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

Show +

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.

References

1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311-1315. DOI: 10.1016/s0140-6736(84)91816-6
2. Robinson K, Atherton JC. The spectrum of helicobacter-mediated diseases. Annual Review of Pathology. 2021;16:123-144. DOI: 10.1146/annurev-pathol-032520-024949
3. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. The New England Journal of Medicine. 1991;325(16):1127-1131. DOI: 10.1056/NEJM199110173251603
4. Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. The New England Journal of Medicine. 1991;325(16):1132-1136. DOI: 10.1056/NEJM199110173251604
5. Amieva M, Peek RM Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology. 2016;150(1):64-78. DOI: 10.1053/j.gastro.2015.09.004
6. Canzian F, Rizzato C, Stein A, Flores-Luna L, Camorlinga-Ponce M, Mendez-Tenorio A, et al. Phylogenetic origin of Helicobacter pylori pathogenicity island and risk of stomach cancer and high-grade premalignant gastric lesions. European Journal of Cancer Prevention. 2023;32(3):301-304. DOI: 10.1097/CEJ.0000000000000779
7. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993;342(8871):575-577. DOI: 10.1016/0140-6736(93)91409-f
8. Floch P, Mégraud F, Lehours P. Helicobacter pylori strains and gastric MALT lymphoma. Toxins (Basel). 2017;9(4):132. DOI: 10.3390/toxins9040132
9. Rossi D, Bertoni F, Zucca E. Marginal-zone lymphomas. The New England Journal of Medicine. 2022;386(6):568-581. DOI: 10.1056/NEJMra2102568
10. D'Elios MM, Appelmelk BJ, Amedei A, Bergman MP, Del Prete G. Gastric autoimmunity: The role of Helicobacter pylori and molecular mimicry. Trends in Molecular Medicine. 2004;10(7):316-323. DOI: 10.1016/j.molmed.2004.06.001
11. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. The Journal of Clinical Investigation. 2007;117(1):60-69. DOI: 10.1172/JCI30111
12. Schistosomes, liver flukes and Helicobacter pylori. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 1994;61:1-241
13. Choi IJ, Kim CG, Lee JY, Kim YI, Kook MC, Park B, et al. Family history of gastric cancer and Helicobacter pylori treatment. The New England Journal of Medicine. 2020;382(5):427-436. DOI: 10.1056/NEJMoa1909666
14. Kuipers EJ, Sipponen P. Helicobacter pylori eradication for the prevention of gastric cancer. Helicobacter. 2006;11(Suppl. 1):52-57. DOI: 10.1111/j.1478-405X.2006.00425.x
15. Lee YC, Dore MP, Graham DY. Diagnosis and treatment of Helicobacter pylori infection. Annual Review of Medicine. 2022;73:183-195. DOI: 10.1146/annurev-med-042220-020814
16. Choi IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. The New England Journal of Medicine. 2018;378(12):1085-1095. DOI: 10.1056/NEJMoa1708423
17. Kalali B, Mejías-Luque R, Javaheri A, Gerhard MH. Pylori virulence factors: Influence on immune system and pathology. Mediators of Inflammation. 2014;2014:426309. DOI: 10.1155/2014/426309
18. Moss SF, Blaser MJ. Mechanisms of disease: Inflammation and the origins of cancer. Nature Clinical Practice. Oncology. 2005;2(2):90-97; quiz 1 p following 113. DOI: 10.1038/ncponc0081
19. Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, et al. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. The Journal of Experimental Medicine. 1998;187(1):135-140. DOI: 10.1084/jem.187.1.135
20. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science. 2003;301(5636):1099-1102. DOI: 10.1126/science.1086871
21. Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, et al. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. The Journal of Experimental Medicine. 2003;198(12):1887-1897. DOI: 10.1084/jem.20030621
22. Schmees C, Prinz C, Treptau T, Rad R, Hengst L, Voland P, et al. Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase. Gastroenterology. 2007;132(5):1820-1833. DOI: 10.1053/j.gastro.2007.02.031
23. Amedei A, Munari F, Della Bella C, Niccolai E, Benagiano M, Bencini L, et al. Helicobacter pylori HP0175 promotes the production of IL-23, IL-6, IL-1b and TGF-b. European Journal of Inflammation. 2013;11(1):261-268. DOI: 10.1177/1721727X1301100127
24. Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A, Benagiano M, et al. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. The Journal of Clinical Investigation. 2006;116(4):1092-1101. DOI: 10.1172/JCI27177. Epub 2006 Mar 16
25. Crabtree JE, Peichl P, Wyatt JI, Stachl U, Lindley IJ. Gastric interleukin-8 and IgA IL-8 autoantibodies in Helicobacter pylori infection. Scandinavian Journal of Immunology. 1993;37(1):65-70. DOI: 10.1111/j.1365-3083.1993.tb01666.x
26. Kaparakis M, Philpott DJ, Ferrero RL. Mammalian NLR proteins; discriminating foe from friend. Immunology and Cell Biology. 2007;85(6):495-502. DOI: 10.1038/sj.icb.7100105. Epub 2007 Aug 7
27. D'Elios MM, Manghetti M, Almerigogna F, Amedei A, Costa F, Burroni D, et al. Different cytokine profile and antigen-specificity repertoire in Helicobacter pylori-specific T cell clones from the antrum of chronic gastritis patients with or without peptic ulcer. European Journal of Immunology. 1997;27(7):1751-1755. DOI: 10.1002/eji.1830270723
28. Meyer F, Wilson KT, James SP. Modulation of innate cytokine responses by products of Helicobacter pylori. Infection and Immunity. 2000;68(11):6265-6272. DOI: 10.1128/IAI.68.11.6265-6272.2000
29. Della, Bella C, D'Elios S, Coletta S, Benagiano M, Azzurri A, Cianchi F, et al. Increased IL-17A serum levels and gastric Th17 cells in Helicobacter pylori-infected patients with gastric premalignant lesions. Cancers (Basel). 2023;15(6):1662. DOI: 10.3390/cancers15061662
