Interleukin 17 and Interferon-Gamma, Key Cytokines for Inflammation and Diagnosis in <i>Helicobacter pylori</i> and Gastric Malignancies

Mario M. D’Elios; Chiara Della Bella

doi:10.5772/intechopen.1005301

Abstract

Helicobacter pylori infection is characterized by an inflammatory infiltrate that might be an important antecedent of gastric cancer. Interferon-gamma (IFN-γ) and interleukin (IL)-17 are key cytokines produced by gastric T cells in Helicobacter pylori-infected patients with gastric malignancies. We studied the levels of serum IL-17A in subjects positive to Helicobacter pylori infection and diagnosed with gastric intestinal metaplasia and dysplasia, as well as in patients with Helicobacter pylori infection and non-atrophic gastritis, along with control subjects. Results showed that Helicobacter pylori can cause inflammation in the stomach, specifically in cases of gastric intestinal metaplasia and dysplasia in infected patients, leading to a significant rise in IL-17A serum levels. Accordingly, we propose to consider measuring serum IL-17A for managing Helicobacter pylori-infected patients, and potentially for predicting the risk of developing gastric cancer.

Keywords

Helicobacter pylori
gastric cancer
gastric inflammation
interleukin 17
interferon-gamma
serum cytokine
T cells

Author Information

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Mario M. D’Elios*
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
Chiara Della Bella
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy

*Address all correspondence to: delios@unisi.it

1. Introduction

Helicobacter pylori (H. pylori) is a spiral, microaerophilic, Gram-negative bacterium. H. pylori infection is one of the most common bacterial infections that afflicts over 50% of the world’s population and leads to persistent infections in the stomach throughout a person’s life. The bacterium is the major contributor to several gastric diseases, including gastric adenocarcinoma, autoimmune gastritis, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, gastric autoimmunity, and peptic ulcer [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]. The World Health Organization classifies H. pylori as an IARC class I carcinogen that is the dominant risk factor for distal gastric cancer [12]. Eradicating H. pylori has been shown to decline the incidence of gastric cancer [13, 14, 15, 16]. The presence of H. pylori infection in the stomach triggers a complex and multiform inflammation characterized by the infiltration of immune cells and the local production of various inflammatory mediators, including cytokines and chemokines [17]. The host’s immune system can either fight the H. pylori infection or the bacterium can evade the host’s defense mechanisms; in the latter case, the chronic infection can lead to the development of gastric cancer [18]. Certain factors of H. pylori, such as the cytotoxin VacA and gamma-glutamyl transpeptidase GGT, can suppress the immune system and impair both innate and acquired immunity. These factors exert their influence on antigen-presenting cells and T cells [19, 20, 21, 22]. Once in the stomach, H. pylori first activates the innate immunity, recruiting macrophages and neutrophils which initiate and sustain the inflammatory cascade. The gastric epithelium reacts to the bacterium; the resident macrophages are activated by Toll-like receptors (TLR) with bacterial products such as LPS, CagA, VacA, HP0175, heat shock proteins such as HP-NAP [23, 24]. Furthermore, H. pylori peptidoglycan may result in activation of the NOD-1 receptors. These stimuli cause a massive release of chemokines such as IL-8, a strong activator for neutrophils, and inflammatory cytokines such as IL-1, IL-6, TNF-α, IFN-α, IL-12, and IL-23. In particular, IL-12 and IL-23 secreted by both macrophages and neutrophils, play a key role in natural host defense and are decisive in driving the subsequent adoptive cell response polarized as Th1. [25, 26].

Studies about host immune responses to H. pylori infection have mainly focused on Th1, Th17, and Th2 cells. Some H. pylori strains may be more virulent than others, and the involved immune responses may depend on the type of the host immune response. A large body of clinical and experimental evidence has demonstrated that H. pylori at any stage of the infection activates the production of high levels of IFN-γ. On the one hand, IFN-γ is necessary for the control of infection; on the other hand, whether its production is abnormally maintained for a very long period might lead to gastric immunopathology and eventually to gastric cancer [27, 28, 29, 30]. In H. pylori infection, the adoptive immunity is predominantly mediated by Th1 and Th17 cells. In patients with gastric precancerous lesions and gastric adenocarcinoma, high gastric IL-17 secretion is associated with IFN-γ production [2, 23, 29, 31, 32, 33].

