Toll/IL-1R家族信号转导机制研究进展

Toll是广泛参与机体天然和获得性免疫应答的分子, 其胞外段可与相应配体结合, 通过胞内段激活细胞内信号转导系统。在研究其胞内信号转导的分子机制时发现, Toll的胞内段与Il 1R家族分子的胞内段(TIR区)有高度同源性, 并都可通过MyD88依赖途径激活细胞内信号转导。另外, Toll家族的个别成员还可在MyD88缺失时通过替代途径 MyD88非依赖途径激活信号转导, 现将其研究进展综述如下。1　Toll/IL 1R家族及其成员的结构特点已知Toll是果蝇胚胎发育过程中控制果蝇腹背模式形成的一类蛋白, 并可介导对多种细菌和真菌感染的天然免疫,目前…     

昆虫天然免疫的研究进展

对果蝇等昆虫天然免疫的研究有利于揭示人类自身的免疫机制,并为感染性疾病和自身免疫病等的治疗提供新思路.昆虫的天然免疫机制包括物理防线、体液免疫和细胞免疫等方面.在病原体入侵昆虫体内后,昆虫可通过模式识别机制识别病原体并通过Toll途径和Imd途径等机制启动昆虫的体液及细胞免疫反应.昆虫的体液免疫和细胞免疫并不是绝然独立的,而是相互联系、相互促进和协作.在昆虫的各种免疫反应中,抗菌肽的产生、黑化包被反应和细胞吞噬作用是最为重要的防御机制.     

Toll—like receptors研究进展

TLR是近年来新发现的一种同源于果蝇Toll的蛋白分子,在宿主的天然免疫中具有重要作用.研究发现,它既可作为CD14作用的信号分子,又能直接作为LPS的受体介导细胞的活化,在LPS的跨膜信号转导中具有重要作 用,成为LPS信号转导研究的热点之一.TLR相关研究的深入,可为临床内毒素休克、SIRS和MODS的防治提供新途径.     

Toll 样受体及其信号转导

天然免疫系统作为宿主第一道防线 ,主要在获得性免疫系统被活化前发挥抗感染作用 ,它依赖胚系基因编码的识别系统对病原微生物起反应。其主要作用方式是通过产生抗菌肽或蛋白以及吞噬作用直接破坏入侵的病原体 ,并判定病原体入侵部位和强度 ,调控获得性免疫反应。新近实验资料显示天然免疫识别微生物机制可能主要归功于Ｔｏｌｌ样受体 (Ｔｏｌｌ ｌｉｋｅｒｅｃｅｐｔｏｒ ,简称ＴＬＲ家族 )。本文对ＴＬＲ家族在机体防御机制中的作用和各种ＴＬＲ对微生物的识别及其信号转导机制的进展作一概述。1　ＴＬＲ家族Ｔｏｌｌ基因最初是在研究果蝇…     

信号分子TRIF的研究进展

Toll样受体(TLRs)作为连接天然免疫和获得性免疫的桥梁,其介导的信号转导通路及其作用一直是人们研究的焦点。由髓样分化因子88(myeloid differentiation primary response protein 88,MyD88)承接的转导途径称为MyD88依赖途径,是几乎所有TLRs信号转导的共同通路(TRL3除外),由β干扰素     

病毒感染的天然免疫识别机制

近年来提出的病原体相关分子模式（pathogen associated molecular pattern，PAMP）以及识别PAMP的模式识别受体（pattern recognition receptor，PRR）标志着天然免疫应答的研究进入新阶段。病毒感染的天然免疫应答依赖于宿主对病毒PAMP的识别，Toll样受体家族和胞内其他病毒模式识别受体介导的天然免疫机制也成为探讨的热点。本文着重概括一些病毒模式识别受体的功能和信号转导途径的研究近况。     

