Mechanisms of innate immune responses mediated by Toll-like receptors

The innate immune response is thought to be a rapid and nonclonal host defense. The recent discovery of Toll-like receptors (TLRs) and analyses of their physiological roles have established the notion that TLRs play a central role in innate immunity. Accumulating evidence suggests that individual TLRs recognize distinct ligands derived from bacterial components to generate specific cellular immune responses. In this review, we delineate the relationships between TLRs and microbial components, the TLR-mediated signaling pathways mainly based on cytoplasmic adaptor molecules containing Toll/interleukin-1R domains, the mechanism of TLR-mediated gene expression, and the involvement of TLRs in septic shock, including up-to-date observations.     

Toll样受体在先天性免疫反应中的作用

先天性免疫识别侵袭的微生物,引起宿主防御反应.然而,先天性免疫识别的分子机制还不清楚.最近,有人发现了Toll样受体家族(TLRs),并阐明了这些受体在微生物识别中的主要作用.TLR基因家族包括11个成员,也可能更多.每种引起TLR先天性免疫反应的微生物类型各不相同.先天性免疫的激活引起特定抗原获得性免疫的发展.因此,TLRs控制先天性免疫反应和获得性免疫反应.     

Innate immune sensing and activation of cell surface Toll-like receptors

The expansion of sensing function by cell surface Toll-like receptors (TLRs) has grown to include not only more diverse viral, bacterial, fungal and protozoan surface components, but also a plethora of endogenous molecules arising from host cell and tissue damage as well as the inflammatory response itself. This flexibility in recognition is accommodated not only by physical and structural features of the TLRs themselves, but also by additional innate immune receptors, soluble molecules and subcellular trafficking mechanisms. These events have begun to reveal a remarkable plasticity and complexity within this critical arm of the host innate immune system.     

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。     

C型凝集素受体对固有免疫应答的双向调节作用

C型凝集素受体（CLR）是模式识别受体家族中有别于TLR的新家族,在机体免疫应答中发挥着重要作用。近年来,人们对CLR对固有免疫应答的调节作用进行了较为广泛的研究,越来越多的研究发现CLRs对固有免疫应答具有双向调节作用：不同的CLR在固有免疫应答中既可以发挥正性调节作用,也能够发挥负性调节作用;在针对不同的病原体或在抗原提呈细胞不同的成熟状态等条件下,同-CLR在固有免疫应答中也可以发挥正负调节两方面的作用。深入探讨CLR对固有免疫应答的双向调节作用,对于进一步理解免疫应答的精细调节及疾病发病机制的复杂性等都有重要的理论意义,同时也为许多疾病的预防与治疗提供了一种新的策略。     

Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis

The serum hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antibodies (AMA), found in 95% of patients. However, nearly every patient with PBC, including those who are AMA-negative, has an elevation in serum IgM. This hyper-IgM is neither representative of other Ig isoforms, nor is due to the levels of AMA. In fact, we have recently reported that the hyper-IgM is an innate immune response and can be induced with CpG-B with concurrent up-regulation of toll-like receptor 9 (TLR9). Based on these observations, we performed a two-tier study. First, we quantitated TLR9 genotypes in patients with PBC and controls and correlated these data with the B cell response to CpG-B. Second, based on these data, we performed an extensive TLR9 genotyping in a large cohort of patients and controls. We report herein that the 2848 AA TLR9 genotype is associated with enhanced gene expression and higher frequency of intracellular IgM(+) B cells following CpG stimulation. Interestingly, however, despite the functional association, there is no difference in the distribution of TLR9 genotypes between patients and controls. Our data emphasize the importance of dissecting the innate immune response in PBC.     

先天免疫Toll样受体在哮喘病中作用的研究进展

哮喘病的高发性和普遍性使哮喘病成为人们极度关注的健康问题,哮喘病的特征是呼吸道阻塞和支气管的过度炎性反应.虽然对后大获得性免疫在哮喘病中的作用已进行了广泛地研究,但是先天免疫在哮喘病中的重要件是最近才被发现的.先大免疫不但提供抗感染的第一道防线,而且调控后天获得件免疫的激活.Toll样受体是先大免疫的关键感受器,它也是研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.本义综述了了目前天于Toll样受体在哮喘病中作用的研究进展.     

