Helicobacter pylori infection and immune thrombocytopenic purpura: an update

Data are accumulating on the association between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) and the significant increase in platelet count after bacterial eradication. The aim of this review was to consider the studies so far published on H. pylori infection and ITP in order to evaluate a possible correlation between these two conditions. A review of the literature showed that 278 out of the 482 ITP patients investigated (58%) were positive for H. pylori infection and that the bacterium was eradicated in 88% of cases. Eradication therapy was accompanied by a complete or partial platelet response in approximately half the cases. Overall, these data show that H. pylori eradication in patients with ITP is effective in increasing platelet count. However, because the studies so far published are few, are sometimes controversial and involve small series of patients, further studies on larger numbers of patients with longer follow-up are needed to confirm these preliminary findings.     

Host response to Helicobacter pylori infection before initiation of the adaptive immune response

Helicobacter pylori persistently colonizes the human stomach. In this study, immune responses to H. pylori that occur in the early stages of infection were investigated. Within the first 2 days after orogastric infection of mice with H. pylori, there was a transient infiltration of macrophages and neutrophils into the glandular stomach. By day 10 postinfection, the numbers of macrophages and neutrophils decreased to baseline levels. By 3 weeks postinfection, an adaptive immune response was detected, marked by gastric infiltration of T lymphocytes, macrophages, and neutrophils, as well as increased numbers of H. pylori-specific T cells, macrophages, and dendritic cells in paragastric lymph nodes. Neutrophil-attracting and macrophage-attracting chemokines were expressed at higher levels in the stomachs of H. pylori-infected mice than in the stomachs of uninfected mice. Increased expression of TNFalpha and IFNgamma (Th1-type inflammatory cytokines) and IL-17 (a Th17-type cytokine) was detected in the stomachs of H. pylori-infected mice, but increased expression of IL-4 (a Th2-type cytokine) was not detected. These data indicate that a transient gastric inflammatory response to H. pylori occurs within the first few days after infection, before the priming of T cells and initiation of an adaptive immune response. It is speculated that inappropriate waning of the innate immune response during early stages of infection may be a factor that contributes to H. pylori persistence.     

The neutrophil-activating protein of Helicobacter pylori (HP-NAP) as an immune modulating agent

During evolution microorganisms have developed several immune modulating strategies. The Helicobacter pylori neutrophil-activating protein (HP-NAP) is a virulence factor that attracts and activates neutrophils, and promotes their endothelial adhesion and the production of oxygen radicals and chemokines, including CXCL8, CCL3 and CCL4. HP-NAP, a TLR2 agonist, is an immune modulator able to induce the expression of interleukin-12 (IL-12) and IL-23 by human neutrophils and monocytes. In fact, HP-NAP has the potential to shift antigen-specific T-cell responses from a predominant Th2 to a polarized Th1 cytotoxic phenotype, characterized by high levels of interferon-gamma and tumor necrosis factor-alpha production. Thus, HP-NAP is a key factor driving Th1 inflammation in H. pylori infection and may be a new tool for future therapeutic strategies aimed at redirecting Th2 into Th1 responses, for example in atopy, vaccinology and cancer immunotherapy.     

Progress in vaccine development against Helicobacter pylori

Based on the very high prevalence of diseases caused by Helicobacter pylori, particularly in the developing world, and the rapid emergence of antibiotic resistance among clinical isolates, there is a strong rationale for an effective vaccine against H. pylori. In this review we describe recent promising candidate vaccines and prophylactic or therapeutic immunization strategies for use against H. pylori, as well as studies to identify immune responses that are related to protection in experimental animals. We also describe identification of different types of immune responses that may be related to protection against symptoms based on comparisons of H. pylori-infected patients with duodenal ulcers or gastric cancer and asymptomatic carriers. We conclude that there is still a strong need to clarify the main protective immune mechanisms against H. pylori as well as to identify a cocktail of strong protective antigens, or recombinant bacterial strains that express such antigens, that could be administered by a regimen that gives rise to effective immune responses in humans.     

