IL-10RA基因多态性与SLE发病关系的临床研究

目的:研究中国北方人群白细胞介素10受体A(IL-10RA)基因多态性分布情况,探讨IL-10RA基因变异与系统性红斑狼疮发病的相关性.方法:利用基因测序、PCR扩增及单链构象多态性(Single-strand Conformation Polymorphism,SSCP)电泳技术,对IL-10RA基因多态性进行筛选及分析,比较系统性红斑狼疮病例组与健康对照组中基因型的分布频率.结果:在IL-10RA第5内含子处存在3种有意义单核苷酸多态性(SNP),即T/T型、C/C型、C/T型.其中T/T型和C/T型在病例组中的出现频率明显增加.结论:IL-10RA内含子5具有多态性并与系统性红斑狼疮的发病相关.     

系统性红斑狼疮患者干扰素γ受体基因多态性研究

目的初步探讨干扰素γ受体(interferonγreceptor,IFNγR)的两个氨基酸位点Val14Met和Gln64Arg多态性与系统性红斑狼疮(systemiclupuserythematosus,SLE)的相关性。方法采用聚合酶链反应单链构象多态性和聚合酶链反应限制性片段长度多态性及DNA测序方法对94例SLE患者和80名健康对照者进行基因分型。结果IFNγR1和IFNγR2基因型与SLE易感性无显著相关(P>0.01)。其中Arg64/Arg64基因型在两组患者间的分布差异有统计学意义(P=0.047,OR=2.481,95%可信区间为0.992～6.203)。此基因型在健康对照组中的分布频数高于SLE患者组,可能是一种具有保护作用的基因型。各个基因型的分布情况和优势比显示各基因型的组合与SLE的发病无显著相关(P>0.01)。其中Val14/Val14与Arg64/Arg64基因型的组合在两组患者间的分布差异有统计学意义(P=0.047,OR=2.481,95%可信区间为0.992～6.203)。此基因型组合在健康对照组中的分布频数高于SLE患者组,故这是一种可能具有保护作用的基因型组合。结论IFNγR1和IFNγR2基因型与SLE易感性无显著相关。     

白细胞介素-18基因多态性与广西壮族系统性红斑狼疮的遗传易感性

目的 探讨白细胞介素-18(interleukin 18,IL-18)基因单核苷酸多态性与广西壮族系统性红斑狼疮(systematic lupus erythematosus,SLE)易感性之间的关系.方法 以115例SLE患者和160名健康对照者为研究对象,应用聚合酶链反应-限制性片段长度多态性和DNA测序的方法对IL-18基因-137G/C、-607C/A单核苷酸多态性进行基因分型.结果 IL-18基因-137G/C多态性在SLE组和正常人群中的分布差异无统计学意义(P>0.05),而IL-18基因-607C/A多态性在两组人群中的分布差异有统计学意义(P<0.05),等位基因频率的相对风险分析发现,-607 C等位基因携带者患系统性红斑狼疮的风险是-607A等位基因的1.619倍(OR=1.619,95%CI:1.150-2.281).联合基因型分析发现,IL-18的-137G/-607C等位基因频率在SLE组中显著高于对照组(P<0.05).-137G/-607C等位基因携带者显著增加了SLE的发病风险(OR=1.484,95%CI:1.056-2.087).结论 IL-18基因-607C/A多态性与SLE的发病具有相关性,其中-607 C等位基因可能是SLE的遗传易感基因.     

系统性红斑狼疮患者血清IL-10的水平及临床意义

目的 观察系统性红斑狼疮(systemic lupus erythematosus,SLE)患者血清IL-10的表达与疾病活动的关系.方法 选取22例SLE患者及24名健康人作为对照,根据狼疮疾病活动指数(SLE disease activity index,SLEDAI)将SLE患者分为活动期组和非活动期组,检测血清抗dsDNA抗体,血清总补体溶血活性(CH50)及C反应蛋白(C reactive protein,CRP),酶联免疫吸附法(ELISA)检测血清IL-10表达.结果 与对照组[(18.11±6.97)ng/L]相比,IL-10在SLE活动期组[(78.54±5.62)ng/L,P＜0.01]及非活动期组[(30.36±10.98)ng/L,P＜0.05]均有所增高,活动期组增高更为明显(与非活动期组相比,P＜0.05).IL-10水平与SLEDAI呈正相关(SLE活动期,r=0.77,P＜0.01;SLE非活动期,r=0.84,P＜0.01),IL-10的水平与抗dsDNA抗体(r=0.71,P＜0.01)、CRP(r=0.63,P＜0.01)和CH50(r=-0.56,P＜0.05)均相关.结论 IL-10在SLE患者血清中表达升高,在疾病活动时更为明显,IL-10能反应疾病活动的程度,可以做为临床观察SLE疾病活动的指标之一.     