Toll样受体与肿瘤

Toll样受体的发现是近二十年整个医学领域的一项重大发现.Toll样受体作为先天免疫的重要组成部分,是一种模式识别受体.它通过识别病原相关分子模式在机体天然免疫应答中发挥重要作用.Toll样受体不仅仅表达在免疫细胞,同样也表达在肿瘤细胞,影响着肿瘤的发生、发展.Toll样受体激活可发挥抗肿瘤的作用,但也可促进肿瘤的进展.人们对这截然相反的结果的发生机制还了解甚少.Toll样受体还能识别损伤相关分子模式形成慢性炎症微环境影响肿瘤的发生、发展、治疗.本文对Toll样受体与肿瘤之间的关系及相应研究最新进展进行综述.     

Toll样受体与急性胰腺炎

急性胰腺炎（AP）是一个临床常见的疾病,在大多数病人是一个良性自限的病程,称为水肿性胰腺炎。而如果病情恶化,伴发胰腺的坏死,炎症细胞因子的活化,从而导致多器官功能衰竭,则称为坏死性胰腺炎。迄今为止,其详细的发病机理是不清楚的。作为固有免疫重要部分的Toll样受体（TLR）在胰腺炎过程中起重要的作用,但也有人提出异议。     

The role of the innate immune response in autoimmune disease

Autoimmune diseases are the clinical correlate of a dysregulation of the immune system, involving multiple steps and multiple components of both the innate and the adaptive immune system. Innate immune cells are sensitive to a very limited repertoire of foreign "patterns" that bind to selective "pattern recognition receptors". In contrast, adaptive auto-reactive T or B cells bear receptors specific for antigens including "self" antigens and are rendered non-reactive by several "quality control" mechanisms. Under special conditions, activation of cells of the innate immune system can break the state of inactivity of auto-reactive cells of the adaptive immune system, thereby provoking autoimmune disease. Here we review examples to illustrate how innate immune activation influences autoimmune disease and point to the implications for the treatment of human autoimmune disease.     

Leptin as immune mediator: Interaction between neuroendocrine and immune system

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

Rapid and inexpensive real-time PCR for genotyping functional polymorphisms within the Toll-like receptor -2, -4, and -9 genes

The discovery of the human Toll-like receptors (TLRs) and the recognition of their pivotal role in sensing microbial pathogens during the last 5 years have resulted in a renewed appreciation of innate immunity. Due to their central role in both, triggering innate immunity as well as linking innate and adaptive immunity, genetic variations within the TLR genes, known to be associated with a variety of infectious diseases, are currently of great interest. Several single nucleotide polymorphisms (SNPs) within TLR genes have been described and seem to be associated with susceptibility to inflammatory diseases. However, methods for genotyping SNPs within the TLR genes, e.g. direct sequencing or polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis, are time-consuming. In this work, we report novel real-time PCR methods for genotyping five TLR SNPs within TLR-2, TLR-4 and TLR-9 that have been associated with various diseases using fluorescence labeled hybridization probes and the LightCycler instrument. In addition, we provide protocols employing a standard Taq polymerase in order to reduce substantially the costs for real-time PCR.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展。特别是在关于模式识别受体的发现和功能研究方面。模式识别受体能识别病原相关的分子模式。先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活。如果没有先天免疫,后天获得性免疫的功能会变得很微弱。Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体。激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达。所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗。     

Toll样受体在卵巢癌中作用的研究进展

卵巢恶性肿瘤是病死率最高的妇科疾病,严重威胁女性的健康.固有性免疫系统发挥重要免疫防御作用,作用的关键是对病原体的识别,这一识别主要是通过Toll样受体(TLRs)完成的.TLRs是近年免疫学研究的焦点,其不仅通过对病原微生物的病原相关分子模式的识别激活固有性免疫应答,还引起细胞因子的释放,上调共刺激分子的表达,为适应性免疫的启动提供必要的活化信号.因此,TLRs在很多疾病的发生和进展中起重要作用.阐明TLRs和固有免疫在卵巢恶性肿瘤中的作用可能会为研究者提供一个更好地了解这种疾病的分子机制.此外,利用TLRs的激动剂或拮抗剂有希望成为对抗卵巢恶性肿瘤的新的免疫治疗方法.     