幽门螺杆菌空泡毒素研究进展

幽门螺杆菌空泡毒素是该菌产生的已知其它细菌毒素无明显源性的唯一蛋白毒素。该毒素是幽门螺杆菌重要的毒力致病因子,它的产生与感染胃肠上皮损伤和溃疡形成密切相关。本就幽门螺杆菌空泡毒素的结构与功能研究进展以及在未来免疫预防与免疫治疗中的作用进行了阐述。     

Expression of T-cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (Tim-1 and Tim-3) in Helicobacter pylori infection

Background: Th immune response plays an important role in Helicobacter pylori (H. pylori) infection. Tim‐1 and Tim‐3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim in H. pylori infection remains unclear. Materials and Methods: (1) Lymphocytes isolated from the spleen of BALB/c mice were co‐cultured with different concentrations of viable H. pylori. Alternatively, mice were challenged by viable H. pylori to set up the H. pylori infection model. (2) The expression of Tim‐1 and Tim‐3 on mRNA level in lymphocytes or spleen of mice was determined by RT‐PCR. The percentage of Tim‐3‐positive cells was determined by flow cytometric analysis. The production of cytokine in supernatants was measured by standard sandwich cytokine ELISA. Results: (1) Co‐culture: At 12 hours, there was markedly decreased production of Tim‐1 and increased production of Tim‐3 in lymphocytes co‐cultured with H. pylori compared with normal control. The change of Th2 cytokine had the similar tendency as that of Tim‐1 expression; alternatively, the change of Th1 cytokine had the similar tendency as that of Tim‐3 expression. (2) Infection: Tim‐1 expression was declined in infected mice compared with control group; in the contrast, Tim‐3 expression was increased. Furthermore, the expression of Tim‐1 and Tim‐3 mRNA in spleen was significantly positively correlated with the level of Th2 and Th1 cytokine in gastric homogenized supernatant, respectively. Conclusion: H. pylori could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1‐biased immune response. The expression of Tim‐1 and Tim‐3 could reflect Th2 and Th1 immune response, respectively, which provide evidence for the prevention and treatment of H. pylori infection and correlation diseases through regulation of Tim‐1 and Tim‐3.     

幽门螺杆菌动物模型研究进展

幽门螺杆菌动物模型用于HP相关疾病和HP疫苗作用的研究。常规实验动物包括悉生猪、悉生狗、非人类灵长动物、猫、雪貂、小鼠、大鼠、沙鼠等。猫螺杆菌和雪貂螺杆菌感染也被用于模型研究。最近,转基因小鼠和基因敲除小鼠也被用作幽门螺杆菌动物模型研究。     

幽门螺杆菌基因组特征及研究进展

幽门螺杆菌是胃相关疾病：慢性胃炎、消化性溃疡、胃癌和MALT淋巴瘤的一个重要的病原体。其毒力因子包括：尿素酶、鞭毛蛋白、粘附素、细胞毒素相关蛋白和空泡毒素等,通过对全基因序列分析研究,对幽门螺杆菌的致病机制有了进一步的了解。     

Helicobacter pylori associated with glossitis and halitosis

BACKGROUND: Helicobacter pylori is a curved microaerophilic Gram-negative bacterium considered as a risk factor for gastric cancer. The aim of this study was to find an association between burning sensations, acid taste, halitosis, and lingual hyperplasia with the effect of H. pylori on the mouth. MATERIALS AND METHODS: A total of 124 subjects with different gastric diseases were studied: 46 patients with burning, halitosis and lingual dorsum hyperplasia and 78 patients with other diseases. RESULTS: The detection of H. pylori in the oral cavity by histopathologic diagnosis and molecular biology was confirmed in 40/46 (87%) patients with burning, halitosis, and lingual hyperplasia, and in 2/78 (2.6%) subjects with other diseases. Chi2: 91.26 (p < .001) Mantel-Haenszel. CONCLUSION: This trial showed an association between H. pylori and burning, halitosis, and lingual hyperplasia, and further considered this bacterium a risk factor for gastric infection.     

