Potential implications of Helicobacter pylori-related neutrophil-activating protein

Abstract

Helicobacter pylori (H. pylori) virulence factors promote the release of various chemoattractants/inflammatory mediators, including mainly the neutrophil-attractant chemokine interleukin-8 and neutrophil-activating protein (NAP), involved in H. pylori-induced gastric pathologies. Co-administration of Chios mastic gum (CMG), which inhibits H. pylori NAP, with an H. pylori eradication regimen might add clinical benefits against H. pylori-related gastric pathologies, but possibly not CMG as main therapy. Although H. pylori NAP and other H. pylori-related cytotoxins [i.e., vaculating cytotoxin (VacA)] appear to play a major role in generating and maintaining the H. pylori-associated gastric inflammatory response and H. pylori NAP is a promising vaccine candidate against H. pylori infection (H. pylori-I), concerns regarding its potential drawbacks, particularly neurogenic ones, due to possible cross-mimicry, should be considered. Possible cross-mimicry between H. pylori NAP and/or bacterial aquaporin (AQP) and neural tissues may be associated with the anti-AQP-4 antibody-related neural damage in multiple sclerosis (MS)/neuromyelitis optica patients. Moreover, the sequence homology found between H. pylori VacA and human Na+/K+-ATPase A subunit suggests that antibodies to VacA involve ion channels in abaxonal Schwann cell plasmalemma resulting in demyelination in some patients. A series of factors have been implicated in inducing blood-brain barrier (BBB) disruption, including inflammatory mediators (e.g., cytokines and chemokines induced by H. pylori-I) and oxidative stress. BBB disruption permits access of AQP4-specific antibodies and T lymphocytes to the central nervous system, thereby playing a major role in multiple sclerosis pathogenesis. Relative studies show a strong association between H. pylori-I and MS. H. pylori-I induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and perpetuating neural tissue damage. Finally, H. pylori NAP also plays a possible pathogenetic role in both gastric and colon oncogenesis.

Key Words: Helicobacter pylori; Neutrophil-activating protein; Chios mastic gum; Cross-mimicry; Multiple sclerosis; Demyelination; Gastric carcinogenesis

TO THE EDITOR

In their recent paper published in this journal, Choli-Papadopoulou et al[1] consider the development of new drugs targeting Helicobacter pylori (H. pylori) neutrophil-activating protein (NAP) and this raises some concerns.

With reference to a study[2] focusing on H. pylori NAP-mediated neutrophil activation before and 2 mo after per os administration of Chios mastic gum (CMG), the authors claimed that “these results indicate a substantial down-regulation of the innate cellular immune effectors, which, according to unpublished clinical data in the context of this study, are accompanied by a significant clinical improvement of the patients’ complaints (dyspepsia, epigastric discomfort, distention)”[1]. However, such clinical benefits cannot be deduced from this study[2] and, as mentioned, relative clinical data on CMG as treatment for H. pylori and peptic ulcer are controversial[2]. Although H. pylori virulence factors promote the release of various chemoattractants/inflammatory mediators including mainly the neutrophil-attractant chemokine interleukin-8 and H. pylori NAP involved in H. pylori-induced gastric pathologies[3], our clinical experience suggests that only co-administration of CMG with an H. pylori eradication regimen might add clinical benefits against H. pylori-related gastric pathologies, but possibly not CMG as main therapy, as the authors claimed[1,2]. In particular, co-administration of CMG might be a potential therapy to reduce damage of gastric mucosa induced by H. pylori NAP. However, large-scale relative prospective studies are needed to elucidate this field.

The authors, further considering data on the safety and immunogenicity of a vaccine comprising H. pylori-induced vaculating cytotoxin (VacA), cytotoxin associated gene and H. pylori NAP, suggested that the obtained neutrophil activation by the C-terminal region of H. pylori NAP opens new pathways for drug design directed at H. pylori inflammation[1]. In particular, both VacA and H. pylori NAP play a major role in generating and maintaining the H. pylori-associated gastric inflammatory response, and H. pylori NAP is a promising vaccine candidate against H. pylori infection (H. pylori-I). However, concerns regarding potential drawbacks of H. pylori NAP, particularly neurogenic ones, should be considered. For instance, possible cross-mimicry between H. pylori NAP and/or bacterial aquaporin (AQP) and neural tissues may be associated with the anti-AQP-4 antibody-related neural damage in multiple sclerosis (MS)/neuromyelitis optica (NMO) patients. In this regard, by using histology, the practical gold standard for the diagnosis of H. pylori-I, we have shown a strong association between H. pylori-I and MS[4]. H. pylori-I induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and perpetuating neural tissue damage[4]. In this respect, H. pylori NAP, as a virulence factor, recruits leukocytes from the vascular lumen, and activates neutrophils, mo-nocytes and mast cells, as mentioned by the authors. Besides, the sequence homology found between H. pylori VacA and human Na+/K+-ATPase A subunit suggests that antibodies to VacA involve ion channels in abaxonal Schwann cell plasmalemma resulting in demyelination in some patients[5]. Moreover, VacA exhibits chemotactic activities to the bone marrow-derived mast cells (BMDMCs) and induces BMDMCs to produce pro-inflammatory cytokines[5]. A series of factors have been implicated in inducing blood-brain barrier (BBB) disruption, including the aforementioned inflammatory mediators (e.g., cytokines and chemokines induced by H. pylori-I) and oxidative stress. BBB disruption permits access of AQP4-specific antibodies and T lymphocytes to the central nervous system, thereby playing a major role in MS/NMO pathogenesis[6]. Therefore, H. pylori NAP and HP-I itself, by inducing several mediators, may influence MS/NMO (including relapsing type) pathophysiology, thereby raising possible concerns regarding even the C-terminal region of H. pylori NAP use as a candidate vaccine. Accordingly, relative studies are also needed to clarify the aforementioned concerns.

Finally, the possible H. pylori NAP pathogenetic role in gastric carcinogenesis, mentioned by the authors, may also apply to colon oncogenesis[2,7].