系统性红斑狼疮患者血清IL-10的水平及临床意义

目的观察系统性红斑狼疮(systemic lupus erythematosus,SLE)患者血清IL-10的表达与疾病活动的关系。方法选取22例SLE患者及24名健康人作为对照,根据狼疮疾病活动指数(SLE disease activity index,SLEDAI)将SLE患者分为活动期组和非活动期组,检测血清抗dsDNA抗体,血清总补体溶血活性(CH50)及C反应蛋白(C reactive protein,CRP),酶联免疫吸附法(ELISA)检测血清IL-10表达。结果与对照组[(18.11±6.97)ng/L]相比,IL-10在SLE活动期组[(78.54±5.62)ng/L,P<0.01]及非活动期组[(30.36±10.98)ng/L,P<0.05]均有所增高,活动期组增高更为明显(与非活动期组相比,P<0.05)。IL-10水平与SLEDAI呈正相关(SLE活动期,r=0.77,P<0.01;SLE非活动期,r=0.84,P<0.01),IL-10的水平与抗dsDNA抗体(r=0.71,P<0.01)、CRP(r=0.63,P<0.01)和CH50(r=-0.56,P<0.05)均相关。结论IL-10在SLE患者血清中表达升高,在疾病活动时更为明显,IL-10能反应疾病活动的程度,可以做为临床观察SLE疾病活动的指标之一。     

IL-18基因多态性与系统性红斑狼疮相关性的Meta分析

目的评价IL-18基因多态性与系统性红斑狼疮(systemic lupus erythematosus,SLE)的关系。方法检索中国学术期刊全文数据库(CNKI)、万方数据库、中国生物医学文献数据库(CBM)、PubMed、Embase和Web of Knowledge数据库,检索时间范围为1997年01月01日至2012年07月01日。按照纳入和排除标准纳入合格文献,并对其进行质量评价,用Stata 11.0软件进行Meta分析。结果共纳入10篇文献,收集到2 646例病例,2 761例对照,Meta分析结果显示欧裔人群中的IL-18-1297C/T(OR=1.388,95%CI=1.242～1.551,P<0.001)和-607A/C(OR=1.158,95%CI=1.014～1.322,P=0.031)多态性与SLE有关,欧裔人群中IL-18-1297在显性模型下(CC+CT vs TT)和隐性模型下(CC vs CT+TT)也发现与SLE有关(显性模型:OR=1.353,95%CI=1.174～1.561,P<0.001;隐性模型:OR=2.216,95%CI=1.695-2.898,P<0.001),但Meta分析发现中国人群-607位点A等位基因对SLE有保护效应(OR=0.606,95%CI=0.396～0.930,P<0.001)。结论欧裔人群中IL-18-1297和-607位点多态性可能与SLE易感性有关,中国人群的IL-18-607位点A等位基因对SLE可能有保护效应。     

系统性红斑狼疮易感基因单核苷酸多态性研究进展

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种复杂的多基因自身免疫性疾病,遗传因素重要而复杂.SLE的易感基因包括人类白细胞抗原(HLA)基因、免疫球蛋白Fc受体(FcR)基因、细胞毒性T细胞相关抗原4(CTLA-4)基因、免疫球蛋白受体同源体(FcRL)基因等.对易感基因单核...     

