A novel role of IL-17A in contributing to the impaired suppressive function of Tregs in psoriasis

BackgroundRegulatory T cells (Tregs) are crucial in maintaining T cell homeostasis and preventing autoimmune responses. Deficiencies in the suppressive function of Tregs contribute to the pathogenesis of various autoimmune diseases, such as psoriasis. However, whether IL-17A upregulation in psoriatic patients contributes to Treg dysfunction is unknown.ObjectiveTo explore the effect and underlying mechanism of IL-17A on the suppressive function of Tregs and to evaluate the restoration of the suppressive function of Tregs in psoriasis during anti-IL-17A (secukinumab) treatment.MethodsIn vitro suppression assays were performed with or without the addition of IL-17A to the coculture system. The release of inhibitory cytokines, including IL-10 and TGF-β, was assessed by qRT-PCR and flow cytometry. RNA-sequencing was conducted to characterize the cellular responses of Tregs. IL-17A signaling activation was analyzed by flow cytometry and immunofluorescence. Blood samples were collected from three psoriasis patients before and after secukinumab treatment.ResultsIL-17A blocked the suppressive function of Tregs, possibly by inhibiting the release of TGF-β and promoting the production of IFN-γ. Moreover, IL-17A activated the NF-κB signaling pathway in Tregs. Inhibition of the NF-κB pathway blocked IL-17A-induced upregulation of IFN-γ without affecting the secretion of TGF-β by Tregs. Clinical treatment in psoriasis with secukinumab restored the suppressive function and increased production of TGF-β in Tregs of psoriasis.ConclusionOur study implies a crucial role of IL-17A in mediating the dysfunction of the Treg suppressive function in psoriasis. Secukinumab, which neutralizes IL-17A signaling, restored the suppressive function of Tregs to exert its antipsoriatic effect.     

寻常型银屑病外周血中Th17细胞及相关因子的表达

目的:检测寻常型银屑病患者外周血中Th17细胞及相关因子IL-17、IL-22表达,分析其与疾病严重程度及病程的相关性,进一步阐明银屑病的发病机制.方法:实验组为寻常型银屑病患者60例,对照组为健康体检者40例,抽取外周血,用三色法流式细胞术检测外周血Th17细胞,ELISA法检测血清中Th17相关因子IL-17、IL-22表达,分析Th17细胞、IL-17、IL-22表达与PASI评分及病程的相关性.结果:实验组外周血Th17细胞百分率(4.71%±2.55%)高于对照组(0.55%±0.39%),差异有统计学意义(P<0.01);Th17细胞与患者PASI评分呈正相关(r=0.47,P<0.01),但与病程无相关性(r=0.09,P>0.05).实验组血清中Th17相关因子IL-17、IL-22表达(24.02±12.31,18.32±8.14)均高于对照组(7.16±4.04,6.53±4.15),差异有统计学意义(P均<0.01);IL-17、IL-22表达与患者PASI评分呈正相关(r=0.46,P<0.01;r=0.51,P<0.01),但与病程无相关性(r=0.03,P>0.05;r=0.19,P>0.05).结论:Th17细胞可能在寻常型银屑病发病机制中发挥重要作用,可作为判断疾病严重程度的免疫学指标,阻断其相关因子IL-17、IL-22表达可能成为治疗银屑病的新靶点.     

