Th17细胞介导的免疫应答在幽门螺旋杆菌相关性疾病中的作用机制

Th17细胞是CD4~+T细胞亚型之一,可分泌IL-17等炎性因子,诱导机体多种疾病。幽门螺旋杆菌(Helicobacter pylori,Hp)感染后,Cag A及Ure B等可影响Th17细胞数量,其机制可能与被感染的巨噬细胞直接诱导细胞分化、激活MyD88等信号通路及趋化因子的趋动有关,最终Th17、Treg细胞数量均较感染前增多,Th17/Treg平衡紊乱,总体向Treg漂移;同时,增多的Th17细胞一方面可通过募集中性粒细胞等参与Hp的清除,另一方面又扩大炎症反应,引起黏膜损伤甚至诱导癌变,从而在Hp感染的免疫应答中扮演着重要角色,参与胃炎、消化性溃疡、胃癌等Hp相关性疾病的发生发展。     

褪黑素在感染性疾病中作用的研究进展

褪黑素(MLT)是一种主要由松果体分泌的胺类激素,主要生理功能为调节昼夜节律。MLT可通过多种途径与机体免疫系统相互作用,从而调节机体免疫系统功能。在感染性疾病中, MLT可通过调节免疫细胞数量、调控细胞因子表达,还可通过减少炎性因子分泌、降低白细胞黏附功能及抗氧化作用来增强免疫系统功能,并减少炎症所致的病理损伤。同时, MLT可通过直接抑制病原体的复制及增殖过程,从而抵抗病原体的感染。因此, MLT可能成为感染性疾病临床治疗的新的靶点和辅助方法。我们对MLT调节机体免疫系统的功能机制及其在感染性疾病中发挥的重要作用的研究进展进行总结。     

幽门螺杆菌诊断现状

幽门螺杆菌(Helicobacter pylori,Hp)1983年由Warren及Marshall首次报道,其感染与消化性溃疡、慢性胃炎、胃切除后残胃炎、胃癌、MALT淋巴瘤、NSAID性溃疡密切相关。人群中Hp感染率约50%-90%,检出率在十二指肠溃疡高达95%-100%,胃溃疡达70%-90%[1]。故重视Hp感染的诊断极为重要     

褪黑素对荷胃癌小鼠胸腺及脾CD4+CD25+调节性T细胞的影响

目的:研究褪黑素在抑制肿瘤过程中对荷胃癌小鼠胸腺及脾CD4+CD25+调节性T(Treg)细胞表达变化的影响.方法:培养小鼠前胃癌细胞株(MFC),采用小鼠荷胃癌模型.用褪黑素干预1周后,测量小鼠胸腺、脾质量;并用流式细胞仪检测胸腺、脾Treg细胞;用实时荧光定量PCR和免疫印迹法检测胸腺、脾叉头型转录因子3 (Foxp3)的表达.结果:与正常对照组相比,小鼠胸腺、脾质量各组之间差异无统计学意义.在褪黑素抗肿瘤过程中,与正常对照组相比,荷瘤空白对照组小鼠胸腺与脾的Treg细胞均上升,褪黑素干预后降至正常水平;褪黑素还能使小鼠胸腺Foxp3 mRNA表达下降,脾Foxp3 mRNA反而上调;而小鼠胸腺、脾scurfin蛋白均明显下降.结论:褪黑素能下调荷胃癌小鼠胸腺、脾的CD4+CD25+Treg细胞及特异性转录蛋白scurfin及胸腺Foxp3 mRNA,使脾Foxp3 mRNA反而上调.褪黑素抗胃癌作用与免疫器官中CD4+CD25+Treg细胞免疫调节有关.     