托样受体3( TLR-3) 信号通路介导的病毒免疫逃逸

<正>天然免疫是机体抵御病毒入侵的首道防线,对病原快速有效地识别是激发天然免疫的前提。动物的天然免疫依赖一类能够识别微生物特定组分的模式识别受体(Pattern recognition receptors,PRRs)。其中,托样受体3(Toll like receptor-3,TLR3)通过识别病毒感染时产生的dsRNA,启动下游的信号转导,上调Ⅰ型干扰素α和β(Interferonα/β,IFNα/β)的表达,Ⅰ型干扰素能够诱导细胞产生抗病毒蛋白(Antivirus protein,AVP),同时也有助于激发机体的适应性免疫~([1])。     

TLR9免疫识别CpG DNA的机制与途径

Toll样受体介导的信号转导通路在对抗外来病原微生物的天然免疫应答中起重要作用。新发现的Toll样受体 9(TLR9)是哺乳动物识别细菌DNA中非甲基化的胞嘧啶 磷酸 鸟嘌呤基序 (CpGDNA)的主要受体。经典的信号转导途径如NF κB活化通路 ,MAPK通路在对CpGDNA的应答中均被启动。     

Toll样受体的信号转导及抗感染免疫研究进展

Toll样受体(Toll-like receptors,TLRs)是进化中比较保守的一个受体家族,至少包括13个成员,Toll样受体能特异识别病原相关分子模式(PAMP),在天然免疫和获得性免疫中都发挥着重要的作用,是连接天然免疫和获得性免疫的桥梁。近年来,对TLRs信号转导的研究,特别是对TLRs负反馈的研究,进展非常迅速,它们在抗感染中起着重要的作用,特别是负反馈机制对信号的平衡调节在抗感染免疫中有重要作用。     

机体对HPV L1免疫应答的研究进展

HPV L1相关的免疫应答是天然免疫和适应性免疫协同作用的结果,目前相关的研究已经渗入了免疫应答的全过程.天然免疫参与HPV L1诱导的免疫应答,但人们对它的认识仍然很有限.适应性免疫研究的进展主要体现在3方面①识别阶段.HPV的相关抗原主要由DC和LC摄取、加工、处理,经胞质溶胶、交叉提呈两种提呈途径提呈给CD8+细胞并使其致敏.②增殖分化阶段.Th1和Th2细胞都有出现,表明HPV L1不仅介导体液免疫,也介导细胞免疫.③效应阶段.L1介导产生的IgG、IgA、IgM类抗体都有其特殊性.     

Immunobiology of TNFSF15 and TNFRSF25

The innate immune response plays a critical role in pathogen clearance. However, dysregulation of innate immunity contributes to acute inflammatory diseases such as sepsis and many chronic inflammatory diseases including asthma, arthritis, and Crohn’s disease. Pathogen recognition receptors including the Toll-like family of receptors play a pivotal role in the initiation of inflammation and in the pathogenesis of many diseases with an inflammatory component. Studies over the last 15 years have identified complex innate immune signal transduction pathways involved in inflammation that have provided many new potential therapeutic targets to treat disease. We are investigating several novel genes that exert spatial and in some cases temporal regulation on innate immunity signaling pathways. These novel genes include Tbc1d23, a RAB-GAP that inhibits innate immunity. In this review, we will discuss inflammation, the role of inflammation in disease, innate immune signal transduction pathways, and the use of spatiotemporal regulators of innate immunity as potential targets for discovery and therapeutics.     

Toll-like receptors in innate immunity

Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.     

Evolutionary perspectives on innate immunity from the study of Caenorhabditis elegans

Genetic and functional genomic approaches have begun to define the molecular determinants of pathogen resistance in Caenorhabditis elegans. Conserved signal transduction components are required for pathogen resistance, including a Toll/IL-1 receptor domain adaptor protein that functions upstream of a conserved p38 MAP kinase pathway. We suggest that this pathway is an ancestral innate immune signaling pathway present in the common ancestor of nematodes, arthropods and vertebrates, which is likely to predate the involvement of canonical Toll signaling pathways in innate immunity. We anticipate that the study of pathogen resistance in C. elegans will continue to provide evolutionary and mechanistic insights into the signal transduction and physiology of innate immunity.     

