IL-33在自身免疫及变态反应性皮肤病中作用的研究进展

IL-33是IL-1细胞因子家族成员,通过与其特异性受体ST2结合后激活下游信号通路,进而诱导产生Th2型细胞因子。IL-33不仅可以调节Th2细胞介导的免疫反应、刺激肥大细胞产生炎症细胞因子,同时可以作为核因子调控基因转录。它在自身免疫性疾病、变态反应性皮肤病中发挥潜在的致病作用。     

T细胞亚群和白细胞介素36在系统性红斑狼疮发病机制中的研究进展

在不同的细胞因子环境下,原始T细胞分化生成的Th1、Th2、Th17及Treg等细胞构成的细胞亚群及其细胞因子在系统性红斑狼疮等自身免疫性疾病的发病中发挥重要作用.白细胞介素36包括白细胞介素36α、363和36 γ,其免疫调节及免疫激活作用较传统白细胞介素1家族成员更强,通过激活丝裂原活化蛋白激酶和核因子κB,参与自身免疫性疾病的生理病理过程.白细胞介素36对T细胞分化的研究能进一步阐明系统性红斑狼疮的发病机制,为系统性红斑狼疮的治疗策略提供思路.     

真皮IL-17分泌型γδT细胞在炎症性皮肤病中起关键作用

表达白细胞介素-23（IL-23）和白细胞介素-17A（IL-17A）的辅助性细胞（Th17细胞）轴在慢性炎症性疾病的银屑病发生发展中起着重要作用。但IL-17等是否来源于Th17细胞尚未明确,其是否在银屑病的炎症浸涧和棘层肥厚皮损形成中起作用是本文研究的重点。     

白细胞介素-23/白细胞介素-17轴与自身免疫性皮肤病的研究进展

白细胞介素（IL）-23/IL-17轴是近年来新发现的炎性通路,主要依靠IL-23介导Th17效应细胞,产生IL-17等细胞因子,引起炎性反应及异常免疫,参与多种炎症及自身免疫性疾病.随着医学研究的不断进步,人们对IL-23/IL-17轴及其相关细胞、细胞因子,如Th17细胞、IL-23及IL-17等有了更加清晰的认识,并对其作用及机制有了进一步的了解.在越来越多的自身免疫性皮肤病中发现了此轴的参与.重点阐述了此轴在4种常见结缔组织病、寻常型天疱疮及坏疽性脓皮病中发挥的不同作用,针对此轴的治疗可能为这些自身免疫性皮肤病提供新的治疗靶向.     

胸腺基质淋巴细胞生成素在特应性疾病相关2型炎症反应中作用机制的研究进展

辅助性T细胞（Th）2细胞介导的炎症级联反应，简称Th2型（2型）炎症反应，是特应性疾病的主要驱动因素。上皮细胞衍生的细胞因子胸腺基质淋巴细胞生成素（TSLP）是驱动皮肤、肺和肠道等部位的屏障表面发生的2型炎症反应的主要调节因子。因此，TSLP是特应性疾病发病机制的关键参与者，有可能作为重要的药物治疗靶点。该文对TSLP及其介导的信号通路参与2型炎症反应的已知分子机制及其在特应性疾病发病机制中的作用作一综述，并进一步探讨TSLP及相关信号通路作为特应性疾病药物治疗靶点的潜在用途。     

Th17在类风湿性关节炎中的研究进展

辅助性T细胞17(T helper17cell,Th17)是一种新发现的与白细胞介素23(interleukin 23,IL-23)相关的、能够分泌IL-17的细胞亚群,它在分化过程和生物学功能方面与Th1和Th2以及调节性T细胞(Treg)细胞亚群均有不同之处.Th17细胞参与前炎症反应,同时也能诱导自身免疫性疾病的...     

