胸腺基质淋巴细胞生成素对重症肌无力患者外周血中调节性T细胞的变化影响

目的：探讨胸腺基质淋巴细胞生成素对重症肌无力患者外周血中调节性T细胞的变化影响。方法：2008年9月到2013年12月选择在我院神经内科诊治的重症肌无力患者120例,都给予胸腺切除手术治疗,对预后情况进行观察与分析,对胸腺基质淋巴细胞生成素的表达与外周血中调节性T细胞的变化进行分析。结果：120例患者术后总有效率为91.7%,术后患者的CD4+CD25 Foxp3 /CD4 值明显高于对照组(P<0.05)。HE染色可见髓质部淋巴细胞增生与部分Hassall小体；免疫组化染色可见中髓质部Hassall小体数量明显减少,染色稍浅。相关性分析显示TSLP阳性表达的Hassall小体计数与CD4 CD25 Foxp3 Treg细胞表达水平之间存在呈线性相关(P<0.05)。Logistic回归模型分析结果表明CD4 CD25 Foxp3 /CD4 值和TSLP阳性表达是影响有效率的独立危险因素(P<0.05)。结论：胸腺切除手术是治疗重症肌无力疗效好,其机制在于能够有效维持免疫稳态功能,调节T细胞与胸腺基质淋巴细胞生成素的表达变化,保持患者健康。     

胸腺基质淋巴细胞生成素与支气管哮喘

胸腺基质淋巴细胞生成素(TSLP)是一种由上皮细胞产生的白介素7样细胞因子,与靶细胞TSLP受体相互作用,可以激活骨髓源性树突状细胞,进而诱导一种特殊类型的炎症型Th2细胞反应,而与支气管哮喘(简称哮喘)相关的致病性T细胞正是这类炎症型T细胞.TSLP还可诱导肥大细胞分泌Th2细胞因子,参与哮喘的发病过程.     

Ox-LDL诱导血管平滑肌细胞胸腺基质淋巴细胞生成素表达

目的:观察氧化低密度脂蛋白(ox-LDL)是否可以诱导血管平滑肌细胞(VSMCs)表达胸腺基质淋巴细胞生成素(TSLP),并探讨核因子-κB(NF-κB)信号通路在其中的作用。方法:原代培养VSMCs,分别用ox-LDL及ox-LDL联合NF-κB特异性抑制剂——吡咯烷二硫代氨基甲酸盐(PDTC)干预。采用免疫组织化学染色检测胞质中TSLP的表达,用ELISA法检测细胞培养上清液中TSLP的浓度,用电泳迁移率实验检测NF-κB的结合活性。结果:正常未经ox-LDL刺激的VSMCs几乎不表达TSLP,经ox-LDL刺激后胞质及上清液中的TSLP表达明显增加,并有浓度和时间依赖性。Ox-LDL刺激VSMCs表达TSLP的同时NF-κB信号通路激活,经PDTC预处理后TSLP表达量显著减少。结论:Ox-LDL能够诱导VSMCs表达TSLP,其作用机制可能为上调NF-κB的结合活性。     

胸腺基质淋巴细胞生成素在肝脏疾病中的作用

胸腺基质淋巴细胞生成素(TSLP)是一种由四条短链的α螺旋束组成的Ⅰ型IL-2家族细胞因子,与IL-7具有同源性。TSLP在很多过敏性疾病或自身免疫性疾病如哮喘、特应性皮炎、嗜酸性食管炎、炎症性肠病等具有重要作用,且促进了这些疾病的发展。目前,也有一些关于TSLP与肝脏疾病的研究报道。关于它在肝脏疾病中作用,有报道其能促进肝脏疾病的发生发展,但也有研究表明其在肝脏疾病中起到保护性的作用。现从TSLP的分子组成及其生物学特性、TSLP与良性肝病、TSLP与肝脏肿瘤三个方面做一综述,阐述TSLP在肝脏疾病中作用的研究进展。     

胸腺基质淋巴细胞生成素与支气管哮喘的关系

支气管哮喘(简称哮喘)是多基因参与的具有遗传易感性的慢性气道变应性炎症.胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin,TSLP)是一种由上皮细胞产生的白介素7(IL-7)样细胞因子,与多种免疫细胞的TSLP受体相互作用,诱导Th2型免疫应答,参与哮喘的发生和发展.多个遗传学研究发现,哮喘是一种遗传易感性疾病,TSLP基因单核苷酸多态性与哮喘易感性密切相关,靶向TSLP治疗有望为今后哮喘免疫治疗带来新的前景.     

