银屑病发病机制中T细胞作用的进展

银屑病是一种Th1细胞介导的自身免疫性皮肤病,近来的研究表明,其他细胞也参与其发病过程,尤其是树突细胞、内皮细胞、Th17细胞及调节性T细胞等,其中T细胞的活化、增殖及分化是发病的主要环节,银屑病特征性的角质形成细胞增殖和异常分化及炎性细胞浸润是继发于T细胞活化后释放的细胞因子.一些黏附分子(E/P选择素等)及皮肤淋巴细胞相关抗原-P选择素糖蛋白配体-1复合体和皮肤淋巴细胞相关抗原-CD43复合体在银屑病发病中也起着一定的作用.     

从转化医学角度谈银屑病发病模式转换及治疗进展

银屑病发病机制复杂,尚未完全阐明。自1979年环孢素被发现用于治疗银屑病后,对银屑病发病机制的认识也由一种增殖分化异常性疾病(即角质形成细胞模式)向免疫相关性疾病(T细胞模式)转变。随着研究深入,T细胞模式中Th1、Th17、Th22、Treg、γδT细胞的作用逐渐被揭示,针对部分细胞及其相关细胞因子已开发出相应药物。     

他克莫司对银屑病皮损分离培养的T细胞分泌γ干扰素和白细胞介素4、17、10的影响

正寻常性银屑病是一种常见的慢性、反复发作的炎症性皮肤病。其发病原因尚未完全明确。研究表明,活化的T细胞在银屑病发病机制中起重要作用~([1])。传统认为银屑病的发病与Th1/Th2细胞因子网络平衡有关,近年来研究表明Th17/Treg的失衡在银屑病发病过程中也有重要作用。多项研究表明,在银屑病早期皮损处已出现T淋巴细胞浸润,外周血淋巴细胞亦发生     

Th17、Treg细胞与银屑病的关系研究进展

Th17和Treg细胞是不同于Th1、Th2细胞的CD4+T细胞亚型,两者在分化及功能上相互调节。Th17细胞主要参与炎症反应及自身免疫性疾病的发生,Treg细胞在维持免疫耐受及防止自身免疫性疾病的发生中有重要作用。本文就Th17和Treg细胞的作用和调节及其与银屑病的关系作一综述,期望可以对银屑病的发病机制有更进一步的认识。     

Th_(17)/Treg细胞在寻常型天疱疮发病机制的研究进展

寻常型天疱疮(PV)是一类严重的慢性黏膜-皮肤自身免疫性大疱性皮肤病。Th17细胞和Treg细胞是初始CD4+T细胞在不同的细胞因子诱导下分化出的新亚群,二者的平衡对于维持机体内环境稳定等有重要的意义,近来发现Th17/Treg细胞失衡在PV的发病中发挥重要作用,本文就Th17/Treg细胞在PV发病机制中的作用作一综述。     

CD4+ CD25+Treg细胞和Th17细胞与寻常型银屑病发病的相关性

CD4+ CD25+ Treg细胞和Th17细胞是CD4+T细胞的新亚群,参与自身免疫病、感染和肿瘤等疾病的发生发展.研究表明CD4+ CD25+ Treg细胞和Th17细胞与寻常型银屑病的发病密切相关.通过对CD4+ CD25+ Treg细胞和Th17分化发育和功能发挥过程中的关键调节因子进行阻断或加强,可以上调或下调CD4+ CD25+ Treg细胞和Th17在寻常型银屑病中的表达,以用于寻常型银屑病的预防和诊治.     

寻常型银屑病皮损中Th17细胞相关因子的表达

目的:研究Th17细胞相关因子在银屑病发病机制中的作用.方法:用逆转录-聚合酶链反应法(RT-PCR)半定量分析寻常型银屑病患者皮损区、非皮损区及正常人皮肤组织中Th17细胞相关因子IL-17和IL-23(p19/p40)、IL-6 mRNA的表达.结果:银屑病患者皮损中IL-17、IL-23p19、IL-23p40和IL-6的 mRNA平均相对表达量分别为1.231±0.843、1.166±0.142、1.125±0.104和1.186±0.222.皮损组织中该4种细胞因子mRNA表达水平均高于非皮损组和正常皮肤组,非皮损组四者表达高于正常对照组,差异均有统计学意义(均P<0.05).结论:Th17细胞相关因子在银屑病患者皮损中过度表达,提示Th17型细胞因子在银屑病的免疫发病机制中可能起着非常重要的作用.     