固有淋巴样细胞与慢性炎症性皮肤病

固有淋巴样细胞是一类新近发现的免疫细胞家族,在细胞表面没有特异性抗原受体（如T细胞受体或B细胞受体）,属于固有免疫的范畴。根据分泌的细胞因子种类和转导因子,固有淋巴样细胞可分为三类：固有淋巴样细胞1、固有淋巴样细胞2和固有淋巴样细胞3,分别对应于Th1, Th2和Th17。它们在黏膜及皮肤上与表面菌群和过敏原相互作用,主要靠分泌细胞因子如白细胞介素5、白细胞介素13、白细胞介素17和白细胞介素22等起作用,在维护组织稳态、抗感染、变态反应和自身免疫性导致的慢性炎症等方面具有重要作用。     

特应性皮炎与2型炎症反应

【摘要】 研究显示,2型炎症及其相关细胞因子白细胞介素4、13等在特应性皮炎（AD）中起关键作用。Th2细胞及2型细胞因子是2型炎症反应的核心驱动因素,主要通过3条路径参与AD发病：加重皮肤屏障缺陷;激活和强化瘙痒反应;调节性T细胞（Treg）病理性重编程为Th2样Treg细胞,从而放大2型炎症反应。本综述探讨2型炎症与AD的关系,希望有助于优化治疗方案,为AD患者提供新的治疗选择。     

度普利尤单抗治疗大疱性类天疱疮的应用进展

2型炎症在大疱性类天疱疮发病中起重要作用。度普利尤单抗特异性结合白细胞介素4受体亚基α(IL-4Rα)后,可阻断白细胞介素(IL)-4和IL-13的信号转导,抑制B细胞的增殖、类别转化,减少嗜酸性粒细胞的募集并抑制IL-4R-Janus激酶(JAK)1通路。目前已有较多应用度普利尤单抗治疗大疱性类天疱疮的报道。该文对度普利尤单抗治疗大疱性类天疱疮的可能机制、临床应用及不良反应作一综述。     

上皮源性细胞因子白细胞介素33、白细胞介素25和胸腺基质淋巴细胞生成素在特应性皮炎发病机制中的作用

【摘要】 表皮屏障功能缺陷及免疫改变是特应性皮炎（AD）发生发展的主要病理生理改变,而皮肤角质形成细胞在各种损伤因素作用下可释放多种炎症因子和介质,其中3种上皮源性因子白细胞介素33、白细胞介素25、胸腺基质淋巴细胞生成素被认为是皮肤或黏膜屏障Th2型免疫应答的有效诱导因子,能够激活免疫细胞,引起Th2型细胞因子分泌,增强Th2型免疫应答,参与AD的发生与发展。本文就3种上皮源性细胞因子在AD发病机制中的作用进展进行总结。     

Insight into newly discovered innate immune modulation in atopic dermatitis

Atopic dermatitis (AD) is a highly pruritic, chronic relapsing inflammatory skin disease characterized by innate and adaptive immune reactions. In AD, innate immune mechanisms such as pattern recognition receptors and antimicrobial peptides have been investigated in detail, but recently, epidermis‐derived cytokines, namely thymic stromal lymphopoietin (TSLP), IL‐25 and IL‐33, were shown to participate in innate immune reactions independently of adaptive immunity. In addition to conventional innate cells, such as mast cells, basophils and eosinophils, Th2 cytokine‐producing invariant natural killer T (iNKT) cells, innate lymphoid cells (ILCs) and Th17/Th22 cytokine‐producing innate cells – iNKT cells and natural killer (NK)‐like cells – can participate in innate immune modulation in AD. Accordingly, early control of innate immune responses in AD before activation of adaptive immune responses by conventional T and B cells that perpetuate chronic skin inflammation may adequately alleviate acute exacerbations of AD. Therefore, we hypothesized that select immune modulators targeting the innate immune response could potentially be used for individualized treatment of AD.     

IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

IL‐33 is a novel pro‐inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2‐mediated responses, IL‐33 was recently found to be involved in arthritis, a Th1/Th17‐mediated disease. Here, we assessed the ability of IL‐33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL‐33 resulted elevated in the skin but not in the serum of psoriasis patients. IL‐33 was secreted by psoriasis KCs and HaCaT cells after TNF‐α stimulation. In HMC‐1, TNF‐α, but not IL‐17, could induce a robust increase in IL‐33 expression. In HaCaT cells, TNF‐α was able to induce IL‐6, MCP‐1 and VEGF, and the addition of IL‐33 reinforced these increases. TNF‐α + IL‐33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL‐33 may be involved in psoriasis biology via MCs and KCs.     

Evidence for a regulatory loop between IFN‐γ and IL‐33 in skin inflammation

Interleukin‐33 has recently gained much attention due to its role in allergic responses. It has been shown to amplify Th2 responses and to act as a damage‐associated molecular pattern. IL‐33 acts on a broad range of cells and has been proposed to link innate and adaptive features of allergic responses. It was the aim of this study to investigate this property of IL‐33 in the inflammatory response characterising atopic dermatitis (AD). We have analysed the response of skin‐resident cells derived from patients with AD and healthy donors with regard to the expression of IL‐33 and its receptor ST2. The functional impact of IL‐33 on CD4+ T cells was investigated. Keratinocytes and dermal fibroblasts clearly differ in their regulation of IL‐33. In fibroblasts, the concerted action of TNF‐α and IL‐1β was the strongest inducer, whereas IFN‐γ is clearly the key molecule that upregulates IL‐33 in keratinocytes with a more pronounced response of cells derived from patients with AD. Keratinocytes from patients with AD showed a markedly higher constitutive expression level of surface ST2. CD4+ T cells respond to IL‐33. Unexpectedly, IL‐33 failed to induce a significant secretion of IL‐5 or IL‐13. By contrast, high amounts of IFN‐γ were detectable if IL‐33 was added to the T‐cell receptor‐stimulated cells or in combination with IL‐12. These results suggest that IL‐33 and IFN‐γ are closely interlinked in epidermal AD inflammation. IFN‐γ induces IL‐33 in keratinocytes and IL‐33 acts on activated T cells to further increase the release of IFN‐γ, therefore contributing to drive skin inflammation towards chronic responses.     

IL-33: a novel danger signal system in atopic dermatitis

IL-33 is a newly recognized cytokine of the IL-1 cytokine family that has recently been attributed to the epithelial "alarmin" defense system. IL-33 is released by the epithelial cells in various tissues and organs, including keratinocytes, endothelial cells, and immune cells. Recent reports have suggested that IL-33 might be a critical part of the innate immunity, although its precise role is as yet poorly understood. In several organs, IL-33 appears to drive T helper type 2 (Th2) responses, suggesting roles in allergic and atopic diseases, as well as in fibrosis. IL-33 exerts its effects by activating the ST2 (suppression of tumorigenicity 2)/IL-1 aR receptor on different types of cells, including mast cells and Th2 cells. The ST2 receptor is either expressed on the cell surface or shed from these cells (soluble ST2, sST2), thereby functioning as a "decoy" receptor. After binding to its receptor, IL-33 activates NF-κB, suggesting that it regulates the outcome of diseases such as atopic dermatitis. On the other hand, several studies have reported on the inhibitory effects of sST2 in inflammatory and fibrotic diseases, suggesting that IL-33/ST2 is a unique cytokine with potential pro- and anti-inflammatory effects.     

Th17细胞与银屑病

银屑病是一种Th1细胞免疫反应介导的慢性炎症性皮肤病.近年发现一种新型的CD4+效应性T细胞--Th17细胞,不同于Th1和Th2细胞,特异性产生IL-17,在许多既往归类于Th1介导的慢性炎症性疾病中(包括银屑病)发挥重要作用.文中将介绍Th17细胞免疫反应在银屑病发病中的作用,同时介绍其在目前银屑病治疗方法中的意义和在新的潜在治疗靶位中的前景.     