树突状细胞对Th17/Treg免疫平衡调节的研究进展

树突状细胞(dendritic cells,DCs)对辅助性T细胞17(T help cell 17,Th17)/调节性T细胞(regulatory T cell,Treg)平衡的调控是免疫学研究中目前最为活跃的研究领域之一.Treg和新近发现的Th17是机体存在的两种不同于Th1和Th2的CD4+T细胞新亚型.Th17细胞介导炎症、延续破坏进程,Treg细胞对抗炎症、维持免疫耐受.机体处于正常状态下二者保持平衡,但新近研究发现,在自身免疫性疾病、感染、肿瘤等诸多疾病中存在Th17/Treg细胞失衡,进而诱导异常免疫应答,导致多种免疫性疾病的发生.作为机体功能最强的专职抗原提呈细胞(antigen-presenting cells,APC) ——DCs对Th17/Treg细胞平衡如何发挥着调控作用备受关注,本文将对其研究进展予以综述.     

褪黑素体内外对小鼠前胃癌细胞的增殖抑制与凋亡诱导作用

目的 探讨褪黑素(MLT)在体内外对小鼠前胃癌(MFC)细胞的增殖抑制与凋亡诱导作用.方法 体内实验:建立荷胃癌小鼠模型,随机分为5组:A.正常对照组;B.荷瘤空白对照组:每日注射生理盐水100 mg/kg;C.小剂量褪黑素组:荷瘤成功后(接种第6天起)每日腹腔注射MLT 25 mg/kg;D.中剂量MLT组:每日腹腔...     

幽门螺旋杆菌引起胃黏膜免疫损伤机制研究进展

幽门螺旋杆菌(Helicobacter plyori,Hp)是消化道疾病最常见的病因,通过多种机制诱导炎症通路激活、免疫细胞及炎症因子释放改变胃黏膜周围微环境引起慢性炎症,持久性的慢性炎症可导致胃黏膜萎缩、甚至诱发胃癌.正常机体T淋巴细胞在免疫反应中起主导作用,其中正向调节与负向调节系统相互诱导和制约T细胞网络维持免疫系统平衡,当Hp感染后两项调节比例出现异常,导致免疫系统紊乱从而引起免疫损伤.近年来免疫细胞的分子生物学研究已经成为临床过继性细胞免疫治疗的理论基础.     

肠道菌群对Th17/Treg免疫平衡和炎症性肠病影响的研究进展

炎症性肠病(inflammatory bowel disease,IBD)是一种慢性、炎症性、自身免疫性疾病,其发病机制尚未明确,目前认为是由宿主易感性基因、环境、肠道菌群等因素的综合作用引发机体异常免疫炎症应答所致。研究证明,CD4~+T细胞分化成的辅助性T细胞17(Th17)以及调节性T细胞(Treg)之间的失衡将导致IBD的发生。近期研究表明肠道菌群除直接参与IBD的发病外,部分菌群可通过分泌炎症细胞因子,或小分子物质如多糖A(polysaccharide A,PSA)、短链脂肪酸(short-chain fatty acids,SCFAs)等介导或影响Th17/Treg分化平衡,进而加重或缓解肠道免疫炎症反应,影响IBD的发病。本文就肠道菌群如何影响Th17/Treg免疫平衡及IBD的发病过程进行了梳理和总结。     

调节性T细胞与动脉粥样硬化关系的研究进展

动脉粥样硬化(atherosclerosis,AS)是一种血管壁的慢性炎症疾病,免疫系统在其发生、发展过程中起着重要作用。最新的研究表明,调节性T细胞(regulatory T cell,Treg)参与了AS的炎症反应,可以抑制炎症、改善AS。本文综述了近年有关Treg细胞与AS关系的文献,探讨了Treg细胞在AS发生发展中的作用,介绍了影响Treg细胞增殖的因子及对AS的治疗研究,并对AS的免疫疗法进行了展望。     

