口腔扁平苔藓基因遗传学的研究进展

口腔扁平苔藓(OLP)的确切病因和发病机制目前尚不明确,对其病因尚未有一种可以完全解释其发病机制的假说,可能是多种因素共同作用的结果。近年来,陆续有OLP家族发病的报道以及关于OLP分子遗传学的研究,认为遗传因素是OLP的一个发病因素。目前已知多种与OLP易感性有关的遗传因素,包括人类DNA错配修复系统基因(MMR)、p53基因及其与家族蛋白、线粒体DNA、(RNA)。国内外学者对关于OLP遗传相关性已做了一定的研究,取得了很大的进展。通过研究多种细胞因子的基因多态性、核糖核酸,有利于从遗传方面阐述OLP的病因和发病机制,有利于对OLP相关联区域的精准定位,进一步找出关键基因,进一步阐明OLP的分子病理机制,并对其进行功能分类,也有利于对OLP的预防、早期诊断、直接有效靶向治疗和防复发以及药物研发提供重要价值。本文从基因、基因多态性、核糖核酸三方面对OLP遗传相关性的研究作一综述。     

Assessment of 14 functional gene polymorphisms in Japanese patients with oral lichen planus: a pilot case-control study

Oral lichen planus (OLP) is a refractory mucosal disease. Its pathogenesis is thought to involve immunologic and genetic alterations. To gain a better understanding of the genetic risk factors, the authors evaluated associations between 14 functional gene polymorphisms and OLP. 32 Japanese patients with OLP and 99 unrelated healthy Japanese controls were genotyped for 14 single nucleotide polymorphisms (SNPs) of genes that regulate host immune responses. Genotyping was performed with a modified version of the serial invasive signal amplification reaction. A trend towards over-representation of tumor necrosis factor receptor 2 (TNFR2) +587 G allele was found in the patients compared with the controls (allele frequency: P = 0.049). The other 13 SNPs were unassociated with OLP. These results suggest that TNFR2 +587 gene polymorphism may be associated with susceptibility to OLP.     

人β防御素2与口腔扁平苔藓相关性的研究进展

口腔扁平苔藓(oral lichen planus,OLP)是一种常见的口腔黏膜慢性免疫性炎症疾病,OLP的病因和发病机理目前尚未阐明,在临床诊疗过程中存在着诸多问题且OLP存在癌变风险,故OLP的发生发展及临床诊疗方面的研究历来受到重视.近年来的一些研究表明,OLP的发生与人β防御素2(humanβdefensin-...     

Inflammation‐related cytokines in oral lichen planus: an overview

Cytokines are powerful mediators which play a central role in both innate and adapted immune responses. Aberrant productions of cytokines may lead to the onset of immune deficiency, allergy or autoimmunity, which are involved in the mechanisms of various immune‐mediated inflammatory diseases. Oral lichen planus (OLP) is a chronic inflammation disease affecting the oral mucosa with unknown aetiology. Previous studies have described the abnormal expression patterns of various inflammation‐related cytokines, such as IL‐1, 2, 4, 5, 6, 8, 10, 12, 17, 18, TGF‐β, IFN‐γ and TNF‐α, in lesions, saliva, serum and peripheral blood mononuclear cells from patients with OLP, which may reflect the immune dysregulation status and emerge as central players in the immunopathogenesis of OLP. Besides, the gene polymorphisms of several cytokines such as IFN‐γ, TNF‐α, IL‐4, IL‐10 have been found to be involved in the susceptibility of OLP. In this review, we gave a brief introduction of the characteristics and biological functions of these inflammation‐related cytokines and summarized for the first time the current knowledge on the involvement of inflammation‐related cytokines in OLP. Further research on the exact roles of these cytokines will aid the understanding of the pathogenesis and the identification of novel therapeutic approaches of OLP.     