咪喹莫特诱导小鼠银屑病样皮损机制的研究进展

咪喹莫特作为治疗人乳头瘤病毒感染的药物,在临床应用中发现可引起银屑病样皮损并能加重银屑病患者病情,而被广泛用于银屑病发病机制及治疗靶点的研究.由咪喹莫特诱发的小鼠银屑病样模型具有操作简单、易于成模的优点.应用咪喹莫特后,小鼠体内有包括Toll样受体信号通路等多条通路被激活,其中部分为协同作用.激活的信号通路进一步诱导角质形成细胞、树突细胞、Th17、γδT细胞、中性粒细胞等产生一系列炎性因子(如白细胞介素1、23、17,干扰素α等),这些炎性因子对银屑病样皮损的形成起到重要的作用.     

Cytokine gene polymorphisms in atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T-helper 2-type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms. OBJECTIVES: To investigate further the role of cytokine gene polymorphisms in AD. METHODS: Polymorphisms in the genes encoding tumour necrosis factor-alpha (TNFA-238 G/A, -308 G/A), interleukin (IL)-1beta (IL1B-511 T/C, +3953 T/C), IL-6 (IL6-174 C/G), IL-10 (IL10-1082 A/G) and the IL-1 receptor antagonist (IL1RN intron 2) were investigated in German patients with AD (n = 94) and in healthy nonatopic individuals (n = 214) by polymerase chain reaction-based methods and direct cycle sequencing. RESULTS: No association was found between AD and any of the polymorphisms analysed. This is in contrast to the recently described association between psoriasis and the TNFA-238 and IL1B-511 polymorphisms. CONCLUSIONS: Our data indicate that cytokine gene polymorphisms may act as specific markers of inflammatory skin diseases rather than contribute to a general disposition towards cutaneous inflammation.     

Th22细胞在自身免疫性疾病中的作用

Th122细胞亚群是近年来新发现的一类CD4+细胞亚群,主要分泌白介素-22、白介素-13、白介素-26等细胞因子,而不产生干扰素-γ和白介素-4.其功能主要通过白介素-22来实现,可介导炎症反应、自身免疫性疾病、肿瘤等,在机体免疫调节、宿主防御及组织修复中发挥重要作用.最重要的是,Th22细胞还能参与细胞增生、分化及凋亡的调节过程.研究表明,多种自身免疫性疾病的白介素-22表达异常,提示Th22细胞与T细胞介导的自身免疫性疾病有关.

Abstract：

Th22 cells are a new subset of CD4+ T cells identified in recent years. They mainly secrete interleukin (IL)-22, IL-13 and IL-26, but not interferon-γ (IFN-γ) or IL-4, and exert their function mainly via IL-22. They can mediate inflammatory reactions, autoimmune diseases, tumors, etc, and play an important role in immune regulation, host defense and tissue repair. Most importantly, Th22 cells can modulate cell proliferation, differentiation and apoptosis. Studies have shown an abnormal expression of IL-22 in a variety of autoimmune diseases, hinting that Th22 cells are involved in T cell-mediated autoimmune diseases.     

Gene–gene interactions in IL23/Th17 pathway contribute to psoriasis susceptibility in Chinese Han population

Background Psoriasis is a common chronic inflammatory skin disease. IL23/Th17 is a newly confirmed pathway in psoriasis. Objective To investigate the gene–gene interactions in IL23/Th17 pathway underlying psoriasis. Methods A total of 299 single‐nucleotide polymorphisms from 11 genes in IL23/Th17 pathway were genotyped on 1139 patients with psoriasis and 1694 controls. Multifactor dimensionality reduction and logistic regression algorithms were applied to explore the gene–gene interactions. Results We found that there were a three‐way interaction among IL21, CCR4 and TNF(χ² = 5.02(1), P = 0.025) and three pair‐wise gene–gene interactions between IL12RB1 and CCR4(χ² = 11.66(4), P = 0.0201), IL22 and CCR4 (χ² = 11.97(4), P = 0.0176), IL12RB1 and IL6 (χ² = 7.31(1), P = 0.0069) in psoriasis. Conclusions Our results might be helpful for explaining the missing heritability of the psoriasis due to epistasis and provide a deep insight into the important role of the IL23/Th17 pathway in the pathogenesis of psoriasis.