慢性萎缩性胃炎胃粘膜病理改变与细胞毒素相关蛋白及空泡细胞毒素的关系

目的研究慢性萎缩性胃炎时胃粘膜不同的病理变化与幽门螺杆菌(Hp)致病因子细胞毒素相关蛋白(CagA)和空泡细胞毒素(VacA)之间的关系.方法 120例Hp阳性的慢性萎缩性胃炎患者按粘膜炎症和粘膜萎缩的程度以及有无肠化生进行分组,并抽取血清,用Western blot法测定血清中特异性抗体CagA(116KD)和VacA(89KD).结果 (1)慢性萎缩性胃炎粘膜炎症的程度与CagA检出的阳性率显著相关,炎症程度严重患者的CagA抗体阳性率显著高于轻度炎症病例(85.1% vs 53.28%,P<0.005);(2)胃粘膜重度萎缩者VacA抗体阳性率显著高于胃粘膜轻度萎缩者(77.8% vs 38.7%,P<0.005);(3)慢性萎缩性胃炎患者VacA抗体阳性者多有肠化生,其肠化生的发生率显著高于VacA抗体阴性患者(84.1% vs 30.3%,P<0.005).结论 CagA的表达同慢性萎缩性胃炎的严重程度密切相关,高阳性率患者的胃粘膜炎症活动度较重,而VacA的表达则同胃粘膜的萎缩及肠化密切相关,胃粘膜重度萎缩与肠化患者VacA的表达率显著高于胃粘膜轻度萎缩与肠化的患者.     

人胃上皮细胞中幽门螺杆菌CagA相关未知磷酸化蛋白和磷酸化位点分析

背景：细胞毒素相关基因A蛋白（CagA）是Ⅰ型幽门螺杆菌（H.pylori）的主要毒力因子。H.pylori胃癌、胃炎相关株和CagA缺失（△CagA）株的蛋白质组学研究尚未发现CagA相关生物标记蛋白。目的：分析H.pyloriCagA阳性株和△CagA株作用后人胃上皮细胞中差异表达的未知磷酸化蛋白和磷酸化位点,为研究CagA的致病机制提供线索。方法：以金属离子亲和吸附富集技术富集经H.pylori标准株和△CagA株作用4h的人胃腺癌细胞株AGS的磷酸化蛋白,双向电泳（2-DE）分离蛋白,飞行时间质谱（TOF-MS）技术鉴定差异蛋白点。结果：H.pylori标准株作用后,AGS细胞FAM50A蛋白276位丝氨酸发生磷酸化,PQBP1蛋白227～251序列中有磷酸化位点。与H.pylori标准株相比,△CagA株作用于AGS细胞可引起至少13种未知磷酸化蛋白的变化,其质谱图中均出现中性丢失峰,其中2种表达量增加,4种表达量降低,6种消失,1种新发生磷酸化。结论：CagA阳性H.pylori感染可致AGS细胞FAM50A和PQBP1蛋白发生磷酸化。所发现的13种未知磷酸化蛋白为揭示CagA的致病机制提供了线索。     

幽门螺杆菌CagA对AGS细胞RNA转录相关磷酸化蛋白的影响

目的研究幽门螺杆菌（Helicobacter pylori，H.pylori）细胞毒素相关蛋白A（CagA）作用后人胃腺癌上皮细胞（AGS）RNA转录相关蛋白磷酸化的变化情况，进一步揭示CagA的致病机制，为寻找生物标记蛋白奠定基础。方法采用金属离子亲和吸附富集技术富集H.pylori、H.pylori CagA缺失株（H.pylori△CagA）与AGS细胞相互作用4h、以及培养相同时间的AGS细胞的磷酸化蛋白，利用二维凝胶电泳技术分离磷酸化蛋门，ImageMaster 2D分析软件比较分析识别差异蛋白，4700型MALDI源蛋白分析器确认蛋白。结果CagA致使AGS细胞的7个RNA相关的磷酸化蛋白出现差异表达，其中1个磷酸化蛋白表达量上调、4个磷酸化蛋白表达量下调、2个新出现磷酸化的蛋白。hnRNP D0 127位的苏氨酸及137位的丝氨酸发生了磷酸化。结论CagA作用后，致使hnRNP D0蛋白磷酸化。AGS细胞与RNA转录相天蛋白磷酸化的变化，呈现出诱导细胞凋亡、增殖及有利于细胞免疫逃逸的趋势。     