Urine metabolic profiling for the pathogenesis research of erosive oral lichen planus

ObjectiveOral lichen planus (OLP) is a relatively common chronic immune-pathological and inflammatory disease and potentially oral precancerous lesion. Erosive OLP patients show the higher rate of malignant transformation than patients with non-erosive OLP. Identifying the potential biomarkers related to erosive OLP may help to understand the pathogenesis of the diseases.MethodsMetabolic profiles were compared in control and patient subjects with erosive OLP by using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods An integrative analysis was used to identify the perturbed metabolic pathways and pathological processes that may be associated with the disease.ResultsIn total, 12 modulated metabolites were identified and considered as the potential biomarkers of erosive OLP. Multiple metabolic pathways and pathological processes were involved in erosive OLP.ConclusionThe dysregulations of these metabolites could be used to explain the pathogenesis of the disease, which could also be the potential therapeutic targets for the disease.     

Epithelial p53 gene expression and mutational analysis, combined with growth fraction assessment, in oral lichen planus

The immunohistochemical detection of epithelial p53 protein expression in oral lichen planus (OLP) biopsies was supplemented with molecular analysis for mutations of the p53 gene using the polymerase chain reaction - single stranded conformational polymorphism (PCR-SSCP) technique. p53 protein expression, in the basal epithelial cell layer, as detected by the DO7 and 1801 antibodies, was significantly more frequent in OLP compared with other oral keratoses and normal mucosa, as was the growth fraction. The 10 OLP biopsies that had the most frequent p53 staining (plus a case of OLP found in continuity with a SCC) were screened by the PCR-SSCP technique, but no mutations were detected in the p53 gene (exons 5–9). The p53 overexpression in the OLP samples may be a physiological response to the hyper-proliferative state, as revealed by the growth fraction determination. This may usefully serve to protect against mutagenesis, and so be a factor in the low incidence of carcinoma associated with OLP.     

TLR2, TLR3, TLR4 and CD14 gene polymorphisms associated with oral lichen planus risk

The aim of this study was to assess whether polymorphisms in toll‐like receptor (TLR) and cluster of differentiation 14 (CD14) genes are associated with oral lichen planus (OLP) risk and clinical course of the disease. The study group consisted of 101 patients with confirmed OLP and 104 healthy blood donors without systemic or oral mucosal diseases. Single nucleotide polymorphisms of TLR2 (rs3804099), TLR3 (rs3775291 and rs5743312), TLR4 (rs4986790 and rs4986791), and CD14 (rs2569190) genes were genotyped using real‐time PCR or PCR‐restriction fragment length polymorphism (PCR‐RFLP). The rs5743312 TLR3 gene polymorphism was associated with increased OLP risk in comparison with the wild type genotype (OR = 15.984, P = 0.011). No association with OLP risk was observed for the polymorphisms studied in TLR2, TLR4 and CD14 genes or for the rs3775291 polymorphism of the TLR3 gene. The polymorphisms of the TLR3 gene were in linkage disequilibrium (D′ = 1, r² = 0.1). Identified haplotypes were not associated with the risk of OLP. The findings of the current study suggest that the TT genotype of the rs5743312 TLR3 gene polymorphism may play a significant role in the aetiology of OLP.     

口腔扁平苔藓与NF-κB通路相关因子IL-8和RANTES的关系研究

目的探讨NF-κB信号通路相关细胞因子白细胞介素-8 (IL-8),受激活调节正常T细胞表达和分泌因子(RANTES)在口腔扁平苔藓(OLP)患者组和健康对照组中的表达,并分析IL-8、RANTES表达的相关性,探讨在口腔扁平苔藓发生发展过程中NF-κB信号传导通路的作用。方法选取30例OLP患者作为实验组,30例健康者为对照组,取其相应黏膜组织。应用RT-PCR法检测NF-κB相关因子IL-8、RANTES在OLP患者组与健康对照组中的表达,分析患者组与对照组的表达差异及二者表达相关性。结果 RT-PCR结果显示IL-8、RANTES在OLP两组中均有表达,但患者组的表达明显高于正常对照组(P<0.05)。OLP患者组中IL-8与RANTES的表达相关(P<0.05)。结论 OLP的发生发展可能与NF-κB引导的炎症通路及其介导的炎症因子IL-8、 RANTES相关,同时IL-8和RANTES在OLP的发病过程中可能具有协同致病作用。     

