provides a level of protection against microbial colonization, the most obvious innate mechanism affording antimicrobial protection in the stomach is the gastric acid. This is one area of adaptation by H. pylori that has been elucidated in detail. As discussed elsewhere in this book, H. pylori has evolved to produce a urease enzyme that possesses specific activity at the low pH found in the stomach. This enables the bacteria to buffer the environment around the organisms by converting urea into ammonia (52, 53). This enzymatic activity is complemented by an elaborate biochemical machinery that optimizes the specific activity of this enzyme (51, 52). Clearly, the presence of the urease enzyme that is functional at a low pH represents a vital step in the evolution of H. pylori in order to permit successful colonization in the acidic environment.

Another feature of the gastric microenvironment that may favor the initial survival of H. pylori is the relative absence of immune and inflammatory cells in the uninfected, normal gastric mucosa. The absence of these effector cells of immunity may be attributed to the fact that few microbes can cope with the innate protection provided by gastric acid. The absence of readily available inductive sites and effector cells could provide the time required for H. pylori to expand and to establish a persistent infection.

Accommodation to Adaptive Responses by H. pylori

Having evaded the innate responses, the bacteria must then deal with the adaptive responses mediated by B and T lymphocytes. There are two major mechanisms by which H. pylori could cope with adaptive responses. First, infection could impair these responses. Second, infection could stimulate a response that fails to confer immunity and may even facilitate survival. The B- and T-cell responses will be discussed separately.

B cells

Once H. pylori infection is established, it is clear that B-cell responses are stimulated. Not only is the number of B cells increased, but also antibody levels are increased in the gastric juice, and antigen-specific antibodies have been identified in the mucosa, gastric juice, and the serum (10, 11, 39, 76, 82). Thus, it seems unlikely that a significant anergy or antigen-specific tolerance is induced in the B-cell population.

Gastric antibodies may be ineffective at limiting the infection for several reasons that are more obvious when one considers how antibodies usually confer protection. First of all, antibodies could bind an organism and facilitate its death and/or clearance by enhancing phagocytosis. In the lumen, this mechanism of antibody-mediated protection seems unlikely since there are very few white cells in the lumen. Hence, the predominant B-cell response in mucosal tissues has adapted to produce secretory IgA and perhaps IgM that can be transported into the lumen to provide an offshore defense by blocking microbial attachment or neutralizing toxins. In so doing, these antibodies might disrupt the microenvironmental niche sufficiently such that an acute infection by a pathogen can be terminated by the overgrowth with a commensal. However, in the stomach, rarely are any other microbial species found that could compete with H. pylori for the niche. Furthermore, since it is likely that H. pylori uses several different host receptors, an antibody response to one ligand would likely be insufficient to block attachment and deter colonization. This situation could be confounded further if the antigenicity of the infection changed due to shifts in the dominant strain within a mixed infection of several distinct strains or by gene mutations that eventually alter the structure of surface molecules on the bacteria.

While mucosal antibody may enhance protection, it may not be sufficient or even necessary. For example, people with IgA deficiency have not been described as having an increased frequency of H. pylori infection compared to subject with normal IgA levels. Furthermore, the ability to reinfect patients and animals with helicobacter organisms shortly after infection was cured with antibiotics, despite the presence of antibodies generated to the initial infection, may be evidence that antibody does not play a meaningful role in defending against colonization (28, 43). Moreover, studies in mice have shown that immunity to Helicobacter spp. can be induced in the absence of B cells (9, 21). Thus, H. pylori must also circumvent other local protective mechanisms.

T cells

Overview of T-cell heterogeneity

Before discussing how H. pylori may have adapted to cope with the host T-cell response, it is important to review some aspects of T-cell biology and their role in the regulation of immunity. Although significant advances have been made in our understanding of immune regulation in the gastrointestinal tract, new evidence suggests it is even more complex than previously thought. Helper T-cell (Th) responses have been viewed as primarily belonging to one of two major subsets, Th1 or Th2, on the basis of their cytokine profile. Through the production of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2), Th1 cells select for a rather specific panel of immune responses, including cell-mediated immunity, while Th2 cells preferentially regulate mucosal IgA responses through the production of transforming growth factor β (TGF-β), IL-4, IL-5, IL-6, and IL-10 (83).