幽门螺杆菌CagA对慢性胃炎患者血清IFN-γ、IL-4、TGF-β和IL-17A表达的影响

目的 探讨幽门螺杆菌（Helicobacter pylori,H.pylori） CagA蛋白对慢性胃炎患者外周血IFN-γ、IL-4、TGF-β和IL-17A表达的影响.方法 检测80例慢性胃炎患者血清中抗CagA抗体,取胃黏膜行病理检查,采用ELISA法检测血清中IFN-γ、IL-4、TGF-β和IL-17A的浓度.结果 CagA抗体阳性组中中性粒细胞的浸润程度显著高于阴性组,两组间H.pylori的菌密度差异无统计学意义,性别对上述因素无显著影响.CagA抗体阳性组血清IFN-γ、IL-17A的表达显著下降,而IL-4、TGF-β的表达显著上升.结论 慢性胃炎CagA 阳性患者的胃黏膜炎症程度更重,机体无法有效清除H.pylori在胃黏膜中的定植,其原因可能与CagA 阳性患者外周血中细胞因子IFN-γ、IL-17A表达水平下降,而IL-4、TGF-β表达水平上升有关.     

幽门螺杆菌免疫分型在胃十二指肠疾病中的应用价值

目的 探讨幽门螺杆菌(Hp)细胞毒素在胃十二指肠疾病中的作用及HP免疫分型的临床应用价值。方法 采用免疫印迹法检测HP感染的胃十二指肠相关疾病的CagA和VacA抗体，并给所选病例三联HP根除方案治疗后，观察其根除率。结果 ①CagA和VacA的阳性率及CagA和VacA双阳性率正常对照组显著低干DU、GU、及GC组(P＜0．05)，而CagA和VacA双阴性率显著高于DU、GU及GC组(P＜0．05)；除DU组CagA阳性率及CagA和VacA的阳性率、CagA和VacA双阳性率显著高于UND组(P＜0．05)外，其余UND、DU、GU及GC组间CagA和VacA双阳性率及双阴性率均无显著性差异(P＞0．05)。②PU较UND的HP根除率高；HP根除成功的病例中CagA阳性率显著高于CagA阴性(P＜0．01)。结论 CagA和VacA与胃十二指肠疾病发生有密切关系，但不能作为判断HP导致特异性胃十二指肠疾病的单一指标。HP免疫分型可能无助干症状及疾病的诊断。同样的根除治疗方案，CagA阳性菌的HP根除率显著高于CagA阴性菌，CagA抗体可作为预测抗菌治疗疗效的有用的指标。     

中国上消化道疾病患者幽门螺杆菌感染根除前后胃粘膜病理改变与空泡毒素活性的关系

目的：观察幽门螺杆菌（H.pylori)阳性消化性溃疡病和慢性胃炎患者H.pylori根除前后胃粘膜病理改变与空泡毒素（VacA)活性的关系。方法：功能性消化不良伴H.pylori感染的中国患者74例,于H.pylori根除前和4－6周后作胃镜检查,根据新悉尼病理分级法按半定量记分对治疗前后的胃粘膜病理变化程度进行分级。结果：VacA^ 菌检出率为80％（59／74）,消化性溃疡病患者的检出率与慢性胃炎患者无明显差别;VacA^ 和VacA^-组患者的H.pylori根除率亦无明显差别。根除治疗前,VacA^ 和VacA^-组患者的胃粘膜慢性炎症、活动性、表面上皮损伤、萎缩、肠化和淋巴滤泡数量无显著差别;治疗后4－6周,两组患者的胃窦粘膜炎症活动性、表面上皮损伤和慢性炎症程度均明显减轻,尤以前者为著（P＜0．0001）,VacA^ 组患者的胃窦部淋巴滤泡数量减少亦稍较VacA^-组明显（P＝0．051）,两组患者的胃粘膜萎缩和肠化程度均无明显好转。结论：中国上消化道疾病患者H.pylori感染根除前后的胃粘膜病理改变与VacA活性无明显关系。成功根除H.pylori感染并不引起萎缩和肠化的逆转。     