Mannose-binding lectin gene (MBL-2) polymorphism in oral lichen planus

TNF-α may be associated with the etiopathogenesis of oral lichen planus (OLP), and it has been suggested that polymorphism of mannose-binding lectin (MBL) increases the in vitro production of TNF- α. The aim of the present study was to assess the relevance of genetic diversity of MBL in OLP. The study sample comprised 90 individuals, 45 OLP patients and 45 healthy volunteers. MBL-2 gene was amplified using real-time PCR. Frequency of A/A genotype was 55.6% in OLP and 53.3% in healthy volunteers. Likewise, A/0 heterozygote genotype was found in 42.2% and 35.6%; 2.2% and 11.1%, had the recessive 0/0 genotype respectively. Frequencies of the “A” and “0” alleles were 77% and 23% in the OLP group and 71.2% in control group. There were no statistically significant differences regarding genotype frequency (p = 0.546) or allele frequency (p = 0.497). In conclusion, no significant association was found between polymorphism of MBL-2 gene and OLP.     

口腔扁平苔藓免疫学因素的研究现状

口腔扁平苔藓(OLP)是一种严重影响患者身心健康的发生于口腔黏膜的非传染性炎症性疾病。OLP的病因尚不明确,可能与多种因素有关。目前的研究表明,OLP的发病与免疫因素密切相关,它是一种以T淋巴细胞介导的免疫应答为特征的慢性疾病。抗原特异性机制和非特异性机制可能参与OLP的免疫过程。首先由树突状细胞摄取、处理未知抗原触发其免疫反应,导致T淋巴细胞和其他免疫细胞在病损处聚集,分泌大量细胞因子,继而破坏基底膜并杀伤角质形成细胞,最终造成口腔黏膜炎症性病损。因此,免疫细胞和复杂的细胞因子网络在OLP的发病过程中起重要作用。本文从免疫机制,免疫细胞和炎症介质三方面对OLP的免疫学研究现状进行综述,旨在为OLP的预防、诊断和临床治疗提供理论参考。     

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??Oral lichen planus ??OLP?? is a common oral mucosal chronic disease??the prevalence rate is 0.1% to 4.0% of the general population??and it occurs mostly in women aged 30 to 60. OLP pathogenesis has not yet been clear??currently it is considered as a class of T cell-mediated autoimmune diseases. It is related to genetics??drug??infection??oral irritation and mental factors. The clinical manifestations are white or gray textures??pimples??plaques??etc.??which may be accompanied by congestion??erosion??blisters and other lesions. Because 1.1% of OLP will develop into oral squamous cell carcinoma??World Health Organization lists it as a potentially malignant disease??and clinicians should pay attention accordingly. Here we summarize the pathogenesis??diagnosis and treatment of OLP.     

凋亡蛋白Bcl-2、Bax在白斑、口腔扁平苔藓中的表达

目的:观察凋亡蛋白Bcl-2、Bax在白斑、口腔扁平苔藓上皮细胞中的表达,探讨其在口腔白斑、口腔扁平苔藓癌变过程中的作用机制。方法:采用免疫组化法检测10例正常口腔黏膜上皮、18例口腔扁平苔藓、23例白斑、22例口腔鳞癌上皮组织中凋亡相关蛋白Bcl-2、Bax的表达水平。结果:Bcl-2在白斑、口腔扁平苔藓上皮细胞层无异常表达,但在口腔扁平苔藓淋巴细胞浸润带过度表达。Bcl-2在鳞癌组织中呈高表达,与正常黏膜相比有显著性差异(P<0.05)。Bax在上皮单纯增生、轻度、中度不典型增生和低分化鳞癌及糜烂型口腔扁平苔藓组织中呈过度表达,与正常黏膜相比有显著性差异(P<0.05)。结论:Bax参与了口腔白斑癌变的早期事件,而Bcl-2在不典型增生转化为鳞癌的阶段并未发生作用。口腔扁平苔藓的发病机制可能与Bcl-2抑制淋巴细胞凋亡,使细胞免疫亢进,从而刺激上皮细胞Bax过度表达,诱导角朊细胞凋亡有关。     

