Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection

Toll-like receptors (TLRs) expressed by mucosal epithelium play an essential role in the defense against microbes by recognizing conserved bacterial molecules. For the first time TLR4, TLR5 and TLR9 have been microanatomically localized in patients with noninflamed gastric mucosa and Helicobacter pylori gastritis by immunohistochemistry. Because polarized expression of TLRs in apical and basolateral epithelial compartments is thought to modulate mucosal immunity, subcellular TLR distribution by gastric epithelium was investigated using confocal microscopy. TLR4, TLR5 and TLR9 were expressed by gastric epithelium in antrum and corpus of all patients with H. pylori gastritis (n = 14) and with noninflamed gastric mucosa (n = 5). TLR4 was expressed at the apical and the basolateral pole of the gastric epithelium as well in noninflamed gastric mucosa as in H. pylori gastritis. TLR5 and TLR9 expression in the noninflamed gastric mucosa was identical to that of TLR4 with localization at the apical and the basolateral epithelial pole. However, in H. pylori gastritis TLR5 and TLR9 expression on the gastric epithelium changed to an exclusive basolateral localization without detectable expression at the apical pole. In the human stomach, the gastric epithelium expressed TLR4, TLR5 and TLR9, which gives it the possibility to interact with H. pylori. Furthermore, gastric epithelial TLR4 expression is highly polarized in an apical and a basolateral compartment, whereas TLR5 and TLR9 polarization seems to be a process dynamically influenced by H. pylori infection. This polarized and dynamically regulated gastric epithelial expression of TLRs supports a sentinel role for these receptors in the mucosal immunity to H. pylori.     

Helicobacter pylori antibodies and gastric cancer in Iceland - The decline in IgG antibody level is a risk factor

H. pylori infection is considered a causal agent of duodenal ulcer and a significant risk factor for gastric cancer. Retrospective cohort studies have demonstrated a significant association between presence of antibody to H. pylori and gastric cancer when using samples obtained years before the diagnosis but not at the time of diagnosis. The present study investigates, in a population-based cohort, whether a decline occurs in H. pylori antibody levels before the diagnosis of stomach cancer. Repeat samples (2 to 5) were available from 23 persons with gastric cancer taken up to 20 years before the diagnosis and 128 control subjects matched for gender, age, time and number of repeat samples. The odds ratio of developing stomach cancer was 1.16 (95% CI 1.05-1.28) for those showing decline in antibody levels of 1 relative antibody activity unit per year versus those with constant or rising levels. We conclude that this decline in antibody levels in cases, and not in controls, supports an active role of H. pylori in the pathogenesis of gastric cancer by causing atrophic gastritis, and provides a better risk assessment for gastric cancer compared to single measurements.     

Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori

In the human stomach Toll-like receptors (TLRs) expressed by the gastric epithelium interact with Helicobacter pylori and mediate production of proinflammatory cytokines and chemokines during H. pylori infection. This results in chronic active gastritis, the background from which gastric carcinoma arises via the epithelial precursor lesions, intestinal metaplasia and dysplasia. Therefore, the question is arising whether gastric carcinoma cells are also able to interact with H. pylori. In this study, TLR4, TLR5 and TLR9 expression was investigated on tumor cells of gastric carcinoma and on its precursor lesions, intestinal metaplasia and dysplasia, by immunohistochemistry. Gastric epithelium with intestinal metaplasia (n=10) and dysplasia (n=3) expressed TLR4 and TLR5. TLR4 was strongly expressed by tumor cells of 17 out of 22 and TLR5 by tumor cells of all 22 patients with gastric carcinoma. TLR9, however, was not detectable in intestinal metaplasia or dysplasia and only focally in 6 out of 22 gastric carcinomas. In contrast to H. pylori gastritis, epithelial TLR expression in intestinal metaplasia, dysplasia and gastric carcinoma was diffusely distributed without subcellular polarization as demonstrated by confocal microscopy. This is the first study describing TLR expression on tumor cells of gastric carcinoma and its precursor lesions. Expression of TLRs enables gastric carcinoma cells to interact with H. pylori. As H. pylori can induce gastric carcinoma-promoting factors, such as IL-8, via epithelial TLR expression, TLR expression by gastric carcinoma cells may have a dangerous potential.     