Mice with H. pylori infection may exhibit a dual Th17/Th1 response, with a first Th17 action followed by the Th1 response. Mice treated with anti-IL-17 antibody showed a notable decrease in H. pylori burden and stomach inflammation, unlike those treated with a control antibody. IL-17(−/−) mice exhibited decreased H. pylori colonization and reduced gastric inflammation as well [34]. The precise mechanisms underlying Th17 involvement in gastric tumorigenesis are yet to be established. However, Kang JH et al. in their study suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway [35]. Furthermore, H. pylori CagY protein mainly induces the production of IFN-γ and IL-17 by T helper lymphocytes in the stomach, enhancing B cell growth and potentially causing gastric MALT lymphoma. The increased production of IL-17 is associated with more severe forms of H. pylori-associated diseases, especially with gastric premalignant and malignant lesions [29, 36].

The severity of symptoms caused by H. pylori infection is related to the predominant subset of T cell-mediated immune response that subsequently occurs. It has been shown that in the infected gastric mucosa, a specific pro-inflammatory response to H. pylori, Th1 polarization, correlates with more severe disease progression. Moreover, in uncomplicated chronic gastritis (UCG), an H. pylori-specific T component Th1/Th2 mixed was found to prevail [27, 37, 38, 39, 40, 41, 42, 43].

In the gastric mucosa infected with H. pylori, the signaling pathway for Th1 is stimulated by IL-12 [44]. A local Th0 response, including interleukin-4 production by Th2 cells, represents an individual host factor that contributes to lowering the degree of gastric inflammation and preventing ulcer complications. Thus, in uncomplicated chronic gastritis, the Th1 response is balanced by a concomitant Th2 response [27]. The immune profile in the reaction to H. pylori infection can be modulated by co-infections (helminth parasitism and “African enigma”) or comorbidities. Some population surveys have shown an inverse association between H. pylori infection and Th2-related pathology like atopy, allergy, and asthma [45, 46, 47, 48]. The pathogenic potential of polarized Th1 responses in H. pylori infection finds indirect support in the phenomenon commonly known as “the African enigma” by which the high prevalence of H. pylori infection in Africa is not supported by a correlated high incidence of peptic ulcer disease and gastric cancer [49, 50]. One possible explanation for this phenomenon is the simultaneous presence of an endemic high parasitic burden, which is known to trigger a Th2-like immune response. The Th2 polarization stimulated by helminth infections could attenuate the Th1-like immune response induced by H. pylori infection and, consequently, the gastro-duodenal pathology induced by the bacteria. This hypothesis has been supported by experimental studies in which co-infection of mice with Helicobacter felis and a natural murine helminth (Heligmosomoides polygyrus) led to a reduction in Th1-mediated gastric atrophy, which is considered a pre-malignant lesion [51]. These Th2 responses may serve to protect individuals with H. pylori infection from developing peptic ulcers and gastric cancer.

Inflammatory cytokines and chemokines can trigger several injurious effects on gastric epithelial cells, including uncontrolled proliferation, resistance to apoptosis, and DNA damage. These deleterious effects can eventually culminate in the cancerous transformation of the gastric cells [52, 53, 54]. The carcinogenic pathway leading to gastric cancer, which is closely associated with inflammation, is a multi-step process that takes place in nearly 1% of individuals affected by chronic H. pylori infection. It is important to note that while non-atrophic gastritis (NAG) develops in almost all patients infected with H. pylori, in some cases the inflammation progresses to more advanced stages of pre-malignancy, such as gastric intestinal metaplasia (IM) and dysplasia (DYS) of the stomach [55, 56]. In the later stages of this inflammation-induced carcinogenic process, various types of genetic instabilities occur, characterized by diverse and potentially harmful clonal assemblies [44, 57, 58, 59, 60]. In this chapter, we will review the different types of inflammation going on in the stomach of patients with H. pylori infection and different clinical outcomes as gastric autoimmunity, gastric MALT lymphoma and we will focus especially on gastric adenocarcinoma and gastric premalignant lesions, such as gastric intestinal metaplasia and gastric dysplasia, as well as on the potential usefulness of interleukin 17A (IL-17A) for the management of patients with H. pylori infection and gastric adenocarcinoma or gastric pre-malignancies.