急性冠状动脉综合征患者血浆胸腺基质淋巴细胞生成素的变化

目的:观察急性冠脉综合征(ACS)患者血浆胸腺基质淋巴细胞生成素(TSLP)水平。方法:经冠状动脉造影证实的冠心病患者98例,其中稳定型心绞痛(SAP)组40例,ACS组58例,另选取20例造影正常者作为对照组。采用ELISA法检测血浆TSLP水平,同时常规检测患者生化指标。结果:ACS组血浆TSLP浓度[(16.5±3.0)pg/ml]显著高于SAP组[(3.3±1.4)pg/ml]和对照组[(2.8±1.3)pg/ml](均P0.01);吸烟患者TSLP浓度[(27.9±14.6)pg/ml]显著高于非吸烟患者[(12.9±4.8)pg/ml](P0.01)。血浆TSLP浓度与血C反应蛋白及LDL正相关(分别r=0.23,P0.05和r=0.38,P0.01)。结论:TSLP介导的炎症反应可能与ACS发生有关。     

胸腺基质淋巴细胞生成素与支气管哮喘的关系

支气管哮喘(简称哮喘)是多基因参与的具有遗传易感性的慢性气道变应性炎症。胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin,TSLP)是一种由上皮细胞产生的白介素7(IL-7)样细胞因子,与多种免疫细胞的TSLP受体相互作用,诱导Th2型免疫应答,参与哮喘的发生和发展。多个遗传学研究发现,哮喘是一种遗传易感性疾病,TSLP基因单核苷酸多态性与哮喘易感性密切相关,靶向TSLP治疗有望为今后哮喘免疫治疗带来新的前景。     

氧化低密度脂蛋白诱导血管内皮细胞表达胸腺基质淋巴细胞生成素

目的:探讨氧化低密度脂蛋白(ox-LDL)是否可以诱导血管内皮细胞产生胸腺基质淋巴细胞生成素(TSLP)。方法:将25mg/L及50mg/L的ox-LDL与原代培养的人脐静脉内皮细胞(HUVEC)共育6h,用RT-PCR检测HUVEC TSLP mRNA的表达、免疫组织化学染色检测HUVEC TSLP蛋白的表达,ELISA法检测培养上清中TSLP的浓度。结果:对照组HUVEC几乎不表达TSLP;ox-LDL刺激6h后,HUVEC可表达TSLPmRNA,胞浆中存在TSLP;上清中TSLP的浓度显著高于对照组,并且随ox-LDL刺激浓度的升高,TSLP的表达升高。结论:ox-LDL可诱导血管内皮细胞产生TSLP,这一作用可能在血管的炎症反应中起作用。     

辅助性T淋巴细胞17/调节性T淋巴细胞比值失衡在HBV相关肝脏疾病进展中的作用

慢性乙型肝炎患者肝脏损害多发生在免疫介导作用下,考虑病毒感染和免疫反应的相互作用是疾病病情进展的重要原因。慢性乙型肝炎可发展至肝纤维化、肝硬化甚至肝细胞癌。回顾了辅助性T淋巴细胞17(Th17)与调节性T淋巴细胞(Treg)的发现起源,叙述了二者自身特性,同时阐述了在维持免疫系统稳定过程中二者所起的作用及作用机制;详细分析了细胞失衡在慢性乙型肝炎、肝纤维化、肝硬化、肝细胞癌等各个阶段中的作用,指出Th17/Treg失衡会促使HBV相关肝脏疾病病情加重。     

效应性T细胞亚群Th17与动脉粥样硬化

效应性T细胞亚群Th17是新近发现的效应性T细胞的又一亚群,因分泌细胞因子IL-17而得名。Th17通过分泌多种效应分子如白细胞介素17、17F、21和肿瘤坏死因子-α等与慢性炎症性疾病、自身免疫性疾病和肿瘤等疾病密切相关。研究发现,动脉粥样硬化的发生发展也与Th17功能的异常密切相关,现拟就此进行综述。     

Thymic stromal lymphopoietin contribution to the recruitment of circulating fibrocytes to the lung in a mouse model of chronic allergic asthma

Objective: Fibrocyte localization to the airways and thymic stromal lymphopoietin (TSLP) overexpression in the lung are features of severe asthma. The aim of this study was to determine whether TSLP contributes to fibrocyte trafficking and airway remodeling in a mouse model of allergic asthma. Methods: We established a chronic asthma animal model by administering house dust mite (HDM) extracts intranasally for up to 5 consecutive weeks. Mouse anti-TSLP monoclonal antibody (mAb) was given intraperitoneally starting the 4^th week. Fluorescence-labeled CD34/collagen I (Col I)-dual-positive fibrocytes were examined by confocal microscopy. The level of TGF-β1 in the bronchoalveolar lavage (BAL) fluid was determined by ELISA. Results: We found significantly increased levels of TSLP and TGF-β1 in the lung of the mice subjected to repeated allergen exposure, which was accompanied by increased number of fibrocytes in the sub-epithelial zone and the BAL fluid. However, blocking TSLP markedly decreased the production of TGF-β1, reduced the number of fibrocytes and subsequently prevented alterations of both airway and vascular structures. Conclusions: Our data suggested that TSLP might function in airway remodeling by promoting circulating fibrocyte recruitment to the lung in the mice subjected to chronic allergen exposure. These results provide a better rationale for targeting the interaction between TSLP and fibrocytes as a therapeutic approach for chronic allergic asthma.     

