H. pylori Infection induces Autoantibodies to Gastric Mucosal Antigens

A considerable number (50 to 60%) of H. pylori-infected patients have serum autoantibodies that are reactive with gastric mucosal antigens (27–29, 52, 53, 67). When sera of H. pylori-infected subjects are screened for autoantibodies reacting against human gastric tissue by immunohistochemistry, two different binding sites for these autoantibodies can be detected (27, 28); first, on the luminal membranes of the foveolar epithelial cells in the antrum and corpus mucosa, and second, on the canalicular membranes of parietal cells (Fig. 1) in the gastric corpus mucosa.

Figure 1

(A) Immunoreactivity of anticanalicular autoantibodies on canalicular membranes within parietal cells of the human gastric corpus mucosa (by immunohistochemistry; original magnification × 20). H. pylori-infected patient serum reacts with a section (more...)

Parietal cells in the corpus secrete gastric acid via the proton pump, i.e., the gastric H⁺,K⁺-ATPase, which is found in the apical secretory canaliculi. Recently, the gastric H⁺,K⁺-ATPase has been identified as the single major autoantigen in chronic H. pylori gastritis with corpus atrophy (15). Whereas in animals H. pylori infection induces autoantibodies through mimicry via Lewis antigens on the gastric proton pump (reviewed in reference 5), in humans this is not the case. Human sera react with recombinant H⁺,K⁺-ATPase that does not express Lewis antigens (15).

Clinical Relevance of Anticanalicular Autoantibodies in H. pylori Gastritis

Because of the high prevalence of antigastric autoantibodies in H. pylori infection, several studies have been aimed to analyze the clinical relevance of these autoantibodies. The major goal of these studies was to determine the impact of autoantibodies on the clinical course of H. pylori gastritis and hence to characterize those patients at a higher risk for a certain long-term complication of the infection. Whereas both antiluminal and anticanalicular antibodies are significantly associated with H. pylori infection, only the presence of anticanalicular antibodies is significantly correlated with histological change, several clinical parameters, and the functional state of the gastric mucosa in H. pylori gastritis (28).

Through conventional histomorphological parameters of chronic H. pylori gastritis such as grade, activity, and distribution of gastritis, as well as the presence of glandular atrophy and intestinal metaplasia (see Table 1), it has been found that gastritis in the corpus mucosa was more severe in patients with anticanalicular autoantibodies than in patients without these types of autoantibodies (28, 53). Furthermore, it has been shown that atrophy in the gastric corpus mucosa also correlates with anticanalicular autoantibodies (27, 28, 53). These findings are paralleled by the demonstration of a significantly increased apoptosis in the glandular epithelium of the corpus mucosa, whereas apoptosis in the foveolar epithelium of the corpus or apoptosis in the antrum is not related to antigastric autoimmunity (66). Therefore, it is concluded that the development of gastric atrophy in H. pylori gastritis is caused by an autoimmune attack against the gastric glands, leading to an increased rate of cell death. Furthermore, the mucosal alterations that are associated with anticanalicular autoreactivity are found in that compartment of the stomach where these autoantibodies show their in situ binding sites, i.e., in the corpus mucosa but not in the antrum.

Table 1

Evidence for the clinical relevance of antigastric autoimmmunity in H. pylori gastritis.

Analyses concerning the fine-specificity of anticanalicular autoantibodies reveal not only that the gastric H⁺,K⁺-ATPase is the major target of these autoantibodies, but also that those patients with autoreactivity against the α and/or β subunit of H⁺, K⁺-ATPase show the highest prevalence of body mucosa atrophy (15). Although a high interobserver variability in the histological diagnosis of gastric atrophy is documented, the correlation between anticanalicular autoantibodies and gastric atrophy has been shown to be independent from the pathologist involved and has been repeatedly found in different European cohorts (77).

On the basis of histological similarities between corpus atrophy in H. pylori-associated antigastric autoimmunity and glandular atrophy in classical AIG/PA, a number of clinical parameters of gastric mucosa atrophy have been subsequently evaluated. Fasting serum gastrin levels are significantly higher in H. pylori-infected patients with anticanalicular autoantibodies (28, 29). In addition, the pepsinogen I:II ratio, which serves as a sensitive marker for body mucosa atrophy, is significantly lower in infected subjects with anticanalicular autoantibodies (28). Interestingly, it has been shown that the presence of anticanalicular autoantibodies also correlates with a decreased gastric acid output in both infected patients with non-ulcer dyspepsia (29) and those with duodenal ulcer (56).

In both histopathological and clinical characteristics, H. pylori-induced gastritis with anticanalicular antibodies and corpus atrophy resembles to some extent classical AIG/PA. It is therefore speculated that H. pylori represents a causative agent for the development of autoimmune gastritis (5, 26). This concept is further emphasized by the observations that histologically defined early stages of autoimmune gastritis can be successfully treated by H. pylori eradication (68, 69, 75) and, on the other hand, that antigastric autoantibodies decrease after cure of infection (30).

