NODs蛋白及其与TLRs相互调控在机体抗病原真菌感染中的作用

宿主的模式识别受体(pattern recognition receptors,PRRs)主要包括Toll样受体(TLRs)和核苷酸结合寡聚化结构域( NODs)两大类受体[1],其中TLRs是胞膜模式识别受体,NODs是近年来新发现的胞质模式识别受体.目前,已有大量关于TLRs与NODs在细菌感染免疫应答中作用的研究,但NODs蛋白在真菌感染中作用的研究报道屈指可数,且NODs与TLRs在抗病原真菌感染中相互调控关系的机制尚不明确.本文主要对NODs蛋白信号通路,NODs与TLRs相互调控关系,NODs蛋白在抗病原真菌感染免疫应答中的作用进行综述.     

脾酪氨酸激酶在抗真菌免疫反应中的作用

真菌感染是免疫功能缺陷或免疫功能低下患者生命健康的一大威胁.机体通过固有免疫和适应性免疫反应发挥抗真菌作用.脾酪氨酸激酶(Syk)为一种非受体型酪氨酸激酶,Syk可以影响T细胞、B细胞和树突状细胞(DC)的活化以及巨噬细胞和中性粒细胞介导的吞噬作用,现研究证实Syk在抗真菌免疫反应中同样起着重要作用.多种模式识别受体(PRRs)包括C型凝集素受体(CLRs)、Toll样受体( TLRs)、补体受体3(CR3)等可以识别真菌并启动抗真菌免疫反应.Syk可通过直接或间接方式与多种PRRs耦联,并在抗真菌免疫反应中发挥不同作用.     

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.     

病毒诱导的细胞microRNA在先天免疫反应中的作用

细胞通过模式识别受体(pathogen-recognition receptors,PRRs)识别病原相关分子模式(pathogen associated molecularpatterns,PAMPs)后,立即启动一系列炎症信号通路,发生先天免疫应答。在这个过程中宿主细胞不仅产生大量microRNAs调节TLRs和RLRs介导的信号通路,防止过度免疫反应对宿主造成伤害,而且病毒还诱导产生了大量microRNAs来下调免疫应答,降低宿主对其清除作用。本文重点就病毒刺激宿主产生的microRNA调节免疫信号的研究做简要介绍。     

真菌细胞壁病原相关分子模式TLR/Dectin-1通路及相关细胞因子的免疫作用

侵袭性真菌感染(IFI)是致ICU患者死亡的重要原因之一。机体通过天然免疫重要的模式识别受体(PRR)Toll样受体(TLR)及C型凝集素受体(CLR)与病原相关分子模式(PAMP)识别后启动抗真菌免疫反应。目前明确磷脂甘露聚糖(PLM)的识别主要依赖TLR2和TLR4;β-葡聚糖经TLR2/树突状细胞相关性C型凝集素-1(Dectin-1)或只经Dectin-1识别。PLM和β-葡聚糖被识别后及经Dectin-1驱动获得性免疫后产生一系列下游细胞因子,一些下游细胞因子的免疫作用对不同组织有所不同、不确定或存在争议,一些免疫反应在细节上还没有详尽描述。因此,深入研究PAMP与PRR相互作用及其细胞因子对免疫调节影响,对IFI的预防治疗有重要意义。     

靶向Toll样受体药物研究进展

Toll样受体(TLRs)家族是主要的模式识别受体,能够识别多种人侵的病原体,启动炎性应答通路而调节或控制固有免疫与适应性免疫.一旦TLRs与其特异配体结合后,可激活信号转导级联,在急性炎症反应、细胞信号转导和细胞凋亡中起重要作用.目前临床上有很多靶向TLRs的药物来治疗炎症、免疫疾病以及肿瘤等,因此,深入研究TLRs信号系统与靶向TLR药物的作用机制,有助于拓宽新药研究思路,从而寻找针对性强而有效的治疗药物.     

