Helicobacter pylori causes gastric lymphoma & is a risk factor for gastric cancer
Helicobacter pylori is a Gram-negative bacterium that chronically infects the stomach of more than 50% of the human population and represents a major cause of gastric cancer, gastric lymphoma, gastric autoimmunity and peptic ulcer diseases Citation[1–3]. The WHO classifies H. pylori as a human carcinogen for distal gastric cancer. Eradicating the bacterium in high-risk populations reduces the incidence of gastric cancer Citation[4]. Likewise, antibiotic treatment leads to regression of gastric mucosa-associated lymphoid tissue (MALT) lymphoma Citation[3]. H. pylori is also proposed to contribute to other conditions, such as vitamin B12 and iron deficiencies, idiopathic thrombocytic purpura and growth retardation in children Citation[5].
H. pylori preferentially elicits Th1 responses
Th1 cells are involved in cellular immune responses and are inhibited by Th2 responses. H. pylori gastric colonization is typically followed by mucosa infiltration of polymorphonuclear leukocytes, macrophages and Th1 lymphocytes, with active production of IL-12 and IFN-γ Citation[6].
In H. pylori infection, a predominant activation of Th1 cells, with the subsequent production of IFN-γ, IL-12, IL-18, IL-23 and TNF-α, occurs in vivo in the stomach of humans and in animal models. Such an immune response is expected to play a role in the pathogenesis of H. pylori-associated diseases in humans Citation[6–7]. Accordingly, a Th1-directed immune response, induced by H. pylori infection, increases gastric inflammation and atrophy, whereas Th2 redirection reduces them Citation[8,9]. Different pathways are responsible for the predominant H. pylori-induced mucosal Th1 response Citation[6–7]. Stimulation of human neutrophils, monocytes and dendritic cells with H. pylori-derived neutrophil-activating protein (HP-NAP) strongly upregulates both IL-12 and IL-23 production, via Toll-like receptor (TLR)2 activation. In the gastric mucosa of H. pylori-infected patients, a considerable proportion of Th cells are specific for different H. pylori antigens, including HP-NAP, CagA, urease, VacA and heat-shock proteins; HP-NAP drives the production of high levels of IFN-γ and TNF-α by gastric Th cells, thus promoting a polarized Th1 response Citation[6–10].
Th2-driven immunopathological responses sustain the development of allergic disease
Asthma, defined by the WHO as a ‘chronic inflammatory disease of the airways’, is a complex disorder characterized by airway hyper-responsiveness to a variety of specific and nonspecific stimuli, and mucus hypersecretion by goblet cells. The histopathological characteristics of bronchial asthma, even in its mild form, are represented by inflammatory infiltrates consisting of T lymphocytes and an accumulation of activated eosinophils, epithelial shedding and basal membrane thickening.
Immunological and molecular studies of bronchial biopsies and bronchoalveolar lavage (BAL) samples obtained in baseline disease or taken after natural or ‘experimentally’ induced asthma exacerbations have shown that complex and fascinating inflammatory mechanisms sustain the pathogenesis of bronchial asthma, including the participation of different types of Th cells and cytokine and chemokine networks Citation[11].
In allergic asthmatic patients, allergen exposure induces a predominant activation of CD4+ Th2 lymphocytes in the airways, which are able to overexpress several Th2 cytokines, including IL-4 and IL-5 Citation[12–13]. Moreover, the degree of IL-5 expression at the bronchial level is associated with disease severity in both atopic and nonatopic asthma Citation[14]. IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) can be considered the most important cytokines for eosinophil accumulation in asthmatic inflammation. Th2 cytokines in bronchial asthma are produced not only by CD4+ but also by CD8+ T cells, which contribute to the development of asthma and to the clinical expression of the disease Citation[15].
An inverse association exists between H. pylori infection & the frequency of allergic asthma
The severity and incidence of asthma have increased drastically in the developed nations of the world over the last decades. Although the underlying reason is still unknown, clinical, epidemiological and experimental evidence indicate that infectious diseases can influence the development of allergic disorders Citation[16]. Accordingly, an inverse correlation has been demonstrated between the onset of allergic disorders and the incidence of infections. This may be the result of an inhibition of allergic Th2 inflammation exerted by Th1 responses; the latter are elicited by infectious agents and are able to induce the production of IFN-γ, IL-12, IL-18 and IL-23 Citation[17]. This view is supported by studies showing that development of asthma can be prevented in animals by administering live or killed bacteria or their components, which induce Th1 responses Citation[18]. We demonstrated that H. pylori inhibited Th2 responses in asthmatic patients Citation[10]. Interestingly, on the basis of large epidemiological studies, a consistent negative association between H. pylori infection and the presence of allergic disorders, such as asthma and rhinitis, has recently been proposed Citation[19]. Although it is an undoubtedly interesting theory, no convincing molecular mechanism has been suggested to support it.
Our studies carried out with H. pylori may help in the understanding of this complex issue. We have shown that the addition of HP-NAP to allergen-induced T-cell lines derived from allergic asthmatic patients led to a drastic increase in IFN-γ-producing T cells and to a decrease in IL-4-secreting cells, thus resulting in a redirection of the immune response from a Th2 to a Th1 phenotype Citation[10]. These results suggest that HP-NAP might be the key element responsible for the decrement of allergy frequency in H. pylori- infected patients.
