Qi Yicheng, Zhou Yulin, Chen Xinxin, Ye Lei, Zhang Qianwei, Huang Fengjiao, Cui Bin, Lin Dongping, Ning Guang, Wang Weiqing, Wang Shu
Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Affiliated Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Front Immunol. 2017 Nov 1;8:1440. doi: 10.3389/fimmu.2017.01440. eCollection 2017.
Aberrant CD4+ T cell function plays a critical role in the process of Graves' disease (GD). MicroRNAs (miRNAs) are important regulators of T cell activation, proliferation, and cytokine production. However, the contribution of miRNAs to CD4+ T cell dysfunction in GD remains unclear.
To investigate how certain miRNA causes aberrant CD4+ T cell function in GD patients.
We compared the expression pattern of miRNAs in CD4+ T cells from untreated GD (UGD) patients with those from healthy controls. The most significantly dysregulated miRNAs were selected and their correlations with clinical parameters were analyzed. The effect of miR-4443 on CD4+ T cells cytokines production and proliferation was assessed. The potential gene target was identified and validated.
GD patients had unique pattern of miRNA expression profile in CD4+ T cells comparing to healthy subjects. miR-10a, miR-125b, and miR-4443 were the three most significantly dysregulated miRNAs. The elevated miR-4443 levels were strongly correlated with clinical parameters in an independent dataset of UGD patients ( = 40), while miR-4443 was normally expressed in GD patients with euthyroidism and negative TRAb level. We found that miR-4443 directly inhibited TNFR-associated factor (TRAF) 4 expression to increase CD4+ T cells cytokines secretion as well as proliferation through the NF-κB pathway. Furthermore, the TRAF4 levels in GD patients were inversely correlated with miR-4443, and knocking down TRAF4 had a similar effect with miR-4443 overexpression.
The increased expression of miR-4443 induced CD4+ T cells dysfunction by targeting TRAF4, which may cause GD.
异常的CD4+ T细胞功能在格雷夫斯病（GD）的发病过程中起关键作用。微小RNA（miRNA）是T细胞活化、增殖和细胞因子产生的重要调节因子。然而，miRNA在GD患者CD4+ T细胞功能障碍中的作用仍不清楚。
研究某些miRNA如何导致GD患者CD4+ T细胞功能异常。
我们比较了未经治疗的GD（UGD）患者与健康对照者CD4+ T细胞中miRNA的表达模式。选择失调最显著的miRNA，并分析它们与临床参数的相关性。评估miR-4443对CD4+ T细胞细胞因子产生和增殖的影响。鉴定并验证潜在的基因靶点。
与健康受试者相比，GD患者CD4+ T细胞中miRNA表达谱具有独特模式。miR-10a、miR-125b和miR-4443是失调最显著的三种miRNA。在一个独立的UGD患者数据集（n = 40）中，miR-4443水平升高与临床参数密切相关，而在甲状腺功能正常且TRAb水平为阴性的GD患者中，miR-4443正常表达。我们发现miR-4443直接抑制肿瘤坏死因子受体相关因子（TRAF）4的表达，通过核因子κB（NF-κB）途径增加CD4+ T细胞细胞因子的分泌和增殖。此外，GD患者中TRAF4水平与miR-4443呈负相关，敲低TRAF4与miR-4443过表达具有相似的效果。
miR-4443表达增加通过靶向TRAF4诱导CD4+ T细胞功能障碍，这可能是GD发病的原因。
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