IL-17 and IL-17R: an auspicious therapeutic target for psoriatic disease

The continuous discovery of new T cell subpopulations in human autoimmune diseases is making the immunopathological network more complex. Th17 cells are one such newly identified subset of T cells, characterized by the production of signature cytokine IL-17. In last few years, several studies have strongly established the regulatory role of Th17 cells and its signature cytokine IL-17 in autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis. Psoriasis and PsA are immune mediated hyperproliferative diseases, affecting skin and joint respectively. Before the discovery of Th17 cells, psoriasis and psoriatic diseases were thought to be chiefly Th1 mediated diseases; later on IL-17 knockout animal studies as well as human experimental data indicate the crucial role of Th17 cells and its signature cytokine IL-17 in the pathogenesis of these diseases. In vitro human studies have shown the abundance of Th17 cells in the psoriatic plaques. Subsequently our research group has extended this observation in psoriatic arthritis and found the abundance of CD4+IL-17+ T cells in the synovial fluid and majority of these T cells are of memory phenotype (CD4RO+CD45RA-CD11a+). In addition, we showed the significant presence of functional IL-17 receptor in synovial fibroblast of psoriatic arthritis patients. Considering the strong association of IL-17 and psoriatic disease, IL-17 targeted therapy have shown promises in preclinical and clinical trials. In this review article, we have discussed the pathogenic role of IL-17 in psoriatic disease and summarized the therapeutic efficacy and safety profile of different anti IL-17 therapy as an anti-psoriatic agent.     

白芍总苷对轻、中度寻常性银屑病患者血清中IL-17和IL-23的影响

目的通过检测白芍总苷(TGP)治疗前后寻常性银屑病(PV)患者血清中Th17细胞的相关细胞因子IL~17和IL-23水平,探讨TGP治疗寻常性银屑病的可能作用机制。方法采用双抗体夹心酶联免疫吸附法(ELISA)检测30例PV患者经TGP治疗前后及20例健康对照组外周血清中IL-17和IL-23水平的改变,并分析这两种炎症因子在治疗前、后与PASI评分的相关性。结果治疗前PV患者血清IL-17和IL-23水平均较健康对照组显著升高(P<0.05);TGP治疗后血清中IL-17和IL-23水平均较治疗前显著降低(P<0.05);治疗前、后患者血清IL-17和IL-23水平与PASI评分均呈正相关(P均<0.05)。结论 TGP可能通过调节Th17细胞相关细胞因子IL-17和IL-23发挥治疗银屑病的作用。     

阿维A对中、重度斑块状银屑病患者Th17细胞相关因子的影响

目的探讨阿维A治疗中、重度斑块状银屑病的疗效以及对银屑病患者血清Th17细胞相关因子IL-17,IL-22及IL-23的影响,进一步阐明阿维A治疗寻常性银屑病的作用机制。方法 35例中、重度斑块状银屑病患者口服阿维A治疗8周,以银屑病皮损面积和严重程度(PASI)评分评价疗效;采用ELISA法检测健康对照组以及银屑病治疗组使用阿维A治疗前后血清IL-17,IL-22及IL-23的水平。结果阿维A治疗前后PASI评分明显下降(P<0.01);银屑病组和健康对照组比较,IL-17,IL-22和IL-23的血清水平均明显增高(P<0.01);阿维A治疗后血清中IL-17的水平(45.38±11.69)pg/mL,IL-22的水平(61.48±18.76)pg/mL及IL-23的水平(139.65±40.28 pg/mL),较治疗前显著下降(P均<0.01)。结论银屑病患者的血清中存在高水平的IL-17,IL-22和IL-23;阿维A治疗中、重度银屑病疗效明显,治疗后血清中IL-17,IL-22和IL-23明显降低;阿维A可能通过影响Th17细胞相关因子来发挥治疗银屑病的作用。     

寻常性银屑病患者血清IL-17和IL-22检测与其PASI评分的相关性分析

目的探讨寻常性银屑病患者血清IL-17和IL-22的水平与皮损面积和严重程度指数(PASI评分)的相关性。方法采用ELISA法检测29例寻常性银屑病患者血清中IL-17和IL-22的水平,并以11例健康人作为对照。结果银屑病患者血清IL-17的水平21.255(37.181)pg/mL高于正常对照组的7.464(29.880)pg/mL,IL-22的水平56.970(42.720)pg/mL高于正常对照组的40.943(62.120)pg/mL,进展期组银屑病患者血清IL-17水平30.884(41.433)pg/mL高于静止期组患者的14.225(22.831)pg/mL,差异均有统计学意义(P均<0.05);静止期组银屑病患者血清IL-22水平56.974(64.394)pg/mL高于进展期组患者的52.876(43.015)pg/mL,但差异无统计学意义(P>0.05)。血清IL-17和IL-22水平与PASI评分结果无直线相关关系(P>0.05)。结论寻常性银屑病患者血清IL-17和IL-22水平上调,可能参与银屑病的发病,但其与PASI评分无相关关系。     

