Toll样受体及其基因多态性与胃黏膜疾病相关性的研究进展

胃黏膜疾病的发生、发展是一个复杂的多因素、多机制过程,不同个体对胃黏膜疾病的遗传易感性有一定差异。众多研究发现Toll样受体(TLRs)作为一类重要的模式识别受体,与多种胃黏膜疾病的发生、发展有着密切的联系。TLRs基因多态性可使其编码蛋白或相关信号转导途径发生改变,使个体对某些胃黏膜疾病呈现出不同的易感性,从而影响疾病的发生、发展和临床结局。本文就TLRs及其基因多态性与胃黏膜疾病的相关性作一综述。     

TLR4基因Asp299Gly及TLR2基因Arg753Glu、Arg677Trp多态性与中国湖北汉族炎症性肠病无相关性

目的:研究TLR4基因Asp299Gly及LTLR2基因 Arg753Glu及Arg677Trp多态性在中国汉族人群中的分布,探讨其与炎症性肠病的相关性．方法:采用聚合酶链反应-限制性片段长度多态性方法,检测120例中国湖北汉族炎症性肠病患者与110例正常对照者TLR4 基因ASp299Gly及TLR2基因Arg753Glu及 Arg677Trp基因型,分析该基因多态性与炎症性肠病以及临床亚型的相关性．结果:炎症性肠病患者和健康对照者均未检测出TLR4基因ASp299Gly及TLR2基因 Arg753Glu及Arg677Trp突变型．结论:TLR4基因Asp299Gly及TLR2基因 Arg753Glu及Arg677Trp基因多态性与中国湖北汉族人群炎症性肠病的易感性无相关性．     

TLR2、TLR4和NOD2/CARD15基因多态性与溃疡性结肠炎相关性的meta分析

背景:近年我国溃疡性结肠炎(UC)的患病率明显增高,Toll样受体2(TLR2)、TLR4和NOD2/CARD15基因多态性与UC的发生、发展可能密切相关。目的:探讨TLR2、TLR4和NOD2/CARD15基因多态性对UC发生的影响。方法:计算机检索Pub Med、中国生物医学文献、中国知网、万方数据库、重庆维普等数据库中所有TLR2、TLR4和NOD2/CARD15基因多态性与UC相关性的研究。按照纳入与排除标准筛选文献、评价质量并提取数据,采用Rev Man 5.3软件进行meta分析。结果:共纳入15项研究。Meta分析结果显示,TLR2 Arg753Gln基因多态性与UC发生风险无关(P 0.05)。除隐性模型外,TLR4 Asp299Gly基因多态性可显著增加UC的发生风险(P 0.05),TLR4 Thr399Ile基因超显性模型可导致UC风险增加(P 0.05),但显性模型和隐性模型与UC无关(P 0.05)。NOD2/CARD15(Arg702Trp、Gly908Arg、Leu1007fsins C)基因多态性均与UC无关(P 0.05)。结论:NOD2/CARD15(Arg702Trp、Gly908Arg、Leu1007fsins C)、TLR2(Arg753Gln)与UC发生风险无关,TLR4(Asp299Gly、Thr399Ile)可增加UC的发生风险。     

Toll样受体4和慢性炎症相关的代谢性疾病

Toll样受体(TLRs)家族是固有免疫中特异的Ⅰ型跨膜受体及病原模式识别受体(PRRs),通过与病原体相关分子模式(PAMPs)及内源性配体结合,激活信号转导通路,进而激发免疫反应.Toll样受体4(TLR4)是最早被发现的哺乳动物TLRs,近几年的研究表明,TLR4和慢性炎症及相关疾病关系密切.以下就TLR4与肥胖、2型糖尿病及动脉粥样硬化的关系做一综述.     