This model is a vast oversimplification of the complex processes regulating multiple genes in Th cells (38) that are now becoming better appreciated. For example, a subset of Th cells that produces TGF-β and inhibits the host response to antigens that persist in the lumen has been referred to as Th3 cells (33). More recently, investigators have described a subset of helper T cells that produce copious amounts of IL-10 and are capable of preventing colitis in a model of aberrant immune regulation to luminal microbiota (30). What these models suggest is that defining T-cell phenotype based on a limited number of cytokines misses important changes in the overall T-cell response. Complicated inter- and intracellular signaling mechanisms will dictate the T-cell phenotype based on the expression or repression of dozens of cytokines of immune effector molecules. In the case of controlling the host response to luminal antigens, it appears that a cell differing from the Th1 or Th2 cell, perhaps a Th3 cell, Tr1 cell, or some hybrid, will be important (Fig. 1).

Figure 1. Helper T cell heterogeneity.

Figure 1

Helper T cell heterogeneity. One of the major immune regulatory mechanisms is the input of helper T cells. As illustrated here, various subsets of Th cells have been described on the basis of their respective cytokine panel. Th1 cells are generally considered (more...)

Gastric T-cell responses

In the context of the stomach, there are not many T cells in the normal tissue. However, the ones that are present appear to be biased toward the Th1 phenotype. This conclusion is based on the fact that IL-12, a major cytokine that selects for Th1 cells, is found in the uninfected stomach (31) along with Th cells that produce cytokines associated with Th1 cells (4). In response to infection with H. pylori, the number of T cells increases and the phenotype is still predominantly Th1 (4, 18, 19, 31, 34, 36, 70). The fact that Th1 cells predominate in uninfected stomach, infected stomach, as well as in association with other causes of gastric inflammation including nonsteroidal anti-inflammatory drug (NSAID)-induced gastritis (36) suggests that the immunological environment in the stomach is overwhelmingly biased toward this type of T-cell response. Thus, in addition to any effects H. pylori may have on the selection of Th1 cells, this species of bacteria may also have chosen a niche in which the host response is already biased toward Th1 responses that cannot orchestrate the clearance of the infection.

Circumvention of protective T-cell responses by H. pylori

There is relatively little direct evidence to explain how H. pylori may deflect the ability of T cells to stimulate a protective immunity. It has been suggested that the bacteria may adapt their immunogenicity by acquiring the ability to express antigens that mimic their host. For example, the Lewis antigen phenotype of H. pylori has been reported to mirror that of the host (80). It is possible that these antigens stimulate local T cells, for example, Th3 or Tr1 cells (see Fig. 1), to secrete "anti-inflammatory" cytokines that could attenuate the reactivity of immune or inflammatory cells in the adjacent vicinity. That is, a small population of T cells that confer tolerance may be activated and impair the immune reactivity of other T cells around them (66). However, the cytokine analyses described to date have not supported this model, since most of the cytokines induced during infection are inflammatory rather than anti-inflammatory (23). The presence of an ineffective T-cell response suggests that the selection of a very limited T-cell subset facilitates persistent infection by H. pylori. Indeed, as discussed below, a Th1 response is far more likely to have adverse effects on the host and actually contribute to gastroduodenal disease.

Another possibility is that a natural infection with H. pylori may selectively inhibit antigen-specific responses. Studies have suggested that the VacA protein produced by H. pylori can impair the ability of antigen-presenting cells to process antigens in the manner required for optimal T-cell activation (55). In addition to disrupting immunogenicity, infection may also directly inhibit T-cell growth (25, 35, 41). This notion is supported by recent studies describing the ability of H. pylori to induce death in T cells through Fas-FasL interactions (J. Wang et al., manuscript submitted). Interestingly, the induction of apoptosis was restricted to H. pylori bearing the cag pathogenicity island (cag PAI) and was not observed with cag PAI-deficient strains or Campylobacter jejuni, suggesting that it is a specific mechanism of immune evasion. Since cag PAI-bearing strains predominate in humans, it is tempting to speculate that this ability to induce apoptosis in T cells confers a selective advantage that complements other mechanisms favoring the persistent growth and survival of these strains. Although T cells recognizing the CagA protein have been cloned (19), it is possible that other molecules transported by a type IV secretion engine encoded by the cag PAI account for the T-cell death. Thus, T cells recognizing CagA or other antigens can be stimulated during natural infection, but gaps in the T-cell receptor repertoire may exist and limit the development of protective immunity. Consequently, many of the gastric T cells induced in response to infection may be nonspecifically recruited and incapable of orchestrating protective immunity to the natural infection.