2. Helicobacter pylori and gastric autoimmunity

H. pylori infection is closely linked to gastric autoimmunity. Numerous clinical and epidemiological studies suggest that a significant majority of patients with autoimmune gastritis (AIG) either currently have or have had H. pylori infection [10]. AIG is a chronic inflammatory disease characterized by autoimmune-mediated destruction of parietal and zymogenic cells of the corpus and fundus of the stomach which leads to atrophy of the gastric corpus mucosa. Pernicious anemia (PA) may develop in advanced AIG, due to the lack of Intrinsic factor (IF) and related cobalamin decrease [61]. Remarkable resemblances can be highlighted between classical AIG and H. pylori-induced corpus atrophic gastritis [62]; moreover, the AIG preclinical stages can be effectively regressed by eradication of the bacteria [63, 64, 65]. H. pylori prompts the production of autoantibodies targeting gastric mucosal protein epitopes in about half of infected individuals [56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70]. The process of molecular mimicry underlying the induction of autoimmunity in AIG takes place against the gastric pump H⁺/K⁺ ATPase antigen, the proton pump located in the secretory canaliculi of the parietal cells [71]. The H⁺/K⁺ ATPase is the primary autoantigen responsible for the immunopathology in autoimmune gastritis (AIG) [72]. In mice, unlike what happens in humans, gastric autoantibody production due to H. pylori infection is caused by a mimicry process with LPS Lewis blood-group antigens and Lewis antigens on the glycosylated α-subunit [62, 63, 73].

In humans with AIG, H. pylori infection activates gastric T cells, a significant proportion of which exhibit cross-reactivity against both H. pylori peptide antigens and H⁺/K⁺ ATPase through a mechanism involving molecular mimicry [10, 74]. The identification of these H. pylori/ATPase-specific T cells explains the correlation between H. pylori infection and corpus atrophic gastritis. The research by Bergman et al. aimed to determine the epitopes of the human gastric ATPase α and β chains recognized by the autoreactive T cell clones infiltrating gastric biopsies of AIG subjects. Their data identified a group of the H⁺/K⁺ ATPase autoantigens that resulted the same in all the enrolled AIG subjects, regardless of H. pylori infection status [75, 76]. Interestingly, these bacterial crossreactive immunogenic antigens were not constituent of the established immunodominant proteins of H. pylori CagA, VacA and Urease, at the base of peptic ulcer [37] and chronic antral gastritis etiopathogenesis [27]. Rather, these H. pylori cross-reactive epitopes mainly are codified by the bacteria housekeeping genes and are HLA-DR-restricted [74]. When stimulated with their specific cross-reactive bacterial peptide, all the ATPase/H. pylori-specific T cell clones obtained by gastric mucosa of AIG patients exhibited a Th1 phenotype, with a cytokine milieu composed of high amount of IFN-γ, without IL-4 and IL-5 secretion [74, 75, 76]. Following activation, all the aforementioned ATPase/H. pylori-specific T cell clones showed cytotoxic activity by Fas-Fas ligand (FasL)-mediated apoptosis or by perforin-mediated cytotoxicity against gastric epithelial cells [55] which, following the action of IFN-γ and TNF-α, showed a heightened receptor Fas on their membrane [77], contributing to their apoptosis induction (Figure 1) [78]. Consequently, in certain patients, likely influenced by unknown genetic or environmental factors, H. pylori infection causes an excessive cellular immune response at the gastric level, leading to gastric autoimmunity through a mechanism of molecular mimicry.

Figure 1.
Immunopathogenesis of autoimmune gastritis (AIG).

3. Helicobacter pylori and gastric MALT lymphoma

Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the third most common type of non-Hodgkin lymphoma [79, 80]. The stomach has the highest incidence of MALT lymphoma, with typical clinical and histopathologic features [81]. The association between H. pylori infection and gastric MALT lymphoma has been established through the finding of the bacteria into a large number of MALT lymphoma biopsies [82]. H. pylori-related low-grade gastric MALT lymphoma serves as a model for studying the interplay between chronic infection, immune response, and lymphomagenesis. This tumor is notable as the first neoplasia that could be totally cured in early stages, thanks to the removal of H. pylori infection by antibiotic therapy [7]. The establishment of low-grade B cell gastric MALT lymphoma is due to H. pylori infection in the presence of H. pylori-specific T cells that provide an uncontrolled help function on tumor cell proliferation. Tumor cells are memory B cells that remain responsive to differentiation signals, such as CD40 costimulation and cytokines produced by bacterial-specific Th cells. Thus, the proliferation of B lymphocytes is strictly dependent on H. pylori-specific T helper lymphocytes [83, 84, 85].