系统性红斑狼疮与CTLA—4基因多态性的相关性研究

系统性红斑狼疮 ( SL E)是自身免疫性疾病的原型 ,以自身抗体的产生和免疫复合物的聚集为特征。而 B淋巴细胞产生自身抗体有赖于 CD4 + T淋巴细胞的活化。细胞毒性 T淋巴细胞相关分子 - 4 ( CTL A- 4 )和 CD2 8结构相似 ,同属免疫球蛋白超家族的成员 ,且结合的配体 ( B7)相同。 CD2 8与 B7分子结合 ,可产生共刺激作用并进一步引起 T细胞的活化 ;相反 ,CTL A- 4与 B7结合对 T细胞活化则起负性调节作用 [1 ] 。 CTL A - 4基因位于人类染色体 2 q3 3 ,已发现其外显子 1第 4 9位碱基 A→ G点突变与 Graves’病和 型糖尿病发病有关…     

Fc受体γ链基因启动子区-29位点基因多态性与系统性红斑狼疮关系的研究

目的:探讨Fc受体γ链基因启动子区-29位点基因多态现象在中国南方人群中的分布及其与系统性红斑狼疮(SLE)易感性和临床表现的关系。方法:采用PCR-RFLP方法检测180例SLE患者和140例正常对照组Fc受体γ链基因启动子区-29位点基因型。结果:SLE患者Fc受体γ链基因启动子区-29位点TT基因型频率(33.3%)及T等位基因频率(54.4%)明显高于正常对照组(17.2%及42.9%)(P＜0.05), 而GG基因型频率(24.4%)及G等位基因频率(45.6%)明显低于正常对照组(31.4%及57.1%)(P＜0.05)。T等位基因的比值比为1.59。SLE患者各基因型频率及各等位基因频率与狼疮性肾炎(LN)无相关关系(P＞0.05)。结论:SLE患者Fc受体γ链基因启动子区-29位点T等位基因与SLE发病相关但与LN的发生无关。     

IL—10在系统性红斑狼疮发病机制中的角色

系统性红斑狼疮的B细胞过度活化,细胞介导的免疫应答受损。而IL－10既是有效的B细胞刺激因子,又能抑制T细胞和抗原递呈细胞的功能,在SLE发病机制的免疫调节紊乱中扮演重要角色：IL－10的基因与SLE易感性有关,在SLE病人的健康亲属体内IL－10也呈高表达,该因子还参与疾病状态下的细胞因子谱偏移及细胞凋亡异常。IL－10分泌增加与狼疮环境的形成密切相关。     

SLE患者外周血淋巴细胞凋亡异常及血清中IL-10的影响

目的：研究SLE患者外周血单个核细胞(PBMCs)中淋巴细胞亚群的凋亡特点。方法：采用三色荧光流式细胞术检测CD3、CD4、CD8、CD19细胞亚群的早期凋亡；ELISA法检测PBMCs培养上清中的sFas、sFasL；实时荧光半定量RT-PCR方法检测细胞内FasmRNA的表达水平。结果：SLE患者PBMCs中CD3^ 细胞凋亡明显增多；CD4^ 和CD8^ 细胞亚群凋亡均有明显增加，但以CD4^ 细胞凋亡增多更为明显；相应地，其PBMCs中CD4^ 、CD8^ 细胞百分率下降，CD4／CD8比值降低。SLE患者血清可诱导CD3^ 、CD4^ 、CD8^ T细胞亚群凋亡增多，sFas、sFasL水平增高及Fas mRNA表达增加；抗-IL-10抗体则可中和SLE血清的上述作用。结论：SLE患者体内T细胞凋亡增多，以CD4^ T细胞凋亡增加更为显著，导致CD4／CD8比值下降；SLE血清中高水平的IL-10可能通过诱导Fas、FasL表达增高而促进T细胞凋亡的发生。     

白细胞介素10信号转导机制对C57BL/6和MRL/lpr~-小鼠腹腔巨噬细胞功能及活性影响的比较

目的：体外比较白细胞介素10（IL-10）信号转导机制对C57BL/6和MRL/lpr-小鼠腹腔巨噬细胞功能及活性的影响。方法：分别分离C57BL/6和MRL/lpr-小鼠腹腔巨噬细胞进行培养；用不同浓度IL-10（0.01、0.1、1和10ng/ml）进行刺激,用MTT法测定比较两种品系小鼠腹腔巨噬细胞的增殖反应能力；Real time PCR分别测定其产生前炎性细胞因子IL-1α、M-CSF、TNF-α的量；用100ng/mlIL-10分别刺激两种品系小鼠腹腔巨噬细胞10分钟,免疫印迹法比较两种细胞中JAK1、TYK2、STAT3及磷酸化水平。结果：C57BL/6小鼠巨噬细胞数及其产生的前炎性细胞因子量随IL-10刺激浓度的增加而递减；MRL/lpr-小鼠巨噬细胞数及其前炎性细胞因子IL-1α、M-CSF的量随IL-10刺激浓度的增加而递增,但巨噬细胞产生TNF-α的量随IL-10刺激浓度的增加而递减；MRL/lpr-小鼠细胞内信号转导分子的磷酸化水平低于C57BL/6。结论：MRL/lpr-小鼠的细胞免疫和炎症反应不能被IL-10抑制,可能是由于其信号转导过程中的缺陷所致。     

