CpG DNA特异性识别的关键蛋白Toll样受体-9

Toll样受体在对抗外来病原微生物的天然免疫应答中发挥中心作用。新发现的一种分子识别模型受体Toll样受体-9（TLR9）,能特异性识别CpG DNA并起动信号转导级联反应,在不同种类中的TLR9具有对序列识别的特异性。本文概述国外在TLR9识别作用机制和生物学活性研究中已取得的进展,并提出了今后研究的发展方向。     

TLR3免疫识别dsRNA病毒的分子机制

1984年,果蝇的Toll样蛋白被发现。13年后,人们发现了第一个与果蝇Toll蛋白同源的人Toll样受体(toll like receptor,TLR)蛋白(hTLR4)。迄今,已有10种TLR蛋白(即hTLR1～10)被发现,它们代表了一类保守的受体家族,分别识别不同的抗原。其中TLR3能专一性地识别双链RNA(double stranded RNA,dsRNA),通过依赖MyD88的信号通路及不依赖MyD88的信号通路,     

TLR9介导DNA病毒的免疫识别

Toll样受体(toll-like receptor,TLR)是免疫细胞表面的模式识别受体(patttern recognition receptoi,PRR),参与微生物病原体相关分子模式(pathogen associated molecular patterns,PAMPs)的识别,从而诱导天然免疫应答。迄今在人类已经确定了10个TLRs家族成员。不同的TLRs识别不同的PAMPs,如TLR9是免疫细胞识别病毒和细菌中非甲基化DNA的必需成分;     

TOLL样受体9在动脉粥样硬化中的作用研究进展

动脉粥样硬化是一种慢性免疫炎症性疾病,它与自身的先天性免疫和适应性免疫密切相关。Toll样受体(Toll-like receptors,TLR)作为激活非特异性免疫的重要受体蛋白,可以识别病原微生物,激活免疫反应。Toll样受体9是TLR家族中的重要一员,是先天免疫系统中识别细菌和病毒Cp G DNA的重要受体,其与动脉粥样硬化(atherosclerosis,AS)的发生发展紧密相关。研究发现,TLR9与动脉粥样硬化的发生、发展(内皮受损和泡沫化细胞形成)密切相关,但也有研究发现TLR9在AS进程中具有潜在的保护效应。本文对Toll样受体9与动脉粥硬化疾病之间关系做一个简要的阐述,简明的总结了TLR9与树突细胞及自噬之间的联系,并为其作为靶点治疗动脉粥样硬化提供新的思路。     

Toll样受体（TLR）介导的天然免疫间的相互调节

模式识别受体（PRR）在宿主细胞识别与抵御微生物病原体中起到了重要作用。Toll样受体（TLR）是研究比较清楚的一类PRR,可以识别多种病原体成份,启动天然免疫反应。此外,近来发现了几类其他模式识别受体,如C型凝集素受体（CLR）,核苷酸寡聚结合域（NOD）样受体（NLR）和视黄酸诱导基因I（RIG—I）样受体（RLR）,表明机体的天然免疫反应受到多种机制的精密调控。本文着重综述TLR与其他PRR在识别病原体和介导天然免疫信号通路间的相互关系。     

Toll样受体与抗结核感染免疫

结核分枝杆菌(MTB)是结核病的致病菌,其发病机制仍未阐明。Toll样受体(TLR)蛋白家族属于动物模式识别受体家族。研究表明,TLR对先天免疫和获得性免疫都有调控作用,与抗结核感染免疫有关的主要是TLR2和TLR4。对TLR的研究为MTB诱导先天免疫反应机制的阐明以及治疗方法的进步提供了新的思路。     

Toll-NF-kB信号途径及其介导的功能

Toll样受体（Toll-like receptor,TLR）家族是宿主细胞识别各种微生物致病成份的主要受体,NF-kB位于TLR下游信号通路的枢纽位置,当细胞受到生物应激刺激后激活NF-kB,活化的NF-kB进入细胞核调节炎性细胞因子的表达,启动针对病原微生物的固有免疫和获得性免疫。因此,对Toll-NF-kB信号途径的研究将有助于对免疫反应、炎症病理的理解。     