抗白细胞介素17生物制剂治疗银屑病的疗效和安全性

银屑病是一种多基因遗传和环境相互作用下,主要由细胞免疫异常介导的慢性炎症性增生性皮肤病,其确切的发病机制尚未完全清楚.目前认为,白细胞介素17细胞因子对角质形成细胞的增生及异常激活十分重要,是银屑病发病机制中的关键环节.新研发的3种针对白细胞介素17通路的生物制剂已应用于银屑病的临床治疗或试验,包括直接拮抗白细胞介素17A的苏金单抗(secukinumab)、ixekizumab及通过拮抗白细胞介素17RA,从而抑制白细胞介素17下游信号分子通路的brodalumab.其治疗寻常性银屑病及关节病性银屑病的有效性和安全性在临床试验中得到肯定,给银屑病患者带来新的治疗选择,但其安全性仍需长远评价.     

银屑病性关节炎患者Th17/Treg相关细胞因子的检测

目的探讨Th17/Treg细胞相关细胞因子IL-17,IL-6,IL-23和TGF-β在银屑病性关节炎(PsA)发病机制中的作用。方法采用酶联免疫吸附法(ELISA)测定31例PsA患者和30例正常对照者血清中IL-17,IL-6,IL-23和TGF-β的水平。结果 PsA患者血清中IL-17,IL-6和IL-23水平明显高于健康对照组,TGF-β的水平低于健康对照组,差异均有统计学意义(P均<0.05)。结论外周血中Th17/Treg细胞相关的细胞因子IL-17,IL-6,IL-23和TGF-β表达异常参与了PsA的发病过程。     

白细胞介素17相关生物制剂治疗银屑病过程中浅部真菌感染的发生及应对策略

本文综述白细胞介素（IL）-17与皮肤黏膜真菌感染易感性的基本机制,以及与IL-17相关的生物制剂,如司库奇尤单抗、依奇珠单抗、布罗达单抗、拜莫克珠单抗和乌司奴单抗在治疗银屑病中发生的浅部真菌感染。与IL-17相关生物制剂治疗相关的浅部真菌感染以轻度或中度为主,多呈局限性,且抗真菌治疗效果良好。此外,本文介绍了对相关浅...     

白细胞介素17A介导银屑病及心血管合并症的研究进展

白细胞介素（IL）-23/IL-17轴是寻常型斑块状银屑病发病的主要通路,IL-17A是相关免疫通路中的关键节点,介导了动脉粥样硬化和银屑病的重叠炎症通路,促进炎症、凝血和血栓形成,在银屑病心血管合并症的发生发展中起重要作用。抑制IL-17A的炎症作用能减少重度银屑病患者心血管合并症的发生率及病死率。本文综述近年来IL...     

IL-15 and IL-23 synergize to trigger Th17 response by CLA+ T cells in psoriasis

IL-15 has emerged as a potentially relevant target in the IL-17 response in psoriasis. However, its mechanism is poorly characterized in humans. IL-15 and IL-23 are constitutively expressed in the psoriatic lesion. Also, IL-15 is considered a susceptibility-associated gene in psoriasis, as are IL-23R, and HLACW6. Here, we studied the effect of IL-15 and IL-23 stimulation on the cytokine response of CLA+/CLA- T cells from 9 psoriasis patients and 3 healthy control subjects. To this end, CLA + and CLA- T cells from blood samples were cultured with epidermal cells from skin biopsies and treated with IL-15 and IL-23. After five days of culture, cytokines in supernatant were measured by ELISA or fluorescent bead-based immunoassay. There was a statistically significant increase in IL-17F and IL-17A production (P < .001) in cocultures of psoriasis skin-homing CLA + T cells with epidermal cells when stimulated with IL-15 and IL-23, but this effect was not observed in the cells of healthy controls. Interestingly, this response was reduced by around 50 to 80% by blocking HLA class I and II molecules. Our results point to the synergic action of IL-15 and IL-23 selectively for CLA + cells in psoriasis, leading to the induction of Th17 cell-related cytokines.     