Characteristics of Helicobacter pylori natural transformation

For Helicobacter pylori, which exhibits substantial genetic diversity, many strains are naturally competent for transformation by exogenous DNA. To better understand the mechanism of natural transformation and its role in the generation of diversity, we sought to systematically identify factors important for natural transformation in H. pylori. We now show that the highest frequency of H. pylori transformation occurs when DNA is introduced prior to exponential phase growth, and that it is a saturable phenomenon. That transformation can be inhibited by DNA from Helicobacter (H. pylori and Helicobacter bilis) but not Escherichia coli suggests specificity based on DNA source. Finally, the cag island was determined to be unnecessary for high-frequency transformation.     

Polymorphisms in cytokine genes and risk of Helicobacter pylori infection among Jamaican children

Background: Infection by Helicobacter pylori is often acquired during childhood. Recent studies suggest that inflammatory cytokines may play a role in susceptibility to, and disease phenotype caused by, H. pylori infection, but the association of host genetic variability with risk of H. pylori infection has not been studied in children. Methods: We investigated the relationship between the risk of H. pylori antibody positivity and cytokine gene polymorphisms among 199 two‐year‐old Jamaicans. H. pylori seropositivity was determined by a validated research enzyme‐linked immunosorbent assay. Real‐time Taqman® polymerase chain reaction was used to determine variants at 17 loci in 11 cytokine genes (IL1A, IL1B, IL2, TNF, TLR4, IL4, IL6, IL10, IL10RA, IL12A and IL13). We estimated the odds ratio and the 95% confidence interval for the association of genetic polymorphisms with H. pylori seropositivity, using logistic regression. Results: Forty (20.1%) of 199 children were seropositive. Children's H. pylori seropositivity correlated highly with maternal H. pylori seropositivity (OR = 7.98, 95% CI = 1.05–60.60, p = .02). Children carrying IL1A?889T had a lower risk of H. pylori positivity, compared to those carrying ?889C, with each T allele associated with 43% risk reduction (OR = 0.57, 95% CI = 0.33–0.99, p‐trend = .05). No other loci we examined were associated with the risk of H. pylori seropositivity. Conclusions: The IL1A?889 T allele, known to express a higher level of cytokine IL‐1α, is associated with a lower risk of H. pylori infection among Jamaican children. Our finding supports the hypothesis that an upregulation of pro‐inflammatory cytokines may protect against persistent H. pylori colonization.     

Organ-specific autoantibodies in children with Helicobacter pylori infection

BACKGROUND: We compared the prevalence of organ-specific autoantibodies in a group of Helicobacter pylori infected children and a group of uninfected children and investigated the relationship between the presence of relevant autoantibodies and the status of the target organs. PATIENTS AND METHODS: One hundred and twenty-four children with dyspepsia (54 boys, 70 girls; mean age 10.5 years; range 4-19) underwent gastroscopy: 56 had H. pylori infection (31 girls, 25 boys), while 68 (37 girls and 31 boys), were H. pylori-negative. All sera were tested for the presence of: parietal cell autoantibodies (PCA), intrinsic factor autoantibodies (IFA), microsomial autoantibodies, thyroglobulin autoantibodies, islet cell autoantibodies, glutamic acid decarboxylase autoantibodies, adrenal cortex autoantibodies, steroid-producing cell autoantibodies; gastrin, pepsinogen A, pepsinogen C and anti-H. pylori antibodies. The histological features and the ureA and cagA genes were also considered. RESULTS: The frequency of organ-specific autoantibodies was higher in patients with H. pylori infection than in uninfected patients (chi2-test p < .0001). Specifically gastric autoantibodies were significantly higher: seven of the 56 H. pylori-positive children were PCA-positive and one was IFA-positive (chi2-test p = .0004). The presence of autoantibodies was not associated with any clinical or biohumoral signs of disease. CONCLUSIONS: Our study detected a relationship between H. pylori infection in childhood and the presence of organ-specific autoantibodies unassociated with any clinical or biohumoral signs of disease. Helicobacter pylori infection in childhood could trigger the onset of clinical autoimmune gastritis, and/or other clinical autoimmune diseases.     