TLR2及TLR4在侵袭性肺曲霉病小鼠中的表达

目的 研究Toll样受体(TLR)2和TLR4在侵袭性肺曲霉病小鼠中的表达,探讨TLR2和TLR4在侵袭性肺曲霉病中的作用. 方法 将小鼠分为3组:A组为正常对照组;B组为未免疫抑制但感染烟曲霉菌组;c组为侵袭性肺曲霉病(IPA)模型组,给予免疫抑制并感染烟曲霉菌.在感染后8、24、48和72 h时相点,处死小鼠,取肺组织,采用组织病理学方法观察肺组织的病理损伤,RT-PCR法检测肺组织各个时相点的TLR2、TLR4、TNF.ot和β-tublin的表达.TLR2、TLR4、TNF-α的PCR产物电泳条带的扫描密度值与同时扩增的β-tublin电泳条带的扫描密度值的比值用以表示TLR2、TLR4和TNF-α的相对表达水平. 结果 病理观察结果显示,对照组小鼠的肺组织结构正常;正常小鼠感染烟曲霉菌后,小鼠的肺组织有炎症细胞浸润、出血等炎症反应,但未见孢子萌芽生成菌丝;而IPA模型小鼠的肺组织病理损伤严重,可见炎症细胞浸润、肺泡塌陷伴随出血,孢子聚积并萌芽生成菌丝.8、24、48 h 3个时间点的TLR4和24、48 h两个时相点的TNF-α在IPA模型小鼠肺组织中的表达要低于烟曲霉菌感染的正常小鼠(P<0.05),而TLR2在烟曲霉菌感染的正常小鼠和IPA模型小鼠肺组织中呈现低表达,但24、72 h时相点的TLR2在IPA模型小鼠的表达要低于烟曲霉菌感染的正常小鼠(P<0.05). 结论 TLR4及其下游分子TNF-α在IPA模型小鼠肺组织中低表达,在组织病理镜检中可见肺曲霉病典型肺组织病理损伤和孢子生成菌丝.     

Innate immune signals in atherosclerosis

Atherosclerosis is a chronic disease characterised by lipid retention and inflammation in the arterial intima. Innate immune mechanisms are central to atherogenesis, involving activation of pattern-recognition receptors (PRRs) and induction of inflammatory processes. In a complex tissue, such as the atherosclerotic lesion, innate signals can originate from several sources and promote atherogenesis through ligation of PRRs. The receptors recognise conserved molecular patterns on pathogens and endogenous products of tissue injury and inflammation. Activation of PRRs might affect several aspects of atherosclerosis by acting on lesion resident cells. Scavenger receptors mediate antigen uptake and clearance of lipoproteins, thereby promoting foam cell formation. Signalling receptors, such as Toll-like receptors (TLRs), lead to induction of pro-inflammatory cytokines and antigen-specific immune responses. In this review we describe the innate mechanisms present in the plaque. We focus on TLRs, their cross-talk with other PRRs, and how their signalling cascades influence inflammation within the atherosclerotic lesion.     

Molecular cloning and expression of TLR in the Eisenia andrei earthworm

Toll-like receptors (TLRs) play an important role in defense responses to pathogens in invertebrates. Here we characterize the first TLR isolated from an oligochaete annelid, namely, Eisenia andrei (EaTLR) and show its expression pattern. The full-length EaTLR cDNA consists of 2615 bp encoding a putative protein of 675 amino acids. The predicted amino acid sequence comprises of an extracellular domain containing 31 amino acid signal peptide and seven leucine-rich repeats (LRR), capped with cysteine-rich N- and C-terminal LRRs followed by a transmembrane domain and cytoplasmic Toll/IL-1R domain (TIR). TIR domains of twenty individual earthworms were sequenced and the variability suggesting the presence of a high number of TLR genes in the genome of E. andrei was observed. Phylogenetic analysis revealed the highest similarity of EaTLR with polychaete annelid, Capitella teleta and TLRs of mollusks and echinoderms. Finally, the highest constitutive expression of EaTLR was observed in the digestive tract. Gene expression was significantly increased in coelomocytes of E. andrei after the challenge with Gram-positive bacteria.