Th17细胞与大疱性类天疱疮相关性研究

大疱性类天疱疮(bullous pemphigoid, BP)是一种获得性自身免疫性皮肤病,好发于老年人.既往研究认为BP为Th2细胞占优势的自身免疫性疾病.随着研究的深入,Th17细胞已成为研究的热点.其在防御胞外细菌感染、介导慢性炎症以及自身免疫病中发挥重要作用[1].白介素(IL)-23是T细胞分泌IL-17的关键触发因素,调节T细胞亚群分泌IL-17或IL-17相关细胞因子,形成IL-23/IL-17免疫应答途径.此途径在慢性肠病、自身免疫性疾病、肿瘤、变态反应性疾病等研究中已见到,而在自身免疫性大疱性皮肤病研究中却很少见到.为研究IL-17/IL-23免疫途径在BP发病中的作用机制及与临床的相关性,我们设计了本课题.     

系统性硬皮病的血管病变发病机制研究进展

系统性硬皮病(SSc)是一种不明病因的自身免疫性疾病，以进行性的皮肤和内脏纤维化、微血管系统改变和多种细胞、体液免疫异常为特征。SSc的临床表现差异较大，从局限的皮肤硬化、轻微的内脏损害到严重的皮肤及多内脏纤维化，形成一个范围较广的病谱．血管病变是SSc多数临床表现的病理学改变基础本文就SSc血管结构及功能的改变、血管活性相关的细胞因子、血管内皮细胞的凋亡、抗内皮细胞抗体等方面的研究进展进行了综述。     

系统性硬化病及相关疾病患者血清中白介素-8及其自身抗体测定

系统性硬化病(SSc)是以皮肤和受累器官的胶原纤维过多的积聚为特征。目前,SSc的发病机理尚不清楚,但有许多细胞因子在组织纤维化的过程中起作用。在成纤维细胞     

生物制剂治疗银屑病患者出现严重感染的风险评估:一项系统性回顾与荟萃分析

<正>肿瘤坏死因子抑制剂英夫利昔单抗、依那西普和阿达木单抗是目前用于治疗银屑病常用的3种生物制剂,新药优特克单抗是IL-12和IL-23拮抗剂,苏金单抗是IL-17受体拮抗剂。生物制剂通过抑制细胞因子,调控银屑病患者紊乱的免疫系统,从而发挥疗效。肿瘤坏死因子等细胞因子在细胞感染免疫应答和肉芽肿形成过程中是不可或缺的重要一员,因此生物治疗是否存在引起严重感染的风险     

IL-12与银屑病

银屑病是一种与遗传、免疫、环境因素有关的复杂疾病,尽管确切的致病机制目前还不清楚,但是T细胞和角质细胞的相互作用是发病的关键.白介素12(IL-12)是一种参与T细胞免疫关键过程细胞因子,在T细胞免疫关键过程中起调节免疫应答和维持免疫平衡的作用.目前的研究证实白介素12与银屑病的发病、治疗密切相关.     

系统性硬化病病理生理机制研究进展

系统性硬化病(SSc)是一种以皮肤增厚和纤维化为特征,同时伴有内脏器官受累的自身免疫性疾病。SSc的发病机制目前仍然不明,通常认为与遗传及环境因素有关。而血管损伤、免疫功能失调、多器官纤维化及三者间的相互作用,则是导致SSc发生和发展的主要因素。该文主要从上述3个方面总结归纳了其病理生理学研究的主要进展,对内皮细胞活化及效应因子的释放、免疫细胞激活及相关免疫因子的表达、基质细胞的激活及促纤维化因子的分泌,以及三者之间的关联作一综述。     

细胞因子在斑秃发病机制中的作用研究进展

斑秃可能是一个由细胞介导的针对生长期毛囊致毛发脱落的自身免疫相关性疾病。细胞因子在其发病过程中发挥了重要作用。在发病最初阶段以Th1细胞因子和IL-1浸润为主,尤以IFN-γ的作用为关键。IL-10和IL-1Ra是具有抗炎症和免疫抑制作用的细胞因子,在治愈斑秃皮损中表达增强,提示可能在治疗斑秃过程中发挥一定作用。     

胞外膜泡与系统性硬化病的关系及应用展望北大核心CSCD

胞外膜泡（extracellularvesicles）具有多种生理病理功能,可介导细胞间的通讯,参与炎症、免疫信号通路、血管生成、应激反应、细胞衰老、增殖和分化等过程,在自身免疫反应的诱导、维持、调节中也起重要作用。系统性硬化病（systemicsclerosis,SSc）是以皮肤纤维化、胶原增殖及血管病变为特点的全身多系统自身免疫性疾病,临床表现呈现很大的异质性,病理生理特征是内皮细胞异常激活、凋亡以及血管生成细胞数量减少,使新血管的生成受损;以血管壁炎症和凝血系统激活为特点的血管损伤在疾病的早期发生,并且是发病机制的核心。本文旨在探讨胞外膜泡在SSc病理机制中的作用及其潜在的临床应用价值。     

白介素-6/gp130信号通路在白癜风T细胞免疫中的作用

细胞因子通过对T细胞的分化影响适应性免疫应答,IL-6一开始被认为具有B细胞生长因子的特点诱导抗体的产生,最近研究表明,IL-6在T细胞免疫中产生重要的作用,IL-6通过膜结合IL-6受体或可溶性IL-6受体结合gp130形成复合体进行信号转导产生作用,可以阻止T细胞凋亡、诱导Th细胞的活化、调节Treg和Th17细胞之间的平衡,且T细胞在白癜风中发挥重要作用,黑素细胞自身抗原的存在使自身反应性T细胞可以通过细胞毒性作用持续性杀伤黑素细胞,导致黑素细胞的毁坏和凋亡,从而引起白癜风.     

