Toll样受体9及其与动物疾病的研究进展

Toll样受体(Toll-like receptors,TLRs)是免疫细胞表面的识别受体,参与病原相关分子模式(pathogen-associated molecular patterns,PAMPs)的识别,包括微生物鞭毛、肽聚糖、脂多糖、 CpG基序、单链和双链RNA等.从而诱导机体的防御系统,如屏障、杀菌、吞噬作用以及细胞因子等.TLR9是TLRs家族成员之一,作为细胞表面的天然模式识别受体,其主要参与病原体CpG基序激活免疫细胞的信号转导,引起大量炎性因子的产生,从而在天然抗感染免疫以及联系天然免疫和获得性免疫中发挥重要作用.     

TLR9的结构、功能及信号传导研究进展

Toll样受体 (Toll likereceptors,TLRs)家族通过识别病原体相关分子模式 (pathogenassoci atedmolecularpattern ,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(pattternrecognitionreceptor,PRR)。本文综述了TLR9的结构、功能及信号传导机制。     

Toll样受体在寄生虫感染过程中的作用

Toll样受体（TLR）是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中具有重要的作用。TLR通过识别病原相关模式分子以激活抗感染的天然免疫应答和适应性免疫应答。TLR信号通路可通过诱导炎性因子的产生在适应性免疫应答中发挥重要作用。本文就TLR在寄生虫感染中发挥的作用作一综述。     

Toll样受体9与自身免疫性疾病

Toll样受体9(TLR9)可识别细菌和病毒DNA中未甲基化的胞嘧啶-磷酸-鸟嘌呤(CpG DNA)序列,激活固有免疫应答和适应性免疫应答,促进宿主抵抗感染性疾病.近年的研究显示,TLR9活化在自身免疫性疾病发生发展中起重要作用,干预或操控TLR9介导的免疫反应有望成为治疗自身免疫性疾病的新策略.     

Toll样受体8激动剂在免疫治疗中的研究进展

Toll样受体8(Toll-like receptor 8,TLR8)激动剂是一种小分子免疫应答调节剂,主要包括天然核苷类化合物和人工合成的化合物,可以有效激活天然免疫并引起适应性免疫应答,具有有效的抗感染、抗肿瘤等性能,并在新生儿免疫中起到独特的作用。因此,有潜力作为疫苗佐剂或者独立的免疫治疗。本文就TLR8受体激动剂在各种临床前及临床免疫治疗中的研究进展作一综述,进而为TLR8为靶点的抗感染、自身免疫性疾病、肿瘤等疾病的治疗提供参考。     

调节免疫反应的CpG-ODN

Toll样受体(TLR)最初被认为在识别病原和激活天然免疫中发挥重要作用,现在发现通过活化TLR可以调节天然免疫和适应性免疫反应。在很多研究中,TLR-9的配体CpG-ODN引起了人们广泛的兴趣,其重要原因之一就是CpG-ODN容易人工合成和进行各种修饰以改变其免疫刺激活性。现在CpG-ODN的研究已从基础研究逐步向临床药物开发方向发展。     

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。     

Toll样受体7在抗感染与自身免疫疾病中的作用

Toll样受体7(TLR7)是表达在哺乳动物细胞内涵体膜表面的跨膜信号传导受体,通过识别单链RNA,激活天然免疫系统,同时通过诱导浆细胞样树突状细胞(pDC)分泌Ⅰ型干扰素(IFN-α)来调控获得性免疫反应。TLR7尤其在抗感染与自身免疫方面发挥重要作用。在深入研究TLR7及其信号通路的基础上,以其作为药物干预靶点,对治疗相关感染性疾病、自身免疫性疾病具有重要的科学意义和应用价值。     

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。     

疫苗:肿瘤特异性杀伤(T淋巴)细胞CTLs的有益助手

人体自然免疫系统通过被类浆细胞化树突状细胞 (pD Cs)和B细胞选择性表达的Toll样受体 9(TLR9)来识别在细菌或病毒DNA中的被称为CpG基序的序列 ,并引起适应性免疫应答的发生 ,这些基序因此被研究作为潜在的新的疫苗佐剂。Hartmann及其同事首次注意到CpGDNA能增强人体免疫系统中CD8+ 细胞毒性T淋巴细胞 (CTL)的应答。他们比较了两种不同类型的合成的CpG反义寡聚脱氧核苷酸 (ODN)—CpG A(D型CpGODN)和CpG B(K型CpGODN)的佐剂作用 ,这两型ODN在其侧翼序列上具有差别 ,因此以两种不同多肽来支持CD8+ T细胞的免疫应答。当…     

Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9

Toll-like receptors (TLRs) activate the innate immune system in response to pathogens. Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. Inhibition of lysosomal proteolysis rendered TLR9 inactive. The carboxy-terminal fragment of TLR9 thus generated included a portion of the TLR9 ectodomain, as well as the transmembrane and cytoplasmic domains. This cleavage fragment bound to the TLR9 ligand CpG DNA and, when expressed in Tlr9(-/-) dendritic cells, restored CpG DNA-induced cytokine production. Although cathepsin L generated the requisite TLR9 cleavage products in a cell-free in vitro system, several proteases influenced TLR9 cleavage in intact cells. Lysosomal proteolysis thus contributes to innate immunity by facilitating specific cleavage of TLR9.     

Effects of particle size on toll-like receptor 9-mediated cytokine profiles

Biomaterials interface with toll-like receptor (TLR) 9-mediated innate immunity in a wide range of medical applications, such as tissue implants and drug delivery systems. The stimulation of TLR9 can lead to two different signaling pathways, resulting in the generation of proinflammatory cytokines (i.e. IL-6) and/or type I interferons (IFNs, i.e. IFN-α). These two categories of cytokines differentially influence both innate and adaptive immunity. Although particle size is known to be a critical parameter of biomaterials, its role in TLR9-mediated cytokine profiles is not clear. Here, we examined how the size of biomaterials impacted cytokine profiles by using polystyrene particles of defined sizes as model carriers for TLR9 agonists (CpG oligonucleotides (CpG ODNs)). CpG ODNs bound to nano- to submicro- particles stimulated the production of both IL-6 and IFN-α, while those bound to micro particles resulted in IL-6 secretions only. The differential TLR9-mediated cytokine profiles were attributed to the pH of endosomes that particles trafficked to. The magnitude of IFN-α production was highly sensitive to the change in endosomal pH in comparison to that of IL-6. Our results define two critical design variables, size and the ability to modulate endosomal pH, for the engineering of biomaterials that potentially interface with TLR9-mediated innate immunity. The fine control of these two variables will allow us to fully exploit the beneficial facets of TLR9-mediated innate immunity while minimizing undesirable side effects.     

Recognition of pathogen-associated molecular patterns by TLR family

Toll-like receptors (TLRs) are type I transmembrane proteins involved in innate immunity by recognizing microbial conserved structures. Recent studies have shown that TLR3 recognizes dsRNA, a viral product, whereas TLR9 recognizes unmethylated CpG motifs frequently found in the genome of bacteria and viruses, but not vertebrates. TLR7 recognizes small synthetic immune modifiers including imiquimod, R-848, loxoribine, and bropirimine, all of which are already applied or promising for clinical use against viral infections and cancers. Plasmacytoid dendritic cells express TLR7 and TLR9, and respond to TLR7 and TLR9 ligands by producing a large amount of interferon (IFN-alpha). These results indicate that TLR3, TLR7 and TLR9 may play an important role in detecting and combating viral infections.     

TLR9 in Health and Disease

Toll-like receptor 9 (TLR9) is specialized for the recognition of pathogenic nucleic acids. TLR9 is expressed in intracellular compartments where it responds specifically to pathogen DNA. Several factors contribute to the ability of TLR9 to discriminate between self and foreign DNA. Regulatory mechanisms of the innate and adaptive immune system exist that balance the immune responses mediated by TLR9. Short synthetic CpG oligodeoxynucleotides are used to induce controlled and directed TLR9-dependent stimulation and are effective immune modulators in preclinical and clinical studies. This review will summarize the interplay between TLR9-dependent opposing stimulatory and regulatory effects in innate and adaptive immunity.     