The role of Helicobacter pylori in primary gastric MALT lymphoma

AIMS: Helicobacter pylori has been claimed to be an important aetiological factor which raises the risk of mucosa-associated tissue lymphoid (MALT) lymphoma. However, some studies on gastric MALT lymphoma revealed a low rate of H. pylori infection suggesting that not all gastric lymphomas are related to H. pylori infection. The aim of this study was to verify the H. pylori infection frequency in a series of patients with primary gastric MALT lymphomas and to examine the relationship between H. pylori and the pathological features of those lymphomas. METHODS AND RESULTS: Thirty-one cases of resected gastric lymphoma were analysed: 10 cases (32%) were low-grade MALT lymphomas and 21 cases (68%) were high-grade MALT lymphomas. Helicobacter pylori was found in only 18 of 31 (58%) cases. Helicobacter pylori infection was significantly correlated with the grade and depth of invasion of MALT lymphoma since 63% of superficial low-grade MALT lymphomas were positive for H. pylori compared with 38% of advanced high-grade MALT lymphomas (P = 0.02). CONCLUSION: We confirmed the relationship between H. pylori infection and a subset of gastric MALT lymphoma. Our results also showed that not all low- and high-grade gastric MALT lymphomas are H. pylori-dependent. This suggests that H. pylori infection may play a promoter role in the development of MALT lymphoma, but its presence is not mandatory for the progression of the lymphoma in view of its low frequency in advanced high-grade MALT lymphoma.     

The EPIYA-ABCC motif of Helicobacter pylori cagA gene and gastric carcinogenesis in Casablanca population

BackgroundH. pylori infection induce atrophic gastritis (AG) and intestinal metaplasia (IM) that can lead to gastric cancer (GC). The severity of gastric lesions is related to H. pylori genetic diversity. The oncogenic potential of H. pylori cagA virulence factor is linked to its high polymorphic EPIYA motifs.ObjectivesOur aim was to evaluate the association of EPIYA motifs with the risk of AG and IM in Casablanca population.MethodsA total of 210 patients suffering from gastric lesions (chronic gastritis, AG, and IM) was enrolled. H. pylori infection and the type of lesions were diagnosed by ureC PCR and histological examination, respectively. Detection of the cagA gene, and the type of EPIYA motifs, were carried out by PCRResultsThe prevalence of H. pylori and cagA gene was 95% and 37%, respectively. CagA-positive strains were associated with the risk of IM. The EPIYA motifs detected were: EPIYA-ABC (58%), EPIYA-ABCC (22%), and EPIYA-AB (20%). The EPIYA-ABCC motif was associated with the risk of IM (p-value = 0.007), compared to AG (p-value = 0.28).ConclusionThe EPIYA-ABCC motif might be a useful marker for the identification of patients at high risk of developing IM that can lead to GC.     

Epidemiology and role of Helicobacter pylori virulence factors in gastric cancer carcinogenesis

Infection with Helicobacter pylori is associated with the development of gastric cancer. Although the prevalence of gastric cancer has declined throughout years due to improvement in early screening strategy, mortality due to gastric cancer has not changed. Incidence and mortality due to gastric cancer are higher in developing countries as compared to developed countries. Diagnosis and prognosis of gastric cancer are still poor with patients usually diagnosed with cancer at an advanced stage. Eradication of H. pylori is pertinent for the prevention of gastric cancer. However, the rise in antimicrobial resistance among H. pylori isolates has complicated the prevention strategy. H. pylori express multiple virulence factors for survival in the hostile acid gastric environment. The expression of oncogenic protein cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and outer inflammatory protein is essential for H. pylori to exert pathogenesis towards the host. Interestingly, <3% of H. pylori-infected subjects develop gastric cancer, suggesting a unique way of interaction between the host's immune response and H. pylori virulence factors. This article is aimed to review the epidemiology and role of H. pylori in gastric carcinogenesis. A better understanding of the interaction between H. pylori virulence factors and host is required for better gastric cancer prevention.     

Helicobacter pylori and gastric carcinoma

A retrospective study was performed on gastric carcinomas to establish the prevalence of Helicobacter pylori infection in gastric epithelium adjacent to the tumour. A total of 105 carcinomas were studied. The overall prevalence of Helicobacter pylori infection was 59%. The prevalence in different age cohorts from patients with gastric carcinoma was compared with that in patients suffering from non-ulcer dyspepsia and, based on serological testing, with that in healthy blood donors. The presence of Helicobacter pylori in cancer patients aged 41-50 and 51-60 was significantly higher than in blood donors. No difference was seen in comparison with non-ulcer dyspepsia patients. The presence of Helicobacter pylori showed an inverse correlation with the extent of intestinal metaplasia. The intestinal type of carcinoma was associated with a higher bacterial load than the diffuse type. These data suggest that the presence of Helicobacter pylori in gastric mucosa could play a role in the pathogenesis of gastric carcinoma, especially in the young age group.     