In the early phases, this tumor is responsive to the withdrawal of H. pylori-induced T cell help, describing the tumor’s inclination to stay in its original location and its clinical resolution following the antibiotic therapy to remove the bacterium. Examining the helper function given by gastric H. pylori-specific T cell clones to B cells has revealed in-depth knowledge on the molecular and cellular processes linked to the development of low-grade gastric MALToma. The T helper cells isolated and amplified by cloning were tested for their antigen specificity for H. pylori, achieving a positivity of 3–20%. The majority of the T cell clones obtained was not specific for the well-known proteins CagA, VacA, Urease or HSP. Each H. pylori-specific T helper clone obtained in vitro from gastric MALToma infiltrate produced IL-2 and a milieu of B cell-activating cytokines, such as IL-4 and IL-13. These clones, after activation with the specific bacterial antigens showed a potent help function for B cell activation and proliferation. B cells in MALToma patients proliferate when exposed to H. pylori, but the B cell growth stimulated by bacterial antigens requires T helper cells to occur [86].

Recently, we could demonstrate that CagY is an important H. pylori antigen and is able to drive mucosal activation and B cell proliferation in gastric low-grade MALT lymphoma [36]. In patients with chronic gastritis, whether with or without ulcers, the helper function toward B cells exerted by H. pylori antigen-stimulated gastric T cell clones was negatively regulated by the concurrent cytolytic killing of B cells [27, 37]. Conversely, gastric T cell clones from MALToma were incapable of downmodulating their antigen-induced help for B cell proliferation. The perforine-mediated cytotoxic function of these T cell clones against autologous B lymphocytes was absent. The Fas-FasL mediated apoptosis toward tumor cells was founded in a small number of H. pylori-specific T helper clones from MALT lymphoma in comparison to the ones obtained from the mucosa of patients with uncomplicated chronic gastritis. The dysfunction of perforin-mediated cytotoxicity and the restricted capacity to induce Fas-FasL mediated apoptosis were unique to T cells that infiltrated MALTomas. T helper lymphocytes specific for H. pylori antigens obtained from the peripheral blood of the same subjects exhibited similar cytolytic potential and proapoptotic activity as T helper cells from patients with chronic gastritis [86]. Mice with cytotoxic T cells deficient in perforin, develop lymphomas with age [87, 88] and, more frequently and earlier, B cell lymphoma occurs in mice lacking both perforin and beta-2 microglobulin (β2m). Furthermore, B cell lymphomas originating from mice lacking both perforin and β2m are rejected by either NK cells or γδ T cells upon transplantation into WT mice, rather than by αβ T cells (as observed in tumors from mice lacking only perforin), emphasizing that the tumor cell’s membrane expression of MHC class I molecules is important in deciding which effector cell provide immune protection [89].

Interestingly, subgroups of lymphoma patients have been found to have mutations in the gene that codes for perforin [90], although, the involvement of this mutation in etiogenesis remains unclear. Mice lacking in the pro-apoptotic cytokine TNF-related apoptosis-inducing ligand (TRAIL) or with a mutate form of the death-inducing protein FasL have also been found to be vulnerable to developing late-onset spontaneous lymphomas [75, 76]. These research unequivocally underscore the important function of cytotoxic mechanisms in immune system regulation and/or suppression of natural tumor growth in mice. It is not clear why gastric T cells of MALToma lack mechanisms to control B cell growth despite providing potent support to B cells. VacA toxin has been shown to block the processing of antigens in antigen-presenting cells (APCs) and T cells, while it does not affect the release of perforin by NK cells [19, 21]. We can hypothesize that in some H. pylori-infected subjects, certain bacterial components can affect the regulatory cytotoxic mechanisms in gastric T cells that control B cell proliferation, thereby allowing exhaustive and unbalanced B cell help and lymphomagenesis to occur (Figure 2) [86, 91, 92].