HP-NAP of H. pylori inhibits Th2 allergic inflammation
Several studies were devoted to the definition of new immune-modulating factors able to inhibit Th2 responses and consequently, different compounds have been proposed for the treatment and prevention of asthma, including several TLR ligands mimicking the effects of microbial components, such as dsRNA, CpG-oligodeoxynucleotides and imidazoquinolines Citation[20–21].
We demonstrated that in allergic asthmatic patients, the typical Th2 responses can be redirected toward Th1 by HP-NAP and that the activity of HP-NAP required the engagement of TLR2 Citation[10,22]. Furthermore, the in vivo administration of HP-NAP prevents the typical eosinophil accumulation in the lung, as well as the increase of serum IgE in a mouse model of allergic asthma Citation[22]. These results suggest the possibility that HP-NAP might be a part of the molecular mechanism underlying the negative association between H. pylori infection and allergy, corroborating the epidemiological observations with a plausible scientific explanation.
To address whether HP-NAP, on the basis of its immune-modulating activity, could be beneficial for the prevention and treatment of bronchial asthma, it was administered via the intraperitoneal or the intranasal route using a mouse model of allergic asthma induced by inhaled ovalbumin (OVA). Groups of nine C57BL/6j, wild-type or tlr2-/- mice were treated with OVA alone, or with OVA plus HP-NAP administered intraperitoneally or mucosally. In both systemic and mucosal protocols, mice were treated with OVA according to a standardized procedure consisting of a first phase of sensitization with intraperitoneal OVA and a second phase of induction of the allergic response with aerosolized OVA on day 8, followed by repeated aerosol challenge with the allergen on days 15–18. Control animals were injected with phosphate-buffered saline (PBS) alone and then exposed to aerosolized PBS. In the systemic protocol, mice were treated with intraperitoneal HP-NAP on day 1, whereas in the mucosal protocol mice received intranasal HP-NAP on days 7 and 8 Citation[22].
After priming and repeated aerosol challenge with OVA, Th2 responses were induced in the mouse lung. Accordingly, following OVA treatment, eosinophils were recruited and activated in bronchial airways, and serum IgE levels increased. Both systemic and mucosal administration of HP-NAP strongly inhibited the development of airway eosinophilia and bronchial inflammation. Likewise, HP-NAP treatment strongly affected the cytokine release in the lung, reducing the production of IL-4, IL-5 and GM-CSF. Systemic HP-NAP also significantly resulted in both the reduction of total serum IgE and an increase in IL-12 plasma levels. However, no suppression of lung eosinophilia and bronchial Th2 cytokines was observed in tlr2-/- mice following HP-NAP treatment Citation[22].
Conclusion
In conclusion, we do not propose the infection of people with H. pylori to treat asthma and allergy, nor do we wish to leave H. pylori infection untreated in asthmatic patients. We propose instead the use of a microbial product derived from H. pylori, such as HP-NAP, for prevention and treatment of allergic diseases. At the same time, we strongly recommend treating H. pylori- infected patients, whether asthmatic or not, according to current guidelines.
Asthma is one of the most common chronic diseases in industrialized countries and consists of airway inflammation, bronchial hyper-responsiveness and airway obstruction. Typical pathological features include infiltration of the airways by activated lymphocytes, particularly Th2 cells and eosinophils. The reason why the severity and incidence of asthma has dramatically increased in developed nations over recent decades is unknown; however, epidemiological studies and experimental data provide evidence suggesting that infectious diseases, such as H. pylori infection, can influence the development of allergic disorders. This phenomenon can be explained by the inhibition of the allergic Th2 inflammation seen when Th1 responses are elicited by infectious agents able to induce the production of IFN-γ, IL-12 and IL-23. HP-NAP, by acting on innate immune cells via TLR2 agonistic interaction, induces an IL-12- and IL-23-enriched milieu, and in such a way it represents a key factor able to induce a Th2–Th1 redirection. Furthermore, HP-NAP administration in vivo resulted in inhibition of the typical Th2-mediated bronchial inflammation of allergic bronchial asthma. Thus, combined, these results support the view that the increased prevalence and severity of asthma and allergy in Western countries may be related, at least in part, to the decline of H. pylori infection, which is able to induce a long-lasting Th1 background, and suggest that the use of a microbial product derived from H. pylori, such as as HP-NAP, may help the prevention and treatment of bronchial asthma and allergic diseases. At the same time, we do not suggest infecting people with H. pylori or leaving a H. pylori infection without antibiotic treatment to treat asthma and allergy.
On the basis of this clinical and experimental evidence and according to current guidelines for the management of H. pylori infection Citation[23], we believe that eradication of H. pylori infection is strongly beneficial for curing peptic ulcer disease, gastric MALT lymphoma and for the prevention of gastric cancer, and it must be done in all H. pylori-infected patients, whether they are asthmatic or not.
Financial & competing interests disclosure
Mario M D’Elios and Marina de Bernard are applicants of EU Patent 05425666.4 for Helicobacter pylori -derived neutrophil-activating protein as a potential therapeutic agent in asthma, allergic and infectious diseases and cancer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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