Toll样受体和内分泌代谢性疾病

经典的内分泌腺通过神经系统、激素、细胞因子、生长因子与其他器官进行广泛的联系.Toll样受体(TLRs)在多种内分泌细胞和免疫细胞中表达,其研究日益受到关注.TLRs的持续高度激活可导致相应内分泌代谢性疾病的发生,其中TLR-2和TLR4的缺陷导致小鼠在类似全身炎性反应综合征(SIRS)条件下,发生肾上腺皮质应激应答功能障碍;TLR-3在甲状腺疾病的发病机制中发挥特殊作用.TLRs信号途径的激活伴有特定细胞因子和趋化因子的上调,可导致内分泌腺肿瘤的发生;而在胰岛中表达的TLRs增加了胰岛对病毒感染的易感性.     

微小隐孢子虫IId亚型早期感染对HCT-8细胞TLRs的影响

目的 研究微小隐孢子虫IId亚型(中国流行株)感染对HCT-8细胞TLRs的影响。方法 微小隐孢子虫IId亚型感染HCT-8细胞4 h及12 h后,提取细胞RNA,利用qRT-PCR方法检测TLRs的表达水平,并通过生物信息学分析表达差异显著的miRNAs与TLRs的关系。结果 HCT-8细胞表达TLR1-TLR10 10种TLRs,并且微小隐孢子虫IId亚型早期感染(4 h和12 h)导致TLR2和TLR4表达量较对照组上调有统计学意义,其它8种TLRs较对照组表达变化无统计学意义。生物信息学分析表明TLR2和TLR4 并不是表达差异显著的miRNAs靶基因,但这些表达差异显著的miRNAs可以靶向27个TLRs信号通路基因。结论 TLR2和TLR4在微小隐孢子虫IId亚型感染HCT-8细胞中可能发挥着一定的作用,差异表达miRNAs的预测靶向中有TLR信号通路相关基因。     

瘦素受体基因Gln223Arg多态性与非酒精性脂肪性肝病的关系

目的 探讨瘦素受体基因多态性与非酒精性脂肪肝患者临床表型间的关系.方法 以非酒精性脂肪肝患者和正常对照人群为研究对象,应用聚合酶链反应及限制性片段长度多态性方法(PCR-RFLP),对167例中国人(包括85例非酒精性脂肪肝患者和82例正常对照)的瘦素受体基因Gln223Arg进行研究,同时进行临床参数的检测.结果 (1)非酒精性脂肪肝患者和正常对照组人群中Gln223Arg基因型频率和等位基因频率差异无显著性(P>0.05).(2)非酒精性脂肪肝男性患者中AA AG基因型者TC、BMI高于GG基因型(P<0.05).(3)进一步用Logistic回归分析发现:在非酒精性脂肪肝男性患者中该基因变异与TC相关(P=0.019).结论 非酒精性脂肪肝男性患者瘦素受体基因Gln223Arg多态性与TC水平相关.瘦素受体基因Gln223Arg可能参与非酒精性脂肪肝的脂质代谢.     

胰岛素受体底物1基因Gly972Arg多态性与海南黎族2型糖尿病的关系

目的 研究胰岛素受体底物1(IRS-1)基因Gly972Arg突变与海南黎族2型糖尿病(T2DM)的关系.方法应用聚合酶链反应-限制性片段长度多态性技术,对78例海南黎族T2DM患者(T2DM组)和78例糖耐量正常人群(对照组)进行IRS-1基因Gly972Arg突变位点基因型检测.结果 对照组IRS-1基因Gly972Arg突变频率5%,T2DM组未发现该基因突变.结论 IRS-1基因Cly972Arg突变可能不是海南黎族T2DM的重要遗传因素.     

TLR4和TNF-α基因多态性与支气管哮喘的相关性研究

目的探讨Toll样受体4和肿瘤坏死因子-α基因多态性与支气管哮喘的关系。方法采用病例对照研究和PCR-DNA测序的方法,检测50例支气管哮喘患者和30例对照组的TLR4的Asp299Gly和TNF-308的基因多态性。结果 （1）在支气管哮喘和健康对照组间,未发现TLR4Asp299Gly突变型。（2）支气管哮喘和正常对照组间未发现存在TNF-308G-A替换多态性。结论 （1）TLR4Asp299Gly基因多态性与支气管哮喘的易感性不相关,TNF-α基因多态性与支气管哮喘的易感性无相关性。     

