Division of Endocrinology and Metabolism (Z.W., J.J.Z., R.R.Z., T.L., W.C.L.) and Division of Rehabilitation Medicine (X.H.F.), Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China; National Glycoengineering Research Center (X.B.), Shandong University, Jinan 250100, China; Central Research Laboratory (Q.Y.Z.), The Second Hospital of Shandong University, Jinan 250033, China; and Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Ministry of Public Health (Q.Y.Z., Z.W.L), Qilu Hospital, Shandong University, Jinan 250100, China.
J Clin Endocrinol Metab. 2014 Dec;99(12):E2620-7. doi: 10.1210/jc.2014-1883.
It is well known that regulatory T cells (Tregs) are abnormal in Graves' disease (GD) and play crucial roles in the breakdown of immune tolerance and GD development. However, there are controversies about whether the quantity and/or function of Tregs is aberrant in GD. The molecular mechanism of Tregs abnormality and its effects on GD development was still unclear, until now.
MiRNAs play important roles in the function and development of the immune system including Tregs. To reveal the Tregs abnormality and its molecular mechanism in GD, we systematically studied the quantity and immunosuppressive function as well as the differential expression profiles of miRNA and mRNA of Tregs in newly diagnosed patients with GD using TaqMan miRNA array and mRNA microarray.
Our results showed that the quantity and immunosuppressive function of Tregs in initial patients with GD was significantly decreased. More importantly, the retinoic acid (RA) pathway was markedly suppressed and its agonist, all-trans retinoic acid, could notably improve the quantity and immunosuppressive function of Tregs from patients with GD in vitro. In addition, many other pathways including protein ubiquitination and circadian rhythm were also significantly regulated in Tregs of GD.
This integrative study first revealed the expression profiles of mRNA/miRNA in Tregs of initial GD and RA pathway might play important roles in GD development. Our results implied that all-trans RA, which had been used for a long time in the clinical setting, had potential value in the treatment of GD and was worthy of additional study.
众所周知，调节性 T 细胞（Tregs）在格雷夫斯病（GD）中异常，在打破免疫耐受和 GD 发展中起着至关重要的作用。然而，关于 Tregs 的数量和/或功能是否在 GD 中异常仍存在争议。Tregs 异常的分子机制及其对 GD 发展的影响至今仍不清楚。
miRNAs 在包括 Tregs 在内的免疫系统的功能和发育中发挥重要作用。为了揭示 GD 中 Tregs 的异常及其分子机制，我们使用 TaqMan miRNA 阵列和 mRNA 微阵列系统地研究了初诊 GD 患者 Tregs 的数量、免疫抑制功能以及 miRNA 和 mRNA 的差异表达谱。
我们的结果表明，初诊 GD 患者 Tregs 的数量和免疫抑制功能明显降低。更重要的是，视黄酸（RA）途径明显受到抑制，其激动剂全反式视黄酸可显著改善 GD 患者 Tregs 的数量和免疫抑制功能。此外，其他许多途径，包括蛋白泛素化和昼夜节律，在 GD 的 Tregs 中也受到显著调节。
这项综合研究首次揭示了初诊 GD 患者 Tregs 中 mRNA/miRNA 的表达谱，RA 途径可能在 GD 发病机制中起重要作用。我们的研究结果表明，全反式 RA 长期以来一直用于临床，在 GD 的治疗中有潜在价值，值得进一步研究。