Toll 样受体与天然免疫

Toll样受体家族是一类模式识别受体,它介导了一个植物,昆虫,哺乳动物共同拥有的高度保守的信号通路。最近几年相继发现了多种人类Toll样受体以及相关的病原微生物配体,这些配体涵盖了病毒,细菌,真菌等微生物上多种保守的病原相关分子模式。可见Toll样受体在多种病原微生物及其产物的识别和免疫防御反应中有重要的作用。     

C型凝集素受体与抗真菌免疫

Toll样受体(TLR)的发现为研究病原生物的识别和免疫应答的起始开辟了新的视角,然而近期研究发现"非-TLR"受体在该过程尤其在抗真菌免疫中亦起着重要作用.其中研究甚为活跃的是C型凝集素受体(CLR)家族的一些成员,包括甘露糖受体、DC-SIGN、Dectin-1、Dectin-2及胶原凝集素.本文对这些受体在真菌识别、摄取、杀伤及其在宿主免疫反应的诱导和调节中所发挥的作用予以综述.     

TLR4及其作用的研究进展

Toll样受体(toll-like receptors,TLRs)因其积极的研究成果而成为近年来广受关注的一种病原体识别受体,TLRs分布相对比较广泛,不但在小肠上皮、呼吸上皮细胞表达,同时也在血管内皮细胞、树突状细胞[1]、大鼠脾及心肌细胞[2]等细胞中表达.研究证实,它属于模式识别受体(pattern recognition receptors,PRRs),病原相关分子模式(pathogen-associated molecule pattern,PAMPs)可被其辨别,然后引发一系列的信号转导,TLRs 是备受关注的一种PRRs.Toll样受体4(toll-like receptor 4,TLR4)是TLRs家族中极为重要的成员,是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中扮演着关键性作用.细菌脂多糖(lipopolysaccharide,LPS)作为一类受体,主要作用是介导信号跨膜转导,尤其对革兰氏阴性菌所引起的感染性炎症起着极为关键的作用.由于近年来对TLR4介导的信号转导及TLR4与疾病的关系研究成为热点,本文就TLR4的信号转导、TLR4与LPS的关系及TLR4信号通路调节进行综述如下.     

Innate immunity: structure and function of TLRs

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate na?ve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.     

抗病毒感染固有免疫应答的信号转导

入侵病毒的探知和适应性免疫应答启动均依靠固有免疫系统。三种模式识别受体(PRRs)在宿主防御系统第一线占据极其重要地位:Toll样受体、维甲酸诱导基因I样受体、核苷酸结合寡聚化结构域样受体。PRRs识别病原相关分子模式(PAMP)或危险信号分子模式(DAMPs)启动和调节固有免疫和适应性免疫应答。每种PRR都有单独的识别配体和细胞定位。激活的PRRs将信号分子传递给其配体分子(MyD88,TRIF,IRAK,IPS-1),配体活化后作为信使激活信号途径下游激酶(IKK复合物,MAPKs,TBK1,RIP-1)和转录因子(NF-κB,AP-1,IRF3),最终产生细胞因子、趋化因子、促炎细胞因子和I型干扰素。本文重点讨论PRRs信号通路及该领域取得的成果,以期为人类健康和免疫疾病防治提供策略。     

Antiviral signaling through pattern recognition receptors

Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.     

How Location Governs Toll-Like Receptor Signaling

Toll-like receptors (TLRs) are a family of innate immune system receptors responsible for recognizing conserved pathogen-associated molecular patterns (PAMPs). PAMP binding to TLRs initiates intracellular signaling pathways that lead to the upregulation of a variety of costimulatory molecules and the synthesis and secretion of various cytokines and interferons by cells of the innate immune system. TLR-induced innate immune responses are a prerequisite for the generation of most adaptive immune responses, and in the case of B cells, TLRs directly regulate signaling from the antigen-specific B-cell receptor. The outcome of TLR signaling is determined, in part, by the cells in which they are expressed and by the selective use of signaling adaptors. Recent studies suggest that, in addition, both the ligand recognition by TLRs and the functional outcome of ligand binding are governed by the subcellular location of the TLRs and their signaling adaptors. In this review we describe what is known about the intracellular trafficking and compartmentalization of TLRs in innate system's dendritic cells and macrophages and in adaptive system's B cells, highlighting how location regulates TLR function.     