The Role of the Host Response in the Pathogenesis of Gastroduodenal Disease

Whereas strains of H. pylori expressing the cag PAI may have an advantage in avoiding a protective response, they stimulate greater levels of gastric inflammation than strains lacking the cag PAI (63, 84, 85). Thus, any association between strains bearing the cag PAI and disease may be governed by the variation in the host response to infection in general and against these strains in particular.

Several experimental approaches have illustrated the principle that the host immune or inflammatory response contributes to disease caused by gastrointestinal infections (Table 1). For example, impeding the host response can attenuate acute disease caused by infection. Pothoulakis and colleagues have shown that the administration of antibodies that impair the homing of immune or inflammatory cells to the gut prevents the manifestation of diarrhea caused by infection with Clostridium difficile (37). Other studies have shown that antibodies neutralizing TNF-α can block intestinal pathology caused by infection with Salmonella spp. (G. Jackson, personal communication). Even cholera toxin cannot exert its pathogenic effect without an intact host response, as administration of the toxin to mice deficient in stem cell factor or its receptor does not induce fluid accumulation in the intestinal lumen (40). Thus, the host response must be considered an essential element of microbial pathogenicity in the digestive tract.

Table 1. Evidence favoring a role for the host response in defining microbial pathogenesis.

Table 1

Evidence favoring a role for the host response in defining microbial pathogenesis.

If the host response contributes to pathogenicity, then it is possible to extend the notion that it can actually define pathogenicity. For example, several experimental models have shown that disruption of the delicate balance in immune regulation renders the otherwise innocuous luminal microbiota extremely dangerous (64). Deletion of the genes encoding IL-2, IL-10, the T-cell receptor alpha chain, class II major histocompatibility complex (MHC), as well as TGF-β resulted in the spontaneous development of colitis in these animal models (42, 56, 73). Subsequently, it was shown that Th1 responses were overrepresented in these animals. On the basis of this, it was predicted that manipulating genes encoding receptors for these cytokines or disrupting signaling mechanisms that favored Th1 development also led to colitis (71, 81). In most of the models tested, disease is completely prevented by housing the animals in germ-free conditions. Therefore, colitis was not due to the introduction of a new pathogen per se, but, rather, the altered immune response rendered some element of the normal microbiota pathogenic. In essence, the host response defined the pathogenicity of the organisms. The same model can be applied to H. pylori. In fact, studies employing Helicobacter felis infection of mice, a murine model for helicobacter-associated gastritis, have revealed that in the absence of T cells the inflammation is minimal to nonexistent (8, 67). Thus, for H. felis infection at least, T cells are actually required for the promotion of disease and therefore actually can define the pathogenicity of the organism.

The Host Response Enhances H. pylori Colonization

While a host response that cannot clear an infection provides an obvious benefit to a pathogen that depends on chronic infection, it is also feasible that the organism benefits more directly from the cytokine profile associated with the infection. For example, it has been suggested that human immunodeficiency virus (HIV)-infected patients may have a lower prevalence of H. pylori infection than expected (49). This phenomenon could be due to antibiotic treatment of HIV-infected subjects, discrepancies between techniques in diagnosis in HIV-infected or uninfected subjects, or changes in gastric acid in HIV-infected patients. However, anecdotal reports suggest that biopsy-confirmed diagnosis in HIV-infected subjects in Africa who have not had the benefit of antibiotics shows that they still have a lower than expected prevalence of H. pylori infection. If true, it may be possible that gastric T-cell responses facilitate the survival of H. pylori.

One mechanism by which the host response could facilitate the infection is by increasing the expression of bacterial receptors. It is counterintuitive to suggest that some selective advantage will be conferred to a host by producing molecules for the express purpose of binding pathogens. Rather, a pathogen evolves to accept whatever hand it is offered.

