TLR7介导抗病毒免疫应答研究进展

Toll样受体(Toll-like receptors,TLRs)是天然免疫中重要的模式识别受体,在机体抗病原体感染中发挥重要的作用,同时也是连接天然免疫与获得性免疫的桥梁。研究表明,Toll样受体7(TLR7)能识别某些小分子的抗病毒化合物和病毒单链RNA(single-stranded RNA,ssRNA),活化的TLR7启动髓系分化因子88(myeloid differentiation factor 88,MyD88)依赖的信号通路,介导抗病毒免疫应答。TLR7的活化需要内体/溶酶体的成熟,目前一些小分子的TLR7配体已用于临床治疗病毒性感染疾病和肿瘤。     

Toll样受体9与红斑狼疮易感性关系的研究进展

Toll样受体（Toll-like receptors, TLRs）作为连接人体天然免疫与获得性免 疫的桥梁,在自身免疫性疾病的发病中起着重要作用。其中TLR9与其特异性配体 CpGDNA结合,然后通过信号转导激活B细胞、树突状细胞,可产生各种细胞因子和自 身抗体。近年来研究发现,系统性红斑狼疮（Systemic lupus erythematosus ,SLE） 的易感性可能与TLR9基因变异有关,目前研究结论不一。本文将从鼠和人两个研究 层次来阐述TLR9与SLE易感性的关系,揭示TLR9在SLE发病中的作用机理。     

小胶质细胞TLR4/NF-κB通路在脑血管疾病中的作用研究近况

<正>大量研究表明,急性炎症参与脑血管疾病(Cerebrovascular diseases,CVD)的病理生理过程[1]。Toll样受体(Toll-like receptors,TLRs)是一种模式识别受体(Pattern recognition receptor,PRR)。到目前为止,在人体内发现至少有11种TLRs,在老鼠体内至少有12种。TLRs的同源物相继被鉴定出来(TLR1~13),其中TLR1~9在人和小鼠体内均被发现,TLR10只在人体内发现,而TLR11则只在小鼠体内被发现。近年来的免疫学研究发现TLRs不仅在天然免疫中发挥重要的作用,而且还可以调节     

Toll样受体在结核病免疫应答中的作用

结核病(Tuberculosis)主要是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)引起的重大传染性疾病。Toll样受体(Toll-like receptors,TLRs)在宿主的抗结核免疫应答中发挥重要作用。研究表明,TLR1、2、4、6和9与宿主抗MTB感染有关,其中TLR2的作用更为突出。免疫应答的早期阶段,TLR2介导了巨噬细胞的活化,通过产生具有直接杀伤效应的分子或者诱导宿主细胞的凋亡抑制MTB的增殖。然而TLR2介导的信号通路也可通过降低MHC-Ⅱ分子的表达来削弱抗原递呈的能力,促进MTB在宿主内的存活。近几年临床研究发现TLRs多态性位点与结核病易感有关也从侧面证实了TLRs在抗MTB感染中发挥重要作用。     

Toll样受体2和Toll样受体4在免疫应答衣原体感染中的作用

衣原体是重要的人类病原体,其能够导致多种疾病的发生.由衣原体引起的许多人类疾病被认为是免疫病理学介导的.已经证明Toll样受体(TLRs)是多种病原体感染的主要模式识别受体( PRRs),在起始固有免疫应答,建立适应性免疫应答中发挥着重要作用.在TLR家族中,TLR2和TLR4与衣原体感染的相关性研究备受关注,在识别衣原体感染、调节宿主的早期免疫应答、炎症反应和病理形成中执行着关键性的作用.研究TLR2和TLR4在免疫应答衣原体感染中的作用可以更好地理解TLRs介导的分子免疫机制,可能有助于研发免疫治疗的分子靶标,最终有效预防、控制衣原体感染引起的疾病.     

