IL-23/Th17轴在变应性哮喘中的研究进展

变应性哮喘是一种由辅助性T细胞（T helper cell,Th cell）调节的慢性炎症性疾病。Th1/Th2的失衡一直被认为是变应性哮喘的发病机制,Th2细胞及其分泌的细胞因子白介素4（interleukin 4,IL-4）、IL-5以及IL-13在变应性哮喘特异性症状的发病中发挥重要作用。最近研究发现Th17细胞及其分泌的IL-17参与变应性哮喘的发展过程,IL-23在Th17细胞维持生存和功能成熟中发挥重要作用,并参与抗原诱导的气道炎症反应。该文对目前IL-23/Th17轴在变应性气道炎症反应中的研究进展作一综述。     

不同RF型类风湿性关节炎患者Th17相关细胞因子表达研究

目的:探讨类风湿因子阳性与阴性类风湿关节炎(rheumatoid arthritis,RA)患者外周血中辅助T细胞(Th17)及相关细胞因子白介素17(interleukin,IL-17),白介素6(interleukin,IL-6)表达的差异。方法:收集RA患者51例,根据RF测定分为RF+、RF-组,健康查体者(对照组)20例,采用流式细胞术检测受检者外周血单个核细胞(PBMC)的Th17细胞的百分率;以酶联免疫吸附法(ELISA)检测受检者血浆中IL-17,IL-6的水平。结果:RA患者CD4+IL-17+T细胞,IL-17、IL-6水平均高于对照组,RF因子阳性与阴性RA患者之间CD4+IL-17+T细胞,IL-17、IL-6表达水平均存在差异有统计学意义。结论:在RA中不同RF型免疫反应和炎症表达的不同,可能与Th17及相关细胞因子表达差异有关。     

不同RF型类风湿性关节炎患者Th17相关细胞因子表达研究

目的：探讨类风湿因子阳性与阴性类风湿关节炎（rheumatoid arthritis,RA）患者外周血中辅助T细胞（Th17）及相关细胞因子白介素17（interleukin,IL-17）,白介素6（interleukin,IL-6）表达的差异。方法：收集RA患者51例,根据RF测定分为RF＋、RF-组,健康查体者（对照组）20例,采用流式细胞术检测受检者外周血单个核细胞（PBMC）的Th17细胞的百分率;以酶联免疫吸附法（ELISA）检测受检者血浆中IL-17,IL-6的水平。结果：RA患者CD4＋IL-17＋T细胞,IL-17、IL-6水平均高于对照组,RF因子阳性与阴性RA患者之间CD4＋IL-17＋T细胞,IL-17、IL-6表达水平均存在差异有统计学意义。结论：在RA中不同RF型免疫反应和炎症表达的不同,可能与Th17及相关细胞因子表达差异有关。     

白细胞介素17在类风湿性关节炎中意义的探讨

白细胞介素17（interleukin-17,IL-17）是近年来发现的一种重要的炎症性细胞因子。主要由CD4＋效应T细胞的亚群-辅助性T细胞17（T help cell 17,Th17）、CD8＋T细胞和γδT细胞产生,能调节并促进多种炎性介质的产生,有强大的招募中性粒细胞的作用,在白细胞的迁移、破骨细胞的活化和骨质的吸收等方面发挥重要作用。近年来研究发现,IL-17与多种炎性疾病、感染、肿瘤、过敏、及自身免疫性疾病均有密切关系,尤其在类风湿性关节炎（rheumatoid arthritis,RA）发病的各个环节中起重要作用。本文对IL-17在类风湿性关节炎的发生、发展、诊断及治疗等方面的作用进行综述。     

Th17/Treg失衡与肝脏免疫病理反应的研究进展

Th17细胞及Th17/Treg失衡在炎症反应、组织损伤及纤维化形成中发挥了重要作用,与多种疾病的发生发展密切相关。前炎性细胞因子可诱导T细胞分化为Th17,使Th17/Treg失衡,导致IL-17、IL-6、趋化因子等促炎性细胞因子大量分泌并有效介导中性粒细胞动员与兴奋,使得机体产生炎症反应与免疫病理反应。就Th17/Treg细胞及其失衡在肝脏免疫病理反应中的研究进展进行了综述。     

Th17分化调节机制及其在器官移植中的研究进展

Th17细胞是新近发现的第三类CD4+ T辅助细胞亚群,其所分泌的IL-17、IL-22等细胞因子在中性粒细胞趋化、组织重塑与修复及介导抗体蛋白的产生等具有重要作用.但Th17分化调节受外界环境影响较大,如转录因子、细胞因子、Th1、Th2和调节T细胞(Tregs)等,这些均具有决定初始CD4+ T细胞向Th17细胞的分化方向和免疫反应方向的调控作用.目前Th17在器官移植物免疫耐受中的作用越来越受到重视,明确Th17分化调节的各种影响因素,将为器官移植免疫耐受研究提供新思路.     