Other observations also indicate an association between H. pylori infection and gastric autoimmunity. A number of studies indicate that a substantial portion of patients with autoimmune gastritis have or have had H. pylori infection (24, 41, 44). Antibodies to H. pylori can be shown in up to 83% of patients with autoimmune gastritis, although actual colonization can rarely be detected. This indicates that a majority of these patients had H. pylori gastritis before the bacteria were cleared by the development of atrophy.

AIG/PA and Experimental Autoimmune Gastritis

Human AIG and experimental murine autoimmune gastritis (EAIG) are similar in that both are characterized by a chronic inflammatory infiltrate in the gastric mucosa accompanied by loss of gastric parietal cells and zymogenic cells. AIG, which leads to PA, affects the fundus and the corpus of the stomach but spares the antrum (74). PA is considered to be the most common cause of vitamin B₁₂ deficiency in Western populations (34). In AIG, autoantibodies to gastric parietal cells are present in the circulation. Anti-parietal cell, anti-intrinsic factor, and antipepsinogen antibodies (46, 47), and occasionally antigastrin antibodies (7), are found in PA. Intrinsic factor is required for the dietary absorption of vitamin B₁₂. The anemic condition in PA is a direct consequence of a decreased intrinsic-factor production, resulting from the loss of parietal cells. Additionally, blocking antibodies present in the gastric juice can prevent formation of the vitamin B₁₂–intrinsic factor complex, and hence absorption of vitamin B₁₂ (74). Clinical characteristics of patients with AIG/PA include hyperplasia of gastrin-producing cells, resulting in high serum gastrin concentration; decreased acid secretion; and decreased pepsinogen I:II ratio. As mentioned previously, this clinical spectrum is also significantly correlated with the presence of anticanalicular autoantibodies in H. pylori infection (28, 29).

Gastric T-Cell and Cytokine Responses in H. pylori Infection

Chronic H. pylori infection induces an inflammatory response in the gastric mucosa, similar to the lymphocytic influx that is observed in AIG and EAIG. Helicobacter-specific cell-mediated immune responses have been extensively studied in humans and in mouse models. The types of cytokines produced during the gastric immune response to H. pylori are able to influence the outcome of Helicobacter infection. The patterns of cytokines that are released during immune responses are characteristic for distinct subsets of CD4⁺ T helper (Th) cells. Th1 cells produce IFN-γ and IL-2 but not IL-4 or IL-5 and promote cell-mediated immunity, macrophage activation, and cytotoxicity, whereas Th2 cells secrete IL-4 and IL-5 but not IFN-γ; induce B-cell activation, differentiation, and production of high levels of antibodies of all isotypes, including IgE; recruit eosinophils and mast cells; and tend to inactivate macrophages (20, 59). IL-4 and IFN-γ exert reciprocal regulatory effects on Th1 and Th2 development, respectively.

The severity of H. pylori-associated gastroduodenal pathologies in both humans and mice depends on the type of immune response upon infection (49). H. pylori-specific CD4⁺ T-cell clones derived from the gastric antrum of infected patients with peptic ulcer (PU) disease have a polarized Th1 profile, whereas gastric antral T-cell clones of patients with uncomplicated chronic gastritis have a Th0 profile; i.e., they are able to secrete Th1 and Th2 cytokines (18, 19). Moreover, increased levels of IFN-γ, TNF α, and IL-12 cytokines are found in the gastric mucosa of H. pylori-infected PU patients (19). Thus, H. pylori-induced uncomplicated chronic gastritis may represent an example of protection exerted by Th2 cytokines against Th1-mediated immunopathology, and this concept is supported by many clinical and experimental observations. It has recently been observed that in kidney graft recipients (usually undergoing strong immune suppression), peptic ulcers and active inflammatory lesions were completely absent, in spite of a high prevalence of H. pylori infection (38). Cyclosporin, used to prevent graft rejection, strongly inhibits almost all T helper effector functions, suggesting that host T-cell responses mediate H. pylori-associated gastric damage. Additionally, during pregnancy (a Th2-dominated condition) patients with PU display significantly reduced symptoms and undergo remission for the time of pregnancy (14).