TLR9的结构、功能及信号传导研究进展

Toll样受体(Toll-1ike receptors，TLRs)家族通过识别病原体相关分子模式(pathogen associated molecular pattern，PAMP)激活免疫细胞，在天然免疫防御病原体中起着重要作用。目前在哺乳类中至少存在10个TLRs(TLR1-10)成员，其中TLR9是识别细菌CpG-DNA的必需的模式识别受体(patttem recognition receptor，PRR)。本文综述了TLR9的结构、功能及信号传导机制。     

TLR7介导抗病毒免疫应答研究进展

Toll样受体（Toll-like receptors，TLRs）是天然免疫中重要的模式识别受体，在机体抗病原体感染中发挥重要的作用，同时也是连接天然免疫与获得性免疫的桥梁。研究表明，Toll样受体7（TLR7）能识别某些小分子的抗病毒化合物和病毒单链RNA（single-stranded RNA，ssRNA），活化的TLR7启动髓系分化因子88（myeloid differentiation factor88，MyD88）依赖的信号通路，介导抗病毒免疫应答。TLR7的活化需要内体，溶酶体的成熟，目前一些小分子的TLR7配体已用于临床治疗病毒性感染疾病和肿瘤。     

TLR2和TLR4的TLR/IL-1 receptor结构与功能

Toll样受体(Toll like receptor,TLR)是架接固有免疫和适应性免疫的桥梁。迄今为止,已鉴定的人TLR有10种,分别命名为TLR1~TLR10,TLR是一种Ⅰ型跨膜蛋白,由胞外富含亮氨酸重复序列(LRR)结构域,胞内保守的Toll/IL-1受体(TIR)结构域和跨膜结构域构成。TLRs在识别病原体相关分子模式后,其信号的特异转导主要取决于TLRs的TIR功能域与下游接头分子的TIR功能域的特异相互作用。然而,TLR2和TLR4的TIR功能域在其与下游接头分子Mal和MyD88相互作用、以及TLRs同源或异源二聚化方面的作用模式存在明显的差异。本文就TLR2和TLR4的TIR结构与功能进行简要综述,有助于我们进一步了解TLR TIR功能域与下游接头分子的相互作用。     

荧光定量PCR检测尖锐湿疣皮损Toll样受体的表达水平

目的 检测尖锐湿疣皮损中Toll样受体(TLRs)的mRNA表达水平,探讨TLRs在人乳头瘤病毒(HPV)感染免疫中的可能作用.方法 提取40例尖锐湿疣患者皮损和35例HPV阴性的慢性宫颈炎患者宫颈刮落细胞的总RNA,逆转录为cDNA后用实时荧光定量PCR法检测TLR1～10的mRNA表达水平,并检测40例尖锐湿疣的HPV分型.结果 40例尖锐湿疣患者以低危型HPV6和11型为主(77.5%和55%).55%尖锐湿疣患者感染两种以上HPV亚型,其中35%合并高危型HPV感染.尖锐湿疣组TLR3、7、8的mRNA表达水平高于其他TLRs,TLR9的mRNA表达水平低于其他TLRs(P均<0.05).尖锐湿疣皮损TLR1～10的mRNA表达水平在HPV6型和HPV11型感染间以及在低危型与合并高危型HPV感染间差异无统计学意义(P均>0.05).尖锐湿疣组TLR1～3、TLR5～8和TLR10的mRNA表达水平均高于HPV阴性的慢性宫颈炎组(P均<0.05),其中TLR2、7、8的mRNA表达水平升高更显著(P均<0.01).而TLR4、TLR9的mRNA表达水平与对照组差异无统计学意义(P>0.05).结论 尖锐湿疣皮损中部分TLRs(3、7、8)表达水平较高,但TLR9表达水平较低.相对于HPV阴性的慢性宫颈炎,尖锐湿疣皮损中TLR1~3、TLR5～8和TLR10的mRNA表达上调.不同HPV型别感染的尖锐湿疣皮损中TLRs表达谱差异无统计学意义.推测尖锐湿疣TLRs表达谱的改变可能与HPV感染有一定关系,是否与HPV感染的免疫逃逸机制及持续感染有关尚有待进一步明确.