辅助性T淋巴细胞极化相关细胞因子在口腔扁平苔藓中的研究进展

口腔扁平苔藓是一种病因不明的皮肤黏膜慢性免疫炎症性疾病,辅助性T淋巴细胞(Thcell)在口腔扁平苔藓的发病机制中起到了重要作用。近年来,口腔扁平苔藓中Th细胞的极化状态引起了较为广泛的关注。研究表明,Th细胞极化相关细胞因子的变化与口腔扁平苔藓的发病密切相关。下文就这些细胞因子在口腔扁平苔藓中的研究进展作一综述。     

Polymorphic drug metabolizing CYP‐enzymes – a pathogenic factor in oral lichen planus?

Background:  Oral lichen planus (OLP) is a chronic mucosal disease with a characteristic clinical phenotype. Environmental exposures, e.g. drugs have been associated with the pathogenesis.
Objectives:  To test the hypothesis that some OLP lesions have a pharmacological pathogenesis related to polymorphisms of the cytochrome P450 enzymes (CYPs) resulting in poor or intermediate CYP metabolism.
Methods:  One hundred and twenty patients with OLP and 180 gender-matched controls without OLP were genotyped for CYP2C9 , CYP2C19 , and CYP2D6 alleles with absent or reduced function.
Results:  The prevalence of poor or intermediate metabolizers was not higher among the OLPs as compared with the controls; however, there were higher numbers of variant CYP2D6 genotypes among the OLP females ( P  < 0.05). There were no differences between the groups with regard to intake of drugs metabolized by polymorphic CYPs or drug or herbal products inhibiting CYPs. The prevalence of CYP2D6*4 alleles among the OLPs was higher [28%; 95% confidence interval (CI) 20–36%] than previously reported among Danes (19%; 95% CI 17–22%). Fifty per cent of the OLPs had a CYP2D6*4 genotype as compared with 30% in the background population ( P  = 0.0001). The CYP2D6*4 protein has sequence homology with human herpes simplex virus type 1 (HSV1) and Candida albicans , which may result in molecular mimicry.
Conclusion:  It was not possible to substantiate a pharmacological pathogenesis of OLP based on poor or intermediate CYP metabolism. However, molecular mimicry between CYP2D6, in particular CYP2D6*4, and common oral pathogens may be involved in the pathogenesis of OLP.     

Elevated serum levels of the apoptosis related molecules TNF-α, Fas/Apo-1 and Bcl-2 in oral lichen planus

BACKGROUND: The serum circulatory levels of apoptosis related molecules measured in patients with oral lichen planus (OLP) and healthy individuals in order to investigate possible alterations associated with the clinical forms of OLP. METHODS: Serum levels of tumor necrosis factor (TNF)-alpha, soluble Fas (sFas) and Bcl-2 studied by enzyme-linked immunosorbent assay in whole blood samples in 13 OLP reticular, 13 OLP atrophic-erosive form patients and 26 healthy subjects. RESULTS: Significantly elevated levels of TNF-alpha and sFas detected in OLP patients as compared with controls. Serum concentrations of Bcl-2 although increased in 17/26 patients, they were not statistically significant. Reticular OLP exhibited slightly elevated TNF-alpha and significantly elevated Bcl-2 serum levels, compared with erosive OLP. CONCLUSIONS: These data suggest that a putative dysfunction in the Fas/FasL mediated apoptosis might be involved in the OLP pathogenesis. A downregulation of Bcl-2 serum levels in the atrophic-erosive OLP may be associated with promotion of the disease activity.     