IL-21/IL-21R信号在TNBS诱导小鼠炎症性肠病病变形成中的作用研究

探讨IL-21/IL21R信号在炎症性肠病病变形成中对肠固有层辅助T细胞应答的调控机制。利用IL-21R基因敲除小鼠(IL-21R KO),建立TNBS诱导的炎症性肠病动物模型。监测小鼠体重及生存率;HE染色观察小鼠肠组织形态结构及炎症反应情况;分离和提取肠固有层淋巴细胞(lamina propria lymphocyte,LPL),应用流式细胞仪检测Th1、Th2、Th17、Treg细胞比例和绝对数;ELISA法检测LPL培养上清中的细胞因子(IFN-γ、IL-4、IL-17A、IL-10)的分泌。结果显示:与WT小鼠相比,IL-21R KO小鼠体重下降更快,生存率明显降低;HE染色显示IL-21R KO小鼠肠管上皮损伤严重、隐窝大面积消失、大量炎性细胞浸润,并侵犯到黏膜肌层;IL-21R KO小鼠肠固有层Th1细胞应答显著增强,相反Th2、Th17和Treg应答明显抑制。因此,IL-21/IL-21R信号通过调节小鼠肠固有层Th细胞应答,在TNBS诱导的肠炎病变形成中发挥重要的保护性作用。     

产白介素-17T细胞在肺部细菌感染中的研究进展

目前产白介素-17(IL-17)T细胞主要包括了产IL-17 CD4+T细胞即Th17细胞、产IL-17γδT细胞和产IL-17 CD8+T细胞等。随着对Th17这一系细胞功能研究的不断深入,发现它们能通过产生IL-17和IL-22等细胞因子参与炎症反应。该文将对产IL-17 T细胞在肺部细菌感染中所起作用的最近研究进展进行综述。     

γδT17细胞活化机制的研究进展

IL-17是一种重要的促炎细胞因子，在炎症性疾病和自身免疫性疾病中发挥重要作用。研究发现，除Th17细胞外，γδT17细胞也是IL-17的重要来源。γδT17细胞参与多种免疫应答过程，与感染性疾病、自身免疫性疾病和肿瘤等疾病的发生发展密切相关，本文综述γδT17细胞活化机制的研究进展，探明γδT17细胞的分化和活化机制将为上述疾病的治疗提供新思路。     

Th17细胞的生物学效应及研究进展

Th17细胞是近年来被发现的一种不同于Th1和Th2细胞并产生IL-17的Th细胞亚群,它具有独立的分化和发育调节机制.Th17的发育、扩增及分泌IL-17主要受TGF-β,IL-6,IL-23等细胞因子的调控.IL-17调节前炎性因子、趋化因子等的产生及分泌,在白细胞的迁移、破骨细胞的活化和骨质的吸收等方面发挥重要作用,并在自身免疫性疾病和感染性疾病中发挥重要调节作用.本综述主要介绍Th17细胞分化的影响因素、产生的细胞因子和在自身免疫病中的作用.     

Th17细胞分化和功能的研究进展

近年研究发现了效应性辅助性T细胞的新亚群-Th17细胞,它主要分泌IL-17、IL-17F、IL-21和IL-22等细胞因子。Th17细胞及其效应分子被认为与自身免疫病和其他多种疾病相关。该文从Th17细胞的发现、人和小鼠Th17细胞的分化、Th17细胞的效应性因子及与健康和疾病的相关性几个方面对目前的研究进展进行了综述。     

Dysregulation of melanocyte function by Th17-related cytokines: significance of Th17 cell infiltration in autoimmune vitiligo vulgaris

The aim of this study was to determine whether CD4(+) IL-17A(+) Th17 cells infiltrate vitiligo skin and to investigate whether the proinflammatory cytokines related to Th17 cell influence melanocyte enzymatic activity and cell fate. An immunohistochemical analysis showed Th17 cell infiltration in 21 of 23 vitiligo skin samples in addition to CD8(+) cells on the reticular dermis. An in vitro analysis showed that the expression of MITF and downstream genes was downregulated in melanocytes by treatment with interleukin (IL)-17A, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Treatment with these cytokines also induced morphological shrinking in melanocytes, resulting in decreased melanin production. In terms of local cytokine network in the skin, IL-17A dramatically induced IL-1β, IL-6, and TNF-α production in skin-resident cells such as keratinocytes and fibroblasts. Our results provide evidence of the influence of a complex Th17 cell-related cytokine environment in local depigmentation in addition to CD8(+) cell-mediated melanocyte destruction in autoimmune vitiligo.     