Figure 2.
Immunopathogenesis of gastric MALT lymphoma.

4. Helicobacter pylori and gastric pre-malignancies

A long-lasting gastric inflammation is considered risky for the development of gastric adenocarcinoma [93]. TNF-α and IL-1β are key cytokines for the development of a gastric niche that favors the onset of gastric cancer [94, 95, 96]. The continuous secretion of cytokines in the stomach, characterized by a chronic pattern, has the potential to influence the progression of gastric cancer [54, 97, 98, 99, 100, 101]. H. pylori is capable of triggering an innate immune response abundant in IL-1β, IL-6, transforming growth factor (TGF)-β, and IL-23 which are able to steer a T cell response towards the Th17 phenotype [96, 102]. Th17 inflammatory responses are orchestrated by T helper 17 cells, which release IL-17 and play a pivotal role in initiating numerous inflammatory pathways within the gastric environment [72]. Elevated levels of IL-17 have been identified in gastric tissues of individuals with H. pylori infection [32, 34, 103].

We recently focused on the type of gastric T cell responses in H. pylori-infected patients with gastric pre-malignant lesions, such as intestinal metaplasia/dysplasia (IM/DYS), by defining the cytokine profile secreted by infiltrating gastric T cells [29]. ELISpot assay for IL-17 demonstrated that gastric-derived T helper cells from H. pylori-infected IM/DYS patients significantly produced IL-17A in response to H. pylori antigen compared to unstimulated conditions and non-H. pylori antigens (tetanus toxoid). No significant IL-4 secretion from the same T cell lines was detected by ELISA. From the T cell infiltrating the gastric mucosa of these H. pylori-infected IM/DYS patients, 242 T cell clones were obtained and characterized for their function and responsiveness to H. pylori. No cytotoxic T cell clone was specific for H. pylori; 12% of CD4⁺ T cell clones proliferated in response to H. pylori antigens and all of them demonstrated IL-17 secretion by the entire population, with 11/29 clones producing both IFN-γ and IL-17. The sera from H. pylori-infected IM/DYS patients, H. pylori-infected patients without IM/DYS and healthy controls were tested for IL-17A by Luminex technology. A significant increase in serum IL-17A was detected in H. pylori-infected patients with gastric premalignant lesions compared to healthy subjects. The serum IL-17A levels were significantly higher in H. pylori-infected patients with gastric premalignant lesions than in H. pylori-infected patients without gastric premalignant lesions.

The gastric precancerous cascade by Correa et al. [55, 56] highlights the progressive changes in the gastric mucosa caused by H. pylori infection and leading to gastric adenocarcinoma. H. pylori infection induces both innate and adoptive immune responses. The amount of IL-17 and the percentage of H. pylori-specific T helper 17 cells are in patients with gastric premalignant lesions and gastric adenocarcinoma significantly more elevated than the amount of IL-17 and Th17 cells found in patients with uncomplicated chronic gastritis. Thus, it is reasonable to hypothesize that the higher serum levels of IL-17 found in patients with gastric premalignant lesions are due to decades of higher activation of H. pylori-specific T helper 17 compartments in their gastric mucosa. Therefore, IL-17A plays a crucial role in causing inflammation in the gastric mucosa of patients with autoimmune atrophic gastritis without H. pylori infection [104], as well as being a key cytokine in the immunopathogenesis of gastric intestinal metaplasia and gastric dysplasia in H. pylori-infected patients, as shown in this study, both in the stomach and in the blood (Figure 3). As this study is a preliminary single-center research, it is crucial to conduct further multi-center inmvestigations on serum IL-17A levels in gastric adenocarcinoma to better understand the proposed test.

Figure 3.
IL-17A as a potential inflammatory marker for gastric cancer.

