原发性干燥综合征microRNA的表达谱研究
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摘要
背景
原发性干燥综合征(Primary Sjogren's syndrome, pSS)是一种以淋巴细胞增殖和进行性外分泌腺体损伤为特征的慢性炎症性自身免疫病。pSS受累器官可见大量淋巴细胞浸润,血清中可检出多种自身抗体,常伴有高免疫球蛋白血症,提示存在免疫细胞功能的紊乱。microRNA(miRNA)是一类在进化上高度保守的小非编码RNA,参与生物体的生长、发育、衰老、凋亡的调控,并与人类疾病相关联。miRNA对机体免疫细胞具有多种调控功能,在固有免疫及适应性免疫中发挥重要作用,并参与自身免疫病的发病机制。对于pSS而言,外周血单个核细胞(PBMC)是免疫细胞的集合体,是探讨该疾病发生机制的重要靶点,但我们对于其在疾病发生中的作用还了解甚少,国内外鲜有相关研究。基于这种现状,本研究拟探索pSS与健康对照(Health Control, HC)者的PBMC为对象,对其中miRNA表达谱的变化及其对pSS的意义进行研究；进一步的,本研究还利用双荧光素酶报告基因系统,对自身抗原SSA/Ro、 SSB/La具有调节作用的miRNA进行分析,旨在发现疾病相关的miRNA分子,探讨其在pSS发病机制中的作用。
目的
本研究通过分析pSS患者中PBMC的miRNA表达谱变化,寻找与pSS相关的miRNAs,并对其相对表达量与pSS临床谱的相关性进行了研究；进一步的,我们对调控自身抗原Ro52(52KD-Ro/TRIM21)、Ro60(60KD-Ro/TROVE2)及SSB表达的miRNAs进行了研究,以期鉴定与疾病的发生和发展相关的miRNA分子。
方法
(1)应用Exiqon miRNA表达谱芯片技术检测1896条人的成熟miRNA及146个人相关病毒的1niRNA在pSS和HC PBMC中表达水平差异,应用分层聚类分析获得pSS差异表达的miRNA谱,并应用实时定量PCR(Quantitive Real-time PCR,qPCR)方法验证。
(2)进一步扩大样本量,采用qPCR方法对miR-181a、miR-155、miR-146a在pSS、HC的表达水平进行检测,其中包括33例pSS患者、10例健康对照,分析其与pSS脏器受累情况、病情活动度及实验室检测指标(IgG、ESR、ANA、hsCRP)的相关性。
(3)分别应用miRecords数据库和Targetscan预测软件,与pSS miRNA芯片比对,筛选出可能以SSA、SSB为靶基因,参与pSS发病机制的miRNA;构建靶基因3'UTR区表达载体,检测过表达相关miRNA对双荧光素报告系统基因活性的影响。
结果
(1) miRNA芯片检测结果表明存在pSS特异性的mniRNA表达谱；共筛选出382个差异表达的miRNA,其中202个miRNA上调,180个miRNA下调。
(2)扩大样本量,qPCR法证实miR-181a在pSS PBMC中上调,与HC组相对表达量为2.81,有统计学差异(P<0.05)。通过与临床谱相关性的分析研究发现miRNA181a与ANA滴度正相关,miRNA155与脏器受累有关,miR-146a与ESR呈弱正相关性。
(3)成功构建含TRIM21、TROVE2-2、SSB3'UTR区载体质粒,并通过双荧光素酶报告系统成功地筛选出可能作用于TRIM213'UTR的miR-1207、miR-4695及作用于SSB3'UTR的miR-229,其荧光素酶活性分别为对照组的47.3%、53%、37.2%。miR-181a可能同时作用于TRIM21、SSB3'UTR区,其荧光素酶活性分别为对照组的75.4%、75.5%。
结论
该研究结果表明pSS PBMC具有特异的miRNA表达谱；1niRNA181a在pSS患者中表达上调,具有一定特异性,并与ANA滴度正相关；miR-181a、miR-1207、 miR-4695、miR-229可作用于SSA、SSB的3'UTR区,可能参与pSS的病理生理过程。
Backgroud
Primary Sjogren's syndrome(pSS) is a chronic autoimmune disease with a broad clinical spectrum that characiterized of lymphocyte proliferation and progressing organ-specific exocrinopathy to systemic manifestations. The pathogenesis of organs involved in pSS we could see lymphocytes infiltration, lots of autoantibodies detected in serum and accompanied with hyperglobulinemia, indicated immunocyte function disorder. MicroRNAs(miRNAs) as small, single-stranded noncoding Ring NAs, many of which have been highly conserved throughout evolution, is known to regulate cellular processes such as growth, development, aging and apoptosis, and associated with human diseases. The miRNAs have multiple regulating potential to broadly influence human immunocytes, and could control the development and function of innate and adaptive immune response by regulating target mRNA expression, and involved in the pathogenesis of autoimmune diseases. In pSS the immunocytes aggregation as the peripheral blood mononuclear cell (PBMC), is the essential target to exploring pathogenesis of the disease. To date, little is known about the roles of miRNAs in pSS pathogenesis and few studies had been published about it. Based on this point, this study was comparing the PBMC of pSS patients with healthy controls (Health Control, HC) to explore which miRNA expression profiling changes and impacts on the significance for the pSS. Furthermore, the dual-luciferase reporter transfection assay was used to analyze the miRNAs on auto-antigens SSA/Ro, SSB/La regulations, aimed at discovering a set of pSS-related miRNAs to investigate their roles in the pathogenesis of pSS.
