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. 2010 Mar 1;7(4):255–259. doi: 10.1038/cmi.2010.2

Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology

Hwei-Fang Tsai 1,2, Ping-Ning Hsu 3
PMCID: PMC4003231  PMID: 20190789

Abstract

Helicobacter pylori infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, gastric carcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Recent studies have shown that apoptosis of gastric epithelial cells is increased during H. pylori infection. Apoptosis induced by microbial infections are factors implicated in the pathogenesis of H. pylori infection. The enhanced gastric epithelial cell apoptosis in H. pylori infection has been suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells via modulation of TRAIL apoptosis signaling. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, there was significantly increased CCR6+CD3+ T-cell infiltration in the gastric mucosa, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These results implicate that the interaction between CCL20 and CCR6 may play a role in recruiting T cells to the sites of inflammation in the gastric mucosa during Helicobacter infection. Through these mechanisms, chemokine-mediated T lymphocyte trafficking into inflamed epithelium is initiated and the mucosal injury in Helicobacter infection is induced. This article will review the recent novel findings on the interactions of H. pylori with diverse host epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation, mucosal damage and development of MALT lymphomas.

Keywords: apoptosis, CagA, chemokine, Helicobacter pylori, TRAIL

Introduction

Helicobacter pylori, a common human pathogen, which infects about 50% of the world's population, is associated with duodenal and peptic ulcer diseases. The clinical consequences range from asymptomatic gastritis to peptic ulceration and gastric malignancy.1, 2 The outcome of the infection is determined by interactions among H. pylori virulence factors, host gastric mucosal factors and the environment. However, the mechanisms by which host factors cause disease remain unclear. The H. pylori infection changes the microenvironment of gastric mucosa. The apoptosis of gastric epithelial cells is increased,3, 4, 5, 6, 7 and direct cytotoxicity as well as inflammatory responses occurs in the gastric mucosa cells.6, 8, 9, 10 It has been demonstrated that T helper type 1 cells selectively increased during H. pylori infection.11, 12, 13, 14, 15 T helper type 1 cytokines, such as gamma interferon (IFN-γ) and tumor-necrosis factor alpha (TNF-α), can increase the release of proinflammatory cytokines, augmenting apoptosis induced by H. pylori.10 H. pylori infection could also induce gastric mucosa damage by increasing expression of Fas in gastric epithelial cells, leading to gastric epithelial cell apoptosis through Fas/FasL interaction with infiltrating T cells.9, 16 These findings suggest a role for immune-mediated apoptosis of gastric epithelial cells during H. pylori infection. Recently, several bacterial pathogens have been found to trigger apoptosis in host cells in vitro or in vivo, and several types of mechanisms have been elucidated.17 It was shown that H. pylori directly triggers cell death by cytotoxins after interaction with gastric epithelial cells.18, 19 Meanwhile, recent reports have shown that H. pylori translocates cytotoxin-associated gene A (CagA) into gastric epithelial cell by type IV secretion, inducing intracellular protein phosphorylation and dysregulate the signal transduction pathways within host cells.20, 21, 22, 23

Modulation of TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by H. pylori

TRAIL (also called Apo2L), a novel TNF superfamily member with strong homology to FasL, is capable of inducing apoptosis in a variety of transformed cell lines in vitro,24, 25 but usually not in normal primary cells. It was shown that T cells can kill target cells via TRAIL/TRAIL receptor interaction,26, 27, 28, 29, 30, 31 indicating that TRAIL might serve as a cytotoxic effector molecule in activated T cells in vivo. These findings suggest that TRAIL/TRAIL receptor interaction is involved in the interaction between infiltrating T cells and gastric epithelium during H. pylori gastritis. In recent reports, Wu et al. demonstrated that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis, suggesting a role for immune-mediated apoptosis of gastric epithelial cells by infiltrating T cells during Helicobacter infection.7, 15 The induction of TRAIL sensitivity by H. pylori is independent of expression of H. pylori virulent factors vacuolating cytotoxin gene A (VacA) and CagA, and is dependent on viable bacteria and direct contact with cells.7 The expression of TRAIL receptors did not change after H. pylori infection, indicating the H. pylori-induced enhanced sensitivity to TRAIL-mediated apoptosis in gastric epithelial cells was not due to upregulation of TRAIL death receptors. H. pylori-induced sensitivity to TRAIL-mediated apoptosis in gastric epithelial cells is dependent on activation of caspase 8 downstream pathway to convey the death signal to mitochondria, leading to activation of mitochondrial pathway and breaking the apoptosis resistance. H. pylori induces TRAIL-mediated apoptosis via enhancing the assembly of TRAIL death-inducing signaling complex and activation of caspase 8 and its downstream apoptosis signaling pathway. Thus, in addition to directly triggering apoptosis, H. pylori induces sensitivity to TRAIL in gastric epithelial cells by modulation of death-receptor signal transduction pathways. Modulation of host cell apoptosis by bacterial interaction adds a new dimension to the immune pathogenesis in Helicobacter infection.