30. Vinagre RMDF, Vinagre IDF, Vilar-E-Silva A, Fecury AA, Martins LC. Helicobacter pylori infection and immune profile of patients with different gastroduodenal diseases. Arquivos de Gastroenterologia. 2018;55(2):122-127. DOI: 10.1590/S0004-2803.201800000-21
31. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annual Review of Immunology. 2007;25:821-852. DOI: 10.1146/annurev.immunol.25.022106.141557
32. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annual Review of Immunology. 2009;27:485-517. DOI: 10.1146/annurev.immunol.021908.132710
33. Capitani N, Codolo G, Vallese F, Minervini G, Grassi A, Cianchi F, et al. The lipoprotein HP1454 of Helicobacter pylori regulates T-cell response by shaping T-cell receptor signalling. Cellular Microbiology. 2019;21(5):e13006. DOI: 10.1111/cmi.13006
34. Shi Y, Liu XF, Zhuang Y, Zhang JY, Liu T, Yin Z, et al. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. Journal of Immunology. 2010;184(9):5121-5129. DOI: 10.4049/jimmunol.0901115
35. Kang JH, Park S, Rho J, Hong EJ, Cho YE, Won YS, et al. IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC. Gastric Cancer. 2023;26(1):82-94. DOI: 10.1007/s10120-022-01342-5. Epub 2022 Sep 20
36. Della Bella C, Soluri MF, Puccio S, Benagiano M, Grassi A, Bitetti J, et al. The Helicobacter pylori CagY protein drives gastric Th1 and Th17 inflammation and B cell proliferation in gastric MALT lymphoma. International Journal of Molecular Sciences. 2021;22(17):9459. DOI: 10.3390/ijms22179459
37. D'Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT, Burroni D, et al. T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease. Journal of Immunology. 1997;158(2):962-967
38. Sommer F, Faller G, Konturek P, Kirchner T, Hahn EG, Zeus J, et al. Antrum- and corpus mucosa-infiltrating CD4(+) lymphocytes in Helicobacter pylori gastritis display a Th1 phenotype. Infection and Immunity. 1998;66(11):5543-5546. DOI: 10.1128/IAI.66.11.5543-5546.1998
39. Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK, et al. Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology. 1998;114(3):482-492. DOI: 10.1016/s0016-5085(98)70531-1
40. de Jonge R, Kuipers EJ, Langeveld SC, Loffeld RJ, Stoof J, van Vliet AH, et al. The Helicobacter pylori plasticity region locus jhp0947-jhp0949 is associated with duodenal ulcer disease and interleukin-12 production in monocyte cells. FEMS Immunology and Medical Microbiology. 2004;41(2):161-167. DOI: 10.1016/j.femsim.2004.03.003
41. Lehmann FS, Terracciano L, Carena I, Baeriswyl C, Drewe J, Tornillo L, et al. In situ correlation of cytokine secretion and apoptosis in Helicobacter pylori-associated gastritis. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2002;283(2):G481-G488. DOI: 10.1152/ajpgi.00422.2001
42. Wen S, Felley CP, Bouzourene H, Reimers M, Michetti P, Pan-Hammarström Q. Inflammatory gene profiles in gastric mucosa during Helicobacter pylori infection in humans. Journal of Immunology. 2004;172(4):2595-2606. DOI: 10.4049/jimmunol.172.4.2595
43. Pellicanò A, Sebkova L, Monteleone G, Guarnieri G, Imeneo M, Pallone F, et al. Interleukin-12 drives the Th1 signaling pathway in Helicobacter pylori-infected human gastric mucosa. Infection and Immunity. 2007;75(4):1738-1744. DOI: 10.1128/IAI.01446-06
44. Touati E, Michel V, Thiberge JM, Wuscher N, Huerre M, Labigne A. Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology. 2003;124(5):1408-1419. DOI: 10.1016/s0016-5085(03)00266-x
45. McCune A, Lane A, Murray L, Harvey I, Nair P, Donovan J, et al. Reduced risk of atopic disorders in adults with Helicobacter pylori infection. European Journal of Gastroenterology & Hepatology. 2003;15(6):637-640. DOI: 10.1097/00042737-200306000-00010
46. Codolo G, Coletta S, D'Elios MM, de Bernard M. HP-NAP of Helicobacter pylori: The power of the immunomodulation. Frontiers in Immunology. 2022;13:944139. DOI: 10.3389/fimmu.2022.944139
47. Borbet TC, Zhang X, Müller A, Blaser MJ. The role of the changing human microbiome in the asthma pandemic. The Journal of Allergy and Clinical Immunology. 2019;144(6):1457-1466. DOI: 10.1016/j.jaci.2019.10.022
48. Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with asthma and allergy. Archives of Internal Medicine. 2007;167(8):821-827. DOI: 10.1001/archinte.167.8.821
49. Jaka H, Smith SI. Forty years of H. pylori: The African perspective. Digestive Diseases. 2023;42(2):161-165. DOI: 10.1159/000535263
50. Holcombe C. Helicobacter pylori: The African enigma. Gut. 1992;33(4):429-431. DOI: 10.1136/gut.33.4.429
51. D’Elios MM, Andersen LP, Del Prete G. Inflammation and host reponse. Current Opinion in Gastroenterology Online. 1998;14(suppl 1):S15-S19
52. Mejías-Luque R, Gerhard M. Immune evasion strategies and persistence of Helicobacter pylori. Current Topics in Microbiology and Immunology. 2017;400:53-71. DOI: 10.1007/978-3-319-50520-6_3
53. Cadamuro AC, Rossi AF, Maniezzo NM, Silva AE. Helicobacter pylori infection: Host immune response, implications on gene expression and microRNAs. World Journal of Gastroenterology. 2014;20(6):1424-1437. DOI: 10.3748/wjg.v20.i6.1424
54. Merrell DS, Falkow S. Frontal and stealth attack strategies in microbial pathogenesis. Nature. 2004;430(6996):250-256. DOI: 10.1038/nature02760
55. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer epidemiology. Lancet. 1975;2(7924):58-60. DOI: 10.1016/s0140-6736(75)90498-5
56. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process—first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Research. 1992;52(24):6735-6740