Abstract：

Objective To investigate the expression of Toll-like receptors(TLRs) in condyloma acuminatum(CA) lesions and their possible roles in the pathogenesis of CA. Methods The expressions of TLR1-10 mRNA level in the lesions of CA and in the cervix scrape cells from the patients with human papillomavirus(HPV) negative chronic cervicitis were detected by real-time quantitative fluorescent PCR. HPV typing was detected by HPV GenoArray test kit. Results Low-risk HPV type 6 and type 11 were the most prevalent types in the forty CA cases with positive rate of 77.5% and 55% respectively. 55% CA patients were found infected with more than two types of HPV. 35% CA patients were concurrently infected with high-risk HPV. The expressions of TLR3, 7, 8 mRNA were higher than other TLRs and the expression of TLR9 mRNA was lower than others in the lesions of CA. No significant differences of the TLR1-10 mRNA levels were found between HPV6 and HPV11 positive CA lesions, so did it between low-risk and high-risk HPV concurrent infected CA lesions. The expressions of TLR1-3, TLR5-8, TLR10 mRNA, especially TLR2, TLR7 and TLR8 in the lesions of CA were significantly higher than that in cervix scrape cells of HPV negative chronic cervicitis. There were no significant differences of TLR4 and TLR9 mRNA levels between the two groups. Conclusion There were higher expressions of some TLRs (3, 7, 8) and lower expression of TLR9 in the lesions of CA. Compared with HPV negative chronic cervicitis, the expressions of TLR1-3, TLR5-8, TLR10 mRNA in the lesions of CA were up-regulated. The expression profile of TLRs in different type of HPV infected CA lesions had no significant differences. Our results suggested that the expression profile of TLRs in CA may be associated with the HPV infection. Whether it was associated with the immune escape mechanism and persistent infection of HPV need further demonstration.     

Toll 样受体7及Ⅰ型干扰素通路在系统性红斑狼疮中的作用研究

探讨Toll样受体7(TLR7)及Ⅰ型干扰素(IFN-α)通路在系统性红斑狼疮(SLE)发病中的作用.采用实时荧光定量PCR方法检测42例SLE患者和34例正常人外周血TLR7mRNA以及4个干扰素调节基因mRNA的表达水平,同时观察TLR7mRNA的表达量与SLE疾病活动相关指标和干扰素积分(IFN score)的关系.结果,SLE患者外周血TLR7mRNA的表达水平显著增高;TLR7mRNA的表达水平与SLEDAI积分,肾脏损伤指数、抗双链DNA(dsDNA)抗体、抗RNA相关抗体水平及干扰素积分呈正相关;与补体C3、C4、白细胞数呈负相关.TLR7-IFN-α通路可能参与了SLE的病理过程.     

Recognition of nucleic acid and nucleic acid analogs by Toll-like receptors 7, 8 and 9

The mammalian immune system senses pathogens through pattern recognition receptors (PRR) and responds with activation. Toll-like receptors (TLRs) that are expressed on immune and non-immune cells play a critical role in this process. As part of the innate immune response, TLRs lead to cellular activation and cytokine production with subsequent initiation of an adaptive immune response. TLR7-9 recognize single-stranded RNA, nucleoside analogs and single-stranded CpG-DNA, respectively, and their activation initiates the immune response against viruses and bacteria. Furthermore, the stimulation of these TLRs may be exploited for adjuvant therapy, vaccination and anti-tumor responses. However, a role in the generation or perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE) has also been suggested.     

The role of toll-like receptors in systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against a relatively limited range of nuclear antigens. These autoantibodies result in the formation of immune complexes that deposit in tissues and induce inflammation, thereby contributing to disease pathology. Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B cells and in the subsequent disease progression after immune complex formation. The endosomal localization of the nucleic acid-sensing Toll-like receptors (TLRs), TLR3, 7, and 9, is believed to contribute to the distinction between endogenous nucleic acids and those of foreign origin. In this article we review recent work that suggests a role for the B-cell receptor and Fcγ receptors in delivering nuclear antigens to intracellular compartments allowing TLR activation by endogenous nucleic acids. A number of in vitro studies have presented evidence supporting a role for TLRs in SLE pathology. However, recent studies that have examined the contributions of individual TLRs to SLE by using TLR-deficient mice suggest that the situation is far more complicated in vivo. These studies show that under different circumstances TLR signaling may either exacerbate or protect against SLE-associated pathology. Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies.     

