Toll样受体信号传导在关节炎发病中的作用

最近的研究证据显示：Toll样受体（TLR）是固有免疫的关键性识别结构。TLR的活化启动了炎症性细胞因子、趋化因子、组织破坏性酶和Ⅰ型干扰素的产生;同时,TLR的信号传导可以通过上调抗原递呈细胞的共刺激分子在适应性免疫系统的活化和发展中扮演重要作用。鉴于TLR信号传导在连接固有免疫和适应免疫中具有重要作用,可以推测TLR信号传导的失调可能与自身免疫性疾病的发生有关。本文将就由对应配体激活的TLR信号转导通路进行一些总结,最后讨论TLR传导通路在类风湿性关节炎致病机制中的作用。     

Toll样受体7激动剂在肝脏疾病中的研究

Toll样受体7(TLR7)是参与固有免疫的一类重要蛋白分子,也是连接固有免疫与适应性免疫的桥梁。TLR7被激活后可通过不同信号通路对肝脏疾病产生作用。近年TLR7激动剂在肝脏疾病中的研究和应用不断增多。本文就TLR7激动剂在不同肝脏疾病中的研究进展作一综述。     

Toll样受体4在幽门螺旋杆菌感染致动脉粥样硬化中的作用

动脉粥样硬化(As)是一种慢性炎症反应性疾病,幽门螺旋杆菌(Hp)感染与As性疾病的相关性研究日益引起关注,其促进As进展的具体机制尚未完全阐明。Toll样受体4(TLR4)是天然免疫反应的重要受体,在微生物致病因子及其产物引起宿主主动和被动免疫中有重要作用,参与动脉硬化的发生和发展。TLR4在As形成的多种细胞均有表达。TLR4通过捕获Hp的致病因子脂多糖后启动细胞内信号途径,进而引起核因子κB依赖的转录,引起一系列细胞因子及化学因子的释放,增强炎症反应而致病。本文就Hp、TLR4信号通路及其在As中的作用作一综述,为As疾病的防治提供新思路。     

Toll样受体9的功能及其致病机制

Toll样受体9(TLR9)是Toll样模式识别受体家族成员之一,表达于免疫细胞,通过与细菌DNA作用而诱导机体的固有免疫反应。近年来的研究发现,TLR9也表达于其他几种非免疫细胞,包括肾小球足细胞,并以线粒体DNA为配体,激活细胞的损伤信号通路,从而参与细胞损伤。本文就TLR9在免疫和非免疫细胞中的作用及其机制作一综述。     

Toll样受体2与缺血性脑白质损害

Toll样受体2(Toll-like receptor 2,TLR2)是Toll样受体家族中表达范围最广的受体,也是固有免疫系统对病原微生物的重要模式识别受体.另外,TLR2还可识别内源性危险信号,参与缺血性损伤等非病原微生物性炎性反应.有关TLR2及其信号转导在缺血性脑白质损害中的作用日益受到关注,文章对TLR2与缺血性脑白质病变的关系进行了综述.     

Toll样受体4与脓毒症性急性肾损伤

脓毒症性急性肾损伤(AKI)发病机制复杂且缺乏有效的药物治疗.Toll样受体4(TLR4)是固有免疫系统中的病原模式识别受体之一,通过识别并结合革兰阴性杆菌细胞壁成分脂多糖,激活信号转导通路.TLR4信号通路激活后释放多种炎症介质如肿瘤坏死因子α、白细胞介素(IL-1)、IL-6介导脓毒症性AKI发生.因此,TLR4信号通路可成为脓毒症性AKI治疗的新靶点;目前TLR4信号通路阻断剂已问世并进入Ⅲ期临床研究阶段,以期为脓毒症性急性肾损伤患者的救治提供全新的思路.     

TLR4及IL-35在肺炎支原体肺炎发病机制中的研究进展

肺炎支原体在社区获得性肺炎中的占比逐年增高,其致病机制复杂,但目前多认为与免疫炎症损伤相关。研究表明Toll样受体4(TLR4)通过TLR4-MyD88-NF-κB信号通路及自噬通路诱导炎症反应,白细胞介素35(IL-35)被证实也参与肺炎支原体肺炎的致病,且与TLR4有着密切的关系。本文就TLR4、IL-35在肺炎支...     