Class II MHC molecules are expressed by the epithelial cells in the neck region of the antrum in the uninflamed stomach. Studies have shown that binding of H. pylori to gastric epithelium, either cell lines or freshly isolated gastric epithelial cells, is directly associated with these molecules (26). Moreover, the H. pylori urease is capable of binding to class II MHC directly (27), thus sharing this property with other bacterial and viral superantigens. While the distribution of class II MHC molecule expression is restricted in the uninflamed stomach, the expression is increased by the host response. In fact, expression in gastritis is seen to spread up and down the gastric pit unit and extends from the antrum to the corpus (20, 75). As it has been suggested that initial infections begin in the antrum and spread to the corpus, it is possible that the apical expression of class II MHC is more than a coincidence but also one factor that enhances colonization. Since the class II MHC molecules are regulated by inflammatory cytokines present during infection, including TNF and IFN-γ, the type of inflammatory response triggered by H. pylori may actually select for increased binding and thereby favor colonization (26). Thus, the inflammatory response triggered by H. pylori may augment the access of the bacteria to receptors on the host cells. Whether other putative receptors for H. pylori are similarly regulated by the host response remains to be determined.

An additional benefit of inflammation to the infection could be the effect of the host response on tissue damage. Disruption of epithelial cell junctions, leakage from blood vessels, and access to interstitial fluids may provide a source of nutrients that enhances the growth of H. pylori (32).

Consequences of T-Cell Subset Selection on Gastroduodenal Disease

The selection of a relatively homogeneous Th1 response prevents the host from taking advantage of the broad, complementary mechanisms of protection that might be afforded by a mixed Th1 and Th2 response. Since the Th1 response cannot clear the infection, the gastric mucosa will be subjected to a lifelong battering by the bacteria and the host response. Since Th1 responses are manifest by cell-mediated immunity, local cells, such as the epithelium, are particularly vulnerable to immune-mediated attack (7, 22). These responses directed against the epithelium could create an immunological scenario that resembles the pathogenesis of more classical autoimmune diseases (45). This notion is supported by recent observations showing that treating H. felis-infected mice with neutralizing antibodies recognizing IFN-γ markedly attenuated gastric inflammation. These results suggest that Th1 cells contribute to the magnitude of the inflammatory response following infection with helicobacter (54). Thus, the inappropriate regulation of the host response to luminal microbiota is paramount in determining whether a host will develop protective immunity or chronic inflammation.

Th1 cells and the associated cell-mediated immunity may be tolerable when kept under control, but an overwhelming Th1 response, in combination with host genetics, specific strains of bacteria, and other environmental factors, could contribute to epithelial cell damage and ulcerogenesis. This idea is supported by data suggesting that Th1 clones were obtained at higher frequency from the mucosa of patients with duodenal ulcers (18); however, as described above, gastric T-cell responses in uncomplicated gastritis appear to be predominantly of the Th1 type. Further definition of the role of T cells in tissue damage will be required before definitive conclusions can be made regarding their role in gastroduodenal disease. Nonetheless, the evidence to date clearly shows that they are incapable of conferring protection and likely contribute to tissue damage.

Th1 cells can cause cell death in gastric epithelial cells through apoptosis (78) as well as increase the apoptosis caused by H. pylori (26, 78). One explanation for the augmentation of apoptosis by IFN-γ is the increase in the expression of receptors for H. pylori as described above. Thus, T cells producing IFN-γ may increase the bacterial load as well as facilitate the delivery of additional "hits" by H. pylori. Additional intercellular interactions between epithelial cells and T cells mediated by Fas-Fas ligand interactions also contribute to apoptosis of epithelial cells (68, 79). This process may be important in regulating cell death and eliminating malignant cells, but it could also induce breaks in the epithelial barrier that create erosions that lead to ulcers (48).

Other Mechanisms of Immune-Mediated Gastric Damage

Th1 cells not only impart damage to the epithelium directly, but also are capable of increasing the recruitment and activation of neutrophils, B cells, mast cells, and macrophages that have already been shown to be capable of damaging gastric structure and function (2, 1315, 22, 57) (Fig. 2).

Figure 2. Immune-mediated epithelial cell damage.