Toll样受体与炎症性肠病

Toll样受体(TLRs)是天然免疫系统中的细胞跨膜受体,可识别病原相关分子模式(PAMP).不同的PAMP激活不同的TLR,TLR在髓样分化蛋白(MD2)、CD14辅助下,通过MyD88依赖型信号通路或非MyD88依赖型信号通路激活核因子-κB(NF-κB)、干扰素调节因子3/7(IRF3/7)及活化蛋白-1(AP-1),最终诱导下游目的基因表达.TLR对肠黏膜天然免疫反应调节发挥关键作用;而病原微生物在IBD的发生中起重要作用.生理情况下,肠上皮细胞持续表达TLR3和TLR5,而TLR2和TLR4几乎无法检测到;但在IBD患者的肠上皮细胞表面,却可检测到TLR2和TLR4的表达.随着对TLR信号通路研究和认识的不断深入,以TLR为靶点的药物研究也正成为一个热点.     

Variant Toll-like receptor4 (Asp299Gly and Thr399Ile alleles) and Toll-like receptor2 (Arg753Gln and Arg677Trp alleles) in colorectal cancer

The innate immune system recognizes the presence of bacterial products through the expression of a family of membrane receptors known as Toll-like receptors (TLRs). Polymorphisms in TLRs have been shown to be associated with increased susceptibility to diseases such as inflammatory bowel disease. The aim of this study was to determine whether there was a correlation between polymorphisms of TLR4 (Asp299Gly; Thr399Ile) and TLR2 (Arg677Trp; Arg753Gln) genes and risk of colorectal cancer. DNA from 60 colorectal carcinoma patients from 3 major races in Malaysia (22 Malays, 20 Chinese and 18 Indians) and blood from 50 apparently healthy individuals were evaluated. Control group were matched to study group by race and age. The polymorphisms were determined by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Genotyping results showed two out of sixty tumour specimens (3.3%) harbored both variant TLR4 Asp299Gly and Thr399Ile alleles. In contrast, DNA isolated from blood cells of 50 apparently healthy individuals harbored wild type TLR4. In the case of TLR2 Arg753Gln genotyping, all of the fifty normal and 60 tumours were of the wild type genotype. TLR2 Arg677Trp genotyping showed a heterozygous pattern in all samples. However, this may not be a true polymorphism of the TLR2 gene as it is likely due to a variation of a duplicated ( pseudogene) region. There was only a low incidence (2/60; 3.3%) of TLR4 polymorphism at the Asp299Gly and Thr399Ile alleles in colorectal cancer patients. All normal and tumour samples harbored the wild type TLR2 Arg753 allele. Our study suggests that variant TLR4 (Asp299Gly and Thr399Ile alleles) as well as TLR2 (Arg753Gln allele) are not associated with risk of colorectal cancer.     

Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease

Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs-Asp299gly and Thr399Ile-within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs-eg, TLR2, which recognises a wide variety of microbial ligands-have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.     

Innate immunogenetics: a tool for exploring new frontiers of host defence

The discovery of innate immune genes, such as those encoding Toll-like receptors (TLRs), nucleotide-binding oligomerisation domain-like receptors (NLRs), and related signal-transducing molecules, has led to a substantial improvement of our understanding of innate immunity. Recent immunogenetic studies have associated polymorphisms of the genes encoding TLRs, NLRs, and key signal-transducing molecules, such as interleukin-1 receptor-associated kinase 4 (IRAK4), with increased susceptibility to, or outcome of, infectious diseases. With the availability of high-throughput genotyping techniques, it is becoming increasingly evident that analyses of genetic polymorphisms of innate immune genes will further improve our knowledge of the host antimicrobial defence response and help in identifying individuals who are at increased risk of life-threatening infections. This is likely to open new perspectives for the development of diagnostic, predictive, and preventive management strategies to combat infectious diseases.     