白细胞介素17A在银屑病发病及治疗中的研究进展

【摘要】 近十余年来的基础和临床研究发现并确立了Th17/白细胞介素17A（IL-17A）在银屑病发病中的核心地位。IL-17A不仅能影响角质形成细胞的增殖活性和细胞功能，对银屑病免疫病理环境中的免疫细胞和相关细胞因子也有很重要的调控作用。近年来针对IL-17A通路的单抗如司库奇尤单抗、ixekizumab、brodalumab等在国内外陆续上市，在临床应用中展现出了显著的疗效。本文介绍IL-17A在银屑病发病机制中的作用以及靶向IL-17A及其受体IL-17RA生物治疗的最新进展。     

Evaluation of the Th17 pathway in psoriasis and geographic tongue

BackgroundPsoriasis is a skin-articular disease with unclear etiopathogenesis. It has been suggested that the disease is immune-mediated by T-lymphocytes, predominantly Th17 cells. Similar to psoriasis, geographic tongue is an inflammatory disease with participation of Th17 cells and direct correlation with psoriasis.ObjectiveTo investigate and compare the inflammatory responses and the Th17 pathway in psoriasis and geographic tongue.MethodsThis was a cross-sectional study with 46 participants that were categorized into three groups: (A) patients with psoriasis vulgaris; (B) patients with geographic tongue and psoriasis; (C) patients with geographic tongue without psoriasis. All patients underwent physical examination, and a skin and oral biopsy for histopathological examination and immunohistochemical analysis with anti-IL6, anti-IL17, and anti-IL23 antibodies.ResultsHistological analysis of all lesions showed mononuclear inflammatory infiltrate. However, moderate intensity was prevalent for the patients with geographic tongue and psoriasis and geographic tongue groups. Immunopositivity for the antibodies anti-IL6, anti-IL17, and anti-IL23 revealed cytoplasmic staining, mainly basal and parabasal, in both psoriasis and geographic tongue. Regarding IL-6, in patients with geographic tongue and psoriasis cases the staining was stronger than in patients with geographic tongue without psoriasis cases. IL-17 evidenced more pronounced and extensive staining when compared to the other analyzed interleukins. IL-23 presented similar immunopositivity for both geographic tongue and psoriasis, demonstrating that the neutrophils recruited into the epithelium were stained.Study limitationThis study was limited by the number of cases.ConclusionThe inflammatory process and immunostaining of IL-6, IL-17, and IL-23 were similar in geographic tongue and psoriasis, suggesting the existence of a type of geographic tongue that represents an oral manifestation of psoriasis.     

寻常性银屑病患者外周血和皮损中Th17细胞及相关因子的表达

目的 探讨寻常性银屑病患者外周血和皮损中Th17细胞及相关因子IL-17、IL-22表达,分析其与疾病严重程度及病程的相关性。方法 抽取44例寻常性银屑病患者和28例正常人对照者外周血,用三色法流式细胞仪检测外周血Th17细胞,ELISA法检测血清中IL-17、IL-22表达。取20例寻常性银屑病患者皮损和8例正常人对照者皮肤,用量子点免疫荧光双标法检测Th17细胞表达。结果 寻常性银屑病患者外周血Th17细胞百分比（4.71% ± 2.55%）高于正常人对照组（0.55% ± 0.39%）,两组差异有统计学意义（P < 0.01）。银屑病患者Th17细胞与银屑病病情严重度评分（PASI）呈显著正相关（r = 0.53,P < 0.01）,但与病程无相关性（r = 0.09,P > 0.05）。银屑病患者血清中IL-17（24.02 ± 12.31 ng/L）、IL-22（18.32 ± 8.14 ng/L）表达均高于正常人对照组（IL-17为7.16 ± 4.04 ng/L,IL-22为6.52 ± 4.15 ng/L）,差异均有统计学意义（P < 0.01和 < 0.05）。银屑病患者血清IL-17、IL-22表达与PASI呈显著正相关（r = 0.47,P < 0.01;r = 0.53,P < 0.01）,与病程无相关性（r = 0.03,P > 0.05;r = 0.19,P > 0.05）。银屑病患者皮损中可见Th17细胞浸润,主要集中在真皮浅层血管周围;而正常人皮肤中仅有微量CD4+ T细胞表达,未见Th17细胞。 结论 Th17细胞参与银屑病的发病,提示阻断相关因子IL-17、IL-22的药物可成为治疗银屑病的又一新靶点。     