Toll样受体介导的固有免疫应答在HBV感染中的研究进展北大核心CSCD

乙型肝炎病毒（hepatitis B virus,HBV）感染仍是全球重大公共卫生问题,HBV入侵机体后产生持续性感染涉及的免疫机制十分复杂,HBV在与宿主免疫系统的博弈中也进化出了一系列策略影响固有免疫效应,异常的固有免疫可能是导致病毒持续性感染的诱因之一.病原体相关分子模式（pathogen associated molecular patterns,PAMPs）被模式识别受体（pathogens recognition recep-tors,PRRs）识别进而启动固有免疫应答.Toll样受体（Toll like receptors,TLRs）是PRRs家族的重要成员,TLRs介导的固有免疫应答在与HBV相互作用并引起HBV感染相关的免疫效应中发挥重要作用,关系到病毒的早期清除和随后特异性免疫应答的激活.本文就TLRs介导的固有免疫应答与HBV之间相互作用的研究进展以及基于TLRs免疫治疗策略的相关成果进行综述.     

模式识别受体Dectin-1的免疫学研究进展

Dectin-1是C型凝集素家族中最重要的受体,它能诱导自身胞内信号传导触发一系列细胞反应,在抗真菌免疫中发挥着重要的作用。该文对Dectin-1的信号传导途径、在抗微生物免疫中的作用、与其他受体的相互作用、在自身免疫及疾病中的作用、在β 葡聚糖诱导的免疫调节中的作用、潜在的临床应用予以综述。     

Toll样受体7作为新靶点在过敏性及自身免疫性疾病中的研究进展

Toll样受体(Toll-like receptors,TLRs)属于模式识别受体(pattern recognition receptors,PRRs)家族,通过迅速识别入侵微生物病原相关分子模式(pathogen-associated molecular patterns,PAMP)激活下游信号传导途径,引发机体的免疫反应,是连接固有免疫与适应性免疫的桥梁.目前在人类发现10种不同TLRs,分别命名为TLR1 ～TLR10.近年的研究显示,TLR7与过敏性疾病、自身免疫性疾病—过敏性哮喘、系统性红斑狼疮(systemic lupus erythematosus,SLE)等有密切的联系.TLR7的激活状态影响上述疾病的发生、发展和预后.这些证据预示TLR7可能作为潜在靶点为哮喘和SLE的治疗提供新的方向.     

树突状细胞相关凝集素受体1和2在真菌免疫领域的研究进展

树突状细胞相关凝集素受体1和2(Dectin1和2)是2C型凝集素受体家族(CLR)的重要成员,作为模式识别受体( PRRs),其有效地识别病原体相关分子模式(PAMPs);Dectin-1识别β-葡聚糖,通过自身免疫受体络氨酸激活基序( ITAM)向胞内转导信号;Dectin-2识别α-甘露聚糖,通过耦联FcRγ链上的ITAM结构转导信号.ITAM招募并激活非受体络氨酸蛋白激酶(Syk),后者激活MAPKs或介导CARD9-Malt1-Bcl10复合体组装,激活核因子-κB(NF-κB),诱导合成炎症因子等一系列细胞活动.其配体β-葡聚糖和甘露聚糖都是真菌细胞壁的主要成分.近年来研究表明,Dectin-1和Dectin-2受体在真菌免疫防御中具有重要作用.     

The role of Syk/CARD9 coupled C-type lectins in antifungal immunity

Fungal infections are affecting an increasing number of people, and the failure of current therapies in treating systemic infection has resulted in an unacceptably high mortality rate. It is therefore of importance that we understand immune mechanisms operating during fungal infections, in order to facilitate development of adjunctive immunotherapies for the treatment of these diseases. C-type lectin receptors (CLRs) are pattern recognition receptors (PRRs) that are critical for immune responses to fungi. Many of these receptors are coupled to Syk kinase, which allows these receptors to signal via CARD9 leading to NF-κB activation, which in turn contributes to the induction of both innate and adaptive immunity. Dectin-1, Dectin-2 and Mincle are all CLRs that share this common signalling mechanism and have been shown to play key roles in antifungal immunity. This review aims to update existing paradigms and summarise the most recent findings on these CLRs, their signal transduction mechanisms and the collaborations between these CLRs and other PRRs.     