Potential role of myeloid cell/eosinophil-derived IL-17 in LPS-induced endotoxin shock

IL-17RA is a shared receptor subunit for several cytokines of the IL-17 family, including IL-17A, IL-17C, IL-17E (also called IL-25) and IL-17F. It has been shown that mice deficient in IL-17RA are more susceptible to sepsis than wild-type mice, suggesting that IL-17RA is important for host defense against sepsis. However, it is unclear which ligands for IL-17RA, such as IL-17A, IL-17C, IL-17E/IL-25 and/or IL-17F, are involved in the pathogenesis of sepsis. Therefore, we examined IL-17A, IL-17E/IL-25 and IL-17F for possible involvement in LPS-induced endotoxin shock. IL-17A-deficient mice, but not IL-25- or IL-17F-deficient mice, were resistant to LPS-induced endotoxin shock, as compared with wild-type mice. Nevertheless, studies using IL-6-deficient, IL-21Rα-deficient and Rag-2-deficient mice, revealed that neither IL-6 and IL-21, both of which are important for Th17 cell differentiation, nor Th17 cells were essential for the development of LPS-induced endotoxin shock, suggesting that IL-17A-producing cells other than Th17 cells were important in the setting. In this connection, IL-17A was produced by macrophages, DCs and eosinophils after LPS injection. Taken together, these findings indicate that IL-17A, but not IL-17F or IL-25, is crucial for LPS-induced endotoxin shock. In addition, macrophages, DCs and eosinophils, but not Th17 cells or γδ T cells, may be sources of IL-17A during LPS-induced endotoxin shock.     

白介素23 及Th17 细胞在炎症性肠病的作用

炎症性肠病(Inflammatory Bowel Diseases,IBD),是一组病因未明的累及胃肠道的慢性炎症性疾病,一般指克罗恩病(Crohn’sdisease,CD)和溃疡性结肠炎(ulcerative colitis,UC)。目前认为它是由多种因素相互作用所致的一种自身免疫性疾病,主要包括免疫、环境以及遗传等因素,其中免疫在IBD的发生过程中起着极其重要的作用。以往研究认为与T辅助细胞(T Helper cells)Th1或Th2细胞反应的增强或减弱有关。然而最近研究发现一类新细胞亚群,称为Th17细胞,与之相关的细胞因子可导致包括肠道在内的多脏器病变。Th17细胞分化过程中又需要IL-23的参与,因此IL-23/Th17细胞在炎症性肠病患者肠道内过度表达可以解释肠组织损伤的新途径,并为制定新的治疗策略提出依据。本文就IL-23/Th17轴在炎症性肠病中的作用的研究进展作一综述。     

The effect of pro-inflammatory cytokines on immunophenotype,differentiation capacity and immunomodulatory functions of human mesenchymal stem cells

Mesenchymal stem cells (MSCs), as cells with potential clinical utilities, have demonstrated preferential incorporation into inflammation sites. Immunophenotype and immunomodulatory functions of MSCs could alter by inflamed-microenvironments due to the local pro-inflammatory cytokine milieu. A major cellular mediator with specific function in promoting inflammation and pathogenicity of autoimmunity are IL-17-producing T helper 17 (Th17) cells that polarize in inflamed sites in the presence of pro-inflammatory cytokines such as Interleukin-1β (IL-1β), IL-6 and IL-23. Since MSCs are promising candidate for cell-based therapeutic strategies in inflammatory and autoimmune diseases, Th17 cell polarizing factors may alter MSCs phenotype and function. In this study, human bone-marrow-derived MSCs (BM-MSC) and adipose tissue-derived MSCs (AD-MSC) were cultured with or without IL-1β, IL-6 and IL-23 as pro-inflammatory cytokines. The surface markers and their differentiation capacity were measured in cytokine-untreated and cytokine-treated MSCs. MSCs-mediated immunomodulation was analyzed by their regulatory effects on mixed lymphocyte reaction (MLR) and the level of IL-10, TGF-β, IL-4, IFN-γ and TNF-α production as immunomodulatory cytokines. Pro-inflammatory cytokines showed no effect on MSCs morphology, immunophenotype and co-stimulatory molecules except up-regulation of CD45. Adipogenic and osteogenic differentiation capacity increased in CD45+ MSCs. Moreover, cytokine-treated MSCs preserved the suppressive ability of allogeneic T cell proliferation and produced higher level of TGF-β and lower level of IL-4. We concluded pro-inflammatory cytokines up-regulate the efficacy of MSCs in cell-based therapy of degenerative, inflammatory and autoimmune disorders.     