寻常性银屑病患者外周血白介素17、白介素23 mRNA的表达及与病情相关性研究

【摘要】 目的 探讨白介素17（IL-17）、白介素23（IL-23）mRNA在寻常性银屑病患者与健康人外周血中的表达差异及其与银屑病皮损面积和严重程度指数（PASI）的相关性;探讨白芍总苷在寻常性银屑病治疗中的作用机制。 方法 采用实时荧光定量PCR方法,检测50例寻常性银屑病患者和40例健康对照者外周血IL-17、IL-23 mRNA的表达量;对42例银屑病患者应用白芍总苷4周后及23例应用8周后外周血IL-17、IL-23 mRNA的表达量进行分析。根据资料性质,利用SPSS16.0软件进行t检验或秩和检验、Pearson相关性分析。 结果 寻常性银屑病患者外周血中IL-17和IL-23 mRNA的表达水平明显高于健康对照组（两组IL-17 mRNA的ΔCt值分别为-5.32 ± 0.80、2.79 ± 0.76;IL-23 mRNA分别为-5.43 ± 0.68、-3.77 ± 0.86,两组比较,均P < 0.05）;患者外周血IL-17和IL-23 mRNA的表达水平与PASI呈正相关（r值分别为0.61、0.52,均P < 0.05）。经白芍总苷治疗4周后,患者外周血IL-17和IL-23 mRNA的表达及PASI均较治疗前明显降低（IL-17 mRNA的ΔCt值分别为-2.24 ± 0.61、-5.30 ± 0.78;IL-23 mRNA分别为-1.97 ± 0.74、-5.44 ± 0.68;PASI分别为5.8 ± 2.7、9.4 ± 4.2,两组比较,均P < 0.05）;治疗8周后,患者外周血IL-17和IL-23 mRNA的表达及PASI比治疗4周后明显降低（IL-17 mRNA的ΔCt值分别为-1.51 ± 0.78、-2.21 ± 0.59;IL-23 mRNA分别为-1.27 ± 0.81、-1.89 ± 0.72;PASI分别为3.8 ± 1.8、7.3 ± 2.5,两组比较,均P < 0.05）。 结论 IL-17和IL-23可能参与了寻常性银屑病的发病过程;应用白芍总苷治疗寻常性银屑病后,IL-17和IL-23 mRNA表达水平下降,且PASI降低。     

Secukinumab: supervivencia en práctica clínica real

Secukinumab, an immunoglobulin G1/κ monoclonal antibody that selectively targets interleukin 17a, is used to treat moderate to severe plaque psoriasis in adults who are eligible for systemic treatment. Indirect comparisons of the efficacy of secukinumab, ustekinumab, and anti-tumor necrosis factor agents have found lower drug survival rates for patients on secukinumab, in spite of that biologic's rapid onset of action and efficacy as demonstrated by the large number of patients reaching a Psoriasis Area and Severity Index of 90 or 100. We present data from a retrospective study of 171 patients treated with doses of 300 mg or 150 mg of secukinumab every 4 weeks in 5 hospitals in the Spanish autonomous community of Andalusia. Eighty-seven percent continued on treatment at 132 weeks, contrasting with reports from previously published case series.     