Heat shock up-regulates TLR9 expression in human B cells through activation of ERK and NF-kappaB signal pathways

Toll-like receptors (TLRs) play a critical role in innate immunity and TLR9 is essential for CpG ODN signaling. As "dangerous signal", heat shock may regulate immune response. However, little is known about TLRs expression and signaling after heat shock. In this study, we investigated regulation of TLR9 expression and function in human B cell line RPMI8226 by heat shock. We demonstrated that TLR9 expression was up-regulated remarkably following heat shock. Coincidently, CpG ODN stimulation significantly increased IL-6 production and up-regulated expressions of MHC I, MHC II and CD86 by heat-shocked B cells. Heat shock activated ERK and NF-kappaB signal pathways, and pretreatment of B cells with specific inhibitors of ERK or NF-kappaB signal pathways inhibited heat shock-induced up-regulation of TLR9 expression. These results demonstrated that heat shock promotes TLR9 expression and signaling through activation of ERK and NF-kappaB signal pathways in B cells, suggesting that heat shock might modulate host immune response by regulating TLR expression.     

TLR9 in health and disease

Toll-like receptor 9 (TLR9) is specialized for the recognition of pathogenic nucleic acids. TLR9 is expressed in intracellular compartments where it responds specifically to pathogen DNA. Several factors contribute to the ability of TLR9 to discriminate between self and foreign DNA. Regulatory mechanisms of the innate and adaptive immune system exist that balance the immune responses mediated by TLR9. Short synthetic CpG oligodeoxynucleotides are used to induce controlled and directed TLR9-dependent stimulation and are effective immune modulators in preclinical and clinical studies. This review will summarize the interplay between TLR9-dependent opposing stimulatory and regulatory effects in innate and adaptive immunity.     

Toll-like receptor agonists induce apoptosis in mouse B-cell lymphoma cells by altering NF-κB activation

Toll-like receptor 9 (TLR9) recognizes microbial DNA containing unmethylated cytosyl guanosyl (CpG) sequences, induces innate immune responses, and facilitates antigen-specific adaptive immunity. Recent studies report that in addition to stimulating innate immunity, TLR9 ligands induce apoptosis of TLR9 expressing cancer cells. To understand the mechanism of TLR9-induced apoptosis, we compared the effects of CpG containing oligodeoxynucleotides (CpG ODN) on a mouse B-cell lymphoma line, CH27, with those on mouse splenic B cells. CpG ODN inhibited constitutive proliferation and induced apoptosis in the CH27 B-cell lymphoma line. In contrast, CpG ODN-treated primary B cells were stimulated to proliferate and were rescued from spontaneous apoptosis. The induction of apoptosis required the ODNs to contain the CpG motif and the expression of TLR9 in lymphoma B cells. A decrease in Bcl-xl expression and an increase in Fas and Fas ligand expression accompanied lymphoma B-cell apoptosis. Treatment with the Fas ligand-neutralizing antibody inhibited CpG ODN-induced apoptosis. CpG ODN triggered a transient NF-κB activation in the B-cell lymphoma cell line, which constitutively expresses a high level of c-Myc, while CpG ODN induced sustained increases in NF-κB activation and c-Myc expression in primary B cells. Furthermore, an NF-κB inhibitor inhibited the proliferation of the CH27 B-cell lymphoma line. Our data suggest that the differential responses of lymphoma and primary B cells to CpG ODN are the result of differences in NF-κB activation. The impaired NF-κB activation in the CpG ODN-treated B-cell lymphoma cell line alters the balance between NF-κB and c-Myc, which induces Fas/Fas ligand-dependent apoptosis.     

Immunotherapeutic potential of CpG oligodeoxynucleotides in veterinary species

Abstract

Innate immunity plays a critical role in host defense against infectious diseases by discriminating between self and infectious non-self. The recognition of infectious non-self involves germ-line encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). The PAMPs are the components of pathogenic microbes which include not only the cell wall constituents but also the unmethylated 2′-deoxy-ribo-cytosine-phosphate-guanosine (CpG) motifs. These CpG motifs present within bacterial and viral DNA are recognized by toll-like receptor 9 (TLR9), and signaling by this receptor triggers a proinflammatory cytokine response which, in turn, influences both innate and adaptive immune responses. The activation of TLR9 with synthetic CpG oligodeoxynucleotides (ODNs) induces powerful Th1-like immune responses. It has been shown to provide protection against infectious diseases, allergy and cancer in laboratory animal models and some domestic animal species. With better understanding of the basic biology and immune mechanisms, it would be possible to exploit the potential of CpG motifs for animal welfare. The research developments in the area of CpG and TLR9 and the potential applications in animal health have been reviewed in this article.