57. Huang KK, Ramnarayanan K, Zhu F, Srivastava S, Xu C, Tan ALK, et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell. 2018;33(1):137-150.e5. DOI: 10.1016/j.ccell.2017.11.018
58. Costa L, Corre S, Michel V, Le Luel K, Fernandes J, Ziveri J, et al. USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis. Gut. 2020;69(9):1582-1591. DOI: 10.1136/gutjnl-2019-318640
59. Guo Y, Huang A, Hu C, Zhou Y, Zhang X, Czajkowsky DM, et al. Complex clonal mosaicism within microdissected intestinal metaplastic glands without concurrent gastric cancer. Journal of Medical Genetics. 2016;53(9):643-646. DOI: 10.1136/jmedgenet-2016-103872
60. Dixon BREA, Hossain R, Patel RV, Algood HMS. Th17 cells in Helicobacter pylori infection: A dichotomy of help and harm. Infection and Immunity. 2019;87(11):e00363-e00319. DOI: 10.1128/IAI.00363-19
61. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. The New England Journal of Medicine. 1997;337(20):1441-1448. DOI: 10.1056/NEJM199711133372007
62. Bergman MP, Vandenbroucke-Grauls CM, Appelmelk BJ, D'Elios MM, Amedei A, Azzurri A, et al. The story so far: Helicobacter pylori and gastric autoimmunity. International Reviews of Immunology. 2005;24(1-2):63-91. DOI: 10.1080/08830180590884648
63. Stolte M, Baumann K, Bethke B, Ritter M, Lauer E, Eidt H. Active autoimmune gastritis without total atrophy of the glands. Zeitschrift für Gastroenterologie. 1992;30(10):729-735
64. Stolte M, Meier E, Meining A. Cure of autoimmune gastritis by Helicobacter pylori eradication in a 21-year-old male. Zeitschrift für Gastroenterologie. 1998;36(8):641-643
65. Tucci A, Poli L, Tosetti C, Biasco G, Grigioni W, Varoli O, et al. Reversal of fundic atrophy after eradication of Helicobacter pylori. The American Journal of Gastroenterology. 1998;93(9):1425-1431. DOI: 10.1111/j.1572-0241.1998.00454.x
66. Faller G, Steininger H, Eck M, Hensen J, Hann EG, Kirchner T. Antigastric autoantibodies in Helicobacter pylori gastritis: Prevalence, in-situ binding sites and clues for clinical relevance. Virchows Archiv. 1996;427(5):483-486. DOI: 10.1007/BF00199508
67. Faller G, Steininger H, Kränzlein J, Maul H, Kerkau T, Hensen J, et al. Antigastric autoantibodies in Helicobacter pylori infection: Implications of histological and clinical parameters of gastritis. Gut. 1997;41(5):619-623. DOI: 10.1136/gut.41.5.619
68. Negrini R, Lisato L, Zanella I, Cavazzini L, Gullini S, Villanacci V, et al. Helicobacter pylori infection induces antibodies cross-reacting with human gastric mucosa. Gastroenterology. 1991;101(2):437-445. DOI: 10.1016/0016-5085(91)90023-e
69. Negrini R, Savio A, Poiesi C, Appelmelk BJ, Buffoli F, Paterlini A, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology. 1996;111(3):655-665. DOI: 10.1053/gast.1996.v111.pm8780570
70. Steininger H, Faller G, Dewald E, Brabletz T, Jung A, Kirchner T. Apoptosis in chronic gastritis and its correlation with antigastric autoantibodies. Virchows Archiv. 1998;433(1):13-18. DOI: 10.1007/s004280050210
71. Toh BH, Sentry JW, Alderuccio F. The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis. Immunology Today. 2000;21(7):348-354. DOI: 10.1016/s0167-5699(00)01653-4
72. Claeys D, Faller G, Appelmelk BJ, Negrini R, Kirchner T. The gastric H⁺, K⁺-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy. Gastroenterology. 1998;115(2):340-347. DOI: 10.1016/s0016-5085(98)70200-8
73. Appelmelk BJ, Faller G, Claeys D, Kirchner T, Vandenbroucke-Grauls CM. Bugs on trial: The case of Helicobacter pylori and autoimmunity. Immunology Today. 1998;19(7):296-299. DOI: 10.1016/s0167-5699(98)01281-x
74. Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, et al. Molecular mimicry between Helicobacter pylori antigens and H⁺, K⁺-adenosine triphosphatase in human gastric autoimmunity. The Journal of Experimental Medicine. 2003;198(8):1147-1156. DOI: 10.1084/jem.20030530
75. D'Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M, De Pont JJ, et al. H⁺, K⁺-ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology. 2001;120(2):377-386. DOI: 10.1053/gast.2001.21187
76. Bergman MP, Amedei A, D'Elios MM, Azzurri A, Benagiano M, Tamburini C, et al. Characterization of H⁺, K⁺-ATPase T cell epitopes in human autoimmune gastritis. European Journal of Immunology. 2003;33(2):539-545. DOI: 10.1002/immu.200310030. Erratum in: Eur J Immunol. 2003 Apr; 33(4):1139
77. Houghton J, Macera-Bloch LS, Harrison L, Kim KH, Korah RM. Tumor necrosis factor alpha and interleukin 1beta up-regulate gastric mucosal Fas antigen expression in Helicobacter pylori infection. Infection and Immunity. 2000;68(3):1189-1195. DOI: 10.1128/IAI.68.3.1189-1195.2000
78. Wang J, Fan X, Lindholm C, Bennett M, O'Connoll J, Shanahan F, et al. Helicobacter pylori modulates lymphoepithelial cell interactions leading to epithelial cell damage through Fas/Fas ligand interactions. Infection and Immunity. 2000;68(7):4303-4311. DOI: 10.1128/IAI.68.7.4303-4311.2000
79. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The non-Hodgkin’s lymphoma classification project. Blood. 1997;89(11):3909-3918
80. Du MQ. MALT lymphoma: Recent advances in aetiology and molecular genetics. Journal of Clinical and Experimental Hematopathology. 2007;47(2):31-42. DOI: 10.3960/jslrt.47.31
81. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983;52(8):1410-1416. DOI: 10.1002/1097-0142(19831015)52:8< 1410::aid-cncr2820520813>3.0.co;2-3
82. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175-1176. DOI: 10.1016/0140-6736(91)92035-z
83. Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet. 1993;342(8871):571-574. DOI: 10.1016/0140-6736(93)91408-e
84. Hussell T, Isaacson PG, Crabtree JE, Spencer J. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. The Journal of Pathology. 1996;178(2):122-127. DOI: 10.1002/(SICI)1096-9896(199602)178:2<122::AID-PATH486>3.0.CO;2-D
85. Greiner A, Knörr C, Qin Y, Sebald W, Schimpl A, Banchereau J, et al. Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. The American Journal of Pathology. 1997;150(5):1583-1593
86. D'Elios MM, Amedei A, Manghetti M, Costa F, Baldari CT, Quazi AS, et al. Impaired T-cell regulation of B-cell growth in Helicobacter pylori—related gastric low-grade MALT lymphoma. Gastroenterology. 1999;117(5):1105-1112. DOI: 10.1016/s0016-5085(99)70395-1. 2002; 2(10): 735-47. DOI: 10.1038/nri911
87. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. The Journal of Experimental Medicine. 2000;192(5):755-760. DOI: 10.1084/jem.192.5.755
88. Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. The Journal of Experimental Medicine. 2002;196(1):129-134. DOI: 10.1084/jem.20020063
89. Street SE, Hayakawa Y, Zhan Y, Lew AM, MacGregor D, Jamieson AM, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. The Journal of Experimental Medicine. 2004;199(6):879-884. DOI: 10.1084/jem.20031981
90. Clementi R, Locatelli F, Dupré L, Garaventa A, Emmi L, Bregni M, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood. 2005;105(11):4424-4428. DOI: 10.1182/blood-2004-04-1477
91. Lehours P, Zheng Z, Skoglund A, Mégraud F, Engstrand L. Is there a link between the lipopolysaccharide of Helicobacter pylori gastric MALT lymphoma associated strains and lymphoma pathogenesis? PLoS One. 2009;4(10):e7297. DOI: 10.1371/journal.pone.0007297
92. Lehours P, Dupouy S, Bergey B, Ruskoné-Foumestraux A, Delchier JC, Rad R, et al. Identification of a genetic marker of Helicobacter pylori strains involved in gastric extranodal marginal zone B cell lymphoma of the MALT-type. Gut. 2004;53(7):931-937. DOI: 10.1136/gut.2003.028811
93. Correa P, Piazuelo MB. The gastric precancerous cascade. Journal of Digestive Diseases. 2012;13(1):2-9. DOI: 10.1111/j.1751-2980.2011.00550.x
94. van Loo G, Bertrand MJM. Death by TNF: A road to inflammation. Nature Reviews. Immunology. 2023;23(5):289-303. DOI: 10.1038/s41577-022-00792-3
95. Ohno M, Kato M, Nakamura T, Saitoh Y. Gene expression for tumor necrosis factor alpha and its production in gastric cancer patients. Japanese Journal of Cancer Research. 1994;85(10):1029-1034. DOI: 10.1111/j.1349-7006.1994.tb02901.x
96. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404(6776):398-402. DOI: 10.1038/35006081. Erratum in: Nature 2001; 412(6842):99
97. Salama NR, Hartung ML, Müller A. Life in the human stomach: Persistence strategies of the bacterial pathogen Helicobacter pylori. Nature Reviews. Microbiology. 2013;11(6):385-399. DOI: 10.1038/nrmicro3016
98. Wroblewski LE, Peek RM Jr, Wilson KT. Helicobacter pylori and gastric cancer: Factors that modulate disease risk. Clinical Microbiology Reviews. 2010;23(4):713-739. DOI: 10.1128/CMR.00011-10
99. Moyat M, Velin D. Immune responses to Helicobacter pylori infection. World Journal of Gastroenterology. 2014;20(19):5583-5593. DOI: 10.3748/wjg.v20.i19.5583
100. Greten FR, Grivennikov SI. Inflammation and cancer: Triggers, mechanisms, and consequences. Immunity. 2019;51(1):27-41. DOI: 10.1016/j.immuni.2019.06.025
101. Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochemical and Biophysical Research Communications. 2008;374(3):533-537. DOI: 10.1016/j.bbrc.2008.07.060
102. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer. Nature. 2001;412(6842):99. DOI: 10.1038/35083631
103. Luzza F, Parrello T, Monteleone G, Sebkova L, Romano M, Zarrilli R, et al. Up-regulation of IL-17 is associated with bioactive IL-8 expression in Helicobacter pylori-infected human gastric mucosa. Journal of Immunology. 2000;165(9):5332-5337. DOI: 10.4049/jimmunol.165.9.5332
104. Della Bella C, Antico A, Panozzo MP, Capitani N, Petrone L, Benagiano M, et al. Gastric Th17 cells specific for H+/K+-ATPase and serum IL-17 signature in gastric autoimmunity. Frontiers in Immunology. 2022;13:952674. DOI: 10.3389/fimmu.2022.952674
105. International Agency for the Research on Cancer (WHO). Global Cancer Observatory – Globocan [Internet]. Lyon, France: International Agency for the Research on Cancer (WHO); 2024. Available from: https://gco.iarc.fr/ [Accessed: January 1, 2024]
106. Alikhani M, Esmaeili M, Tashakoripour M, Mohagheghi MA, Eshagh Hosseini M, Touati E, et al. Alteration in serum levels of tumor necrosis factor alpha is associated with histopathologic progression of gastric cancer. Iranian Biomedical Journal. 2023;27(1):72-78. DOI: 10.52547/ibj.3847
107. Amedei A, Niccolai E, Della Bella C, Cianchi F, Trallori G, Benagiano M, et al. Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma. Cancer Immunology, Immunotherapy. 2009;58(11):1819-1830. DOI: 10.1007/s00262-009-0693-8
108. Fragoulis GE, Siebert S, McInnes IB. Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annual Review of Medicine. 2016;67:337-353. DOI: 10.1146/annurev-med-051914-021944. Epub 2015 Nov 4
109. Sun K, Xu R, Ma F, Yang N, Li Y, Sun X, et al. scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nature Communications. 2022;13(1):4943. DOI: 10.1038/s41467-022-32627-z
110. Li S, Cong X, Gao H, Lan X, Li Z, Wang W, et al. Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. Journal of Experimental & Clinical Cancer Research. 2019;38(1):6. DOI: 10.1186/s13046-018-1003-0