Helicobacter pylori and gastric adenocarcinoma

Gastric cancer is the second most common cause of cancer death worldwide. A large body of evidence supports a causal role of Helicobacter pylori in the majority of gastric malignancies. Great strides have been made in understanding the pathogenesis of this relationship, but much remains to be learned. Moreover, because of the high prevalence of infection, the lack of definitive trials, and the challenges of H. pylori treatment, there remains no consensus on the role of routine screening and treatment of this infection to prevent cancer. This article reviews the current knowledge on H. pylori and gastric cancer and presents some of the clinical and public health challenges associated with this pathogen.     

Helicobacter pylori stains and association between H. pylori and inflammation in gastric specimens

Gastric cancer has been strongly associated with presence of the bacterium Helicobacter pylori. To improve techniques in identifying H. pylori so that gastric cancer may be predicted early, this project was formulated to determine whether one particular stain is more effective in displaying H. pylori microscopically. In addition, this study attempted to determine whether the degree of inflammatory elements present in tissue could be used to predict the likelihood of H. pylori presence. Protocols for the staining techniques, Steiner and alcian yellow/toluidine blue (AY/TB), were employed on specimens to semi-quantitate H. pylori presence. Serial sections from the same specimens were stained with hematoxylin and eosin to determine the amount of inflammation. Spearman rho correlation was used to evaluate the association between amount of H. pylori and inflammation in each case. It was determined that AY/TB was more easily performed, more effective in demonstrating H. pylori, and more cost effective than the Steiner stain. Additionally, it was determined that a moderate positive association was indicated between high levels of inflammation and marked presence of H. pylori.     

Response of IgG1 and IgG2 subclasses to Helicobacter pylori in subjects with chronic inflammation of the gastric mucosa, atrophy and gastric cancer in a country with high Helicobacter pylori infection prevalence

Polarized immune response to Helicobacter pylori and induction of chronic inflammation may increase the risk of gastric atrophy and adenocarcinoma. We studied the association of the response of IgG1 and IgG2 antibodies to H. pylori with grade of gastric chronic inflammation and atrophy in a population with a high prevalence of H. pylori, and compared these data with the data obtained from the study of gastric cancer patients, as well as with the data for CagA positivity. Altogether, 114 persons from two adult population samples from Estonia and 45 consecutive gastric cancer patients were studied. All patients were positive for the H. pylori antibody determined by ELISA. Adenocarcinoma was classified histologically according to the Laurén's system. The response of the IgG subclasses to H. pylori (acid glycine-extracted whole cell proteins) was determined by ELISA and the results were compared with the ELISA results for the recombinant fragment of the CagA protein. Helicobacter pylori IgG level was lower in atrophic gastritis compared with nonatrophic gastritis (chronic inflammation) (p=0.001). In the group of cancer patients, the response of IgG and IgG1 was lower compared with both gastritis groups (p=0.01 and p=0.0002 for IgG, and p=0.001 and p=0.0005 for IgG1). IgG2 was lower for gastric cancer localized in the corpus (p=0.03). In conclusion, atrophic gastritis and gastric cancer were associated with a significant decline in IgG and IgG1 response to H. pylori compared with nonatrophic gastritis. Higher value of CagA antibodies was seen in gastric cancer and in gastric atrophy compared with nonatrophic gastritis; in gastric cancer patients, IgG1 response to H. pylori was correlated with CagA status.     

Epithelial damage by Helicobacter pylori in gastric ulcers

On review of 136 consecutive biopsies of benign gastric ulcer, Helicobacter pylori was detected in 78 cases (57.3%). The gastric epithelium colonized by Helicobacter pylori showed a characteristic constellation of changes, including loss of apical mucous portion of individual cells, drop-out of epithelial cells, epithelial pits, erosions and cellular tufts, indicative of cellular injury and regeneration. Among the 58 Helicobacter-negative cases, similar changes were not observed in the ulcer edges, except for two cases which exhibited some cellular tufts. Thus, the topographic association of Helicobacter pylori with epithelial damage in the gastric ulcer edges in more than half of the cases suggests that this organism probably plays an aetiological role in ulcerogenesis, at least in these cases. Furthermore, the epithelial changes are so distinctive that they can serve as a helpful histological indicator for the presence of Helicobacter pylori in gastric biopsies.     