Toll样受体7在抗感染免疫中的作用

Toll样受体7 (Toll-like receptor 7, TLR7)是一种模式识别受体,细胞静息状态下主要定位于浆细胞样树突状细胞、巨噬细胞、 T淋巴细胞、中性粒细胞等免疫细胞,以及上皮细胞、内皮细胞、角质形成细胞等非免疫细胞的内质网上。病原体感染时,TLR7从内质网转移到效应细胞的内体膜上。TLR7可直接识别单链RNA或核酸类似物等配体,与特异性招募蛋白结合并激活核因子-κB、丝裂原活化蛋白激酶和干扰素等调控因子,从而启动固有免疫应答和适应性免疫应答,参与抗感染免疫。本文就TLR7及其配体的结构与功能、 TLR7在抗感染免疫中的作用及其相关信号通路等进行综述,以期为TLR7在抗感染免疫中的作用机制研究提供科学依据。     

Toll样受体7/8与肾脏疾病

Toll样受体(TLR)是机体固有免疫系统中非常重要的模式识别受体之一,同时也是肾脏器官区域免疫调控网络中的关键节点分子,TLR的异常激活可导致多种肾脏疾病.其中,TLR7/8在免疫调控及其肾脏疾病发生发展中的作用备受关注.本文将重点阐述TLR7/8在肾脏疾病研究领域的进展,为进一步阐明区域免疫在肾脏疾病发病中的分子机...     

Toll样受体3与自身免疫性内分泌疾病

Toll样受体(TLR)3可识别病毒dsRNA或其人工合成类似物聚肌苷酸聚胞苷酸[Poly(I:C)]和宿主来源的mRNA,通过髓样细胞分化因子(MyD)88依赖型和MyD88非依赖型两种信号通路,激活固有免疫,并为激活适应性免疫提供共刺激信号.TLR3在自身免疫性疾病尤其是在1型糖尿病和自身免疫性甲状腺疾病的发生、发展中起重要作用,该作用主要是通过Ⅰ型干扰素(IFN)介导实现的.     

Innate immunity to mycobacterial infection in mice: critical role for toll-like receptors

Toll-like receptors (TLRs) play a critical role in the recognition of several pathogens, including Mycobacterium tuberculosis. Mycobacterial antigens recognize distinct TLRs resulting in rapid activation of cells of the innate immune system. Ablation of most of the TLR signalling as in mice deficient for the common adaptor protein MyD88 reveals that TLR is crucial for the activation of an innate immune response. MyD88-deficient mice are unable to clear virulent mycobacteria and succumb to acute necrotic pneumonia. Despite the profound defect of the innate immune response, MyD88 deficiency allows the emergence of an adaptive immunity. These data demonstrate that activation of multiple TLRs contributes to an efficient innate response to mycobacteria, while MyD88-dependent signalling is dispensable to generate adaptive immunity.     

Platelet toll-like receptors are crucial sensors of infectious danger moieties

In addition to their haemostatic role and function in the repair of damaged vascular epithelium, platelets play a defensive role in innate immunity, having the capacity to produce and secrete various anti-infectious factors, as well as cytokines, chemokines and related products, to interact with other immune cells to modulate immune responses to pathogens. Thus, it is now widely acknowledged that platelets participate in inflammatory processes and infection resolution, most notably by expressing and using receptors to bind infectious pathogen moieties and contributing to pathogen clearance. The ability of platelets to sense external danger signals relates to the expression of certain innate immunity receptors, such as toll-like receptors (TLRs), and the activation of efficient cell signalling machinery. TLR engagement triggers platelet response, which results in adapted degranulation according to: the type of TLR engaged, the nature of the ligand and the milieu; together, the TLR-mediated event and other signalling events may be followed by aggregation. Platelets thus use complex tools to mediate a whole range of functions upon sensing danger. By linking the inflammatory and haemostatic platelet response to infection, TLRs play a central role. The extent of the inflammatory response to pathogen clearance is still a debatable issue and is discussed in this short review.     