阿维A通过下调Th17细胞相关因子改善硬皮病小鼠模型皮肤及肺组织纤维化程度

目的通过对系统性硬皮病(systemic scleroderma,SSc)小鼠模型外周血、皮肤和肺部Th17和Treg细胞及相关细胞因子表达的检测,探讨阿维A治疗SSc小鼠皮肤和肺纤维化病变可能的作用机制。方法 32只BALB/c小鼠随机均分为PBS对照组、博来霉素模型组、阿维A低剂量(6mg/kg)组和高剂量(12mg/kg)组,给药4周后处死。观察小鼠皮肤及肺部炎症和纤维化的病理切片,流式细胞仪检测外周血中Th17和Treg在CD4~+T细胞比例,通过ELISA检测小鼠血清IL-17A,IL-10,IL-6,TGF-β1的水平,RT-PCR检测皮肤和肺组织中IL-17A,RORγT,IL-6,TGF-β1,Fox P3 mRNA的表达,并分析这些结果的相关性。结果与模型组相比,高/低浓度阿维A组小鼠皮肤厚度和炎症评分均有明显的下降(P0.01),肺部的纤维化评分和炎症评分也有显著降低(P0.05)。流式细胞仪检测发现,经阿维A干预的两组小鼠外周血中Th17细胞比例都有显著增加(P0.01),而Treg细胞比例的变化差异无统计学意义(P0.05)。ELISA检测发现,与模型组比较,治疗组小鼠外周血中IL-17A,TGF-β1,IL-6水平均有显著下降(P0.05),而IL-10的表达均未发生明显变化(P0.05)。RT-PCR检测发现,治疗组皮肤和肺组织中Th17细胞相关因子IL-17A,RORγT,IL-6,TGF-β1表达水平显著下降(P0.05),而皮肤和肺组织中Treg相关的Fox P3 Treg mRNA表达在阿维A干预前后没有明显变化(P0.05)。结论阿维A能够通过降低Th17相关细胞因子的水平,减轻免疫炎症反应,改善硬皮病小鼠皮肤和肺组织纤维化的程度。     

Innate immunity in the pathogenesis of psoriasis

Psoriasis is a common, immune-mediated inflammatory skin disorder. T helper(h)1 and Th17 lymphocytes contribute to the pathogenesis of psoriasis through the release of inflammatory cytokines that promote further recruitment of immune cells, keratinocyte proliferation and sustained inflammation. The innate immune system is the first line of defence against infection and plays a crucial role in the initiation of the adaptive immune response. The presence of innate immune cells and their products in psoriatic skin plaques suggests a role for innate immunity in this disease. In addition, the innate immune system can direct the development of pathogenic Th cells in psoriasis. In this article, we will summarise the role of the innate immune system in psoriasis with particular emphasis on the role of cytokines, signalling pathways and cells of the innate immune system.     

Abnormal B Lymphocyte Activation and Function in Systemic Sclerosis

Systemic sclerosis (SSc) is characterized by tissue fibrosis and autoimmunity. Although the pathogenic relationship between autoimmunity and clinical manifestations of SSc remains unknown, SSc patients display abnormal immune responses including the production of disease-specific autoantibodies. Previous studies have demonstrated that B cells play a critical role in systemic autoimmunity and disease expression through various functions such as induction of the activation of other immune cells in addition to autoantibody production. CD19 is a crucial regulator of B cell activation. Recent studies demonstrated that B cells from SSc patients showed an up-regulated CD19 signaling pathway that induced SSc-specific autoantibody production in SSc mouse models. CD19 transgenic mice lost tolerance for autoantigen and generated autoantibodies spontaneously. B cells from SSc patients exhibited an overexpression of CD19 that induced SSc-specific autoantibody production in transgenic mice. Moreover, SSc patients displayed intrinsic B cell abnormalities characterized by chronic hyper-reactivity of memory B cells, which was possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a genetic model of SSc, showed augmented CD19 signaling. In bleomycin-induced SSc mouse models, endogenous ligands for toll-like receptor 4 induced by bleomycin stimulated B cells to produce various fibrogenic cytokines and autoantibodies. Remarkably, the loss of CD19 resulted in the inhibition of B cell hyper-reactivity and autoantibody production, which are associated with improvements in fibrosis and a parallel decrease in fibrogenic cytokine production by B cells. Taken together, the findings suggest that altered B cell function may result in tissue fibrosis as well as autoimmunity in SSc.     