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.     

Porcine Toll-like receptors: the front line of pathogen monitoring and possible implications for disease resistance

Toll-like receptors (TLRs) are the most famous pattern-recognition receptors (PRRs); they monitor pathogen-associated molecular patterns and play a critical role in activation of the immune system against infection. TLR gene mutations may affect the gene products in terms of their ligand-binding ability or their signal transduction ability after ligand binding; such changes have a great influence on pathogen monitoring and disease resistance. Thirteen mammalian TLRs have been identified, and genes corresponding to all 10 TLR genes identified in humans have been fully cloned in pigs. Porcine TLR gene coding sequences possess a large number of nonsynonymous single nucleotide polymorphisms (SNPs). They are concentrated in ectodomains, and may increase the variability of pathogen recognition in pig populations. We summarize the current knowledge of TLR molecules in mammals and livestock (particularly pigs) and speculate on the relationship between SNPs in porcine TLRs and their application to vaccine design and disease-resistance breeding.     

Toll样受体信号通路中MyD88的研究进展

MyD88是Toll样受体信号通路中的重要转导蛋白,其依赖的信号通路以及调控的基因产物在固有免疫和适应性免疫中均发挥着关键作用。本文对MyD88及其依赖的信号通路做一简要综述,以期为临床预防和治疗疾病提供新的思路和方法。     

Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins

Pattern-recognition receptors (PRRs) detect molecular signatures of microbes and initiate immune responses to infection. Prototypical PRRs such as Toll-like receptors (TLRs) signal via a conserved pathway to induce innate response genes. In contrast, the signaling pathways engaged by other classes of putative PRRs remain ill defined. Here, we demonstrate that the beta-glucan receptor Dectin-1, a yeast binding C type lectin known to synergize with TLR2 to induce TNF alpha and IL-12, can also promote synthesis of IL-2 and IL-10 through phosphorylation of the membrane proximal tyrosine in the cytoplasmic domain and recruitment of Syk kinase. syk-/- dendritic cells (DCs) do not make IL-10 or IL-2 upon yeast stimulation but produce IL-12, indicating that the Dectin-1/Syk and Dectin-1/TLR2 pathways can operate independently. These results identify a novel signaling pathway involved in pattern recognition by C type lectins and suggest a potential role for Syk kinase in regulation of innate immunity.     

Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses

Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ line-encoded receptors have been identified for microbial products such as mannan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to be involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS-resistant strains instrumental in its identification as a transmembrane LPS signal transducer. Structural similarities between TLRs and receptor molecules involved in immune responses such as CD14 and the IL-1 receptors (IL-1Rs), as well as functional analysis qualified TLR2 as candidate receptor for LPS and other microbial products. Targeted disruption of the TLR9 gene in mice led to identification of TLR9 as CpG-DNA signal transducer. Involvement of TLR5 in cell activation by bacterial flagellin has been demonstrated. Further understanding of recognition and cellular signaling activated through the ancient host defense system represented by Toll will eventually lead to means for its therapeutic modulation.     

Toll-like receptors in the skin

Toll-like receptors (TLRs) are important pattern-recognition receptors involved in host defense against a variety of pathogenic microorganisms. Activation of TLRs leads to the production of cytokines, chemokines, antimicrobial peptides, and upregulation costimulatory and adhesion molecules involved in innate and adaptive immune responses. TLRs are expressed on a variety of cell types found in the skin, including keratinocytes and Langerhans cells in the epidermis, resident and trafficking immune-system cells such as macrophages, dendritic cells, T and B cells, and mast cells in the dermis, endothelial cells of the skin microvasculature, and skin stromal cells such as fibroblasts and adipocytes. There have been an increasing number of reports demonstrating that TLRs play a key role in cutaneous host defense mechanisms against bacterial, fungal, and viral pathogens. In addition, TLRs have also been implicated in the pathophysiology of various inflammatory skin diseases.