Sexual disparities in the incidence and course of SLE and RA

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) disproportionately affect females compared to males, with female to male prevalence ratios of 7–9:1 for SLE and 2–3:1 for RA. Interestingly, epidemiologic studies indicate that men that develop SLE may have more morbidity than women, but the same is not true for RA. Given the sex and age bias of SLE and RA, sex hormones may influence the pathogenesis of these diseases. However, the ways in which, and to what degree, sex hormones affect disease incidence and severity remain unclear and is the topic of ongoing research. Recent findings have implicated interactions between sex hormones, the immune system, genetic factors, and epigenetic modifications in influencing SLE and RA disease activity. This article reviews current hypotheses regarding the potential impact of sex hormones and genetics on disease pathogenesis, incidence, and severity of SLE and RA.     

FcγRIIa polymorphism in systemic lupus erythematosus (SLE): no association with disease

An allotypic variant of FcγRIIa, FcγRIIa-HR (FcγRIIa-R131), has been shown in vitroto reduce the capacity of phagocytic cells to bind and internalize IgG-containing immune complexes. Our aim was to determine whether this allotypic variant was associated with susceptibility to SLE and the development of lupus nephritis, as previous studies have suggested. FcγRIIA genotype analysis was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 215 Caucasoid, 70 Afro-Caribbean, and 46 Chinese patients with SLE, and in 259, 77, and 49 ethnically matched controls, respectively. Distribution of FcγRIIa genotypes between the patients and ethnically matched controls was not significantly different in the three populations studied. No association between the FcγRIIa-HR allotype and nephritis was found. Our results suggest that the FcγRIIa-HR allotype is not a major factor predisposing to the development of SLE, or to lupus nephritis.     

TLR5rs5744168基因多态性与广西壮、汉族人系统性红斑狼疮的相关性研究

目的:探讨TLR5rs5744168基因单核苷酸多态性与广西壮、汉族系统性红斑狼疮易感性的相关性以及种族间差异,初步阐明其在壮、汉族SLE发生发展中的作用.方法:采用聚合酶链反应PCR技术和直接测序的方法对33例壮族、44例汉族系统性红斑狼疮患者和72名壮、汉族健康对照者的TLR5rs5744168C/T基因多态性进行分析,比较组间基因型和等位基因频率的差异,并与主要临床指标进行相关性分析.结果:(1)广西地区壮、汉族SLE的TLR5 rs5744168的TT基因型均缺失;CC基因型频率在各组中均在90.0％～100.0％之间.(2)广西壮族SLE患者TLR5基因rs5744168 CC、CT基因型频率分别是0.939、0.061,汉族SLE患者相应基因型频率分别是0.977、0.023,与相应民族正常对照组间以及壮、汉族SLE间差异均无统计学意义(分别x2 =2.001 x2=2.235和x2 =0.723;均P＞0.05);壮族SLE患者的TLR5rs5744168 C、T等位基因频率分别是0.970、0.030,汉族SLE相应的C、T等位基因频率分别是0.989、0.011,与相应民族正常对照组间以及壮、汉族SLE间差异均无统计学意义(分别x2=1.970、x2 =2.166和x2=0.708;均P＞0.05).(3)TLR5rs5744168 CC、CT基因型及C、T等位基因与广西壮汉族SLE患者ds-DNA、ANA、肾损害临床表现和实验室检查均无相关性(均P＞0.05).结论:TLR5rs5744168基因多态性与广西壮、汉族SLE的易感性以及ds-DNA、ANA、肾损害临床实验室主要指标均无明显相关性,壮、汉族间亦不存在明显民族差异性.     