IL-17A、VEGF在寻常型银屑病皮损中的表达及其与PASI评分相关性的研究

目的研究白细胞介素17A(IL-17A)、血管内皮生长因子(VEGF)在寻常型银屑病患者皮损中的表达,并分析其与患者银屑病皮损面积和严重程度指数(PASI)的相关性,从而进一步探讨IL-17A、VEGF在银屑病发病机制中的作用。方法采用免疫组织化学法检测寻常型银屑病皮损组织和健康对照组皮肤组织中IL-17A、VEGF的表达水平并进行比较。结果寻常型银屑病患者皮损中IL-17A、VEGF的表达水平显著高于健康对照组,差异有统计学意义(均P0.05),皮损中IL-17A、VEGF的表达水平与患者PASI呈正相关(r_1=0.61,P0.01;r_2=0.58,P0.01)。结论 IL-17A、VEGF在银屑病发病过程中起着重要作用,在皮损中的表达水平可作为反映银屑病严重程度的一个指标。     

Th17细胞相关因子与寻常性进行期银屑病的相关性研究

目的探讨Th17细胞相关因子白细胞介素(IL)-17A、IL-17F、IL-21、IL-22与寻常性进行期银屑病发病的相关性。方法通过实时定量反转录聚合酶链式反应(RT-PCR)分别检测30例患者和20名正常人外周血单个核细胞(PBMC)、12例患者皮损、12名正常皮肤组织中上述4种细胞因子的mRNA表达水平。结果患者组PBMC中IL-17A、IL-17F、IL-21和IL-22的mRNA表达水平较正常组显著升高(P均0.05),患者组皮损中4种细胞因子的mRNA表达明显高于正常组(P均0.05)。结论 Th17细胞因子IL-17A、IL-17F、IL-21和IL-22的mRNA水平在患者组PBMC及皮肤组织中明显升高,提示Th17细胞因子可能与寻常性银屑病的发病有一定相关性。     

IL-17 and infections

IL-17 immunity has been shown to be essential for mucocutaneous protection against Candida albicans in mice and humans. However, mice with defective IL-17 immunity display broader susceptibility, as they are also prone to infections with diverse infectious agents at various sites. Humans with genetic defects affecting their IL-17 immunity usually suffer from chronic mucocutaneous candidiasis (CMC): recurrent or persistent infections of the skin, nails, and mucosae with C. albicans, with or without other clinical signs. Most patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) due to STAT3 deficiency or AD STAT1 gain-of-function display impaired IL-17-producing T-cell development, and CMC is one of their principal clinical manifestations. Similarly, patients with autosomal recessive (AR) autoimmune polyendocrine syndrome type 1 (APS-1) caused by AIRE deficiency have high levels of neutralizing autoantibodies against IL-17A, IL-17F and/or IL-22 and present CMC as their only infectious disease. Finally, CMC is the main clinical phenotype observed in patients with inborn errors specifically affecting IL-17 immunity. Indeed, patients with AD IL-17F deficiency or AR IL-17RA or ACT1 deficiency display CMC and, to a lesser extent, superficial staphylococcal diseases. Candida infection was recently reported in psoriasis patients treated with anti-IL-17A antibodies. Careful monitoring for CMC is thus important during anti-IL-17 treatment.     

CCL20、CCR6及IL-17A在寻常型银屑病患者血清中的表达及意义

目的观察趋化因子CCL20及其受体CCR6、白细胞介素(IL)-17A在银屑病患者血清中的变化,并探讨其在银屑病发病中的作用。方法采用酶联免疫吸附法测定26例斑块型、7例点滴型银屑病患者及8名健康人血清中CCL20、CCR6及IL-17A的浓度,并对银屑病皮损面积和严重程度指数(PASI)评分、病程进行相关性分析。结果斑块型银屑病患者血清CCL20、CCR6及IL-17A浓度(748.74±268.72,10.20±3.75,39.22±13.21)均显著高于健康对照组(578.45±204.93,6.79±4.61,25.54±13.04)(P分别0.05,0.01,0.01)。点滴型银屑病与对照组差异无统计学意义。CCL20、CCR6与PASI评分呈正相关(r=0.416,r=0.350)(P0.05)。CCL20、CCR6及IL-17A三者之间均存在显著正相关(r=0.852,r=0.801,r=0.825)(P0.001),与病程无明显相关性。结论 CCL20、CCR6及IL-17A参与斑块型银屑病的病理过程。