Th22细胞及其细胞因子在银屑病发病机制中的作用

银屑病是一种由T细胞介导的疾病,以表皮过度增殖、角质形成细胞异常分化伴血管增生及皮损处免疫细胞浸润为特征.近来发现了一群独立于Th1、Th2及Th17细胞的新型CD4+记忆性T细胞--Th22细胞,其在银屑病等一些炎症性皮肤病中不同程度升高,使免疫调节机制进一步完善,通过了解其作用机理或许可开展将其作为一个治疗银屑病的新型靶点的研究.本文就Th22细胞及其细胞因子在银屑病中的作用机制进行综述.     

UVA1和窄波UVB光疗治疗斑块型银屑病的随机对照研究

目的探讨及对比UVA1及窄波UVB光疗治疗斑块型银屑病的临床疗效,为银屑病患者的治疗提供临床依据。方法将收集的20例斑块型银屑病患者随机分为2组,分别给予UVA1和窄波UVB光疗治疗,治疗频次均为隔日治疗,2组疗程均为3个月,治疗前及治疗后,对患者进行银屑病皮损面积及严重程度指数(PASI)评分,并采集静脉血及皮损,分析对比外周血及组织中Th17、Treg及STAT3蛋白的表达情况。结果 UVA1组治疗前外周血及皮损中Th17细胞的比例、皮损中STAT3蛋白的表达显著高于治疗后,差异有统计学意义(P0.01);外周血及皮损中Treg细胞的比例显著低于治疗后,差异有统计学意义(P0.01);UVB组治疗前外周血及皮损中Th17细胞的比例、皮损中STAT3蛋白的表达显著高于治疗后,差异有统计学意义(P0.01);外周血及皮损中Treg细胞的比例显著低于治疗后,差异有统计学意义(P0.01);UVA1组治疗后外周血及皮损中Th17细胞的比例、皮损中STAT3蛋白的表达显著低于UVB组,差异有统计学意义(P0.01);UVA1组治疗后外周血及皮损中Treg细胞的比例显著高于UVB组,差异有统计学意义(P0.01)。结论 Th17、Treg细胞可能对银屑病的发病至关重要,UVA1治疗较传统UVB治疗更能调节患者外周血及皮损处Th17、Treg细胞的比例,以及皮损中STAT3蛋白的表达,从而达到更有效治疗银屑病的目的。     

与银屑病相关的T辅助细胞研究进展

银屑病是一种由多种免疫细胞和细胞因子介导参与的慢性炎症性免疫性疾病。关于银屑病的确切发病机制尚未阐明,研究发现可能与Th1、Th2、Th17、调节性T淋巴细胞(Treg)细胞、Th22细胞及Th9细胞的异常活化并释放大量细胞因子有关。该文围绕这些免疫细胞及其相关细胞因子主要从近年所发现的Th细胞亚群及其相关细胞因子角度综述了近年来与银屑病T辅助细胞的实验研究进展,阐述各个辅助细胞及相关细胞因子在银屑病发病过程中的作用及关联机制,以期能帮助笔者更深入地了解银屑病的发病机制并为今后的实验研究提供依据。     

Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T‐cell lymphoma?

Secukinumab is an interleukin (IL)‐17 monoclonal antibody inhibiting T‐helper (Th)1‐mediated immune response. It has proven high efficacy for moderate to severe psoriasis but data on its long‐term toxicities are limited. We describe two patients who received secukinumab for clinically presumed psoriasis, but were subsequently diagnosed with mycosis fungoides (MF) following skin biopsies triggered by skin deterioration while on secukinumab. Previous studies suggested decreased numbers of regulatory T cells (Tregs) with increasing stage of MF, which may lead to the shift in the Treg/Th17 balance towards the Th17 pathway. Theoretically, the use of IL‐17 monoclonal antibodies to inhibit Th17 pathway may lead to further immunosuppression and disease progression in cutaneous T‐cell lymphoma (CTCL) by shifting the balance towards Tregs, although this hypothesis has not been proven. With uncertainty over the role of IL‐17 and Treg/Th17 as well as diagnostic challenges in CTCL, we recommend that patients should have a confirmatory skin biopsy prior to the commencement of biologic therapy.     