MT2受体介导褪黑素对小鼠前胃癌细胞的抑制作用

目的探讨褪黑素(MLT)通过褪黑素膜受体MT2抑制小鼠前胃癌(MFC)细胞增殖及其与丝裂原活化蛋白激酶(MAPKs)、磷脂酰肌醇-3激酶(PI3K)-Akt信号通路的关系。方法应用siRNA技术沉默MT2表达,观察褪黑素对小鼠前胃癌细胞的抑制作用及ERK1/2、Akt的磷酸化的影响。结果 1.siRNA介导的MT2沉默能明显拮抗褪黑素对胃癌细胞增殖的抑制作用;2.沉默MT2可部分阻断褪黑素抑制ERK1/2、Akt磷酸化的作用。结论褪黑素可通过MT2受体抑制ERK1/2、Akt的磷酸化从而抑制胃癌细胞增殖。     

Concurrent infection with Heligmosomoides polygyrus suppresses anti‐Plasmodium yoelii protection partially by induction of CD4+CD25+Foxp3+ Treg in mice

Malaria and intestinal nematode infection are widespread and co‐infection frequently occurs. We investigated whether co‐infected intestinal nematodes modulate immunity against co‐existing malaria parasites. Infection of C57BL/6 mice with Plasmodium yoelii 17XNL (Py) was transient and self‐limiting, but preceding infection with Heligmosomoides polygyrus (Hp), a mouse intestinal nematode, exacerbated malaria resulting in higher parasite burdens and poor survival of the mice. Co‐infection with Hp led to reduced Py‐responsive proliferation and IFN‐γ production of spleen cells, and higher activation of CD4⁺CD25⁺Foxp3⁺ Treg. In vivo depletion of Treg recovered anti‐Py immunity and rescued co‐infected mice from exacerbated malaria. However, we did not observe any obvious ex vivo activation of Treg by either Hp products or living worms. Our results suggest that intestinal nematodes moderate host immune responses during acute malaria infection by aggressive activation of Treg. Elucidation of the mechanisms of Treg activation in situ is a target for future analyses.     

Diagnosis and treatment of Helicobacter pylori infection

National Danish guidelines for the diagnosis and treatment of Helicobacter pylori (Hp) infection have been approved by the Danish Society for Gastroenterology. All patients with peptic ulcer disease, gastric cancer, and MALT lymphoma should be tested for Hp. We also recommend testing in first degree relatives to patients with gastric cancer, in NSAID-naive patients, who need long-term NSAID therapy, and in patients presenting with dyspepsia and no alarm symptoms. Non-endoscoped patients can be tested with a urea-breath test or a faecal antigen test. Endoscoped patients can be tested with a rapid urease test. Proton pump inhibitor therapy should be stopped at least 1 week prior to Hp testing. All infected patients should be offered Hp eradication therapy. First-line treatment is 7-day triple therapy with a proton pump inhibitor and clarithromycine in combination with metronidazole or amoxicilline. Quadruple therapy for 2 weeks with bismuthsubsalicylate, tetracycline, metronidazole and a proton pump inhibitor is recommended in case of treatment failure. Hp testing should be offered to all patients after eradication therapy but is mandatory in patients with ulcer disease, noninvasive gastric cancer or MALT lymphoma. Testing after eradication should not be done before 4 weeks after treatment has ended.     