Chemokine-mediated lymphocyte trafficking of T lymphocytes in gastric inflammation during H. pylori infection

Previous studies have indicated that T lymphocytes play an important role in the pathogenesis of Helicobacter gastritis.11, 32 Inflammation of the gastric mucosa develops in response to the host immune reaction against the pathogens. The stimulation of epithelial cells with H. pylori contributes to the recruitment of neutrophils and lymphocytes. The activation of macrophages results in the release of cytokines, including IL-1, IL-6, IL-8, IL-12, TNF-α and IFN-γ. As described, the features of H. pylori-induced inflammatory immune response are orchestrated by sequential elaboration of proinflammatory cytokines including IL-10, IFN-γ, TNF-α and IL-1β. Accordingly, factors involved in regulating cytokine responses may confer susceptibility to or protection against H. pylori-associated diseases. All these results indicate that immune reaction and inflammation mediators to H. pylori play an important role in the pathogenesis of H. pylori-associated diseases. Among the T cells in response to H. pylori infection, the gastric infiltrating T cells mostly are CD45RO+CD69+CD4+ T cells, indicating that there was accumulation of activated memory CD4+ T cells during Helicobacter infection.15 Recent reports indicated that the T helper type 1 response is induced during infection with H. pylori,11, 13, 14, 33 and the levels of IFN-γ and TNF-α, are increased in the gastric mucosa during H. pylori infection, augmenting the apoptosis induced by H. pylori.6, 7, 10 These results suggest a role for immune-mediated apoptosis of gastric epithelial cells by infiltrating T cells during Helicobacter infection. Therefore, in addition to bacterial virulence factors, the degree of gastric mucosa damage is also determined by the inflammation response induced during H. pylori infection. However, the induction of immune response and the immunopathogenic mechanism(s) of mucosal inflammation in H. pylori infections are still not clear, and chemokines are thought to play an important role in this process.34, 35, 36, 37 Chemokines are small, 6–14-kDa heparin binding proteins, which play a role in a variety of biological processes, most notably leukocyte chemotaxis.38, 39 Chemokines are involved in acute and chronic inflammatory processes by attracting neutrophils, monocytes and T cells to the site of inflammation via their corresponding chemokine receptors.38, 39 Recent reports have shown that there are specific chemokines that mediate the homing of lymphocytes in the intestines,37, 40, 41 suggesting that some chemokines may be involved in lymphocyte trafficking in the gut. It has been demonstrated that distinct sets of chemokines and their receptors are responsible for directing lymphocytes to inflammatory sites.35, 36, 40, 42, 43 A set of proinflammatory chemokines has been shown to be involved in H. pylori gastritis: Gro-α, IL-8, RANTES, IFN-γ-inducible protein-10 (CXCL10), a monokine induced by IFN-γ (CXCL11) and CCL20 (MIP-3α/LARC/exodus).15, 44, 45, 46 It has been demonstrated that the gastrointestinal epithelium senses the invading microorganisms and produces cytokines/chemokines that attract lymphocytes and dendritic cells to the site of inflammation.35, 47, 48 Recently, it was reported that CCR6 mediates dendritic cell localization, lymphocyte homeostasis and immune responses in mucosal tissue.49 CCR6, a specific β-chemokine receptor for CCL20, is selectively expressed on dendritic cells and some memory T cells48, 50, 51, 52 and may play a role in chemokine-mediated lymphocyte trafficking during gastric inflammation. It has also shown that CCL20, the ligand of CCR6, is abundantly expressed in mouse and human inflammatory enteric mucosa.53, 54 The production of CCL20 was upregulated in response to H. pylori in gastric epithelial cells when there was stimulation by the proinflammatory cytokines IL-1β and TNF-α.15, 55, 56, 57 These results implicate that the interaction between CCL20 and CCR6 may play a role in recruiting CD45RO+ memory T cells to the sites of inflammation in the gastric mucosa during Helicobacter infection.