Association study of Toll-like receptor 5 (TLR5) and Toll-like receptor 9 (TLR9) polymorphisms in systemic lupus erythematosus

OBJECTIVE: Toll-like receptors (TLR) play an important role in both adaptive and innate immunity. Variations in TLR genes have been shown to be associated with various infectious and inflammatory diseases. We investigated the association of TLR5 (Arg392Stop, rs5744168) and TLR9 (-1237T-->C, rs5743836) single nucleotide polymorphisms (SNP) with systemic lupus erythematosus (SLE) in Caucasian American subjects. METHODS: We performed a case-control association study and genotyped 409 Caucasian women with SLE and 509 Caucasian healthy female controls using TaqMan allelic discrimination (rs5744168) or polymerase chain reaction-restriction fragment length polymorphism analysis (rs5743836). RESULTS: None of the 2 TLR SNP showed a statistically significant association with SLE risk in our cohort. CONCLUSION: Our results do not indicate a major influence of these putative functional TLR SNP on the susceptibility to (or protection from) SLE.     

The investigation of toll-like receptor 3, 9 and 10 gene polymorphisms in Turkish rheumatoid arthritis patients

Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system or adaptive immune responses. Genetic variations within human TLRs have been reported to be associated with a range of immune-related diseases. This study was conducted to investigate the frequencies of TLR3 rs3775290, TLR9 rs187084, and TLR10 rs4129009 polymorphisms and to detect between polymorphisms and autoantibody positive as RF, collagen type II, anti-RNP, and anti-CCP in patient group. We performed a case–control study of 100 rheumatoid arthritis (RA) cases and 100 healthy controls matched on age, sex, and residence. All polymorphisms in TLRs were determined by polymerase chain reaction-based restriction fragment length polymorphism. Serum autoantibody level was measured using quantitative ELISA. SNPs were genotyped in all samples. Our results showed that TT genotype for SNP 1237 T/C increased the RA risk significantly (p < 0.05). No statistically significant differences were found in the TLR3 and TLR10 genotypes or allele distribution between RA patients and control individuals. No associations were noted with autoantibody production and TLR3, TLR9, and TLR10 polymorphisms genotypes (p > 0.05). Our study suggests that a single nucleotide polymorphism (rs187084) in TLR9 gene may be a susceptibility factor for RA in Turkish population. Further studies are required to explore the role of TLRs gene polymorphisms in the risk of RA, especially in ethnically different populations to confirm our results.     

Toll-like receptors and their signaling mechanisms

Toll-like receptors (TLRs) play a crucial role in the recognition of invading pathogens and the activation of subsequent immune responses against them. Individual TLRs recognize distinct pathogen-associated molecular patterns (PAMPs). The TLR family harbors an extracellular leucine-rich repeat (LRR) domain as well as a cytoplasmic domain that is homologous to that of interleukin-1 receptor (IL-1R). Upon stimulation, TLR recruits IL-1R-associated protein kinases via adaptor MyD88, and finally induces activation of nuclear factor-kappaB and mitogen-activated protein kinases. However, the response to TLR ligands varies, indicating the diversity of TLR signaling pathways. Besides MyD88, several novel adaptor molecules have recently been identified. Differential utilization of these adaptor molecules may provide the specificity in the TLR signaling. Characterization of each TLR signaling pathway will reveal the molecular mechanism of self-tolerance as well as cross-tolerance in response to a variety of PAMPs.     

Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation

L. Zhou, B. Wei, C. Xing, H. Xie, X. Yu, L. Wu, S. Zheng. Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation
Transpl Infect Dis 2011: 13: 250–258. All rights reserved Background Hepatitis B virus (HBV) recurrence is one of the more severe complications following liver transplantation. Toll‐like receptors (TLRs) play a key role in human immunity by recognizing various bacteria, viruses, fungi, and parasites. Single nucleotide polymorphisms (SNPs) in the TLRs are thought to have an impact on the susceptibility to some pathogens. This study focused on the association between polymorphisms in the TLRs and HBV recurrence after liver transplantation in Han Chinese patients. Methods. A total of 41 tag SNPs in TLRs were detected by the snapshot technique in 125 patients with primary HBV‐related diseases receiving liver transplantation in our center from 2004 to 2008. Results. By comparing the genetic variations and clinical data between the HBV recurrence patients and nonrecurrence patients, we found that the variant genotype of rs11536889 (TLR4) was significantly associated with HBV recurrence after liver transplantation (P=0.040, odds ratio was 0.390, 95% confidence interval 0.159–0.957). Conclusion. Our findings indicate that polymorphism in 3′‐untranslated regions of the TLR4 gene may be related to protection from HBV recurrence after liver transplantation in Han Chinese patients.     