Genetic variations in toll-like receptor pathway genes influence asthma and atopy

Innate immunity is a pivotal defence system of higher organisms. Based on a limited number of receptors, it is capable of recognizing pathogens and to initiate immune responses. Major components of these innate immunity pathogen recognition receptors are the toll-like receptors (TLRs), a family of 11 in humans. They are all membrane bound and through dimerization and complex downstream signaling, TLRs elicit a variety of specific and profound effects. In recent years, the role of TLRs signaling was not only investigated in infection and inflammation but also in allergy. Fuelled by the hygiene hypothesis, which suggests that allergies develop because of a change in microbial exposure and associated immune signals early in life, it had been speculated that alterations in TLRs signaling could influence allergy development. Thus, TLR genes, genetic variations of these genes, and their association with asthma and other atopic diseases were investigated in recent years. This review provides an overview of TLR genetics in allergic diseases.     

Toll-like receptor gene polymorphisms are associated with susceptibility to graves' ophthalmopathy in Taiwan males

Background  

Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which plays a role in eliciting innate/adaptive immune responses and developing chronic inflammation. The polymorphisms of TLRs have been associated with the risk of various autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis and rheumatorid arthritis. The aim of this study was to evaluate whether TLR genes could be used as genetic markers for the development of Graves' ophthalmopathy (GO).     

Development of TLR inhibitors for the treatment of autoimmune diseases

Summary The innate immune system is a critical element of protection from invading pathogens. The specific receptors that recognize various components of the pathogens trigger signals that result in the production of proinflammatory cytokines as well as the activation of antigen-presenting cells, which activate the adaptive immune system. The discovery of the Toll-like receptors (TLRs) as important components of pathogen recognition has brought new understanding of the key signaling molecules involves in innate immune activation. Interestingly, it appears that most TLRs can recognize self-ligands as well and that mechanisms are required to discriminate between self and non-self ligands. One of these mechanisms is the expression of all the nucleic acid-specific TLR in endosomal compartments and not on the cell surface. Inappropriate activation of TLRs by self-components can result in sterile inflammation or autoimmunity. For example, TLR7 and TLR9 activation by endogenous RNA and DNA, transported to the endosomes in the form of immune complexes or non-covalently associated with cationic peptides, could be an important mechanism involved in promoting diseases such as systemic lupus erythematosus and psoriasis. In this review, we discuss the rationale for self-recognition by TLR7 and TLR9 as an important part of the development of lupus and other autoimmune diseases. We describe novel inhibitors of these receptors and provide evidence to support their use as novel therapeutic agents for autoimmunity.     

Toll样受体与树突状细胞

Toll样受体(TLR)在介导固有免疫和适应性免疫应答中有重要作用,可以表达于多种免疫细胞,包括树突状细胞(DC).了解Toll样受体的免疫学基础、与DC之间的联系以及其在免疫耐受干预方面的作用很有必要.     

Toll-Like Receptors in Human Papillomavirus Infection

Infection with human papillomaviruses (HPVs) often causes cutaneous benign lesions, cervical cancer, and a number of other tumors. The mechanisms of host immune system to prevent and control HPV infection still remain poorly understood. Toll-like receptors (TLRs) are specific pattern recognition molecules that bind to microbial components to trigger innate immunity and direct adaptive immunity in the face of immunological danger. TLRs have been established to play an essential role in sensing and initiating antiviral immune responses. Recent accumulating evidence demonstrated that HPVs modulate TLR expression and interfere with TLR signaling pathways, leading to persistent viral infection and carcinogenesis. This review summarizes current knowledge on the roles of TLR during HPV infection, focusing on TLR recognition, modulation of TLR expression and signaling, regulatory receptors involved in TLR signaling, and cross-talk of TLRs with antimicrobial peptides. Immunotherapeutic strategies based on TLR agonists have emerged to be one of the novel promising avenues in treatment of HPV-associated diseases in the future.