H. pylori CagA protein and the development of mucosa-associated lymphoid tissue (MALT) lymphomas

It has been established that the cagA gene product, CagA, can be directly injected into bacterium-attached host gastric epithelial cells via the bacterial type IV secretion system.20, 21, 22, 23 Infection by cagA-positive H. pylori is associated with gastric carcinomas and gastric MALT lymphomas.1, 58 The development of gastric MALT lymphomas is closely associated with H. pylori infection. The pathogenic role of H. pylori infection in gastric MALT lymphomas was observed in in vitro experiments and clinical evaluations of the effects of eradication on the progression of gastric MALT lymphomas.59, 60 Epidemiological studies further indicated that cagA-positive H. pylori is present in the gastric mucosa of most patients with gastric MALT lymphomas.61, 62 Clinical observations that eradication of H. pylori by antibiotic therapy can lead to the complete remission of MALT lymphomas60 provide evidence that cagA-positive H. pylori plays an important role in the development and/or maintenance of MALT lymphomas. The development of gastric MALT lymphomas is dependent on H. pylori infection. Bacterial colonization of the gastric mucosa triggers lymphocyte infiltration.15, 63 and the formation of acquired MALTs. Previous studies suggested that MALT lymphoma cells preserve B-cell properties and that their growth may be partially driven by antigenic stimulation. H. pylori stimulates lymphoma B cells through tumor-infiltrating T cells, involving CD40 and CD40L costimulatory molecules.64, 65 However, the pathogenesis and how H. pylori induces the development of B-cell MALT lymphomas are still not clear. Much attention has been focused on the role of the cagA gene product, CagA, in the malignant transformation of cells. CagA was directly injected from bacteria into attached gastric epithelial cells by a type IV secretion system, encoded by the cag pathogenicity island,20, 66 and underwent tyrosine phosphorylation.23, 67, 68, 69 In human B lymphocytes, overexpression of cagA via transfection induces activation of extracellular signal-related kinase and their downstream apoptosis regulators, indicating that CagA has effects on the growth and survival of B lymphocytes and may play a role in the development of MALT lymphomas.70, 71 H. pylori infection stimulates immune lymphocytes in the gastric mucosa and induces the formation of MALTs, from which MALT lymphomas of B-cell origin develop. Immune cells constituting MALTs migrate to and infiltrate the site of H. pylori infection in the stomach. In such circumstances, CagA may be injected into lymphocytes as well as gastric epithelial cells. Recent results in our laboratory have demonstrated that CagA could be directly translocated into human B cells from H. pylori. This implies the direct role and importance of CagA in the development of H. pylori-associated MALT lymphomas.

Summary

Human gastric epithelial cells sensitized to H. pylori conferred susceptibility to TRAIL-mediated apoptosis. Although the induction of TRAIL sensitivity by H. pylori in gastric epithelial cells was independent of H. pylori virulent factors CagA and VacA, the degree of apoptosis was linked to the presence of H. pylori and the associated inflammatory response. Therefore, the degree of mucosal damage was also determined by the inflammatory response induced by H. pylori within gastric epithelium. These results suggest a role for immune-mediated apoptosis and mucosa damage by infiltrating T cells during Helicobacter infection (Figure 1). In conclusion, H. pylori enhances susceptibility of gastric epithelial cells to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent upon direct contact of viable bacteria with gastric epithelial cells. Modulation of host cell apoptosis by bacterial interaction adds a new dimension to the immune pathogenesis in chronic Helicobacter infection. The interplay between H. pylori and immune cells may induce activation of B lymphocytes via direct interaction or indirect immune stimulation leading to the development of H. pylori-associated MALT lymphomas.

Figure 1.

Figure 1

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Immune pathogenesis of gastric mucosa damage in H. pylori infection. In the absence of H. pylori infection, there are very few T cells infiltrating into the gastric mucosa, which do not induce apoptosis in gastric epithelial cells. In contrast, in the presence of H. pylori infection, H. pylori induce inflammation and production of chemokine CCL20 to recruit CCR6 expressing activated CD4+ T cells infiltrated to the sites of inflammation in the gastric mucosa. The TRAIL expressing T cells subsequently induce apoptosis in the H. pylori-infected gastric epithelia cells. Meanwhile, immune cells constituting MALTs migrate to and infiltrate the site of H. pylori infection in the gastric mucosa, and in such circumstances, CagA may be injected into lymphocytes as well as gastric epithelial cells. When CagA is transloacted into B lymphocytes, it may induce activation of B lymphocytes to proliferate. The molecular mechanism of H. pylori-induced susceptibility to TRAIL-mediated apoptosis in gastric epithelia cells is shown in the lower inlet of the figure. In the absence of H. pylori infection, TRAIL engagement with death receptors on gastric epithelial cells induces only weak activation of caspase 8, and is not able to activate the caspase 8 downstream signals to trigger cell death. In contrast, in the presence of H. pylori infection, H. pylori enhance the assembly of TRAIL death-inducing signaling complex (DISC) after TRAIL engagement, to augment the activation of caspase 8 and to convey the death signal to mitochondria via cleavage of Bid, leading to activation of mitochondrial pathway and breaking the apoptosis resistance. CagA, cytotoxin-associated gene A; FADD, Fas-associated protein with death domain; MALT, mucosa-associated lymphoid tissue; TRAIL, tumor-necrosis factor-related apoptosis-inducing ligand.

Acknowledgments

This work was supported by grants from the National Health Research Institute (NHRI-EX95-9532SI), National Science Council, Taiwan (NSC90-2314B-075B003 and NSC91-2320B-002) and China Medical University (CMU96-266, CMU97-299).

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