上消化道黏膜病变病理诊断结果分析

目的 探讨上消化道黏膜病变的病理类型和临床特点的关系,为临床诊治该病提供参考依据。方法 回顾性分析 2014 年1 月~2018 年 12 月我院收集的 9659 例上消化道黏膜活检病理诊断结果,观察胃炎、息肉、溃疡和肿瘤病变与年龄、性别、幽门螺杆菌（Hp）感染情况的关系。结果 ①胃炎:不同年龄段慢性炎症、萎缩、肠化、上皮内瘤变人数比较,差异有统计学意义（P<0.05）。女性慢性炎症轻度和中度人数高于男性,差异有统计学意义（P<0.05）;不同性别萎缩、肠化、上皮内瘤变人数比较,差异无统计学意义（P>0.05）;慢性炎症、萎缩、肠化、上皮内瘤变不同严重程度 Hp（+）人数高于 Hp（-）,差异均有统计学意义（P<0.05）。②息肉;不同年龄段胃息肉、贲门息肉、食道息肉病变人数比较,差异有统计学意义（P<0.05)。女性胃息肉、食道息肉人数高于男性,差异有统计学意义（P<0.05）;不同性别贲门息肉、十二指肠息肉人数比较,差异无统计学意义（P>0.05）。胃息肉、贲门息肉不同类型 Hp（+）人数高于 Hp（-）,差异有统计学意义（P<0.05）;食道息肉、十二指肠息肉 HP 感染人数比较,差异无统计学意义（P>0.05）。③溃疡和肿瘤病变:不同年龄段胃溃疡、胃癌、食管癌人数比较,差异有统计学意义（P<0.05）;不同年龄段贲门溃疡人数比较,差异无统计学意义（P>0.05）。男性胃溃疡、食道溃疡、贲门溃疡、胃癌、食管癌人数高于女性,差异有统计学意义（P<0.05）。胃溃疡、食道溃疡、贲门溃疡、胃癌、食管癌Hp（+）人数高于Hp（-）,差异有统计学意义（P<0.05）。结论 轻度慢性胃炎好发于青中年性、息肉、溃疡、肿瘤病变好发于中老年人,轻度慢性胃炎、息肉病变好发于女性,溃疡和肿瘤病变好发于男性,胃炎相关病变、息肉、溃疡、肿瘤与 Hp 感染密切相关。     

幽门螺杆菌相关性十二指肠溃疡患者血清、胃窦粘膜组织中胃泌素、生长抑素水平变化

目的：探讨幽门螺杆菌相关性胃窦炎症病理变化程度对血清、胃窦部粘膜组织中胃泌素水平的影响。方法：对Hp阳性的活动性DU患者30例、Hp阴性的活动性DU患者10例、Hp阴性且病理表现仅有轻度浅表性胃炎的10例正常对照患者进行内镜、胃粘膜组织学、幽门螺杆菌和血清、胃粘膜组织胃泌素水平检测，并分析其相互关系。结果：幽门螺力阳性患者血清、胃粘膜组织中胃泌素水平较幽门螺杆菌阴性患者显著升高（P＜0．01）。胃窦组织中生长抑素水平明显降低（P＜0．01）。结论：幽门螺杆菌感染后胃泌素、生长抑菌变化与DU的发生关系密切，并在疾病的发生发展中起一定作用。     

复方嗜酸乳杆菌联合常规四联疗法治疗幽门螺旋杆菌感染消化性溃疡的疗效

目的 观察复方嗜酸乳杆菌联合常规四联疗法治疗幽门螺旋杆菌（Hp）感染消化性溃疡的疗效。方法 选择2018年5月~2019年5月在我院诊治的幽门螺旋杆菌感染消化性溃疡患者112例,采用随机数字表法分为对照组和观察组,各56例。对照组采用常规四联疗法治疗,观察组在对照组基础上加用复方嗜酸乳杆菌治疗,比较两组临床治疗总有效率、临床症状（反酸、上腹痛、饱胀、呕吐）评分、Hp根除率以及临床不良反应发生情况。结果 观察组治疗总有效率为94.64%,高于对照组的80.35%,差异有统计学意义（P＜0.05）;观察组反酸、上腹痛、饱胀、呕吐症状评分均低于对照组,差异有统计学意义（P＜0.05）;观察组Hp根除率为92.85%,高于对照组的78.57%,差异有统计学意义（P＜0.05）;观察组不良反应发生率为3.57%,低于对照组的16.07%,差异有统计学意义（P＜0.05）。结论 复方嗜酸乳杆菌联合常规四联疗法治疗Hp感染消化性溃疡疗效确切,可促进Hp根除,有助于减轻临床症状,降低临床症状评分,且临床不良反应少。     