Synthesis and immunostimulatory activity of sugar-conjugated TLR7 ligands

Toll-like receptors (TLRs) are a type of pattern recognition receptors (PRRs), which are activated by recognizing pathogen-associated molecular patterns (PAMPs). The activation of TLRs initiates innate immune responses and subsequently leads to adaptive immune responses. TLR agonists are effective immuomodulators in vaccine adjuvants for infectious diseases and cancer immunotherapy. In exploring hydrophilic small molecules of TLR7 ligands using the cell-targeted property of a vaccine adjuvant, we conjugated 1V209, a small TLR7 ligand molecule, with various low or middle molecular weight sugar molecules that work as carriers. The sugar-conjugated 1V209 derivatives showed increased water solubility and higher immunostimulatory activity in both mouse and human cells compared to unmodified 1V209. The improved immunostimulatory potency of sugar-conjugates was attenuated by an inhibitor of endocytic process, cytochalasin D, suggesting that conjugation of sugar moieties may enhance the uptake of TLR7 ligand into the endosomal compartment. Collectively our results support that sugar-conjugated TLR7 ligands are applicable to novel drugs for cancer and vaccine therapy.     

Molecular Cloning and Expression Profile of Toll-Like Receptor 3 from an Indian Coldwater Fish,Schizothorax richardsonii(Gray)

The innate immune system recognizes pathogens through pattern recognition receptors (PRRs), and toll-like receptors (TLRs) are one of the most important PRRs. TLR3 is a unique member of TLR family that recognizes double-stranded RNA (dsRNA), a viral replication intermediate. There is a variation in its response among diverse fish species toward the same stimulants. We identified and cloned TLR3 from Indian snow trout, Schizothorax richardsonii and carried out its expression analysis in un-induced and poly (I:C) challenged fish. It has an open reading frame (ORF) of 2712 bases that encodes a polypeptide of 904?amino acids. The molecular weight of the polypeptide was predicted to be 102.4482?kDa with an isoelectric point of 7.40. Quantitative real time PCR (qRT-PCR) was carried out after 24 hours of poly (I:C) treatment and expression of TLR3 was analyzed in different tissues. As compared with untreated fish the poly (I:C) challenged fish revealed significantly high expression of TLR3 in kidney followed by liver and gills.     

Toll-Like Receptors and Human Disease: Lessons from Single Nucleotide Polymorphisms

Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.     

Pattern recognition receptors—Molecular orchestrators of inflammation in inflammatory bowel disease

Pattern recognition receptors (PRRs) are a family of germline encoded receptors responsible for the detection of “pathogen associated molecular patterns” (PAMPs) or host derived “damage associated molecular patterns” (DAMPs) which induce innate immune signalling to generate a pro-inflammatory profile within the host. Four main classes of PRRs are recognised, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs) and C-type lectin receptors (CLRs). Abnormal activation of PRRs has been implicated in various autoimmune and inflammatory conditions including rheumatoid arthritis and asthma. Recent growing evidence has implicated these PRRs as contributory elements to the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Here, the current literature which implicates PRRs in IBD and CAC is comprehensively reviewed.     

Functions of toll-like receptors: lessons from KO mice

The innate immune response is a first-line defense system in which individual Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns (PAMPs) and exert subsequent immune responses against a variety of pathogens. TLRs are composed of an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic domain that is homologous to that of the IL-IR family. Upon stimulation, TLR recruits a cytoplasmic adaptor molecule MyD88, then IL-IR-associated kinase (IRAK), and finally induces activation of NF-kappaB and MAP kinases. However, the responses to TLR ligands differ, indicating the diversity of TLR signaling pathways. Besides MyD88, several novel adaptor molecules have recently been identified. Differential utilization of these adaptor molecules may provide the specificity in the TLR signaling.     

靶向 Toll 样受体的免疫调节剂研究进展

Toll 样受体是一类相对保守的模式识别受体,可以识别损伤相关分子模式和病原相关分子模式,从而启动天然免疫应答,在天然免 疫过程中发挥非常重要的作用。其介导的信号通路失调会引发各种炎症反应、癌症和自身免疫病等疾病。综述近年与 Toll 样受体有关的免 疫调节剂的研究进展,并概括与之相关的疾病,为靶向 Toll 样受体的免疫调节剂的研发提供一定参考。