Objective
Our aim was to analysis microRNA expression profile in PBMC of patients with pSS, searching for the special miRNAs associated with pSS and investigate the relative expression of special miRNAs of relevance to pSS clinial spectrum. Furthermore, to explore miRNAs which regulate the expression of antigen of Ro52(52KD-Ro/TRIM21), Ro60(60KD-Ro/TROVE2)and SSB.
Methods
(1) Using the Exiqon miRNA expression profile chip contains1896mature human miRNAs and146human-related virus miRNAs, the expression of miRNAs in pSS and HC PBMC was detected. Hierarchical clustering analysis was applied for determining pSS differentially expressed micrornas spectrum, and the method of quantitive Real-time PCR (qPCR) was applied for validation.
(2) The expression level of miR-181a, miR-155and miR-146a was detected by qPCR method in larger sample size, including33cases of patients with pSS and10cases of healthy controls. We analysised the expression levels of those miRNAs with the pSS patients'organ involvement condition, disease activity index and laboratory tests (IgG, ESR, hsCRP and the titre of ANA).
(3) Based on the result of miRNA chip profile, miRecords database and Targetscan software was applicated to predict miRNAs which may target genes of SSA and SSB. We built targeted gene3' UTR region expression vector and detected regulation effects identified by dual luciferase reporter assay.
Results
(1) The miRNA profiling microarray results shown that a set of pSS-specific miRNAs expression spectrum which contain382differentially expressed miRNAs, of which202miRNAs upregulated and180miRNAs downregulated.
(2) miR-181was detected upregulated in pSS PBMC by qPCR method in an expanded sample size and the relative expression to HC is2.81, with statistical significant difference (P<0.05). The analysis of spectrum correlation with clinical profiles shown that miR-181a was positively related to the titre of ANA, miR-155possibly associated with organ involvement, miR-146a is weak positively related to the ESR.
(3) We successfully built recombinant plasmid vector which contained TRIM21, TROVE2-2SSB and3' UTR region respectively. The result of dual luciferase reporter assay shown that miR-1207, miR-4695regulated TRIM21and miR-229regulated SSB, the luciferase activity in each control group was47.3%,53%and47.3%respectively. MiRNA-181a was dectected possible regulation effect on TRIM21, SSB and the luciferase activity in the control group was75.4%and75.5%respectively.
Conclusion The research results shown that the pSS PBMC have a specific miRNA expression profile. Overexpression of miR-181a was detected in pSS PBMC, which was positively correlated with the titer of ANA. MiR-181a, miR-1207, miR-4695and miR- 229was confirmed to have regulation effect on SSA/SSB3'UTR region which was probably involved in process of pathophysiological.