十二指肠溃疡与萎缩性胃炎相关性研究

背景:愈来愈多的迹象表明胃溃疡(GU)与胃癌发生的危险性增加相关,而十二指肠溃疡(DU)则与胃癌的发生负性相关.目的:研究DU与萎缩性胃炎的相关性.方法:对DU、GU和复合性溃疡(CU)患者胃窦、胃窦胃体交界处和胃体黏膜以及慢性胃炎(CG)患者胃窦黏膜活检标本进行组织学检查,统计各自胃黏膜的萎缩、肠化、慢性炎症、活动性和幽门螺杆菌(H.pylori)感染的发生率及其严重程度.结果:DU患者胃窦、胃窦胃体交界处和胃体黏膜的萎缩发生率分别为54.2%、9.5%和12.4%,肠化发生率分别为18.9%、2.5%和1.5%.其胃窦黏膜肠化的发生率明显低于相应的GU、CU或CG者.3种消化性溃疡和CG患者均存在胃窦部慢性炎症,且消化性溃疡患者胃体部炎症的发生率较高,其胃炎活动性以胃窦部为主,且均较CG者高(P<0.05).DU、GU和CU患者胃窦部Ⅰ型肠化的发生率分别为68.1%、43.8%和45.0%;而其Ⅲ型肠化的发生率则分别为6.4%、25.0%和20.0%(P<0.05).结论:DU患者的胃窦部可有灶性萎缩和肠化发生,其胃窦黏膜肠化发生率和Ⅲ型肠化的发生率最低,这可能是DU患者罹患胃癌危险性较低的原因之一.     

幽门螺杆菌cagA基因3''''端可变区和CagA蛋白EPIYA基序研究进展

细胞毒素相关基因A（cagA）编码CagA蛋白，是研究最多的幽门螺杆菌（H．pylori）基因之一。CagA蛋白经由Ⅳ型分泌系统进入Hpylori黏附的胃上皮细胞，其C-端发生酪氨酸磷酸化，磷酸化的CagA可引起细胞骨架重排、诱导细胞发生形态学变化、增强细胞动力，造成细胞异常运动和增殖．最终导致癌变。因此cagA阳性H．pylori菌株较cagA阴性菌株毒力更强。cagA基因3’端可变区重复序列数目的差异造成了cogA基因结构的多态性以及CagA蛋白大小、功能和细菌毒力（致病性）的差异。因此，cagA基因3’端可变区及其蛋白的EPIYA基序与H．pylori感染临床结果的相关性，成为目前H.pylori研究的热点之一。     

幽门螺杆菌CagA与宿主细胞相互作用机制的研究进展

细胞毒素相关蛋白A（CagA）是幽门螺杆菌（Helicobacter pylori,H.pylori）感染导致宿主产生炎性反应的重要效应蛋白。H.pylori感染后通过cag PAI编码的Ⅳ型分泌系统将CagA注入宿主细胞内并发生磷酸化,导致细胞内信号传导等一系列的反应。作为H.pylori的一个重要致病因子,CagA蛋白是目前研究的热点之一。本文主要概述了CagA的特征,以CagA易位进入胃黏膜上皮细胞直至引起细胞内信号传导发生改变为主线,综述了近年来与之相关的研究和发现。     