Role of YAP-related T cell imbalance and epidermal keratinocyte dysfunction in the pathogenesis of atopic dermatitis

BackgroundAtopic dermatitis (AD) is characterized by impaired skin barrier function and immune system dysfunction. The expression and role of Yes-associated protein (YAP) in AD are unclear.ObjectiveTo characterize the role of the YAP in T cell imbalance and epidermal keratinocyte dysfunction in the pathogenesis of AD.MethodsWe included 35 patients with AD (21 acute and 14 chronic). An AD mouse model was constructed using 2,4-dinitrofluorobenzene, and AD-like inflammatory cell model was constructed using TNF-α/IFN-γ-activated HaCaT cells. The proportion of Th1/Th2/Th17/Treg cells was detected using flow cytometry. After mononuclear cells were obtained from human peripheral blood or mouse spleen and induced to differentiate into different T cell subsets, YAP mRNA and protein expression were analyzed. Up-regulation of YAP was induced by lentivirus and down-regulation of YAP was induced by its specific inhibitor verteporfin (VP). The expression of YAP in skin lesions and infiltrating T cell subsets was detected using immunohistochemistry and double immunofluorescence staining, respectively.ResultsWe found differing degrees of Th1/Th2/Th17/Treg imbalance in acute and chronic AD. YAP expression was downregulated in Treg cells and upregulated in Th17 cells; YAP expression was downregulated in the AD epidermis. After YAP overexpression, the proportion of both Th17 and the Treg cells differentiated from mouse spleen mononuclear cells increased. There was an opposite trend after YAP inhibition. The proliferation and migration decreased and apoptosis increased after YAP inhibition in HaCaT cells.ConclusionChange of YAP expression may cause T cell imbalance and hamper the healing of the epidermis in AD.     

A tale of two plaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis and atherosclerosis

Psoriasis and atherosclerosis are diseases in which effector T lymphocytes such as Helper T cells type 1 (Th1) and 17 (Th17) play integral roles in disease pathogenesis and progression. Regulatory T cells (Treg) also exert clinically important anti-inflammatory effects that are pathologically altered in psoriasis and atherosclerosis. We review the immunological pathways involving Th1, Th17 and Treg cells that are common to psoriasis and atherosclerosis. These shared pathways provide the basis for mechanisms that may explain the epidemiologic observation that patients with psoriasis have an increased risk of heart disease. Improved understanding of these pathways will guide future experiments and may lead to the development of therapeutics that prevent or treat cardiovascular complications in patients with psoriasis.     

IL-22在银屑病发病机制中的作用

研究显示,白介素22能促进上皮细胞产生异常炎症介质.白介素22是一种重要的细胞因子,主要由Th17细胞产生,参与炎性细胞浸润,细胞增殖,细胞迁移及防御作用等.在银屑病皮损中,白介素22水平升高,其通过与角质形成细胞表面白介素22受体结合,导致细胞因子和炎症介质改变,起到趋化炎性细胞,促角质形成细胞增殖,抑制角质形成细胞分化的作用,是银屑病发病中重要的细胞因子.介绍银屑病皮疹中白介素22促进炎症细胞浸润和角质化细胞增殖的作用,以及银屑病中角质形成细胞活化产物的变化并通过白介素22治疗银屑病的疗效应证实其作用.

Abstract：

Studies have shown that IL-22 could promote epithelial cells to produce abnormal inflammatory mediators.IL-22 is an important cytokine mainly produced by Th17 cells and participates in inflammatory cell infiltration, cell proliferation, migration, defense, and so on.In psoriatic lesions, the expression level of IL-22 is elevated.By binding to its receptor on the surface of keratinocytes, IL-22 can alter the expressions of cytokines and inflammatory mediators, induce the chemotaxis of inflammatory cells, promote the proliferation and inhibit the differentiation of keratinocytes.Therefore, IL-22 is an important cytokine in the pathogenesis of pasoriasis.This paper describes the upregulatory effect of IL-22 on inflammatory cell infiltration and keratinocyte proliferation, alterations in products of activated keratinocytes in psoriasis, as well as the role of IL-22 in the pathogenesis of psoriasis which has been evidenced by the therapeutic effect of IL-22 on psoriasis.     

miRNA miR‐17‐92 cluster is differentially regulated in the imiqumod‐treated skin but is not required for imiqumod‐induced psoriasis‐like dermatitis in mice

MicroRNAs (miRNAs) play very important roles in the control of immune cell and keratinocyte development and function and are implicated in skin inflammatory diseases, including psoriasis. miRNA miR‐17‐92 was reported to promote the differentiation of Th1 and Th1 cells and to regulate cell proliferation and apoptosis. Here we showed that imiquimod (IMQ) differentially regulates the expression of miR‐17‐92 cluster in the mouse skin, upregulating miR‐17 and miR‐19 families and downregulating miR‐92. To investigate whether miR‐17‐92 cluster is functionally involved in the psoriasis, we have generated three mutant mice with specific deletion or overexpression of miR‐17‐92 cluster in keratinocytes, or with deletion of miR‐17‐92 cluster in T cells. Interestingly, deletion or overexpression of miR‐17‐92 cluster in keratinocytes, or deletion of miR‐17‐92 in T cells did not significantly affect IMQ‐induced psoriasis‐like dermatitis development in the mutant mice compared with wild‐type littermates. Thus, miRNA miR‐17‐92 cluster may not be a key factor regulating imiqumod‐induced psoriasis‐like dermatitis.     