胃大部切除术后残胃幽门螺杆菌感染的临床研究

目的探讨胃大部切除术后残胃病变与幽门螺杆菌(Hp)感染的关系。方法采用快速尿素酶试验、组织切片W arth in-Starry银染及尿素呼气试验检测682例残胃病患者Hp感染情况,并进行流行病学分析。结果682例残胃病患者Hp感染检出率为27.42%,与年龄、性别以及术后时间无关;B illroth I式术后残胃Hp检出率(40.07%)明显高于B illroth II式术后残胃Hp检出率(17.37%),而伴有胆汁返流的残胃Hp感染阳性率(7.98%)明显低于不伴胆汁返流的残胃阳性率(33.53%)。同时,因溃疡、穿孔、出血行手术的残胃Hp检出率(47.88%)高于因胃癌手术的检出率(22.66%);不同病理学残胃中,残胃溃疡和残胃癌的Hp感染率明显高于慢性残胃炎及吻合口炎的Hp感染率。结论胃大部切除术后残胃病变与Hp感染密切相关,尤其是残胃癌,应及早进行Hp治疗,可减轻残胃病变,减少残胃癌的发生。     

幽门螺杆菌感染与胃癌关系的系统评价

目的:探讨幽门螺杆菌(Helicobacter pylori,Hp)感染与胃癌的关系.方法:纳入22篇关于Hp感染与胃癌关系的文献,应用Review Manager 4.2软件进行Meta分析,计算合并优势比(odd ratio,OR)及OR值95%可信区间(confidence interval,CI),倒漏斗图法定性评价发表性偏倚.结果:Meta分析得出Hp感染与胃癌发病合并OR值为2.47(95 %CI为1.74～3.52,χ2 =144.18,P<0.01).本研究倒漏斗分析图形不对称,但经敏感性分析和计算失安全系数证明发表性偏倚的影响较小.结论:Hp感染是胃癌发生的危险因素.     

Xenophagy in Helicobacter pylori‐ and Epstein–Barr virus‐induced gastric cancer

Helicobacter pylori and Epstein–Barr virus (EBV) account for roughly 80% and 10%, respectively, of gastric carcinomas worldwide. Autophagy is an evolutionarily conserved and intricately regulated cellular process that involves the sequestration of cytoplasmic proteins and organelles into double‐membrane autophagosomes that eventually fuse with lysosomes for degradation of the engulfed content. Emerging evidence indicates that xenophagy, a form of selective autophagy, plays a crucial role in the pathogenesis of H. pylori‐ and EBV‐induced gastric cancer. Xenophagy specifically recognizes intracellular H. pylori and EBV and physically targets these pathogens to the autophagosomal–lysosomal pathway for degradation. In this connection, H. pylori or EBV‐induced dysregulation of autophagy may be causally linked to gastric tumourigenesis and therefore can be exploited as therapeutic targets. This review will discuss how H. pylori and EBV infection activate autophagy and how these pathogens evade recognition and degradation by the autophagic pathway. Elucidating the molecular aspects of H. pylori‐ and EBV‐induced autophagy will help us better understand the pathogenesis of gastric cancer and promote the development of autophagy modulators as antimicrobial agents. Published by John Wiley & Sons, Ltd     

High frequency of CagA+ Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas

A high incidence of Helicobacter pylori infection has been found in patients with gastric MALT (mucosa-associated lymphoid tissue) B-cell lymphoma. Recent studies have indicated that the aggressive strains of the bacterium containing the CagA gene may have direct effects on tumourigenesis. To investigate the involvement of CagA+ strains in MALT lymphomagenesis, a sensitive polymerase chain reaction (PCR)-based detection assay for the gene was developed. DNA extracts from paraffin sections of 123 H. pylori-related gastric biopsies from Italy were analysed, including 56 cases of chronic gastritis, 37 low-grade, and 30 high-grade MALT lymphomas: 30·3 per cent (17/56) of the gastritis cases, 37·8 per cent (14/37) of the low-grade, and 76·7 per cent (23/30) of the high-grade MALT lymphomas were found to contain the CagA gene. The frequency of CagA+ strain infection was signfiicantly higher (P<0·05) in high-grade than in low-grade MALT lymphoma or gastritis. These results suggest that high-grade gastric MALT lymphoma transformation may be more likely to occur following infection by CagA+ strains of H. pylori. © 1998 John Wiley & Sons, Ltd.     