Many different animal models, such as mice, ferrets, dogs, and cats, have been used for studying Helicobacter infection, and particularly Helicobacter felis-infected mice provided a useful model resembling gastric pathological changes in human H. pylori infection. H. felis infection of B- and T cell-deficient (RAG-1^−/−) mice and T cell-deficient (TCRβδ^−/−) mice (60) and H. pylori infection of SCID mice (23) result in high levels of colonization but no gastric pathology. Infection of B-cell-deficient (μMT) mice results in severe gastric alterations identical with those seen in immunocompetent, infected mice (60). These results demonstrate that T cells, not B cells, nor their secreted antibodies or direct bacterial contact with the mucosa, are the effectors of the immune-mediated gastric damages seen after Helicobacter infection. H. felis infection in C57BL/6 mice induces antigen-specific cellular immune responses (49) that are significantly correlated with the development of Helicobacter-associated gastric pathology (60). On the other hand, in BALB/c mice, which are genetically predisposed to a high IL-4 production in response to different pathogens, H. felis infection induces minimal gastritis despite excellent bacterial colonization (62). In infected C57BL/6 mice, Helicobacter-specific T-cell responses display a predominant Th1 phenotype as shown by the production of IFN-γ, with no detectable production of IL-4 or IL-5, by spleen and gastric lamina propria cells (49). In vivo neutralization of IFN-γ in H. felis-infected mice, through injection of IFN-γ-specific antibodies, dramatically reduces the severity of gastric inflammation, further supporting the contribution of Th1 cellular immune responses in disease pathogenesis (49). As previously described, IFN-γ also plays a key role in onset of EAIG, and induction of this disease can also be abrogated by neutralizing this Th1 cytokine in vivo (9). To investigate the role of distinct CD4⁺ T helper cell subsets in Helicobacter-associated disease, IL-4-gene targeted (IL-4^−/−) mice that lack Th2 cells were infected with H. felis (50). Compared to infected immunocompetent (IL-4^+/+) mice, infected IL-4^−/− mice surprisingly show reduced gastric inflammation but increased bacterial colonization, suggesting that Th1 as well as Th2 responses contribute to gastric inflammation during Helicobacter infection. Adoptive transfer, prior to infection, of H. felis-specific Th1-type spleen cells from infected mice into naive recipients results in enhanced gastric inflammation in recipients (50). However, when an H. felis-specific T-cell line, artificially pushed toward a Th2 phenotype by long-term culture, or bulk spleen cells containing primarily Th1 cells but also a minor population of Th2 cells are adoptively transferred, recipients show significant reduction in bacterial load upon infection (50). Together, these findings suggest that a Th2 response is crucial for the control of harmful Th1 responses, and that an induced Th2 response is down-regulated by the predominantly Th1 response that is found after natural infection with Helicobacter.

Helminthic infection results in a polarized Th2 response (20). The progression of Helicobacter-associated gastritis and gastric atrophy in C57BL/6 mice coinfected with H. felis and Heligmosomoides polygyrus, a murine enteric helminthic parasite, has been recently described (32). Compared to mice infected with H. felis alone, in coinfected mice Helicobacter-associated gastric atrophy is reduced, despite increased colonization. This correlates with a decreased production of Th1 cytokines and Th1-associated chemokines and an increased production of Th2 cytokines in coinfected mice. In Africa, Helicobacter-associated gastric cancer and peptic ulcer rates are lower than those in countries, such as Peru and Colombia, with equally high prevalence rates of H. pylori. Coinfection with helminths, which are endemic in Africa, has been proposed as one possible explanation (17) for this so-called "African enigma" (37).

In summary, the host immune response is an important determinant of Helicobacter-associated disease. In H. pylori infection, a polarized Th1 response correlates with severe gastric pathology, whereas the ability of the host to raise a combination of Th1 and Th2 responses is considered to be protective of destructive H. pylori gastritis.

Gastric Epithelial Cells during H. pylori Infection

The autoantigen recognized by H. pylori-induced antigastric autoantibodies is the gastric proton pump H⁺,K⁺-ATPase (15). Gastric H⁺,K⁺-ATPase is also the major autoantigen in AIG/PA (13, 36, 40, 72) and has been proven to be the target for autoreactive T cells that are responsible for the destruction of gastric epithelium in EAIG (54, 71, 73). Furthermore, H. pylori gastritis patients with anticanalicular autoantibodies develop pathology and symptoms similar to those in AIG/PA patients (26, 28, 29). These observations suggest that a similar autoimmune response, involving parietal cell autoantigens, might be responsible for corpus atrophy in H. pylori gastritis. Although no autoreactive T cells have been reported in H. pylori infection, several findings suggest a role for autoantigen-specific destruction of the gastric glandular epithelium by CD4⁺ T cells in H. pylori infection with gastric corpus atrophy, similar to the glandular damage seen in AIG/PA.