原发性干燥综合征(Primary Sjogren's syndrome, pSS)是一种以淋巴细胞增殖和进行性外分泌腺体损伤为特征的慢性炎症性自身免疫病。pSS受累器官可见大量淋巴细胞浸润,血清中可检出多种自身抗体,常伴有高免疫球蛋白血症,提示存在免疫细胞功能的紊乱。microRNA(miRNA)是一类在进化上高度保守的小非编码RNA,参与生物体的生长、发育、衰老、凋亡的调控,并与人类疾病相关联。miRNA对机体免疫细胞具有多种调控功能,在固有免疫及适应性免疫中发挥重要作用,并参与自身免疫病的发病机制。对于pSS而言,外周血单个核细胞(PBMC)是免疫细胞的集合体,是探讨该疾病发生机制的重要靶点,但我们对于其在疾病发生中的作用还了解甚少,国内外鲜有相关研究。基于这种现状,本研究拟探索pSS与健康对照(Health Control, HC)者的PBMC为对象,对其中miRNA表达谱的变化及其对pSS的意义进行研究；进一步的,本研究还利用双荧光素酶报告基因系统,对自身抗原SSA/Ro、 SSB/La具有调节作用的miRNA进行分析,旨在发现疾病相关的miRNA分子,探讨其在pSS发病机制中的作用。
目的
本研究通过分析pSS患者中PBMC的miRNA表达谱变化,寻找与pSS相关的miRNAs,并对其相对表达量与pSS临床谱的相关性进行了研究；进一步的,我们对调控自身抗原Ro52(52KD-Ro/TRIM21)、Ro60(60KD-Ro/TROVE2)及SSB表达的miRNAs进行了研究,以期鉴定与疾病的发生和发展相关的miRNA分子。
方法
(1)应用Exiqon miRNA表达谱芯片技术检测1896条人的成熟miRNA及146个人相关病毒的1niRNA在pSS和HC PBMC中表达水平差异,应用分层聚类分析获得pSS差异表达的miRNA谱,并应用实时定量PCR(Quantitive Real-time PCR,qPCR)方法验证。
(2)进一步扩大样本量,采用qPCR方法对miR-181a、miR-155、miR-146a在pSS、HC的表达水平进行检测,其中包括33例pSS患者、10例健康对照,分析其与pSS脏器受累情况、病情活动度及实验室检测指标(IgG、ESR、ANA、hsCRP)的相关性。
(3)分别应用miRecords数据库和Targetscan预测软件,与pSS miRNA芯片比对,筛选出可能以SSA、SSB为靶基因,参与pSS发病机制的miRNA;构建靶基因3'UTR区表达载体,检测过表达相关miRNA对双荧光素报告系统基因活性的影响。
结果
(1) miRNA芯片检测结果表明存在pSS特异性的mniRNA表达谱；共筛选出382个差异表达的miRNA,其中202个miRNA上调,180个miRNA下调。
(2)扩大样本量,qPCR法证实miR-181a在pSS PBMC中上调,与HC组相对表达量为2.81,有统计学差异(P<0.05)。通过与临床谱相关性的分析研究发现miRNA181a与ANA滴度正相关,miRNA155与脏器受累有关,miR-146a与ESR呈弱正相关性。
(3)成功构建含TRIM21、TROVE2-2、SSB3'UTR区载体质粒,并通过双荧光素酶报告系统成功地筛选出可能作用于TRIM213'UTR的miR-1207、miR-4695及作用于SSB3'UTR的miR-229,其荧光素酶活性分别为对照组的47.3%、53%、37.2%。miR-181a可能同时作用于TRIM21、SSB3'UTR区,其荧光素酶活性分别为对照组的75.4%、75.5%。
结论
该研究结果表明pSS PBMC具有特异的miRNA表达谱；1niRNA181a在pSS患者中表达上调,具有一定特异性,并与ANA滴度正相关；miR-181a、miR-1207、 miR-4695、miR-229可作用于SSA、SSB的3'UTR区,可能参与pSS的病理生理过程。
Backgroud
Primary Sjogren's syndrome(pSS) is a chronic autoimmune disease with a broad clinical spectrum that characiterized of lymphocyte proliferation and progressing organ-specific exocrinopathy to systemic manifestations. The pathogenesis of organs involved in pSS we could see lymphocytes infiltration, lots of autoantibodies detected in serum and accompanied with hyperglobulinemia, indicated immunocyte function disorder. MicroRNAs(miRNAs) as small, single-stranded noncoding Ring NAs, many of which have been highly conserved throughout evolution, is known to regulate cellular processes such as growth, development, aging and apoptosis, and associated with human diseases. The miRNAs have multiple regulating potential to broadly influence human immunocytes, and could control the development and function of innate and adaptive immune response by regulating target mRNA expression, and involved in the pathogenesis of autoimmune diseases. In pSS the immunocytes aggregation as the peripheral blood mononuclear cell (PBMC), is the essential target to exploring pathogenesis of the disease. To date, little is known about the roles of miRNAs in pSS pathogenesis and few studies had been published about it. Based on this point, this study was comparing the PBMC of pSS patients with healthy controls (Health Control, HC) to explore which miRNA expression profiling changes and impacts on the significance for the pSS. Furthermore, the dual-luciferase reporter transfection assay was used to analyze the miRNAs on auto-antigens SSA/Ro, SSB/La regulations, aimed at discovering a set of pSS-related miRNAs to investigate their roles in the pathogenesis of pSS.