Influence of IL-1 gene cluster polymorphisms on the development of H. pylori associated gastric ulcer

BACKGROUND AND AIMS: Chronic H. pylori infection is the main cause of ulcer disease which depicts a major burden of our healthy care systems. The individual host immune response plays a pivotal role in the outcome of the infection but genetic susceptibility to develop gastric ulcer is unknown. IL-1beta and its natural receptor antagonist IL-1ra are involved in the inflammatory response to H. pylori infection. Thus, we investigated the influence of functional genetic variants in the IL-1 gene cluster on the development of gastric ulcer disease. PATIENTS AND METHODS: 390 H. pylori infected patients were genotyped for IL-1B -31 and +3954 by TaqMan technology. Alleles of IL-1RN 86VNTR were determined by gel electrophoresis after amplification. Three hundred and sixty healthy blood donors were included as healthy controls. RESULTS: Carriage of the IL-1B -31 C allele conferred a increased but not significant risk for H. pylori infection (OR: 1.3, Wald 95% CI: 0.8相似文献   

Cytotoxic-T-lymphocyte-associated antigen 4 blockade abrogates protection by regulatory T cells in a mouse model of microbially induced innate immune-driven colitis

Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4⁺ CD25⁺ CD45RB^low regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2^−/− mice without Treg cell transfer. Despite high numbers of Foxp3⁺ Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody-treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines gamma interferon and interleukin-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.     

Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells

During Helicobacter pylori infection, T cells are recruited to the gastric mucosa, but the host T-cell response is not sufficient to clear the infection. Some of the recruited T cells respond in a polarized manner to a Th1 response, while others become anergic. We have previously shown that T-cell anergy may be induced during infection by the interaction of T cells with B7-H1, which is up-regulated on the gastric epithelium during H. pylori infection. Recently, regulatory T (Treg) cells with a CD4(+) CD25(high) FoxP3(+) phenotype were found at an increased frequency in the gastric mucosa of biopsy specimens from H. pylori-infected patients. While Treg cells are important in maintaining tolerance, they can also suppress immune responses during infection. In this study, we examined the induction of the Treg phenotype when na?ve T cells were incubated with gastric epithelial cells exposed to H. pylori. The frequency of this phenotype was markedly decreased when B7-H1 was blocked with monoclonal antibodies or its expression was blocked with small interfering RNA. The functional role of these Treg cells was assessed in proliferation assays when the cells were cocultured with activated T cells, which effectively decreased proliferation of the cells.     

Naturally Occurring Self-Reactive CD4^＋CD25^＋ Regulatory T Cells： Universal Immune Code

Naturally occurring thymus-arisen CD4^＋CD25^＋ regulatory T （Treg） cells are considered to play a central role in self-tolerance. Precise signals that promote the development of Treg cells remain elusive, but considerable evidence suggests that costimulatory molecules, cytokines, the nature of the TCR and the niche or the context in which the T cell encounters antigen in the thymus play important roles. Analysis of TCR from Treg cells has demonstrated that a large proportion of this population has a higher avidity to self-antigen in comparison with TCR from CD4^＋CD25^＋ cells and that peripheral antigen is required for their development, maintenance, or expansion. Treg cells have been shown to undergo expansion in the periphery, likely regulated by the presence of self-antigen. Many studies have shown that the involvement of Treg cells in the tolerance induction is antigen-specific, even with MHC-mismatched, in transplantation/graft versus host disease （GVHD）, autoimmunity, cancer, and pregnancy. Theses studies concluded a vital role for self-reactive Treg cells in maintenance of the body integrity. Based on those studies, we hypothesize that self-reactive Treg cells are shared among all healthy individuals and recognize same self-antigens and their TCR encodes for few dominant antigens of each organ which defines the healthy self. These dominant self antigens can be regarded as ＂universal immune code＂. Cellular ＆ Molecular Immunology.