[1] 1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1(8390):1311-1315. DOI: 10.1016/s0140-6736(84)91816-6

[2] 2. Robinson K, Atherton JC. The spectrum of helicobacter-mediated diseases. Annual Review of Pathology. 2021;16:123-144. DOI: 10.1146/annurev-pathol-032520-024949

[3] 3. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. The New England Journal of Medicine. 1991;325(16):1127-1131. DOI: 10.1056/NEJM199110173251603

[4] 4. Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. The New England Journal of Medicine. 1991;325(16):1132-1136. DOI: 10.1056/NEJM199110173251604

[5] 5. Amieva M, Peek RM Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology. 2016;150(1):64-78. DOI: 10.1053/j.gastro.2015.09.004

[6] 6. Canzian F, Rizzato C, Stein A, Flores-Luna L, Camorlinga-Ponce M, Mendez-Tenorio A, et al. Phylogenetic origin of Helicobacter pylori pathogenicity island and risk of stomach cancer and high-grade premalignant gastric lesions. European Journal of Cancer Prevention. 2023;32(3):301-304. DOI: 10.1097/CEJ.0000000000000779

[7] 7. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993;342(8871):575-577. DOI: 10.1016/0140-6736(93)91409-f

[8] 8. Floch P, Mégraud F, Lehours P. Helicobacter pylori strains and gastric MALT lymphoma. Toxins (Basel). 2017;9(4):132. DOI: 10.3390/toxins9040132

[9] 9. Rossi D, Bertoni F, Zucca E. Marginal-zone lymphomas. The New England Journal of Medicine. 2022;386(6):568-581. DOI: 10.1056/NEJMra2102568

[10] 10. D'Elios MM, Appelmelk BJ, Amedei A, Bergman MP, Del Prete G. Gastric autoimmunity: The role of Helicobacter pylori and molecular mimicry. Trends in Molecular Medicine. 2004;10(7):316-323. DOI: 10.1016/j.molmed.2004.06.001

[11] 11. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. The Journal of Clinical Investigation. 2007;117(1):60-69. DOI: 10.1172/JCI30111

[12] 12. Schistosomes, liver flukes and Helicobacter pylori. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 1994;61:1-241

[13] 13. Choi IJ, Kim CG, Lee JY, Kim YI, Kook MC, Park B, et al. Family history of gastric cancer and Helicobacter pylori treatment. The New England Journal of Medicine. 2020;382(5):427-436. DOI: 10.1056/NEJMoa1909666

[14] 14. Kuipers EJ, Sipponen P. Helicobacter pylori eradication for the prevention of gastric cancer. Helicobacter. 2006;11(Suppl. 1):52-57. DOI: 10.1111/j.1478-405X.2006.00425.x

[15] 15. Lee YC, Dore MP, Graham DY. Diagnosis and treatment of Helicobacter pylori infection. Annual Review of Medicine. 2022;73:183-195. DOI: 10.1146/annurev-med-042220-020814

[16] 16. Choi IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. The New England Journal of Medicine. 2018;378(12):1085-1095. DOI: 10.1056/NEJMoa1708423

[17] 17. Kalali B, Mejías-Luque R, Javaheri A, Gerhard MH. Pylori virulence factors: Influence on immune system and pathology. Mediators of Inflammation. 2014;2014:426309. DOI: 10.1155/2014/426309

[18] 18. Moss SF, Blaser MJ. Mechanisms of disease: Inflammation and the origins of cancer. Nature Clinical Practice. Oncology. 2005;2(2):90-97; quiz 1 p following 113. DOI: 10.1038/ncponc0081

[19] 19. Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, et al. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. The Journal of Experimental Medicine. 1998;187(1):135-140. DOI: 10.1084/jem.187.1.135

[20] 20. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science. 2003;301(5636):1099-1102. DOI: 10.1126/science.1086871

[21] 21. Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, et al. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. The Journal of Experimental Medicine. 2003;198(12):1887-1897. DOI: 10.1084/jem.20030621

[22] 22. Schmees C, Prinz C, Treptau T, Rad R, Hengst L, Voland P, et al. Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase. Gastroenterology. 2007;132(5):1820-1833. DOI: 10.1053/j.gastro.2007.02.031

[23] 23. Amedei A, Munari F, Della Bella C, Niccolai E, Benagiano M, Bencini L, et al. Helicobacter pylori HP0175 promotes the production of IL-23, IL-6, IL-1b and TGF-b. European Journal of Inflammation. 2013;11(1):261-268. DOI: 10.1177/1721727X1301100127

[24] 24. Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A, Benagiano M, et al. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. The Journal of Clinical Investigation. 2006;116(4):1092-1101. DOI: 10.1172/JCI27177. Epub 2006 Mar 16

[25] 25. Crabtree JE, Peichl P, Wyatt JI, Stachl U, Lindley IJ. Gastric interleukin-8 and IgA IL-8 autoantibodies in Helicobacter pylori infection. Scandinavian Journal of Immunology. 1993;37(1):65-70. DOI: 10.1111/j.1365-3083.1993.tb01666.x

[26] 26. Kaparakis M, Philpott DJ, Ferrero RL. Mammalian NLR proteins; discriminating foe from friend. Immunology and Cell Biology. 2007;85(6):495-502. DOI: 10.1038/sj.icb.7100105. Epub 2007 Aug 7

[27] 27. D'Elios MM, Manghetti M, Almerigogna F, Amedei A, Costa F, Burroni D, et al. Different cytokine profile and antigen-specificity repertoire in Helicobacter pylori-specific T cell clones from the antrum of chronic gastritis patients with or without peptic ulcer. European Journal of Immunology. 1997;27(7):1751-1755. DOI: 10.1002/eji.1830270723

[28] 28. Meyer F, Wilson KT, James SP. Modulation of innate cytokine responses by products of Helicobacter pylori. Infection and Immunity. 2000;68(11):6265-6272. DOI: 10.1128/IAI.68.11.6265-6272.2000

[29] 29. Della, Bella C, D'Elios S, Coletta S, Benagiano M, Azzurri A, Cianchi F, et al. Increased IL-17A serum levels and gastric Th17 cells in Helicobacter pylori-infected patients with gastric premalignant lesions. Cancers (Basel). 2023;15(6):1662. DOI: 10.3390/cancers15061662

[30] 30. Vinagre RMDF, Vinagre IDF, Vilar-E-Silva A, Fecury AA, Martins LC. Helicobacter pylori infection and immune profile of patients with different gastroduodenal diseases. Arquivos de Gastroenterologia. 2018;55(2):122-127. DOI: 10.1590/S0004-2803.201800000-21

[31] 31. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annual Review of Immunology. 2007;25:821-852. DOI: 10.1146/annurev.immunol.25.022106.141557

[32] 32. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annual Review of Immunology. 2009;27:485-517. DOI: 10.1146/annurev.immunol.021908.132710