Pancreatic stellate cells express Toll-like receptors

BACKGROUND: Toll-like receptors (TLRs) are proteins involved in recognition of foreign pathogen-associated molecular patterns (PAMPs) and activation of innate immunity. This study aimed to clarify whether pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, expressed TLRs and responded to PAMPs. METHODS: PSCs were isolated from rat pancreas tissue, and expression of TLRs was examined. PSCs were treated with lipoteichoic acid (a ligand for TLR2), polyinosinic-polycytidylic acid (a ligand for TLR3), lipopolysaccharide (a ligand for TLR4), or flagellin (a ligand for TLR5). The effects of the TLR ligands on key cell functions and activation of signaling pathways were examined. The ability of PSCs to perform endocytosis and phagocytosis was also examined. RESULTS: PSCs expressed TLR2, 3, 4, and 5, as well as the associated molecules CD14 and MD2. All of the TLR ligands activated nuclear factor-kappaB, and three classes of mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase). TLR ligands induced expression of monocyte chemoattractant protein 1, cytokine-induced neutrophil chemoattractant 1 (a rat homolog of interleukin-8), and inducible nitric oxide synthase, but not proliferation or type I collagen production. PSCs could perform fluid-phase and receptor-mediated endocytosis, as well as phagocytosis of Escherichia coli. CONCLUSIONS: PSCs expressed a variety of TLRs and responded to TLR ligands, leading to the activation of signaling pathways and proinflammatory responses. PSCs could process exogenous antigens by endocytosis and phagocytosis. PSCs might play a role in the immune functions of the pancreas through the recognition of PAMPs.     

Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy

Toll-like receptors (TLRs) are involved in recognition of and response to Plasmodium falciparum. In 304 primiparous Ghanaian women, we examined whether common TLR4 and TLR9 polymorphisms influence susceptibility to and manifestation of malaria during pregnancy. The TLR variants did not affect P. falciparum prevalence or parasite density. However, in P. falciparum-infected women, both the TLR4 Asp299Gly and the TLR9 T-1486C polymorphisms increased the risk of low birth weight in term infants 6-fold, and, additionally, TLR4 Asp299Gly increased the risk of maternal anemia 5-fold; preterm delivery was not associated with these TLR variants. These findings suggest that TLR4 and TLR9 play a role in the manifestation of malaria during pregnancy.     

Toll-Like Receptor 2 Gene Polymorphisms Arg677Trp and Arg753Gln in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, with a continually rising mortality rate. As COPD is driven by abnormal pulmonary and systemic inflammation, Toll-like receptors (TLRs) seem to be important. TLRs play a key role in innate response, and in particular TLR2 gene polymorphisms Arg677Trp and Arg753Gln have been linked to an increased risk of infection. The purpose of this study was to investigate whether there is a link between polymorphisms in TLR2 and the onset or course of COPD. We analyzed 149 Caucasian COPD patients and 150 healthy individuals by using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. To further characterize the disease, patients were classified according to GOLD and divided into two subgroups comprising a stable (60/149) course and an unstable (89/149) course. The TLR2 Arg677Trp mutant allele was not found in any of the subjects. With a prevalence of 8.72% (13/149) for TLR2 Arg753Gln, the patients did not differ from the controls, with a prevalence of 10.67% (16/150). No significant difference was apparent (P = 0.571). None of the individuals showed homozygosity for TLR2 Arg753Gln. With regard to the course of COPD, the prevalence of TLR2 Arg753Gln in the control group did not differ significantly either from the stable subgroup (P = 0.196) or from the unstable subgroup (P = 0.891). Our results suggest that there is no association of the TLR2 polymorphisms Arg677Trp and Arg753Gln with either the onset or the course of COPD.