Decreased expression of thymic stromal lymphopoietin in salivary glands of patients with primary Sjögren’s syndrome is associated with increased disease activity

Objectives: Thymic Stromal Lymphopoietin (TSLP) is a potent immunomodulatory cytokine involved in Th2- and Th17-mediated immune responses in different autoimmune diseases. TSLP expression in relation to disease activity was studied in salivary glands of primary Sjögren’s syndrome (pSS) patients as compared to non-SS sicca (nSS) controls.

Methods: Tissue sections of minor salivary glands from pSS and nSS patients were stained with monoclonal antibodies against human TSLP, CD3, CD19 and cytokeratin high molecular weight (CK HMW) or stained for Alcian blue to detect mucus production. The number of TSLP-expressing cells was quantified and expression was correlated to local and systemic disease parameters.

Results: The number of TSLP-expressing cells was significantly lower in pSS patients than in nSS controls and correlated with a range of disease markers. In pSS patients, TSLP was expressed outside of lymphocytic infiltrates at sections that also encompassed high numbers of intact acinar cells. This difference was independent of tissue destruction.

Conclusions: Reduced TSLP expression in pSS patients is associated with increased local and systemic inflammatory markers. Loss of TSLP expression may contribute to Th1/Th17-associated immunopathology in pSS, in line with previous studies demonstrating that TSLP promotes a protective Th2 milieu at mucosal sites.     

NP30 stimulates Th17 differentiation through DC in Schistosomiasis Japonicum

The murine monoclonal anti‐idiotypic antibody, NP30, is a potential vaccine candidate against Schistosoma japonicum. Previous studies have revealed that NP30 has an immunoregulatory effect, but the underlying mechanism for this effect remains unknown. This study shows that NP30 induces dendritic cell (DC) maturation and increases the production of pro‐inflammatory cytokines. The expression of CD86 and MHC II was upregulated in DCs following stimulation with NP30 in vitro. Moreover, NP30 induced Th17 polarization by increasing the production of IL‐6 and TGF‐β. In vivo, Th17 differentiation was induced by the production of key pro‐inflammatory cytokines, including IL‐6and TGF‐β, from DCs of NP30‐immunized mice. These results indicate that NP30 promotes Th17 polarization through DC activation, preventing serious schistosomiasis.     

Immune regulatory cells in umbilical cord blood: T regulatory cells and mesenchymal stromal cells

A major goal in haematopoietic cell transplantation (HCT) is to retain the lymphohaematopoietic potential of the cell transfer without its side effects. In addition to the physical injury caused by the conditioning regimen, donor T cells can react to alloantigens of the recipient and cause graft- versus -host disease (GVHD), which accounts for the largest share of morbidity and mortality after HCT. Immune modulator cells, such as regulatory T cells (Tregs) and mesenchymal stromal cells (MSCs) have shown promise in their ability to control GVHD and yet, in preclinical models, preserve the graft- versus -malignancy effect. Initially, MSCs and Tregs have been isolated from adult sources, such as bone marrow or peripheral blood, respectively. More recent studies have indicated that umbilical cord blood (UCB) is a rich source of both cell types. We will review the current data on UCB-derived Tregs and MSCs and their therapeutic implications.     