[33] 33. Capitani N, Codolo G, Vallese F, Minervini G, Grassi A, Cianchi F, et al. The lipoprotein HP1454 of Helicobacter pylori regulates T-cell response by shaping T-cell receptor signalling. Cellular Microbiology. 2019;21(5):e13006. DOI: 10.1111/cmi.13006

[34] 34. Shi Y, Liu XF, Zhuang Y, Zhang JY, Liu T, Yin Z, et al. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. Journal of Immunology. 2010;184(9):5121-5129. DOI: 10.4049/jimmunol.0901115

[35] 35. Kang JH, Park S, Rho J, Hong EJ, Cho YE, Won YS, et al. IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC. Gastric Cancer. 2023;26(1):82-94. DOI: 10.1007/s10120-022-01342-5. Epub 2022 Sep 20

[36] 36. Della Bella C, Soluri MF, Puccio S, Benagiano M, Grassi A, Bitetti J, et al. The Helicobacter pylori CagY protein drives gastric Th1 and Th17 inflammation and B cell proliferation in gastric MALT lymphoma. International Journal of Molecular Sciences. 2021;22(17):9459. DOI: 10.3390/ijms22179459

[37] 37. D'Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT, Burroni D, et al. T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease. Journal of Immunology. 1997;158(2):962-967

[38] 38. Sommer F, Faller G, Konturek P, Kirchner T, Hahn EG, Zeus J, et al. Antrum- and corpus mucosa-infiltrating CD4(+) lymphocytes in Helicobacter pylori gastritis display a Th1 phenotype. Infection and Immunity. 1998;66(11):5543-5546. DOI: 10.1128/IAI.66.11.5543-5546.1998

[39] 39. Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK, et al. Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology. 1998;114(3):482-492. DOI: 10.1016/s0016-5085(98)70531-1

[40] 40. de Jonge R, Kuipers EJ, Langeveld SC, Loffeld RJ, Stoof J, van Vliet AH, et al. The Helicobacter pylori plasticity region locus jhp0947-jhp0949 is associated with duodenal ulcer disease and interleukin-12 production in monocyte cells. FEMS Immunology and Medical Microbiology. 2004;41(2):161-167. DOI: 10.1016/j.femsim.2004.03.003

[41] 41. Lehmann FS, Terracciano L, Carena I, Baeriswyl C, Drewe J, Tornillo L, et al. In situ correlation of cytokine secretion and apoptosis in Helicobacter pylori-associated gastritis. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2002;283(2):G481-G488. DOI: 10.1152/ajpgi.00422.2001

[42] 42. Wen S, Felley CP, Bouzourene H, Reimers M, Michetti P, Pan-Hammarström Q. Inflammatory gene profiles in gastric mucosa during Helicobacter pylori infection in humans. Journal of Immunology. 2004;172(4):2595-2606. DOI: 10.4049/jimmunol.172.4.2595

[43] 43. Pellicanò A, Sebkova L, Monteleone G, Guarnieri G, Imeneo M, Pallone F, et al. Interleukin-12 drives the Th1 signaling pathway in Helicobacter pylori-infected human gastric mucosa. Infection and Immunity. 2007;75(4):1738-1744. DOI: 10.1128/IAI.01446-06

[44] 44. Touati E, Michel V, Thiberge JM, Wuscher N, Huerre M, Labigne A. Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology. 2003;124(5):1408-1419. DOI: 10.1016/s0016-5085(03)00266-x

[45] 45. McCune A, Lane A, Murray L, Harvey I, Nair P, Donovan J, et al. Reduced risk of atopic disorders in adults with Helicobacter pylori infection. European Journal of Gastroenterology & Hepatology. 2003;15(6):637-640. DOI: 10.1097/00042737-200306000-00010

[46] 46. Codolo G, Coletta S, D'Elios MM, de Bernard M. HP-NAP of Helicobacter pylori: The power of the immunomodulation. Frontiers in Immunology. 2022;13:944139. DOI: 10.3389/fimmu.2022.944139

[47] 47. Borbet TC, Zhang X, Müller A, Blaser MJ. The role of the changing human microbiome in the asthma pandemic. The Journal of Allergy and Clinical Immunology. 2019;144(6):1457-1466. DOI: 10.1016/j.jaci.2019.10.022

[48] 48. Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with asthma and allergy. Archives of Internal Medicine. 2007;167(8):821-827. DOI: 10.1001/archinte.167.8.821

[49] 49. Jaka H, Smith SI. Forty years of H. pylori: The African perspective. Digestive Diseases. 2023;42(2):161-165. DOI: 10.1159/000535263

[50] 50. Holcombe C. Helicobacter pylori: The African enigma. Gut. 1992;33(4):429-431. DOI: 10.1136/gut.33.4.429

[51] 51. D’Elios MM, Andersen LP, Del Prete G. Inflammation and host reponse. Current Opinion in Gastroenterology Online. 1998;14(suppl 1):S15-S19

[52] 52. Mejías-Luque R, Gerhard M. Immune evasion strategies and persistence of Helicobacter pylori. Current Topics in Microbiology and Immunology. 2017;400:53-71. DOI: 10.1007/978-3-319-50520-6_3

[53] 53. Cadamuro AC, Rossi AF, Maniezzo NM, Silva AE. Helicobacter pylori infection: Host immune response, implications on gene expression and microRNAs. World Journal of Gastroenterology. 2014;20(6):1424-1437. DOI: 10.3748/wjg.v20.i6.1424

[54] 54. Merrell DS, Falkow S. Frontal and stealth attack strategies in microbial pathogenesis. Nature. 2004;430(6996):250-256. DOI: 10.1038/nature02760

[55] 55. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer epidemiology. Lancet. 1975;2(7924):58-60. DOI: 10.1016/s0140-6736(75)90498-5

[56] 56. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process—first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Research. 1992;52(24):6735-6740

[57] 57. Huang KK, Ramnarayanan K, Zhu F, Srivastava S, Xu C, Tan ALK, et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell. 2018;33(1):137-150.e5. DOI: 10.1016/j.ccell.2017.11.018

[58] 58. Costa L, Corre S, Michel V, Le Luel K, Fernandes J, Ziveri J, et al. USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis. Gut. 2020;69(9):1582-1591. DOI: 10.1136/gutjnl-2019-318640