细胞毒素相关基因A阳性幽门螺杆菌感染与脑梗死的关系

目的：研究幽门螺杆菌（HP）及其细胞毒素相关蛋白A（CagA）阳性菌株感染与脑梗死的相关性。方法：采用病例对照研究研究，选择发病1周内的脑梗死住院患者（病例组，n=70）以及年龄和性别相匹配的门诊体检人群（对照组，n=30），检测血清HP IgG抗体和HPCagA阳性菌株IgG抗体的浓度和阳性率，调查两组传统高危因素分布情况、生活习惯、幼时和成人期社会经济状况，探讨HP和CagA阳性菌株血清抗体浓度和阳性率与脑梗死及其病因学亚型的关系。结果：病例组血清HPIgG抗体阳性率和水平与对照组无显著差异，血清CagAIgG抗体阳性率（P〈0．05）和浓度（P〈0．01）均显著高于对照组。多因素回归分析显示，CagA菌株血清学阳性为脑梗死发病的独立危险因素。亚组分析表明，大动脉粥样硬化性脑梗死组血清CagA菌株IgG抗体的阳性率和浓度显著高于对照组（P〈0．05）。结论：产CagA的高毒力HP菌株感染可能是脑梗死的高危因素。     

Clinical relevance of Helicobacter pylori CagA-positive strains: gastroduodenal peptic lesions marker.

OBJECTIVES: peptic ulcer is characterized by its recurrent nature, which necessitates maintenance treatment in most patients. But this natural history can be changed in patients with peptic ulcer associated to Helicobacter pylori, as shown by the low rates of recurrence and decreased hemorrhagic recidivism associated with this infection. Whether CagA or VacA strains are associated with a greater risk of peptic ulcer is controversial. This study was designed to examine endoscopic findings and their relation with H. pylori phenotype (CagA or VacA). METHODS: 106 selected dyspeptic patients underwent upper gastrointestinal tract endoscopic examination between September 1996 and May 1997 [69 with H. pylori (Hp) and 37 without this infection]. Endoscopic findings were classified as gastric ulcer (GU), duodenal ulcer (DU), gastric erosions (GE), duodenitis (Du), chronic gastritis (CG) and normal mucosa (NM). Hp phenotype was analyzed with a western blot test. RESULTS: 75% of H. pylori strains were CagA-positive and 54.2% were VacA-positive. 82.4% of the cases of DU were associated with a CagA+ phenotype, but the association was not statistically significant. Otherwise 100% of gastric ulcers were associated with CagA+ strains (p < 0.005). VacA phenotype was not associated with any particular endoscopic finding. Peptic ulcer (DU or GU) was also associated with the CagA+ phenotype (p < 0.05). CONCLUSIONS: the CagA+ H. pylori phenotype seems to be a peptic lesion marker, but was more frequently related with GU than with DU in our sample of Spanish patients.     

Serum anti-Lewis X antibody is associated with VacA seropositivity but not atrophic gastritis in patients with Helicobacter pylori infection

OBJECTIVES: Lipopolysaccharides of Helicobacter pylori have an antigenic structure that mimics Lewis X occurring in gastric mucosa. The pathogenic role of antigenic mimicry in H. pylori-induced gastritis has been of recent interest. The aim of this study was to examine the relevance of anti-Lewis X antibody in the development of atrophic gastritis in H. pylori infection. METHODS: A total of 72 patients were studied. Serum samples were collected to measure IgG antibodies to H. pylori, CagA, VacA and Lewis X. Biopsy specimens were obtained from the antrum and the corpus to examine the grade and the type of atrophic gastritis. RESULTS: Mean anti-Lewis X antibody titres were higher in 38 VacA-seropositive patients than in 13 seronegative patients (P < 0.05). The difference was not significant between patients with diffuse-type atrophic gastritis and those with multi-focal type. No significant correlation was observed between the titre of anti-Lewis X antibody and the grade of glandular atrophy, whereas CagA seropositivity was associated with glandular atrophy. CONCLUSIONS: Anti-Lewis X antibody may play a role in persistent gastric inflammation, particularly in VacA-seropositive H. pylori infection. However, anti-Lewis X antibody does not seem itself to be associated with atrophic gastritis in patients with H. pylori infection.     

