Carlsen Anting Liu, Schetter Aaron J, Nielsen Christoffer T, Lood Christian, Knudsen Steen, Voss Anne, Harris Curtis C, Hellmark Thomas, Segelmark Mårten, Jacobsen Søren, Bengtsson Anders A, Heegaard Niels H H
Statens Serum Institut, Copenhagen, Denmark.
Arthritis Rheum. 2013 May;65(5):1324-34. doi: 10.1002/art.37890.
To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE).
Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcription-polymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients.
Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 × 10(-9) ). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis.
Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor β signaling pathways. Other targets include regulation of apoptosis, cytokine-cytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.
评估系统性红斑狼疮（SLE）中无细胞循环微小RNA（miRNA）表达模式的特异性。
从血浆中纯化总RNA，使用定量逆转录-聚合酶链反应测定法测定45种不同的特异性成熟miRNA。共从364例不同的SLE患者、健康对照者和其他自身免疫性疾病对照者中获取了409份血浆样本。在62例SLE患者和29例健康对照者的初始队列中的结果在2个独立队列中得到验证：一个验证队列包括68例SLE患者和68例健康对照者，一个疾病对照队列包括20例SLE患者（其中19例来自另一个验证队列）、46例健康对照者、38例血管炎患者、18例类风湿关节炎患者和20例免疫抑制患者。
7种miRNA在SLE患者血浆中的表达存在统计学显著差异。miRNA-142-3p（miR-142-3p）和miR-181a的表达增加，而miR-106a、miR-17、miR-20a、miR-203和miR-92a的表达降低。此外，活动性肾炎的SLE患者中miR-342-3p、miR-223和miR-20a的表达显著降低。基于2种或4种miRNA的SLE预测模型在独立验证时可将SLE患者与对照者区分开（准确率76%）（P < 2×10⁻⁹）。使用4-miRNA模型可在SLE组和疾病对照组之间实现高度显著的区分，但血管炎患者除外。
SLE中循环miRNA发生系统性改变。一个4-miRNA特征可诊断SLE，并且特定的miRNA谱子集与肾炎相关。所有特征性miRNA均靶向转化生长因子β信号通路中的基因。其他靶点包括细胞凋亡调节、细胞因子-细胞因子受体、T细胞发育和细胞骨架组织。这些发现突出了SLE中可能失调的通路，并表明循环miRNA模式可将SLE与其他免疫炎症表型区分开来。