Expression of Lewis antigens and their precursors in gastric mucosa: relationship with Helicobacter pylori infection and gastric carcinogenesis

Lewis (Le)-associated antigens are carbohydrates that are related biochemically to the ABO blood groups, and may have a role in Helicobacter pylori adherence. To evaluate their relationship to clinicopathological outcomes, gastric Le expression, including type 1 precursor, type 1 H, Le(a), Le(b), Le(x), Le(y) and sialylated Le(a) (CA19-9), was evaluated immunohistochemically in 233 gastric biopsy specimens obtained at routine gastroscopy. Expression was also investigated in gastric tissues showing chronic gastritis, intestinal metaplasia, and carcinoma from 42 patients with gastric cancer. A polymerase chain reaction was performed for H. pylori and the bacterial babA2 gene. We identified type 1 precursor expression in 34.3%, type 1 H in 55.8%, Le(a) in 44.2%, Le(b) in 82.0%, Le(x) in 44.2%, Le(y) 56.7%, and CA19-9 in 16.3% of the 233 gastric biopsy specimens. Expression of type 1 H, Le(b), and CA19-9 was significantly associated with H. pylori infection and histological features (p < 0.05), and expression of type 1 H was an independent predictive factor for H. pylori infection by multivariate logistic regression (p = 0.020). Positivity for the babA2 genotype correlated significantly with H. pylori infection and type 1 H expression in gastric biopsy specimens (p < 0.05). The babA2 genotype was more frequent in gastric mucosa from the gastric cancer patients than in gastric biopsy specimens from routine gastroscopy (p = 0.009). In the 42 gastric cancer patients, the frequency of type 1 precursor, Le(a), and Le(x) expression was significantly higher in intestinal metaplasia and carcinoma than in chronic gastritis (p < 0.05), but the frequency of type 1 H and Le(b) expression was significantly lower in intestinal metaplasia and carcinoma (p < 0.05). In conclusion, Le expression, especially that of type 1 H, was significantly associated with clinicopathological features. In gastric cancer patients, Le expression was altered in intestinal metaplasia and carcinoma in comparison with chronic gastritis.     

TLR2及TLR4在侵袭性肺曲霉病小鼠中的表达

目的 研究Toll样受体(TLR)2和TLR4在侵袭性肺曲霉病小鼠中的表达,探讨TLR2和TLR4在侵袭性肺曲霉病中的作用. 方法 将小鼠分为3组:A组为正常对照组;B组为未免疫抑制但感染烟曲霉菌组;c组为侵袭性肺曲霉病(IPA)模型组,给予免疫抑制并感染烟曲霉菌.在感染后8、24、48和72 h时相点,处死小鼠,取肺组织,采用组织病理学方法观察肺组织的病理损伤,RT-PCR法检测肺组织各个时相点的TLR2、TLR4、TNF.ot和β-tublin的表达.TLR2、TLR4、TNF-α的PCR产物电泳条带的扫描密度值与同时扩增的β-tublin电泳条带的扫描密度值的比值用以表示TLR2、TLR4和TNF-α的相对表达水平. 结果 病理观察结果显示,对照组小鼠的肺组织结构正常;正常小鼠感染烟曲霉菌后,小鼠的肺组织有炎症细胞浸润、出血等炎症反应,但未见孢子萌芽生成菌丝;而IPA模型小鼠的肺组织病理损伤严重,可见炎症细胞浸润、肺泡塌陷伴随出血,孢子聚积并萌芽生成菌丝.8、24、48 h 3个时间点的TLR4和24、48 h两个时相点的TNF-α在IPA模型小鼠肺组织中的表达要低于烟曲霉菌感染的正常小鼠(P<0.05),而TLR2在烟曲霉菌感染的正常小鼠和IPA模型小鼠肺组织中呈现低表达,但24、72 h时相点的TLR2在IPA模型小鼠的表达要低于烟曲霉菌感染的正常小鼠(P<0.05). 结论 TLR4及其下游分子TNF-α在IPA模型小鼠肺组织中低表达,在组织病理镜检中可见肺曲霉病典型肺组织病理损伤和孢子生成菌丝.     

Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer

Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.     

固有免疫分子DC-SIGN在幽门螺杆菌感染胃黏膜上皮细胞表达意义

探讨固有免疫分子DC-SIGN在幽门螺杆菌(H.pylori)感染的胃上皮细胞表达,及其与胃黏膜损伤的关系.选取经胃镜及组织病理检查确诊的72例慢性胃炎患儿胃黏膜活检标本,采用免疫组化检测胃黏膜上皮细胞DC-SIGN表达.体外建立幽门螺杆菌感染胃上皮细胞模型,采用流式细胞术检测幽门螺杆菌刺激的胃上皮细胞DC-SIGN以...