5. Helicobacter pylori and gastric adenocarcinoma

Gastric cancer remains a significant global public health challenge, ranking as the seventh most prevalent form of cancer worldwide and the fifth leading cause of cancer-related death, according to data from GLOBOCAN 2020. Globally, approximately 1.9 million individuals are currently diagnosed with gastric cancer, accounting for 3.6% of all cancer diagnoses. Furthermore, it stands as the fourth most common cause of cancer-related deaths on a global scale. These statistics underscore the ongoing importance of addressing gastric cancer as a major health concern [105]. It has been shown that there is a predominant T helper 17 and T helper 1 response in H. pylori-infected patients with gastric adenocarcinoma and in H. pylori-negative patients with autoimmune atrophic gastritis [33, 104, 106]. There were no clues on which H. pylori antigen was able to drive IL-17 production. It has been shown that the H. pylori HP0175 antigen can activate the inflammation of T cells in the stomach. T cell lines were obtained from Tumor-Infiltrating Lymphocyte (TIL) cells derived from the stomach of gastric adenocarcinoma patients and were tested for their IL-17 secretion after HP0175, TT, or PPD stimulation in ELISpot microplates. A significant proportion of all gastric-derived T cell lines specifically reacted to HP0175 by producing IL-17 in a dose-dependent manner, while non-H. pylori antigens like TT and PPD were ineffective at any concentration used.

Gastric biopsies obtained by H. pylori-infected patients showed an inflammatory infiltrate full of H. pylori-specific T cells actively producing IL-17. The IL-17 is produced by T cells following priming given by innate cells producing IL-23, TGF-β, etc. [23, 29, 31, 32, 33, 107, 108]. TILs were also characterized at the clonal level [101] for their HP0175 specificity, obtaining no CD8⁺ clone significantly proliferated. In contrast, 7% of the CD4⁺ T cell clones showed significant proliferation to HP0175. It is of note that H. pylori 0175 was able to induce the production by monocytes and neutrophils of several cytokines (IL-23, IL-1β, TGF-β, IL-6) known to have the ability to induce the production of IL-17 [23]. A similar study was carried out by testing the T cell response toward HP1454 in the gastric mucosa of H. pylori-positive patients with chronic gastritis and gastric adenocarcinoma [99]. T-cell blasts were recovered from gastric mucosa samples and cloned through limiting dilution. All CD4⁺ and CD8⁺ T cell clones obtained from gastric biopsies of H. pylori-positive subjects underwent testing for proliferation response to HP1454 in the presence of irradiated APCs. In uncomplicated chronic gastritis, 2.09% of the CD4⁺ T cell clones were specific for HP1454, while in gastric adenocarcinoma 7.78% of the CD4⁺ T cell clones exhibited significant proliferation to HP1454. Notably, none of the CD8⁺ clones was specific for HP1454. Among the HP1454 specific T helper clones from uncomplicated chronic gastritis, 1/3 produced IFN-γ alone, 40% produced IL-17 alone, and 27% four produced both cytokines. Conversely, in gastric adenocarcinoma, upon stimulation with HP1454, 30% of HP1454-specific T cell clones produced IFN-γ alone, 23% produced IL-17 alone and 47% produced both IFN-γ and IL-17. Remarkably, HP1454-specific clones from the gastric mucosa of patients with gastric adenocarcinoma produced higher levels of tumor necrosis factor α and IL-17 compared to the HP1454-specific clones from patients with uncomplicated chronic gastritis. These findings collectively suggest that the protein HP1454, released by H. pylori-infected patients, plays a role in driving Th1 and Th17 inflammatory responses during chronic H. pylori infection and in patients with distal adenocarcinoma.

Sun et al. in a recent elegant study characterized in patients with gastric cancer the clonotype and trajectory analysis of gastric T cells by single-cell RNA-sequencing (scRNA-seq) [109]. They found that also CD8⁺ T cells from gastric cancer patients produce IL-17 and promote tumor progression through IL-17, IL-22, and IL-26 signaling. IL-17 can, in turn, activate the STAT3 signaling pathway and promote epithelial-to-mesenchymal transition, migration, and invasiveness of gastric cancer cells [110]. Th17 immune response is directly driven by several H. pylori antigens such as the above-mentioned HP0175, HP1454, CagY. T cells specific for HP0175, HP1454, CagY, and other H. pylori antigens, are activated in the stomach by H. pylori and secrete IL-17. The number of H. pylori-specific Th17 cells present in the gastric mucosa is significantly elevated in patients with gastric premalignant and malignant lesions than in patients with uncomplicated chronic gastritis. Thus H. pylori drives abnormal and long-lasting IL-17 production in some predisposed individuals leading to gastric cancer [33, 36, 102, 110]. All these results point out that H. pylori is strongly able to promote Th17 and Th1 inflammation in gastric cancer (Figure 4).