雌二醇对系统性红斑狼疮小鼠模型肾组织芳香酶表达的影响

目的：研究雌二醇对系统性红斑狼疮（ Systemic lupus erythematosus, SLE）小鼠模型肾组织芳香酶表达的影响。方法：BALB／c小鼠卵巢切除后采用ConA活化的同系脾细胞诱导SLE，同时给予不同剂量苯甲酸雌二醇，并设立对照组。于4、6、8和10周用ELISA法检测外周血和肾组织雌二醇（Estradiol，E2）水平，RT-PCR检测肾组织芳香酶mRNA的表达。结果：SLE模型小鼠外周血和肾组织E2水平随着外源性给予苯甲酸雌二醇剂量的加大而升高，与未进行SLE模型诱导的小鼠相比较，SLE模型鼠外周血和肾组织E2水平升高（P〈0．05）；正常BALB／c小鼠肾组织芳香酶mRNA低表达；随着SLE炎症的诱导及E2水平的升高，肾组织芳香酶mRNA的表达增加。结论：E2通过促进SLE小鼠模型肾组织芳香酶mRNA的表达影响SLE发生发展。     

Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus

Recent studies have shown elevated IL-10 levels in several rheumatic autoimmune diseases, and particularly in systemic lupus erythematosus (SLE). Such changes may have a genetic basis. We studied two novel polymorphic dinucleotide repeats in the IL-10 promoter region (IL 10.G and IL 10.R) in order to investigate their possible significance in association with this condition in a group of 56 Caucasian SLE patients compared with 102 ethnically matched controls. The results show that there is an allelic imbalance between SLE patients and controls at the IL 10.G microsatellite; this observation is supported by a significant difference in genotype distribution. The nature of autoantibody production and the presence or absence of renal involvement also appeared to be associated with certain IL 10.G microsatellite alleles, although the small size of individual clinical sub-groupings may have influenced this result. No association with the IL 10.R microsatellite was observed. Overall, the differences observed at the IL 10.G microsatellite between SLE patients and controls suggest that the IL-10 locus contributes to the genetic background important for the development of this disease. Although the moderate sample size described in this study requires that the results be interpreted carefully, they provide an interesting and useful framework for future study.     

Cytokine IL-6 and IL-10 as Biomarkers in Systemic Lupus Erythematosus

There is a great deal of interest in the identification of biomarkers that are closely associated with disease activity in systemic lupus erythematosus (SLE), but few biomarkers have been validated. Cytokines play an important role in the pathogenesis of SLE. Therefore, we evaluated the levels of cytokines and their possible association with disease activity. In the present study, we found that the SLE patients had higher IL-6, IL-10, IL-12, and IFN-γ levels, but lower IL-2, than normal controls. Serum IL-6 level was significantly elevated in active SLE patients and correlated with the SLE activity index (SLEDAI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Serum IL-10 level was also significantly elevated in active SLE patients and revealed positive correlation with SLEDAI and anti-double-stranded DNA (dsDNA) titer and negative correlation with C3, C4, and lymphocyte counts. No significant differences in the levels of cytokines were observed between SLE patients with nephritis and those without nephritis. These data suggest that IL-6 and IL-10 may be a useful biomarker for disease activity in SLE.     

IL-10 stimulates production of platelet-activating factor by monocytes of patients with active systemic lupus erythematosus (SLE)

IL-10 displays modulatory properties on the synthesis of platelet-activating factor (PAF), a potent inflammatory mediator of vascular injury. Despite the fact that IL-10 is considered to be an anti-inflammatory cytokine, IL-10 levels correlate with disease activity in SLE. Moreover, in SLE IL-10 is unable to exert its immunosuppressive and anti-inflammatory effects. We have investigated the ability of IL-10 to stimulate PAF production from monocytes of SLE patients. Spontaneous and IL-10-stimulated PAF production by peripheral blood monocytes was measured in active (n = 13) and inactive (n = 14) SLE patients and in 15 normal control subjects. We observed that monocytes derived from patients with active SLE, but not from controls or inactive SLE, spontaneously produced significant amounts of PAF. Moreover, IL-10 enhanced the synthesis of PAF from monocytes of active SLE patients only. IL-10-induced PAF production correlated with the severity of the disease and with the extent of proteinuria. These results indicate that IL-10 only stimulates the synthesis of PAF from monocytes of SLE patients when immunologically active, suggesting that IL-10 may possess a paradoxical proinflammatory effect in SLE by promoting the production of PAF, a secondary mediator of inflammation.