[59] 59. Guo Y, Huang A, Hu C, Zhou Y, Zhang X, Czajkowsky DM, et al. Complex clonal mosaicism within microdissected intestinal metaplastic glands without concurrent gastric cancer. Journal of Medical Genetics. 2016;53(9):643-646. DOI: 10.1136/jmedgenet-2016-103872

[60] 60. Dixon BREA, Hossain R, Patel RV, Algood HMS. Th17 cells in Helicobacter pylori infection: A dichotomy of help and harm. Infection and Immunity. 2019;87(11):e00363-e00319. DOI: 10.1128/IAI.00363-19

[61] 61. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. The New England Journal of Medicine. 1997;337(20):1441-1448. DOI: 10.1056/NEJM199711133372007

[62] 62. Bergman MP, Vandenbroucke-Grauls CM, Appelmelk BJ, D'Elios MM, Amedei A, Azzurri A, et al. The story so far: Helicobacter pylori and gastric autoimmunity. International Reviews of Immunology. 2005;24(1-2):63-91. DOI: 10.1080/08830180590884648

[63] 63. Stolte M, Baumann K, Bethke B, Ritter M, Lauer E, Eidt H. Active autoimmune gastritis without total atrophy of the glands. Zeitschrift für Gastroenterologie. 1992;30(10):729-735

[64] 64. Stolte M, Meier E, Meining A. Cure of autoimmune gastritis by Helicobacter pylori eradication in a 21-year-old male. Zeitschrift für Gastroenterologie. 1998;36(8):641-643

[65] 65. Tucci A, Poli L, Tosetti C, Biasco G, Grigioni W, Varoli O, et al. Reversal of fundic atrophy after eradication of Helicobacter pylori. The American Journal of Gastroenterology. 1998;93(9):1425-1431. DOI: 10.1111/j.1572-0241.1998.00454.x

[66] 66. Faller G, Steininger H, Eck M, Hensen J, Hann EG, Kirchner T. Antigastric autoantibodies in Helicobacter pylori gastritis: Prevalence, in-situ binding sites and clues for clinical relevance. Virchows Archiv. 1996;427(5):483-486. DOI: 10.1007/BF00199508

[67] 67. Faller G, Steininger H, Kränzlein J, Maul H, Kerkau T, Hensen J, et al. Antigastric autoantibodies in Helicobacter pylori infection: Implications of histological and clinical parameters of gastritis. Gut. 1997;41(5):619-623. DOI: 10.1136/gut.41.5.619

[68] 68. Negrini R, Lisato L, Zanella I, Cavazzini L, Gullini S, Villanacci V, et al. Helicobacter pylori infection induces antibodies cross-reacting with human gastric mucosa. Gastroenterology. 1991;101(2):437-445. DOI: 10.1016/0016-5085(91)90023-e

[69] 69. Negrini R, Savio A, Poiesi C, Appelmelk BJ, Buffoli F, Paterlini A, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology. 1996;111(3):655-665. DOI: 10.1053/gast.1996.v111.pm8780570

[70] 70. Steininger H, Faller G, Dewald E, Brabletz T, Jung A, Kirchner T. Apoptosis in chronic gastritis and its correlation with antigastric autoantibodies. Virchows Archiv. 1998;433(1):13-18. DOI: 10.1007/s004280050210

[71] 71. Toh BH, Sentry JW, Alderuccio F. The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis. Immunology Today. 2000;21(7):348-354. DOI: 10.1016/s0167-5699(00)01653-4

[72] 72. Claeys D, Faller G, Appelmelk BJ, Negrini R, Kirchner T. The gastric H⁺, K⁺-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy. Gastroenterology. 1998;115(2):340-347. DOI: 10.1016/s0016-5085(98)70200-8

[73] 73. Appelmelk BJ, Faller G, Claeys D, Kirchner T, Vandenbroucke-Grauls CM. Bugs on trial: The case of Helicobacter pylori and autoimmunity. Immunology Today. 1998;19(7):296-299. DOI: 10.1016/s0167-5699(98)01281-x

[74] 74. Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, et al. Molecular mimicry between Helicobacter pylori antigens and H⁺, K⁺-adenosine triphosphatase in human gastric autoimmunity. The Journal of Experimental Medicine. 2003;198(8):1147-1156. DOI: 10.1084/jem.20030530

[75] 75. D'Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M, De Pont JJ, et al. H⁺, K⁺-ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology. 2001;120(2):377-386. DOI: 10.1053/gast.2001.21187

[76] 76. Bergman MP, Amedei A, D'Elios MM, Azzurri A, Benagiano M, Tamburini C, et al. Characterization of H⁺, K⁺-ATPase T cell epitopes in human autoimmune gastritis. European Journal of Immunology. 2003;33(2):539-545. DOI: 10.1002/immu.200310030. Erratum in: Eur J Immunol. 2003 Apr; 33(4):1139

[77] 77. Houghton J, Macera-Bloch LS, Harrison L, Kim KH, Korah RM. Tumor necrosis factor alpha and interleukin 1beta up-regulate gastric mucosal Fas antigen expression in Helicobacter pylori infection. Infection and Immunity. 2000;68(3):1189-1195. DOI: 10.1128/IAI.68.3.1189-1195.2000

[78] 78. Wang J, Fan X, Lindholm C, Bennett M, O'Connoll J, Shanahan F, et al. Helicobacter pylori modulates lymphoepithelial cell interactions leading to epithelial cell damage through Fas/Fas ligand interactions. Infection and Immunity. 2000;68(7):4303-4311. DOI: 10.1128/IAI.68.7.4303-4311.2000

[79] 79. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The non-Hodgkin’s lymphoma classification project. Blood. 1997;89(11):3909-3918

[80] 80. Du MQ. MALT lymphoma: Recent advances in aetiology and molecular genetics. Journal of Clinical and Experimental Hematopathology. 2007;47(2):31-42. DOI: 10.3960/jslrt.47.31

[81] 81. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer. 1983;52(8):1410-1416. DOI: 10.1002/1097-0142(19831015)52:8< 1410::aid-cncr2820520813>3.0.co;2-3

[82] 82. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175-1176. DOI: 10.1016/0140-6736(91)92035-z

[83] 83. Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet. 1993;342(8871):571-574. DOI: 10.1016/0140-6736(93)91408-e

[84] 84. Hussell T, Isaacson PG, Crabtree JE, Spencer J. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. The Journal of Pathology. 1996;178(2):122-127. DOI: 10.1002/(SICI)1096-9896(199602)178:2<122::AID-PATH486>3.0.CO;2-D