树突状细胞Toll样受体介导的信号传导通路

树突状细胞(DC)是体内功能最强的抗原提呈细胞,是机体联系固有免疫应答和适应性免疫应答的桥梁.DC表面的Toll样受体(TLRs)在接受外界刺激信号和诱导机体产生免疫应答方面具有核心作用.TLRs介导的胞内信号传导通路主要有两条:髓样分化蛋白88(MyD88)依赖途径与MyD88非依赖途径.这两条传导通路中的大部分接头蛋白分子是一致的,但在某些关键点上又有所不同,因此决定了它们的功能既相互交叉又彼此独立.     

Toll-like receptor]

Toll-like receptors (TLRs) have been revealed to recognize specific patterns of microbial components. Recognition of microbial components by TLRs initiates signal transduction pathways, triggering expression of genes, which products control innate immune responses and further instruct development of antigen-specific acquired immunity. TIR domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, play pivotal roles in TLR signaling pathways. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. TLR-mediated activation of innate immunity, when in excess, leads to immune disorders such as inflammatory bowel diseases. Therefore, several mechanisms that negatively control TLR signaling pathways and thereby prevent overactivation of innate immunity have been elucidated. Nuclear IkappaB proteins, such as Bcl-3 and IkappaBNS, have been revealed to be responsible for this process, by differentially inhibiting TLR-dependent cytokine production.     

Nitric oxide contributes to induction of innate immune responses to gram-negative bacteria in Drosophila

Studies in mammals uncovered important signaling roles of nitric oxide (NO), and contributions to innate immunity. Suggestions of conservation led us to explore the involvement of NO in Drosophila innate immunity. Inhibition of nitric oxide synthase (NOS) increased larval sensitivity to gram-negative bacterial infection, and abrogated induction of the antimicrobial peptide Diptericin. NOS was up-regulated after infection. Antimicrobial peptide reporters revealed that NO triggered an immune response in uninfected larvae. NO induction of Diptericin reporters in the fat body required immune deficiency (imd) and domino. These findings show that NOS activity is required for a robust innate immune response to gram-negative bacteria, NOS is induced by infection, and NO is sufficient to trigger response in the absence of infection. We propose that NO mediates an early step of the signal transduction pathway, inducing the innate immune response upon natural infection with gram-negative bacteria.     

NF-kappaB and the innate immune response

In the innate immune reaction, microbial pathogens activate phylogenetically conserved cellular signal transduction pathways that regulate the ubiquitous nuclear factor-kappaB (NFkappaB). NF-kappaB has pleiotropic functions in immunity; however, it is also critical for development and cellular survival. Many aspects of how the different pathways utilize a common kinase complex that ultimately activates NF-kappaB have been clarified by gene inactivation and biochemical analysis.     

Interleukin-1/Toll receptor family members: receptor structure and signal transduction pathways.

Interleukin-1 (IL-1) is a central mediator of the inflammatory response. It plays a role in both systemic and local immune responses to invading microbes. There are two receptors (IL-1RI and IL-1RII) that mediate the cellular responses. These receptors belong to a family of receptors based on homologous receptor structure within the intracellular signaling domain. Other family members include the Drosophila protein Toll, the recently discovered mammalian Toll-like receptors (TLR), and the IL-18 receptor. Engagement of these receptors by their diverse ligands results in activation of very similar signal transduction cascades through use of common signaling intermediates. These signal transduction cascades lead to the activation of cellular responses that are known to regulate the innate immune response. Therefore, elucidating the function and redundancy of this receptor family is essential to the understanding of the innate immune response. This review examines each member of this receptor family and emphasizes similarities and potential differences in both receptor structure and signal transduction pathways to further the understanding of this complex receptor family.     

Toll and Toll-like proteins: an ancient family of receptors signaling infection

Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to microbes. It involves intracellular signaling pathways in the fruit-fly Drosophila and in mammals that show striking similarities. Recent genetic and biochemical data have revealed, in particular, that proteins of the Toll family play a critical role in the immediate response to infection. We review here the recent developments on the structural and functional characterization of this evolutionary ancient and important family of proteins, which can function as cytokine receptors (Toll in Drosophila) or pattern recognition receptors (TLR4 in mammals) and activate similar, albeit non identical signal transduction pathways, in flies and mammals.