Th17 immune response to adipose tissue-derived mesenchymal stromal cells

Adipose tissue-derived mesenchymal stromal cells (ASCs) hold the promise of achieving successful immunotherapeutic results due to their ability to regulate different T-cell fate. ASCs also show significant adaptability to environmental stresses by modulating their immunologic profile. Cell-based therapy for inflammatory diseases requires a detailed understanding of the molecular relation between ASCs and Th17 lymphocytes taking into account the influence of inflammation and cell ratio on such interaction. Accordingly, a dose-dependent increase in Th17 generation was only observed in high MSC:T-cell ratio with no significant impact of inflammatory priming. IL-23 receptor (IL-23R) expression by T cells was not modulated by ASCs when compared to levels in activated T cells, while ROR-γt expression was significantly increased reaching a maximum in high (1:5) unprimed ASC:T-cell ratio. Finally, multiplex immunoassay showed substantial changes in the secretory profile of 15 cytokines involved in the Th17 immune response (IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-22, IL-21, IL-23, IL-25, IL-31, IL-33, IFN-γ, sCD40, and TNF-α), which was modulated by both cell ratio and inflammatory priming. These findings suggest that Th17 lymphocyte pathway is significantly modulated by ASCs that may lead to immunological changes. Therefore, future ASC-based immunotherapy should take into account the complex and detailed molecular interactions that depend on several factors including inflammatory priming and cell ratio.     

21例侵袭性肺曲霉病患者Th以及Treg细胞的检测

目的：分析侵袭性肺曲霉病患者辅助性T细胞（Th）以及调节性T细胞（Treg）在外周血中单个核细胞中的表达情况及其临床相关性,探讨Th和Treg细胞介导的免疫反应在侵袭性肺曲霉病中的作用。方法分离21例侵袭性肺曲霉病患者及19例健康人外周血的单个核细胞,采用流式细胞术分析Th1、Th2、Th17、Treg细胞群的表达情况,Real-timePCR方法检测相关转录因子T-bet、GATA-3、RORγt以及Foxp3的表达,ELISA法检测血清中相关细胞因子IFN-γ、IL-4、IL-17以及TGF-β的表达。结果与健康人对照组相比,侵袭性肺曲霉病患者Th1细胞以及Treg细胞占CD4＋T细胞的比例较之对照组明显降低;Th1、Th17、Treg细胞相关转录因子T-bet、RORγt、Foxp3以及相关细胞因子IFN-γ、IL-17A、TGF-β与对照组相比表达明显降低。结论IPA患者的Th1、Th17以及Treg细胞所介导的免疫反应受抑制。     

IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis?

Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis. Data from experimental arthritis indicate IL-17 receptor signaling as a critical pathway in turning an acute synovitis into a chronic destructive arthritis. The identification of six IL-17 family members (IL-17A-F) may extend the role of this novel cytokine family in the pathogenesis of chronic destructive joint inflammation. Whether the successful anti-IL-17A cytokine therapy in murine arthritis can be effectively translated to human arthritis need to be tested in clinical trials in humans. Interestingly, IL-17A and IL-17F are secreted by the novel T helper subset named Th17. This novel pathogenic T cell population induces autoimmune inflammation in mice and is far more efficient at inducing Th1-mediated autoimmune inflammation in mice than classical Th1 cells (IFN-gamma). In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26. Th17 cells have been established as a separate lineage of T helper cells in mice distinct from conventional Th1 and Th2 cells. Whether this also applies to human Th17 and whether RA is a Th1 or a Th17 mediated disease is still not clear. This review summarizes the findings about the role of IL-17 in arthritis and discusses the impact of the discovery of the novel Th17 cells for arthritis. Further studies are needed to unravel the role of Th17 cells and the interplay of IL-17 and other Th17 cytokines in the pathogenesis of arthritis and whether regulating Th17 cell activity will have additional value compared to neutralizing IL-17A activity alone. This might help to reach the ultimate goal not only to treat RA patients but to prevent the development of this crippling disease.