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.     

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.     

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.     

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.     

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。     

髓样细胞表达的触发受体-1与炎症信号转导的研究进展

研究表明髓样细胞表达的触发受体-1(TREM-1)参与了炎性反应的级联放大过程.细菌的某些成分可以上调细胞表面TREM-1的表达,并且能和TREM-1配体协同激活TREM-1受体向下游传递信号.TREM-1被激活后会诱导前炎性因子的产生并引起相关的炎症反应.由于TREM-1是明显放大内毒素脂多糖(LPS)所引起的炎性反应的关键介质,因此对于TREM-1激活炎症信号通路的研究取得了一定的进展.然而,TREM-1在协同Toll样受体激活炎性反应的信号通路的具体机制尚未完全明晰.专注于TREM-1的信号转导,阐明与此通路相关的信号分子,如TLR、DAP-12、MAPKs、NTAL、CARD9、NLRs的作用,为进一步揭示脓毒症的发病机制并寻找新的治疗靶点.     

Toll-like Receptors and Cancer

先天免疫是机体抗细菌、抗病毒和抗肿瘤等的第一防线.Toll样受体(Toll-like recep-tors)是先天免疫的关键受体.它可以识别致病微生物的分子模式(pathogen associated moleculal pat-terns)而激活先天免疫细胞和进一步调整后天免疫系统.近来发现的Toll样受体在癌症的发生和发展中也扮演着重要角色.Toll样受体的激活因子在抗癌免疫疗法中可用作免疫调节剂(immunoadju-vants)或细胞毒素的药物.在这里,我们将简述当前关于Toll样受体的研究进展和在癌症的发生发展和癌症免疫疗法的作用.     

脂多糖通过TLR4对幼年哮喘大鼠气道炎症的调节作用

以前的研究表明，TH2细胞的优势应答是导致嗜酸性粒细胞性哮喘发生发展的主要免疫学基础。近年研究发现，Toll样受体（TLR）信号通路激活诱导TH1免疫应答的作用可用来防治有害的TH2优势应答，如哮喘病的发生发展。然而在免疫激活的初始阶段TLR4刺激物脂多糖（LPS）的不同构型、不同浓度以及不同作用时间会影响适应性免疫应答的极化方向，目前对LPS在哮喘的气道炎症发生发展中的作用仍有争论。     

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样受体在皮肤中的表达和功能

Toll样受体在皮肤角质形成细胞、树突状细胞、成纤维细胞和肥大细胞中都有表达,但表达的种类有明显区别.不同细胞的同一Toll受体激活后引起的反应亦有所不同.Toll样受体与其相应的配体结合可以诱导细胞产生多种炎症因子和抗菌肽,在皮肤介导的固有免疫和炎症反应中有重要作用.     

The role of Toll-like receptors and related receptors of the innate immune system in asthma

PURPOSE OF REVIEW: The biology of the innate immunity receptors is of central importance in the host response to the environment. Identifying genetic variants that alter the innate immune response is highly relevant to understanding asthma pathogenesis. This review summarizes recent studies of the role of innate immunity receptors, including Toll-like receptors and CD14, in the pathogenesis of asthma. RECENT FINDINGS: The majority of studies published since 2004 have been genetic association studies in various clinical settings, which have found positive associations of single nucleotide polymorphisms in TLR2, TLR4, TLR6 and TLR10 with asthma or atopy, although the number of studies is small and the results not yet replicated. The designs for CD14 genetic studies have been more sophisticated and have included gene-environment interaction. The results of CD14 gene associations with asthma and atopy are suggestive but have not been fully replicated. Potential reasons for non-replication of TLR and CD14 association studies include insufficient power, type I error, population heterogeneity and different phenotypes studied. In addition, there may be differences in CD14 genetic effects between childhood and adulthood, and between levels of endotoxin exposure. SUMMARY: The evidence is still being accumulated for the role of Toll-like receptor polymorphisms in the pathogenesis of asthma. There is emerging evidence for the role of CD14 polymorphisms in the development of asthma and atopy. Further studies of innate immunity in asthma and allergy are required, using rigorous study design, measurement of environmental exposure and intermediate phenotypes to demonstrate single nucleotide polymorphism functionality.     