毛细支气管炎患儿胸腺基质淋巴细胞生成素的表达水平与复发性喘息的相关性分析

目的分析毛细支气管炎患者胸腺基质淋巴细胞生成素的表达水平与发生复发性喘息的相关性。 方法选择2015年1月至2017年1月我院收治的151例毛细支气管炎患儿，根据治疗后1年内是否发生复发性喘息分为复发性喘息组(45例)，及对照组(106例)，并对两组患者的一般资料、呼吸窘迫评估工具(RDAI评分)及脉氧饱和度、细胞间黏附分子-1(ICAM-1)、尿白细胞三烯E4(尿LTE4)、血嗜酸性细胞阳离子蛋白(血ECP)及胸腺基质淋巴细胞生成素(TSLP)指标进行比较，并采用COX多因素分析对上述影响复发性喘息的危险因素进行分析，并应用受试者工作曲线(ROC)评估相关危险因素预测复发性喘息的诊断价值及诊断效能。 结果两组患者性别相比较无明显差异；复发性喘息组患者的年龄、出生体重及脉氧饱和度均明显低于对照组，住院天数、合并先天性心脏病患者的人数、RDAI评分、ICAM-1、尿LTE4、血ECP及TSLP均明显高于对照组(均P<0.05)；Cox回归分析示高RDAI评分及高ICAM-1、尿LTE4、血ECP、TSLP水平是复发性喘息的独立危险因素(HR＝1.323，1.008，1.003，1.051，1.125；均P<0.05)，而未合并先天性心脏病是保护因素(HR＝0.117；P<0.05)；ROC曲线示TSLP在预测复发性喘息方面具有较高的诊断效能(AUC＝0.844)，明显高于ECP、ICAM-1、尿LTE4、RDAI评分及合并先心病(Z＝3.143，2.683，3.173，3.251，5.532，均P<0.05)，其中，TSLP诊断的最佳截点为>54 ng/ml，此时其预测复发性喘息的敏感性为75.6%，特异性为84.0%。 结论患儿体内的TSLP水平在预测患儿是否出现复发性喘息方面，具有较高的诊断价值及诊断效能。     

Recent advances in the pathological understanding of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergen-mediated inflammatory disease of the esophagus. This inflammation leads to feeding difficulties, failure to thrive and vomiting in young children, and causes food impaction and esophageal stricture in adolescents and adults. In the 20 years since EoE was first described, we have gained a great deal of knowledge regarding the genetic predisposition of disease, the inflammatory mileu associated with EoE and the long-term complications of chronic inflammation. Herein, we summarize the important breakthroughs in the field including both in vitro and in vivo analysis. We discuss insights that we have gained from large-scale unbiased genetic analysis, a multitude of genetically and chemically altered mouse models of EoE and most importantly, the results of clinical trials of various pharmacologic agents. Understanding these successes and failures may be the key to developing more effective therapeutic strategies.     

Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells

The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been linked to apoptosis, IgM binding, and innate immune responses. In this study, we used Toso-deficient mice to investigate the importance of Toso in tolerance and autoimmunity. We found that Toso^−/− mice do not develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model for the human disease multiple sclerosis. Toso^−/− dendritic cells were less sensitive to Toll-like receptor stimulation and induced significantly lower levels of disease-associated inflammatory T-cell responses. Consistent with this observation, the transfer of Toso^−/− dendritic cells did not induce autoimmune diabetes, indicating their tolerogenic potential. In Toso^−/− mice subjected to EAE induction, we found increased numbers of regulatory T cells and decreased encephalitogenic cellular infiltrates in the brain. Finally, inhibition of Toso activity in vivo at either an early or late stage of EAE induction prevented further disease progression. Taken together, our data identify Toso as a unique regulator of inflammatory autoimmune responses and an attractive target for therapeutic intervention.More than 5% of the populations of Western countries suffer from inflammatory autoimmune diseases (1). In all cases, a hyperactivated immune system is responsible for the initiation of autoimmunity. In the periphery, inflammatory T cells such as IL-17–producing Th (Th17) and IFN-γ–producing Th1 cells are controlled by suppressive regulatory T (Treg) cells (2). Numeric or functional imbalance of these various T-cell populations can result in autoimmunity or immunodeficiency. How the immune system limits self-reactive inflammatory responses in healthy individuals, and how these mechanisms fail in patients, is still under intensive investigation.The transmembrane receptor Toso belongs to the Ig superfamily, and its cytoplasmic domain shows homology to Fas-activated serine/threonine kinase (3). Toso has been implicated in the regulation of CD95 (Fas/Apo1)- and TNF receptor (TNFR)-dependent T-cell apoptosis, and is highly overexpressed in apoptosis-resistant B-cell lymphomas (3–6). Toso also functions as an Fc receptor for IgM, and so may be important for B-cell development (7–10). Recently, Toso expression was detected on granulocytes and monocytes and Toso was linked to the homeostasis and activation of the innate immune system (11–13). However, the precise physiological relevance of Toso’s multifaceted functionality is still unknown.In this study, we investigated the impact of loss of Toso on inflammatory autoimmune responses. Toso-deficient (Toso^−/−) mice were less susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). Disease resistance was dependent on Toso’s function in dendritic cells (DCs). DCs from Toso^−/− mice initiated less intense inflammatory CD4⁺ and CD8⁺ T-cell responses that were associated with reduced immunopathology. Toso^−/− DCs induced more Tregs than controls. Finally, interference with Toso activity in vivo significantly decreased the burden of EAE disease following induction. Our findings indicate that Toso is a crucial mediator of inflammatory autoimmune responses in vivo.