Immunité innée et allergie : les cellules dendritiques

The innate immune system provides a quick response to infection, notably by using sensor receptors such as Toll-like receptors (TLR), but it also informs and directs the adaptive immune response through dendritic cells (DC). In the allergic reaction, DC play a fundamental role by transporting allergen to lymph nodes and by inducing allergen-specific T cell responses. The polarized Th2 response induced in allergic patients by DC can be modified by the participation of certain TLR, thereby inhibiting the development of the allergic reaction. Therapeutic approaches using allergens combined with TLR ligands are being evaluated to increase the efficacy of specific immunotherapy.     

Characterization of the innate immune signalling pathways in hepatocyte cell lines

Hepatitis B virus (HBV) infection is a major cause of liver-related morbidity and mortality. Toll-like receptors (TLRs) have recently been recognized to play an important role in the pathogenesis of chronic hepatitis B (CH-B). Furthermore, manipulation of TLR signalling pathways shows potential as an antiviral therapeutic strategy. Whether hepatocytes themselves possess intact TLR signalling pathways remains controversial. It is critical that cell culture models be developed to allow investigation of the interaction between HBV and the TLR signalling pathways. We have screened three hepatocyte cell lines for the integrity of pro-inflammatory responses and antiviral cytokines following stimulation with interleukin-1 (IL-1) and different TLR ligands. We observed that Huh-7, HepG2 and PH5CH8 cells selectively responded to IL-1 and TLR2 ligands, leading to the activation of NF-kappaB. In addition, the PH5CH8 cell lines were able to induce type 1 interferon (IFN) via both TLR3 and RIG-I following stimulation with poly I:C, HepG2 cells mounted an IFN response via RIG-I only, whereas Huh-7 cells were unresponsive. We conclude that the hepatocyte cell lines investigated display a repertoire of TLR signalling, albeit limited, suggesting that hepatocytes may themselves play an active role in innate immune responses to viruses such as HBV. Furthermore, particular hepatoma cell lines are suitable for investigating the interaction between HBV and hepatocyte-expressed pattern recognition receptors.     

Role of Toll-like receptors in Helicobacter pylori infection and immunity

The gram-negative bacterium Helicobacter pylori(H. pylori) infects the stomachs of approximately half of the world's population. Although infection induces an immune response that contributes to chronic gastric inflammation, the response is not sufficient to eliminate the bacterium. H. pylori infection causes peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma. Disease outcome is linked to the severity of the host inflammatory response. Gastric epithelial cells represent the first line of innate immune defence against H. pylori, and respond to infection by initiating numerous cell signalling cascades, resulting in cytokine induction and the subsequent recruitment of inflamma-tory cells to the gastric mucosa. Pathogen recognition receptors of the toll-like receptor(TLR) family mediate many of these cell signalling events. This review dis-cusses recent findings on the role of various TLRs in the recognition of H. pylori in distinct cell types, describes the TLRs responsible for the recognition of individual H. pylori components and outlines the influence of innate immune activation on the subsequent development of the adaptive immune response. The mechanistic iden-tification of host mediators of H. pylori-induced patho-genesis has the potential to reveal drug targets and opportunities for therapeutic intervention or prevention of H. pylori-associated disease by means of vaccines or immunomodulatory therapy.     

Toll样受体与支气管哮喘

Toll样受体(Toll-like receptors,TLR)是近年发现的一组天然受体,其不仅依赖胚系基因编码的保守序列识别病原微生物和激活天然免疫,而且调节获得性免疫和诱导免疫耐受,与支气管哮喘密切相关.其宿主通过TLR识别大量病原体相关结构,利用细胞信号转导途径激活机体免疫细胞,一方面参与早期的宿主防御,在天然免疫应答中发挥重要作用;另一方面通过分泌细胞因子、趋化因子、黏附分子等参与炎症反应,最终激活获得性免疫系统.本文就近年来有关TLR的结构功能、信号通路及TLR与支气管哮喘关系作一综述.     