Differential expression of toll-like receptor 2 on dendritic cells from asymptomatic and symptomatic atopic donors

Background: Early microbial exposure may reduce the risk for developing allergies on an atopic genetic background. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns of microbes and modulate innate and adaptive immunity. Different expression of TLRs in symptomatic and asymptomatic atopic donors may contribute to the development of allergic disease. Methods: Monocytes and monocyte-derived dendritic cells (DCs) from symptomatic (n = 12) and asymptomatic atopic donors (n = 11), healthy nonatopics (n = 14) and from patients with psoriasis (n = 13) were analyzed for their expression of TLR2, TLR4 and TLR9 by real-time PCR. Results: Monocytes did not show any differences in TLR2, TLR4 and TLR9 expression between the 4 groups. In contrast, DCs from asymptomatic donors showed an enhanced expression of TLR2 over DCs from nonatopics (p = 0.038) and just failed to reach significance when compared to symptomatic atopic patients (p = 0.060). TLR2 expression kinetics from monocytes to monocyte-derived DCs showed sustained expression of TLR2 in DCs only from asymptomatic donors but downregulation in the other groups. In DCs from symptomatic atopic donors, the expression of TLR2 correlated significantly with total IgE values in the serum (p = 0.01994). Conclusion: Differential expression and functional regulation of TLR2 expression by DCs from symptomatic and asymptomatic atopic donors may be important for the manifestation of allergic disease. Increased and sustained TLR2 expression on DCs, possibly as a result of an increased exposure to microorganisms or as a mechanism enhancing the sensitivity of microbe detection, may be of functional importance for the maintenance of clinical unresponsiveness toward allergens.     

Genetic variation in Toll-like receptors and disease susceptibility

Toll-like receptors (TLRs) are key initiators of the innate immune response and promote adaptive immunity. Much has been learned about the role of TLRs in human immunity from studies linking TLR genetic variation with disease. First, monogenic disorders associated with complete deficiency in certain TLR pathways, such as MyD88-IRAK4 or TLR3-Unc93b-TRIF-TRAF3, have demonstrated the specific roles of these pathways in host defense against pyogenic bacteria and herpesviruses, respectively. Second, common polymorphisms in genes encoding several TLRs and associated genes have been associated with both infectious and autoimmune diseases. The study of genetic variation in TLRs in various populations combined with information on infection has demonstrated complex interaction between genetic variation in TLRs and environmental factors. This interaction explains the differences in the effect of TLR polymorphisms on susceptibility to infection and autoimmune disease in various populations.     

Toll-like receptor 2 as a major gene for asthma in children of European farmers

BACKGROUND: The finding that the prevalence of asthma and allergies is less frequent in children raised on animal farms has led to the conjecture that exposure to microbial products modifies immune responses. The toll-like receptors (TLRs) represent an evolutionarily conserved family of innate immunity receptors with microbial molecules as ligands. OBJECTIVES: We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations. METHODS: Farmers' and nonfarmers' children living in rural areas in Austria and Germany and who were enrolled in the cross-sectional ALEX study were genotyped for single nucleotide polymorphisms in the TLR2 and TLR4 genes. The frequencies of asthma, allergic rhinitis, and atopic sensitization were compared between the genotypes in relation to exposure to farming and endotoxin. RESULTS: Among farmers' children, those carrying a T allele in TLR2/-16934 compared with children with genotype AA were significantly less likely to have a diagnosis of asthma (3% vs 13%, P = .012), current asthma symptoms (3% vs 16%, P = .004), atopic sensitization (14% vs 27%, P = .023), and current hay fever symptoms (3% vs 14%, P = .01). The association between TLR2/-16934 and asthma among children of farmers was independent of atopy. No such association was found among children from the same rural communities but not living on farms. CONCLUSION: Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.     