Association of Helicobacter pylori IgA antibodies with the risk of peptic ulcer disease and gastric cancer

AIM: To compare the prevalence of Helicobacter pylori (H pylori) IgG and IgA antibodies between adult subjects, with defined gastric diseases, nondefined gastric disorders and those representing the population. METHODS: Data on H pylori IgG and IgA antibodies, determined by enzyme immunoassay, were analyzed in 3 252 subjects with DGD including 482 patients with gastric ulcer, 882 patients with duodenal ulcer, 1 525 patients with chronic gastritis only and 363 subjects with subsequent gastric cancer, 19 145 patients with NoDg and 4 854 POPUL subjects. The age-adjusted prevalences were calculated for 1-and 20-year age cohorts. RESULTS: The prevalences of IgG antibodies were equally high (89-96%) in all 20-year age cohorts of the DGD groups, whereas the prevalences of IgG antibodies were lower and increased by age in the POPUL and NoDg groups. The prevalences of IgA antibodies were also higher in the DGD groups; among them CA (84-89%) and GU groups (78-91%) showed significantly higher prevalences than DU (68-77%) and CG patients (59-74%) (OR 2.49, 95%CI 1.86-3.34 between the GU and DU groups). In the CA, GU, and DU groups, the IgA prevalences showed only minor variation according to age, while they increased by age in the CG, POPUL, and NoDg groups (P≤0.0001). The IgA response, but not the IgG response, was associated with an increased risk of CA (OR 2.41, 95%CI 1.79-3.53) and GU (OR 2.57, 95%CI 1.95-3.39) in comparison with CG patients. CONCLUSION: An IgA antibody response during H pylori infection is significantly more common in CA and GU patients as compared with CG patients.     

Comparison of gastric histology among Swedish and Japanese patients with peptic ulcer and Helicobacter pylori infection

BACKGROUND: The natural course of Helicobacter pylori gastritis may vary between different ethnic groups. Gastric histopathology and the occurrence of H. pylori organisms in the stomach were investigated in healed duodenal (DU) and gastric (GU) ulcer patients recruited in Sweden (S) and Japan (J) in an identical trial. METHODS: In 203 patients (JGU = 39, JDU = 55, SDU = 109), various morphological gastritis variables and H. pylori were assessed from biopsy specimens obtained using a specific sampling protocol and interpreted according to guidelines of the updated Sydney grading system. RESULTS: The ratio of GU:DU was observed to be very different between the recruited Japanese (39:55) and Swedish (0:109) patients. A comparison of data from SDU and JDU showed that the prevalence of H. pylori infection and the antral predominant gastritis demonstrated by both SDU and JDU were essentially identical. A comparison of data from JDU and JGU demonstrated a greater prevalence of H. pylori infection in the antrum, but not corpus, of JDU compared to JGU patients. The prevalence of atrophy and intestinal metaplasia was higher in both the antrum and corpus of JGU compared to JDU in all patients. CONCLUSIONS: The site specified biopsy methodology and standardized interpretation criteria utilized in this study clearly show that the histotopographic profile of Swedish and Japanese DU patients is essentially the same.     

Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy

BACKGROUND: Atrophic gastritis has been shown to be one of the long term sequelae of Helicobacter pylori infection. AIMS: To determine the prevalence of atrophic gastritis in outpatients, to study the accuracy of serological methods for revealing atrophy, and to define the association of H pylori infection with atrophic gastritis in these patients. PATIENTS/METHODS: A total of 207 consecutive outpatients referred for gastroscopy were included. Biopsy specimens from the antrum and corpus were assessed histologically according to the Sydney system. Serum samples were studied for H pylori IgG and IgA antibodies by enzyme immunoassay, CagA antibodies by immunoblot, pepsinogen I by an immunoenzymometric assay, gastrin by radioimmunoassay, and parietal cell antibodies by indirect immunofluorescence. RESULTS: Histological examination revealed atrophic gastritis in 52 (25%) of 207 patients. H pylori and CagA antibodies were strongly associated with atrophic antral gastritis but poorly associated with atrophic corpus gastritis. Low serum pepsinogen I was the most sensitive and specific indicator of moderate and severe atrophic corpus gastritis. All six patients with moderate atrophic corpus gastritis had H pylori infection but eight of 10 patients with severe atrophic corpus had increased parietal cell antibodies and nine had no signs of H pylori infection. CONCLUSIONS: Atrophic antral gastritis was strongly associated with CagA positive H pylori infection. Severe atrophic corpus gastritis was not determined by H pylori tests but low serum pepsinogen I, high gastrin, and parietal cell antibodies may be valuable in detecting these changes.     

Anti-CagA and anti-VacA antibodies in Helicobacter pylori-infected patients with and without peptic ulcer disease in Serbia and Montenegro

BACKGROUND: The expression of two Helicobacter pylori proteins, CagA and VacA, is associated with more severe pathogenesis and clinical outcomes of the infection. However, this association varies among geographical regions and ethnic groups. We therefore evaluated CagA and VacA seroprevalence in H. pylori-positive dyspeptic patients in Serbia and Montenegro. METHODS: In 173 consecutive dyspeptic patients referred to endoscopy (67M, mean age 49 +/- 15, 76 smokers), immunoblot assay was used to detect serum antibodies against CagA and VacA. Presence of H. pylori infection was assessed using a rapid urease test (RUT), routine histology and serology (anti-IgG ELISA). Duodenal ulcer (DU) was diagnosed in 28, gastric ulcer (GU) in 3 and non-ulcer dyspepsia (NUD) in the remaining 142 patients. RESULTS: 129 (74.6%) patients were H. pylori-positive, 27 (96.4%) with DU, 3 (100%) with GU and 99 (69.7%) with NUD (P < 0.01); 121 (93.8%) patients carried anti-CagA antibodies and there was no difference between the DU and NUD groups. VacA antibodies were detected in sera of 50 (38.75%) and were more prevalent in patients with DU compared to the NUD group (P < 0.05). CONCLUSIONS: In Serbia and Montenegro there is high seroprevalence of CagA-positive H. pylori strains in dyspeptic patients with and without peptic ulcer, while VacA-positive strains are more closely related to peptic ulcer disease.     

Anti‐CagA and anti‐VacA antibodies in Helicobacter pylori‐infected patients with and without peptic ulcer disease in Serbia and Montenegro

Background: The expression of two Helicobacter pylori proteins, CagA and VacA, is associated with more severe pathogenesis and clinical outcomes of the infection. However, this association varies among geographical regions and ethnic groups. We therefore evaluated CagA and VacA seroprevalence in H. pylori‐positive dyspeptic patients in Serbia and Montenegro. Methods: In 173 consecutive dyspeptic patients referred to endoscopy (67M, mean age 49?±?15, 76 smokers), immunoblot assay was used to detect serum antibodies against CagA and VacA. Presence of H. pylori infection was assessed using a rapid urease test (RUT), routine histology and serology (anti‐IgG ELISA). Duodenal ulcer (DU) was diagnosed in 28, gastric ulcer (GU) in 3 and non‐ulcer dyspepsia (NUD) in the remaining 142 patients. Results: 129 (74.6%) patients were H. pylori‐positive, 27 (96.4%) with DU, 3 (100%) with GU and 99 (69.7%) with NUD (P?P?Conclusions: In Serbia and Montenegro there is high seroprevalence of CagA‐positive H. pylori strains in dyspeptic patients with and without peptic ulcer, while VacA‐positive strains are more closely related to peptic ulcer disease.