调节性T淋巴细胞和Th17细胞与银屑病的研究进展

银屑病是一种与T淋巴细胞相关的自身免疫性疾病,新近研究发现,除了与Th1细胞有关外,调节性T淋巴细胞尤其叉头/翅膀状螺旋转录因子诱导表达的调节性T细胞和Th17细胞在银屑病的发病过程中起着非常重要的作用。其中,叉头/翅膀状螺旋转录因子（＋）调节性T细胞平衡免疫抑制和免疫激活的转换在银屑病加重方面起到关键作用,Th17细胞分泌的细胞因子IL-17A、IL-17F、IL-22、IL-23、IL-36及肿瘤坏死因子α等在皮肤疾病发生发展中起到重要的作用。银屑病是由调节性T细胞和Th17细胞等多种免疫细胞和细胞因子共同参与的疾病。     

Lymphocyte inhibition is compromised in mesenchymal stem cells from psoriatic skin

Background

Psoriasis is a chronic inflammatory skin disorder associated with a host of immune abnormalities. Mesenchymal stem cells (MSCs) have immunosuppressive properties and, in earlier studies, we found that the bone marrow MSCs of patients with psoriasis exhibit abnormal cytokine secretion. Since MSCs can be isolated from skin, we hypothesized that the biological characteristics of MSCs in psoriatic skin lesions might reflect the pathogenesis of psoriasis.

Objective

To investigate the effects of MSCs from psoriatic skin lesions on T-cell proliferation.

Materials and Methods

MSCs obtained from psoriatic skin lesions and healthy human skin were examined by flow cytometry and cell differentiation assays. MSCs were co-cultured with normal peripheral blood T cells to assess changes in T-cell proliferation. Concentrations of interleukin (IL)-6, IL-11, hepatocyte growth factor (HGF), and transforming growth factor (TGF)-β1 in the MSC culture supernatants were measured by enzyme-linked immunosorbent assays.

Results

Surface markers and differentiation capacity were similar in MSCs from both sources. MSCs in psoriatic skin lesions were weaker inhibitors of T-cell proliferation (p<0.05) and exhibited increased secretion of IL-11 and reduced secretion of IL-6 and HGF (p<0.05). Secretion of TGF-β1 was unchanged (p>0.05).

Conclusion

This study demonstrated abnormalities in MSCs derived from psoriatic skin lesions. We suggest that the attenuated inhibitory effect on T-cell proliferation might be one of the pathogenic mechanisms of psoriasis.

     

Th17细胞／Treg细胞及其失衡在慢性自发性荨麻疹发病机制中的作用

慢性自发性荨麻疹是一种常见的皮肤黏膜变态反应性疾病,以反复出现风团或红斑伴剧烈瘙痒为特征。介导免疫耐受的CD4＋CD25调节性T细胞和介导炎症反应的Thl7细胞是两类不同的CD4q＇细胞。两者数量此消彼长,功能拮抗,调节性T细胞和Thl7细胞数量和功能的平衡对维持免疫稳态起重要作用,失衡可引起免疫应答异常,导致包括慢性自发性荨麻疹在内的自身免疫性疾病的发生。初始CD4＋T细胞的细胞因子对他们之间的关系起到调节作用。     

Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells

The importance of T helper 17 (Th17) cells in inflammation and autoimmunity is now being appreciated. We analyzed psoriasis skin lesions and peripheral blood for the presence of IL-17-producing T cells. We localized Th17 cells predominantly to the dermis of psoriasis skin lesions, confirmed that IL-17 mRNA increased with disease activity, and demonstrated that IL-17 mRNA expression normalized with cyclosporine therapy. IL-22 mRNA expression mirrored IL-17 and both were downregulated in parallel with keratin 16. Th17 cells are a discrete population, separate from Th1 cells (which are also in psoriasis lesions), and Th2 cells. Our findings suggest that psoriasis is a mixed Th1 and Th17 inflammatory environment. Th17 cells may be proximal regulators of psoriatic skin inflammation, and warrant further attention as therapeutic targets.