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis

Skin’s innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin’s regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.     

Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity

Natural killer (NK) cells are innate immune effectors that produce various immunoregulatory cytokines. Recent studies have shown that NK cells are involved in the initiation of autoimmunity. In this study, we determined abnormalities of NK cells in systemic sclerosis (SSc), an autoimmune connective tissue disease, by assessing the frequency and absolute number, activation marker expression, cytokine production, and killing activity. The frequency and absolute number of NK cells increased in diffuse cutaneous SSc (dcSSc), whereas they were normal in limited cutaneous SSc (lcSSc). NK cells from both dcSSc and lcSSc patients exhibited activated phenotypes characterized by up-regulated CD16 and CD69 expression and downregulated CD62L expression. Interferon (IFN)-gamma production by non-stimulated NK cells from both dcSSc and lcSSc patients was increased compared to the normal control, whereas on stimulation, a reduced amount of IFN-gamma was produced. Interleukin (IL)-5 and IL-10 production by non-stimulated NK cells and IL-6 production by stimulated NK cells were augmented in dcSSc patients, but not in lcSSc patients. Despite the augmented cytokine production by non-stimulated NK cells, natural cytotoxicity activity and granzyme B secretion was reduced in NK cells from dcSSc and lcSSc patients. These results suggested that altered NK cell function contributes to immunological abnormalities in SSc.     

IL-18在免疫相关皮肤病中的作用机制究进展

白介素18是由单核细胞、巨噬细胞等多种细胞产生的一种具有多功能和多效应的前炎性因子,是固有和适应性免疫之间的一种重要联系,是细胞及体液免疫的调节物.通过激活多个信号转导途径、诱导干扰素γ的产生、调节免疫细胞功能参与机体免疫,其作用也体现在支持不同的Th细胞亚型的分化,促进Th1和Th2两型免疫应答.研究显示,白介素18在某些炎症、自身免疫性疾病和肿瘤中表达异常,提示白介素18与这些疾病的发生有一定的相关性.     

Systemic sclerosis

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by vasculopathy and tissue fibrosis of the skin and various internal organs. A series of genetic and epidemiological studies have demonstrated that SSc onset is determined by the accumulation of predisposing factors related to environmental influences, while genetic factors affect the susceptibility to and the severity of this disease. This notion has been confirmed by recent advance in animal models. The initial trigger of SSc is believed to be autoimmune attacks to endothelial cells, which occur in individuals with the genetic susceptibility to autoimmune diseases and/or the cumulative exposure to certain SSc‐related environmental influences. Then, endothelial cells are aberrantly activated or damaged, leading to the development of vascular structural changes, such as destructive vasculopathy and proliferative obliterative vasculopathy, and tissue fibrosis. In parallel, inflammatory cells activate SSc fibroblasts and modify the metabolism of extracellular matrix by soluble factors and autoantibodies. Prior to or during these processes, SSc fibroblasts acquire the ability to selectively respond to profibrotic growth factors and cytokines, persistently producing excessive amount of extracellular matrix. SSc fibroblasts also modify immune responses, at least those of CD4⁺ T cells, in the microenvironment through the secretion of immune regulatory molecules. Thus, various types of individually activated cells interact with each other and coordinately drive an SSc‐specific disease cascade, leading to the development of unique clinical symptoms. This article provides an overview of the current understanding of the pathogenesis of SSc with the recent advance in the research field of this disease.     

Immune response modifiers--mode of action

The innate immune system governs the interconnecting pathways of microbial recognition, inflammation, microbial clearance, and cell death. A family of evolutionarily conserved receptors, known as the Toll-like receptors (TLRs), is crucial in early host defense against invading pathogens. Upon TLR stimulation, nuclear factor-kappaB activation and the interferon (IFN)-regulatory factor 3 pathway initiate production of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, and production of type I IFNs (IFN-alpha and IFN-beta), respectively. The innate immunity thereby offers diverse targets for highly selective therapeutics, such as small molecular synthetic compounds that modify innate immune responses. The notion that activation of the innate immune system is a prerequisite for the induction of acquired immunity raised interest in these immune response modifiers as potential therapeutics for viral infections and various tumors. A scenario of dermal events following skin cancer treatment with imiquimod presumably comprises (i) an initial low amount of pro-inflammatory cytokine secretion by macrophages and dermal dendritic cells (DCs), thereby (ii) attracting an increasing number type I IFN-producing plasmacytoid DCs (pDCs) from the blood; (iii) Langerhans cells migrate into draining lymph nodes, leading to an increased presentation of tumor antigen in the draining lymph node, and (iv) consequently an increased generation of tumor-specific T cells and finally (v) an accumulation of tumoricidal effector cells in the treated skin area. The induction of predominately T helper (Th)1-type cytokine profiles by TLR agonists such as imiquimod might have further benefits by shifting the dominant Th2-type response in atopic diseases such as asthma and atopic dermatitis to a more potent Th1 response.     

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.