HERG1在口腔扁平苔藓和口腔鳞状细胞癌中的表达

目的：研究钾离子通道蛋白HERG1在正常口腔黏膜（normal oral mucosa,NOM）、口腔扁平苔藓（oral lichen planus,OLP）、口腔鳞状细胞癌（squamous cell carcinoma,OSCC）中的表达及意义。方法：免疫组织化学技术检测16例NOM、20例OLP、30例OSCC组织中HERG1的表达。采用χ2检验,P〈0.05为差异具有统计学意义。结果：HERG1在OSCC中的表达强度高于OLP（P〈0.05）,HERG1在OLP组织的表达高于正常组织（P〈0.05）,且糜烂型OLP中的表达高于非糜烂型OLP（P〈0.05）,差异均具有统计学意义。结论：HERG1可能与OLP及OSCC的发生发展有一定的关系。     

T细胞免疫和细胞凋亡在口腔扁平苔藓发病中的作用

目的通过探讨口腔扁平苔藓（OLP）中细胞凋亡情况及CD4＋、CD8＋T细胞和CD4/CD8比例的变化分析细胞免疫与细胞凋亡的关系,进一步了解OLP的发病机制。方法应用免疫组化SP法检测27例OLP组织中CD4＋、CD8＋T细胞的表达水平,并用原位末端转移酶标记法（TUNEL）定位检测17例OLP中细胞凋亡情况。结果OLP组固有层中CD4＋、CD8＋T细胞明显高于对照组（P＜0.05）,CD4/CD8值降低。OLP组中上皮内细胞凋亡指数高于对照组,固有层淋巴细胞凋亡指数明显低于对照组。结论OLP组固有层中CD4＋、CD8＋T细胞浸润的增加、CD4/CD8比值的变化及OLP中上皮细胞和固有层淋巴细胞凋亡异常,说明细胞免疫功能紊乱和细胞凋亡异常在OLP发病中起重要作用。     

Investigation of functional gene polymorphisms interleukin-1β, interleukin-6, interleukin-10 and tumor necrosis factor in individuals with oral lichen planus

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease. There are some studies in the literature demonstrating association between cytokines genes polymorphisms and susceptibility to develop some immune-mediate conditions. The purpose of this study was to investigate cytokine gene polymorphisms in a sample of Brazilian patients with OLP. Fifty-three patients with OLP (mean age = 43.1 years; range 20-68 years) and 53 healthy volunteers (mean age = 42.9 years; range 21-67) were genotyped for IL-1beta +3954 (C/T), IL-6-174 (G/C), IL-10-1082 (G/A) and TNFA-308 (G/A) gene polymorphisms. Statistical analysis was based on the use of logistic regression (P-values below 0.05 were considered as significant). IL-6 and TNFA homozygous genotypes were significantly more often detected in OLP patients. These genotypes were associated with an increased risk of OLP development (OR 6.89 and 13.04, respectively). IL-1beta and IL-10 gene polymorphisms were not related to OLP development. Our findings clearly demonstrate an association between inheritance of IL-6 and TNFA gene polymorphisms and OLP occurrence, thus giving additional support for genetic basis of this disease.     

口腔白斑、扁平苔藓细胞凋亡相关蛋白Bax表达的研究

目的 :探讨口腔白斑、扁平苔藓的癌变机理及发病机制。方法 :采用免疫组化法检测 10例正常口腔黏膜上皮 ,18例扁平苔藓 ,2 3例白斑 ,2 2例口腔鳞癌上皮组织中凋亡相关蛋白Bax的表达水平。结果 :白斑中上皮单纯增生、轻度、中度不典型增生和低分化鳞癌及糜烂型扁平苔藓的Bax蛋白显过度表达 ,与正常口腔黏膜上皮相比有显著性差异。结论 :Bax参与了口腔白斑癌变的早期过程 ,Bax的表达水平可作为临床监测白斑癌变倾向的参考指标。扁平苔藓的发病机制可能与细胞免疫亢进刺激Bax过度表达诱导角朊细胞凋亡有关 ,扁平苔藓的癌变机理有待进一步研究