Figure 2

Immune-mediated epithelial cell damage. This figure shows the various means by which the gastric Th1 cells may mediate epithelial cell damage. First, through the direct effect, Th1 cells can induce epithelial cell death. T-cell-derived cytokines can also (more...)

The importance of B cells in the pathogenesis of gastritis is based on evidence that monoclonal antibodies directed against H. pylori could recognize an epitope on the gastric epithelium of mice and humans (reviewed in reference 2). Moreover, administration of these antibodies to mice resulted in gastritis and caused mild erosions (61). More recently, it has been shown that antibodies to H. pylori lipopolysaccharide cross-react with antigens on epithelial cells (3). In humans, it appears that there is an antibody response to the H+,K+-ATPase in the gastric parietal cell that is driven by H. pylori infection. However, no cross-reactivity between H. pylori and the H+,K+-ATPase has yet been identified (2). Other studies have shown that IgM antibodies produced from immortalized B cells obtained from the gastric mucosa recognize the gastric epithelium (76).

Additional evidence suggests that B cells within a MALToma express a repertoire that recognizes a determinant shared by both IgA and IgM (29). Thus, antibodies within the gastric mucosa may recognize epithelial cells or act as rheumatoid factors. This could lead to immune complex-mediated disease that directly damages the epithelium. This hypothesis is supported by the observation that activated complement is found adjacent to gastric epithelium during infection (6). While anti-H. pylori antibodies cross-reactive with host molecules may contribute to the gastric pathology associated with infection, it has been demonstrated, at least in mice, that lack of immunoglobulins does not diminish gastritis following infection with H. felis (9).

In addition to the inflammation caused by auto-reactive lymphocytes, activated neutrophils, macrophages, or even mast cells (58) could contribute to tissue damage. It is interesting to note that "virulent" type I strains of H. pylori have recently been described as resistant to killing by macrophages following phagocytosis (1). This study suggests yet another possible immune evasion mechanism of H. pylori and might help explain the ability of this bacterium to persist in the face of a robust inflammatory response.

The presence of cells from both the acute and chronic aspects of the inflammatory response can be explained by the stimulation of neutrophil chemokines by other cytokines produced by mononuclear cells (86). A classic example is IL-8. Throughout most of the infection with H. pylori in adults, IL-8 levels can be detected in the gastric mucosa, particularly in the epithelial cell layer (16), and the IL-8 response by the gastric epithelium is boosted by the Th1-derived cytokines IFN-γ and TNF-α (86). This chemokine is particularly specific for neutrophils and likely accounts for the "active" component that is mixed with the infiltrate associated with chronic gastritis.

One can easily imagine the damage activated neutrophils and other leukocytes can cause. Neutrophils are able to migrate across the epithelium and, in so doing, disrupt the epithelial cell permeability (46). In addition, the secretion of mediators from neutrophils or mast cells, such as histamine (17), proteases (77), adenosine (47), or H2O2, (5), can also modify the barrier and/or ion transport function of epithelial cells. Reactive oxygen and nitrogen species from neutrophils and macrophages can also induce cellular damage including apoptosis and DNA injury (12). Thus, the longer the exposure of a tissue to activated immune or inflammatory cells and mediators, the more cellular damage may accumulate.


Since humans are believed to be a major reservoir for H. pylori, the continued survival of the bacterial species depends largely on human-to-human transmission. H. pylori is not as easily transmitted as other pathogens such as rotavirus; therefore, persistent infection would increase the chance that the infection can be disseminated. On the basis of the discussion above, it appears that H. pylori has selected a niche that favors survival based on many factors, including the inability of gastric innate or adaptive responses to clear a natural infection. Further favoring the persistent infection of humans is the fact that bacterial virulence factors are sufficiently attenuated to avoid the premature death of most infected hosts. Together, these aspects of the host-bacterial interaction ensure continued carriage of viable organisms so that dissemination of H. pylori and its continued existence would not be compromised. Unfortunately, the persistent infection and typical Th1-driven host response to H. pylori contribute to epithelial damage and gastroduodenal disease. However, this dependence on a particular immune response to favor survival may also become an Achilles' heel, as vaccines that artificially modify the gastric immunological milieu may enable the infection to be cleared or the adverse consequences of infection to be attenuated.


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