A Model for the Pathogenesis of H. pylori-associated Antigastric Autoimmunity

There are striking similarities in pathological changes of the gastric corpus mucosa as well as clinical features between AIG/PA and H. pylori-associated atrophic gastritis, suggesting an initiating role for H. pylori in these gastric autoimmune disorders. However, most published studies investigating the association of AIG/PA and H. pylori infection indicate that patients with pernicious anemia are infected with H. pylori less often than age-matched controls (57). In a long-term follow-up study, a subgroup of H. pylori-infected patients initially had gastritis in the antrum that later progressed into severe atrophy in the corpus (76), a process that was often accompanied by normalization of the antral mucosa, disappearance of H. pylori and appearance of parietal cell antibodies. In our opinion, the data described in this chapter strongly support a causative role of H. pylori in at least a subpopulation of patients with gastric autoimmunity. The model for H. pylori-induced gastric autoimmunity proposed here is an extension of the model previously described by Appelmelk and colleagues (5).

In the noninflamed gastric mucosa, only a few gastric periglandular lymphocytes can be detected. Like the onset of AIG, chronic infection with H. pylori is marked by an inflammatory influx of T and B lymphocytes and macrophages (15). This is followed by the acquisition of properties that are required (see above) for antigen presentation by epithelial cells, probably induced by the predominant Th1 cytokine milieu that results directly from H. pylori infection (8, 19). Presentation by epithelial cells of gastric H⁺,K⁺-ATPase to CD4⁺ H⁺,K⁺-ATPase β subunit-specific T cells that have escaped negative selection in the thymus may result in T-cell activation and proliferation (Fig. 2A), and autoreactive T cells could provide help for B-cell stimulation and autoantibody production. Activated T cells expressing FasL could subsequently kill Fas⁺ parietal cells by either antigen-dependent Fas-FasL interaction or by Fas-mediated bystander lysis, resulting in destruction of glands (atrophy). The predominance of H⁺,K⁺-ATPase in parietal cells, the high rate of normal turnover of epithelial cells plus the lack of expression in the thymus might favor presentation of H⁺,K⁺-ATPase over other autoantigens that are present in the gastric mucosa. In the course of the antigastric cellular immune response described above, epitope-spreading may occur to other autoantigens such as intrinsic factor and pepsinogen. Loss of H. pylori and normalization of the antrum may parallel increasing corpus atrophy. In this stage the autoimmune T-cell responses have become independent of H. pylori but are presumably still influenced by the predominant Th1 cytokine milieu, and a gastric autoimmune response indistinguishable from AIG/PA perpetuates.

Figure 2

A model of the pathogenesis in H. pylori-associated atrophic corpus gastritis. H. pylori infection leads to an inflammatory influx of T and B lymphocytes and macrophages, results in a predominant Th1 cytokine milieu in the gastric mucosa, and induces (more...)

This model does not rule out alternative pathways of antigen presentation and Fas-mediated killing of epithelial cells, but these alternative pathways (described below) are not in contradiction with the model. H⁺,K⁺-ATPase will probably also be presented to H⁺,K⁺-ATPase-specific T cells by professional APCs such as dendritic cells and macrophages, after they have encountered the autoantigen (Fig. 2B). T-cell activation might take place either in the gastric mucosa or in the lymph nodes draining the stomach, by macrophages and trafficking dendritic cells, respectively. In addition to autoantigen-dependent Fas-mediated lysis, epithelial/parietal cells may also be killed by bystander effect of any activated gastric T cell (61, 78). Although H. pylori in most cases resides in the antrum and is not invasive, leakage of bacterial antigens deep into the corpus mucosa cannot be ruled out. Presentation of bacterial antigens by professional APCs may result in activation of H. pylori-specific T cells that could kill Fas-expressing parietal cells by bystander lysis (Fig. 2C). CD4⁺ H. pylori-specific Th1 cells have been cloned from both antrum and corpus of H. pylori-infected patients (D'Elios et al., unpublished results). H. pylori-specific T cells may be able to be activated by epithelial/parietal cells presenting bacterial antigens and subsequently kill the cells by induction of autoantigen-independent and H. pylori antigen-dependent Fas-mediated apoptosis (Fig. 2D).

In addition to Fas-FasL interaction, direct binding of H. pylori to epithelial MHC class II molecules induces apoptosis of epithelial cells (31). However, the role of direct bacterium-epithelium contact-mediated apoptosis in atrophic corpus gastritis may be questioned, since colonization usually takes place in the antrum and H. pylori is not invasive, but apoptosis occurs deep in the mucosa.

The loss of glands in the mucosa, that is, the development of gastric atrophy, may thus be caused by an H. pylori-induced autoimmune T-cell attack against epithelial and parietal cells rather than through autoantibodies. In analogy with EAIG, CD4⁺ T cells, and not B cells or autoantibodies, are the critical mediators in Helicobacter-associated gastric pathology (21, 54, 60, 70, 71). Consequently, antigastric autoantibodies may only serve as a marker for ongoing antigastric autoimmunity mainly carried out by autoreactive T cells.

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