Objective
Our aim was to analysis microRNA expression profile in PBMC of patients with pSS, searching for the special miRNAs associated with pSS and investigate the relative expression of special miRNAs of relevance to pSS clinial spectrum. Furthermore, to explore miRNAs which regulate the expression of antigen of Ro52(52KD-Ro/TRIM21), Ro60(60KD-Ro/TROVE2)and SSB.
Methods
(1) Using the Exiqon miRNA expression profile chip contains1896mature human miRNAs and146human-related virus miRNAs, the expression of miRNAs in pSS and HC PBMC was detected. Hierarchical clustering analysis was applied for determining pSS differentially expressed micrornas spectrum, and the method of quantitive Real-time PCR (qPCR) was applied for validation.
(2) The expression level of miR-181a, miR-155and miR-146a was detected by qPCR method in larger sample size, including33cases of patients with pSS and10cases of healthy controls. We analysised the expression levels of those miRNAs with the pSS patients'organ involvement condition, disease activity index and laboratory tests (IgG, ESR, hsCRP and the titre of ANA).
(3) Based on the result of miRNA chip profile, miRecords database and Targetscan software was applicated to predict miRNAs which may target genes of SSA and SSB. We built targeted gene3' UTR region expression vector and detected regulation effects identified by dual luciferase reporter assay.
Results
(1) The miRNA profiling microarray results shown that a set of pSS-specific miRNAs expression spectrum which contain382differentially expressed miRNAs, of which202miRNAs upregulated and180miRNAs downregulated.
(2) miR-181was detected upregulated in pSS PBMC by qPCR method in an expanded sample size and the relative expression to HC is2.81, with statistical significant difference (P<0.05). The analysis of spectrum correlation with clinical profiles shown that miR-181a was positively related to the titre of ANA, miR-155possibly associated with organ involvement, miR-146a is weak positively related to the ESR.
(3) We successfully built recombinant plasmid vector which contained TRIM21, TROVE2-2SSB and3' UTR region respectively. The result of dual luciferase reporter assay shown that miR-1207, miR-4695regulated TRIM21and miR-229regulated SSB, the luciferase activity in each control group was47.3%,53%and47.3%respectively. MiRNA-181a was dectected possible regulation effect on TRIM21, SSB and the luciferase activity in the control group was75.4%and75.5%respectively.
Conclusion The research results shown that the pSS PBMC have a specific miRNA expression profile. Overexpression of miR-181a was detected in pSS PBMC, which was positively correlated with the titer of ANA. MiR-181a, miR-1207, miR-4695and miR- 229was confirmed to have regulation effect on SSA/SSB3'UTR region which was probably involved in process of pathophysiological.
引文
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[16]Pan W, et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1[J]. J Immunol,2010,184:6773-81.
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[20]Nakamachi Y, et al. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis[J]. Arthritis Rheum,2009,60:1294-1304.
[21]Nakasa T, et al. expression of microRNA-146 in rheumatoid arthritis synovial tissue[J]. Arthritis Rheum,2008,58:1284-1292.
[22]Pauley KM, et al. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients[J]. Arthritis Res. Ther,2008,10:101.
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