Unraveling the factors and mechanism involved in persistence: Host-pathogen interactions in Helicobacter pylori

Helicobacter pylori and humans have one of the most complex relationships in nature. How a bacterium manages to live in one of the harshest and hostile environments is a topic of unraveling mysteries. H. pylori is a prevalent species and it colonizes the human gut of more than 50% of the world population. It infects the epithelial region of antrum and persists there for a long period. Over the time of evolution, H. pylori has developed complex strategies to extend the degree of inflammation in gastric mucosa. H. pylori needs specific adaptations for initial colonization into the host environment like helical shape, flagellar movement, chemotaxis, and the production of urease enzyme that neutralizes acidic environment of the stomach. There are several factors from the bacterium as well as from the host that participate in these complex interactions. On the other hand, to establish the persistent infection, H. pylori escapes the immune system by mimicking the host antigens. This pathogen has the ability to dodge the immune system and then persist there in the form of host cell, which leads to immune tolerance. H. pylori has an ability to manipulate its own pathogen-associated molecular patterns, which leads to an inhibition in the binding with specific pattern recognition receptors of the host to avoid immune cell detection. Also, it manipulates the host metabolic homeostasis in the gastric epithelium. Besides, it has several genes, which may get involved in the acquisition of nutrition from the host to survive longer in the host. Due to the persistence of H. pylori, it causes chronic inflammation and raises the chances of gastric cancer. This review highlights the important elements, which are certainly responsible for the persistence of H. pylori in the human host.     

Helicobacter pylori Infection in Children

The review summarizes the articles published on Helicobacter pylori in children between April 2007 and March 2008. Evidence is emerging in different populations including developing countries that the prevalence of H. pylori is declining in all age groups. The reasons for this are unclear but it is unlikely that treatment of infection or improvement in socioeconomic conditions fully explains the decline. For the first time, differences in the inflammatory response between adults and children have been well characterized in a group of adults and children from Chile with similar levels of H. pylori infection. This study suggests that the reduced inflammatory response to H. pylori at a cellular level in children could be the consequence of an enhanced Treg cell response, which in turn down-regulates H. pylori -induced inflammation. The publication of the Paediatric European Register for Treatment of Helicobacter pylori study (PERTH) is important as it demonstrates the advantages of different centers working in collaboration for the benefit of children. It also highlights the fact that while bismuth-based treatment is more effective than proton pump inhibitor-based treatment in children, bismuth preparations are not widely available for use in children.     

Optimized conditions for the fermentation of Helicobacter pylori and production of vacuolating cytotoxin

Abstract We report here improvements to the growth media and fermentation conditions which result in a substantial increase of Helicobacter pylori growth and in the enhanced production of vacuolating cytotoxin. Addition of glucose to the medium resulted in the increase of cell yield, cell viability and a significant improvement in the production of vacuolating cytotoxin.     

Role of Immune Serum in the Killing of Helicobacter pylori by Macrophages

Background: Helicobacter pylori infection can lead to the development of gastritis, peptic ulcers and gastric cancer, which makes this bacterium an important concern for human health. Despite evoking a strong immune response in the host, H. pylori persists, requiring complex antibiotic therapy for eradication. Here we have studied the impact of a patient’s immune serum on H. pylori in relation to macrophage uptake, phagosome maturation, and bacterial killing. Materials and Methods: Primary human macrophages were infected in vitro with both immune serum‐treated and control H. pylori. The ability of primary human macrophages to kill H. pylori was characterized at various time points after infection. H. pylori phagosome maturation was analyzed by confocal immune fluorescence microscopy using markers specific for H. pylori, early endosomes (EEA1), late endosomes (CD63) and lysosomes (LAMP‐1). Results: Immune serum enhanced H. pylori uptake into macrophages when compared to control bacteria. However, a sufficient inoculum remained for recovery of viable H. pylori from macrophages, at 8 hours after infection, for both the serum‐treated and control groups. Both serum‐treated and control H. pylori phagosomes acquired EEA1 (15 minutes), CD63 and LAMP‐1 (30 minutes). These markers were then retained for the rest of an 8 hour time course. Conclusions: While immune sera appeared to have a slight positive effect on bacterial uptake, both serum‐treated and control H. pylori were not eliminated by macrophages. Furthermore, the same disruptions to phagosome maturation were observed for both serum‐treated and control H. pylori. We conclude that to eliminate H. pylori, a strategy is required to restore the normal process of phagosome maturation and enable effective macrophage killing of H. pylori, following a host immune response.