CpG Oligodeoxynucleotides as TLR9 Agonists

Unmethylated cytosine-phosphate-guanine (CpG) dinucleotides in microbial DNA sequences activate Toll-like receptor (TLR) 9, and previous studies have shown that oligodeoxynucleotides (ODNs) containing CpG in specific base sequence motifs (CpG ODNs) can reiterate the majority of the immunomodulatory effects produced by bacterial DNA. Many of the manifestations in allergic diseases are primarily due to T helper (T_h)-2 cell-type responses. CpG ODNs can induce T_h1 and T-regulatory (T_reg) cell-type cytokines that can suppress the T_h2 response. The therapeutic application of TLR9 has been explored extensively in recent years, and many studies are being conducted to assess the safety and efficacy of TLR9 agonists in various diseases, including atopic and infectious diseases, and cancer. Studies in murine models have shown that the development of atopic airway disease can be prevented by treatment with CpG ODNs. Various clinical trials are currently ongoing to determine the efficacy of CpG ODNs as a therapeutic tool for atopic diseases. In this review, we discuss the therapeutic application of CpG ODNs in allergy and asthma. CpG ODNs may be used alone or as an adjuvant to immunotherapy to treat these disorders.     

Host defense genes in asthma and sepsis and the role of the environment

PURPOSE OF REVIEW: There is growing evidence that innate immunity genes contribute to asthma pathogenesis. At the core of the innate immune response are ubiquitous, soluble fragments of bacterial lipopolysaccharide or endotoxin, and chronic exposure to domestic endotoxin has been shown to influence asthma severity. Asthmatic and atopic individuals are more sensitive to endotoxin than nonallergic individuals, suggesting a role for genetics in the innate immunity response, and the potential for gene-environment interactions. Variants in genes associated with classic innate immunity-related disorders, such as sepsis, may be unique candidates for asthma susceptibility. RECENT FINDINGS: Candidate genes for asthma and allergic diseases co-associated with sepsis including innate immunity receptors and related molecules (CD14, TLR4 and AOAH) and novel genes such as MYLK provide good examples of pleitropic effects of innate immunity genes, where variants conferring risk to specific traits (i.e. sepsis) under one set of genetic and environmental circumstances confer a reduced risk in a different (but possibly related) clinical outcome (i.e. allergic asthma), and support the 'common variant/multiple disease' hypothesis. SUMMARY: Collectively, these observations suggest a greater role for the innate immunity response in allergic asthma than previously assumed, and implicate host defense genes in disease pathology.     

Putative association of a TLR9 promoter polymorphism with atopic eczema

BACKGROUND: Toll-like receptors (TLR) play a pivotal role in the induction of first-line defense mechanisms of the innate immune system and trigger adaptive immune responses to microbial pathogens. Genetic variations in innate immunity genes have been reported to be associated with a range of inflammatory disorders. Deficiencies on the level of immunity receptors such as pathogen-recognition receptors are suspected to affect the maturation of our immune system and to avail thereby the high prevalence of atopic diseases and susceptibility of atopic patients to microbial infections. AIMS OF THE STUDY: We evaluated TLR9 as susceptibility gene for atopic eczema (AE). METHODS: Analyses of four tag single-nucleotide polymorphisms in two panels of families containing a total of 483 parent-affected offspring trios as well as a cohort of 274 unrelated adult AE cases and 252 hypernormal population-based controls have been performed. RESULTS: In both family cohorts, polymorphism C-1237T, which is located within the promoter region of the TLR9 gene, was significantly associated with AE, in particular the intrinsic subtype of AE. No associations were seen in the case-control cohort. Luciferase reporter gene assays revealed significantly higher promoter activity of the TT allelic variant at this single nucleotide polymorphism site. CONCLUSION: These observations suggest that the TLR9 promoter polymorphism C-1237T might affect AE susceptibility in particular in patients with the intrinsic variant of AE.