Toll样受体4与动脉粥样硬化

动脉粥样硬化是一种慢性炎症疾病。Toll样受体家族(TLRs)识别抗原相关的分子模式(PAMPs)后激发先天性免疫反应。TLR4不仅识别外源性配体脂多糖(LPS),也识别动脉损伤过程中表达的内源性配体。越来越多的研究表明TLR4可能在动脉粥样硬化病变的发生和发展过程中发挥主要作用。现对近年有关TLR4在动脉粥样硬化中的作用的研究进展作一综述。此外,还将讨论对TLR4信号的可能干预措施。     

Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria

Toll-like receptors (TLRs) are key components of the immune system that detect microbial infection and trigger antimicrobial host defense responses. TLR5 is a sensor for monomeric flagellin, which is a component of bacterial flagella known to be a virulence factor. In this study we generated TLR5-deficient mice and investigated the role of TLR5 signaling in the detection of flagellin and antibacterial immune responses to Salmonella typhimurium and Pseudomonas aeruginosa. We found that TLR5 is essential for the recognition of bacterial flagellin both in vivo and ex vivo. TLR5 contribution to antibacterial host response to i.p. infection with S. typhimurium or intranasal administration of P. aeruginosa may be masked by TLR4 or other sensing mechanisms. By using radiation bone marrow chimera, we showed that upon i.p. injection of flagellin immune responses are mediated by lymphoid cells, whereas resident cells are required for the initiation of response upon intranasal flagellin administration. These results suggest that flagellin recognition in different organs is mediated by distinct TLR5-expressing cells and provide insights into the cooperation of the TLR5 and TLR4 signaling pathways used by the innate immune system in the recognition of bacterial pathogens.     

Mechanisms of disease: Toll-like receptors in cardiovascular disease

The innate immune system detects highly conserved, relatively invariant structural motifs of pathogens. Toll-like receptors (TLRs) have been identified as the primary innate immune receptors. TLRs distinguish between different patterns of pathogens and activate a rapid innate immune response; however, TLRs can also be activated by host-derived molecules. In addition to being expressed in immune cells, TLRs are expressed in other tissues, such as those of the cardiovascular system. TLRs could, therefore, be a key link between cardiovascular disease development and the immune system. Indeed, evidence that TLR activation contributes to the development and progression of atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure, is convincing. Although much has been learned about TLR activation in cellular components of the cardiovascular system, the role individual TLR family members have in the pathophysiology of cardiovascular diseases and hence in clinical practice remains to be defined. Here we review the rapid progress that has been made in this field, which has improved our understanding of vascular as well as myocardial TLR function in basic and clinical science.     

Disparate innate immune responses to persistent and acute Chlamydia pneumoniae infection in chronic obstructive pulmonary disease

RATIONALE: Chlamydia pneumoniae (Cpn) infection may play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Few data are available comparing persistent and acute infection of this pathogen in the human respiratory tract. OBJECTIVES: To study Cpn-induced innate immune responses in lung tissue from patients with COPD and control subjects ex vivo and in vitro. METHODS: Cpn detection was done by nested polymerase chain reaction, in situ hybridization, and immunohistochemistry ex vivo in unstimulated tissue and in vitro using an acute Cpn infection model. As main endpoints for the assessment of early cellular responses, nuclear factor (NF)-kappaB activation and CXC chemokine ligand (CXCL)-8 expression were evaluated. The role of Toll-like receptors (TLRs) as recognition molecules in Cpn-induced innate responses was tested by blocking experiments. MEASUREMENTS AND MAIN RESULTS: Fifteen percent of patients with COPD were chronically infected with Cpn in contrast to 0% of control subjects (p < 0.05). There were no differences in CXCL-8 and NF-kappaB expression between infected and noninfected COPD tissue ex vivo. In contrast, acute in vitro infection induced an intense innate immune response including up-regulation of TLR2. Blocking experiments demonstrated the predominant role of TLR2 in induction of the early immune response, whereas no influence on chlamydial infection rates was observed. CONCLUSIONS: Acute in vitro infection of human lung tissue with Cpn elicited a marked innate response via TLR2, whereas chronic chlamydial infection in patients with COPD was not associated with enhanced cellular activation. These findings suggest different roles of Cpn during acute and chronic stages of pulmonary infection.