[85] 85. Greiner A, Knörr C, Qin Y, Sebald W, Schimpl A, Banchereau J, et al. Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. The American Journal of Pathology. 1997;150(5):1583-1593

[86] 86. D'Elios MM, Amedei A, Manghetti M, Costa F, Baldari CT, Quazi AS, et al. Impaired T-cell regulation of B-cell growth in Helicobacter pylori—related gastric low-grade MALT lymphoma. Gastroenterology. 1999;117(5):1105-1112. DOI: 10.1016/s0016-5085(99)70395-1. 2002; 2(10): 735-47. DOI: 10.1038/nri911

[87] 87. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. The Journal of Experimental Medicine. 2000;192(5):755-760. DOI: 10.1084/jem.192.5.755

[88] 88. Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. The Journal of Experimental Medicine. 2002;196(1):129-134. DOI: 10.1084/jem.20020063

[89] 89. Street SE, Hayakawa Y, Zhan Y, Lew AM, MacGregor D, Jamieson AM, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. The Journal of Experimental Medicine. 2004;199(6):879-884. DOI: 10.1084/jem.20031981

[90] 90. Clementi R, Locatelli F, Dupré L, Garaventa A, Emmi L, Bregni M, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood. 2005;105(11):4424-4428. DOI: 10.1182/blood-2004-04-1477

[91] 91. Lehours P, Zheng Z, Skoglund A, Mégraud F, Engstrand L. Is there a link between the lipopolysaccharide of Helicobacter pylori gastric MALT lymphoma associated strains and lymphoma pathogenesis? PLoS One. 2009;4(10):e7297. DOI: 10.1371/journal.pone.0007297

[92] 92. Lehours P, Dupouy S, Bergey B, Ruskoné-Foumestraux A, Delchier JC, Rad R, et al. Identification of a genetic marker of Helicobacter pylori strains involved in gastric extranodal marginal zone B cell lymphoma of the MALT-type. Gut. 2004;53(7):931-937. DOI: 10.1136/gut.2003.028811

[93] 93. Correa P, Piazuelo MB. The gastric precancerous cascade. Journal of Digestive Diseases. 2012;13(1):2-9. DOI: 10.1111/j.1751-2980.2011.00550.x

[94] 94. van Loo G, Bertrand MJM. Death by TNF: A road to inflammation. Nature Reviews. Immunology. 2023;23(5):289-303. DOI: 10.1038/s41577-022-00792-3

[95] 95. Ohno M, Kato M, Nakamura T, Saitoh Y. Gene expression for tumor necrosis factor alpha and its production in gastric cancer patients. Japanese Journal of Cancer Research. 1994;85(10):1029-1034. DOI: 10.1111/j.1349-7006.1994.tb02901.x

[96] 96. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404(6776):398-402. DOI: 10.1038/35006081. Erratum in: Nature 2001; 412(6842):99

[97] 97. Salama NR, Hartung ML, Müller A. Life in the human stomach: Persistence strategies of the bacterial pathogen Helicobacter pylori. Nature Reviews. Microbiology. 2013;11(6):385-399. DOI: 10.1038/nrmicro3016

[98] 98. Wroblewski LE, Peek RM Jr, Wilson KT. Helicobacter pylori and gastric cancer: Factors that modulate disease risk. Clinical Microbiology Reviews. 2010;23(4):713-739. DOI: 10.1128/CMR.00011-10

[99] 99. Moyat M, Velin D. Immune responses to Helicobacter pylori infection. World Journal of Gastroenterology. 2014;20(19):5583-5593. DOI: 10.3748/wjg.v20.i19.5583

[100] 100. Greten FR, Grivennikov SI. Inflammation and cancer: Triggers, mechanisms, and consequences. Immunity. 2019;51(1):27-41. DOI: 10.1016/j.immuni.2019.06.025

[101] 101. Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochemical and Biophysical Research Communications. 2008;374(3):533-537. DOI: 10.1016/j.bbrc.2008.07.060

[102] 102. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer. Nature. 2001;412(6842):99. DOI: 10.1038/35083631

[103] 103. Luzza F, Parrello T, Monteleone G, Sebkova L, Romano M, Zarrilli R, et al. Up-regulation of IL-17 is associated with bioactive IL-8 expression in Helicobacter pylori-infected human gastric mucosa. Journal of Immunology. 2000;165(9):5332-5337. DOI: 10.4049/jimmunol.165.9.5332

[104] 104. Della Bella C, Antico A, Panozzo MP, Capitani N, Petrone L, Benagiano M, et al. Gastric Th17 cells specific for H+/K+-ATPase and serum IL-17 signature in gastric autoimmunity. Frontiers in Immunology. 2022;13:952674. DOI: 10.3389/fimmu.2022.952674

[105] 105. International Agency for the Research on Cancer (WHO). Global Cancer Observatory – Globocan [Internet]. Lyon, France: International Agency for the Research on Cancer (WHO); 2024. Available from: https://gco.iarc.fr/ [Accessed: January 1, 2024]

[106] 106. Alikhani M, Esmaeili M, Tashakoripour M, Mohagheghi MA, Eshagh Hosseini M, Touati E, et al. Alteration in serum levels of tumor necrosis factor alpha is associated with histopathologic progression of gastric cancer. Iranian Biomedical Journal. 2023;27(1):72-78. DOI: 10.52547/ibj.3847

[107] 107. Amedei A, Niccolai E, Della Bella C, Cianchi F, Trallori G, Benagiano M, et al. Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma. Cancer Immunology, Immunotherapy. 2009;58(11):1819-1830. DOI: 10.1007/s00262-009-0693-8

[108] 108. Fragoulis GE, Siebert S, McInnes IB. Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annual Review of Medicine. 2016;67:337-353. DOI: 10.1146/annurev-med-051914-021944. Epub 2015 Nov 4

[109] 109. Sun K, Xu R, Ma F, Yang N, Li Y, Sun X, et al. scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nature Communications. 2022;13(1):4943. DOI: 10.1038/s41467-022-32627-z

[110] 110. Li S, Cong X, Gao H, Lan X, Li Z, Wang W, et al. Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. Journal of Experimental & Clinical Cancer Research. 2019;38(1):6. DOI: 10.1186/s13046-018-1003-0

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

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

Continue reading from the same book

Towards the Eradication of Helicobacter pylori Infection