Figure 4.
Th17 and Th1 immunopathology in gastric adenocarcinoma.

6. Conclusions

H. pylori infection is the primary reason for gastroduodenal issues, however, only a small portion of H. pylori-positive individuals will experience long-term and serious conditions like gastric cancer, B cell lymphoma, autoimmune gastritis, or peptic ulcer. The type of host immune response against the bacterium is crucial for the outcome of the infection. We investigated gastric immune responses in patients with gastric cancer, gastric autoimmunity, peptic ulcer, and gastric lymphoma. A predominant immune-pathological Th1 response, characterized by high IFN-γ, TNF-α, and IL-12 production is a hallmark of H. pylori infection, whereas combined secretion of both Th1 and Th2 cytokines are present in H. pylori infection with uncomplicated gastritis. We showed that a polarized gastric Th1/Th17 response is built-up in H. pylori-positive subjects with gastric adenocarcinoma, as well as in patients with gastric intestinal metaplasia and dysplasia (IM, DYS). In H. pylori-infected patients, autoimmune gastritis occurs due to cytolytic T cells that are activated following the cross-recognition of different epitopes of H. pylori proteins and H⁺/K⁺-ATPase autoantigen via molecular mimicry. In H. pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the neoplastic B cells proliferate in response to H. pylori only in the presence of autologous T cells that are essential for B cell proliferation. Different H. pylori antigens, such as Cag Y drive gastric inflammation in low-grade MALT lymphoma. Gastric T cells infiltrating MALT lymphoma mucosa have impaired ability to kill B cells through perforin and Fas-FasL pathways, leading to excessive support for B cell growth. This indicates that uncontrolled H. pylori-induced activation of T lymphocytes can contribute to the development and progression of low-grade B cell lymphoma. The International Agency for Research on Cancer has categorized H. pylori as a type I oncogenic factor for gastric adenocarcinoma.

The development of stomach cancer is a multi-step process that can take many years and can progress to pre-cancerous stages like gastric intestinal metaplasia and dysplasia (IM and DYS) before becoming a tumor. We recently analyzed the serum IL-17A levels in individuals with gastric IM and DYS, and observed a significant rise in IL-17A serum levels among these patients. Based on the results obtained so far, we propose that testing serum IL-17A levels could help in handling H. pylori-infected subjects and possibly even in predicting the onset of gastric cancer.

Acknowledgments

We thank the Italian Ministry of University and Research (PRIN project - Grant n. 2010P3S8BR_005) for supporting our studies. We thank Mary Wilkins for the English editing of the manuscript.

Conflict of interest

The authors certify that there is not any actual or potential conflict of interest.

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Interleukin 17 and Interferon-Gamma, Key Cytokines for Inflammation and Diagnosis in Helicobacter pylori and Gastric Malignancies

Towards the Eradication of Helicobacter pylori Infection - Rapid Diagnosis and Precision Treatment

Abstract

Keywords

Author Information

Mario M. D’Elios*

Chiara Della Bella

1. Introduction

2. Helicobacter pylori and gastric autoimmunity

Figure 1.

3. Helicobacter pylori and gastric MALT lymphoma

Figure 2.

4. Helicobacter pylori and gastric pre-malignancies

Figure 3.

5. Helicobacter pylori and gastric adenocarcinoma

Figure 4.

6. Conclusions

Acknowledgments

Conflict of interest

References

Invasive and Non-Invasive Methods of Diagnosing H. pylori Infection: A Review of Current Practice

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Interleukin 17 and Interferon-Gamma, Key Cytokines for Inflammation and Diagnosis in Helicobacter pylori and Gastric Malignancies

Towards the Eradication of Helicobacter pylori Infection - Rapid Diagnosis and Precision Treatment

Abstract

Keywords

Author Information

Mario M. D’Elios*

Chiara Della Bella

1. Introduction

2. Helicobacter pylori and gastric autoimmunity

Figure 1.

3. Helicobacter pylori and gastric MALT lymphoma

Figure 2.

4. Helicobacter pylori and gastric pre-malignancies

Figure 3.

5. Helicobacter pylori and gastric adenocarcinoma

Figure 4.

6. Conclusions

Acknowledgments

Conflict of interest

References

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Towards the Eradication of Helicobacter pylori Infection

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