Soluble glucocorticoid-induced tumor necrosis factor receptor regulates Helios expression in myasthenia gravis
Soluble glucocorticoid-induced tumor necrosis factor receptor regulates Helios expression in myasthenia gravis
复制标题
可溶性糖皮质激素诱导的肿瘤坏死因子受体调节重症肌无力中Helios的表达
DOI：
10.1186/s12967-019-1916-1
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发表时间：
2019-05-22
影响因子：
7.4
通讯作者：
Yin, Weifan
中科院分区：
文献类型：
--
作者：
Li, Yi;Yang, Shumei;Yin, Weifan
背景Helios对调节性T细胞(Tregs)的功能和表型稳定性具有重要意义。然而，太阳神在自身免疫性疾病中的作用及其调控仍不清楚。本研究旨在探讨Helios+Tregs在重症肌无力(MG)中的作用及糖皮质激素诱导的肿瘤坏死因子受体(GITR)及其配体(GITRL)在调节Helios中的作用。采用酶联免疫吸附试验(ELISA法)测定血浆中可溶性GITRL/GITR水平。用磁选法分离Tregs，用重组GITRL和GITR-Fc处理。结果泛发性MG患者(n = 14例)与HD(n = 14例)和眼部MG(n = 16例)患者相比，Helios+Tregs和可溶性GITR均明显降低。与Helios−Treg相比，Helios+Treg具有更强的免疫抑制能力。进一步分析表明，可溶性GITR与MG定量评分呈负相关，促进Helios的表达，增强Tregs的功能，而不依赖于细胞膜GITR。结论MG患者体内存在Helios+Tregs和可溶性GITR的异常变化，GITR在Tregs的作用下对Helios有直接的调节作用。这项工作为GITR在Helios调控途径和MG发病机制中的作用提供了新的见解。
BackgroundHelios is important for functional and phenotype stability of regulatory T cells (Tregs). However, the role of Helios in autoimmune diseases and its regulation remains unclear. This study aimed to investigate the role of Helios+Tregs in myasthenia gravis (MG) and glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) in the modulation of Helios.MethodMulticolor flow cytometry was performed to analyze Helios+Tregs in peripheral blood from MG patients and healthy donors (HDs). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of soluble GITRL/GITR in plasma. Tregs were isolated via magnetic separation and treated with recombinant GITRL and GITR-Fc. Membrane GITRL on Tregs and expression of Helios and other markers (FOXP3, CD25, CD39, CTLA-4, PD-L1 and IL-10) involved in immunosuppressive activity were determined by flow cytometry.ResultBoth Helios+Tregs and soluble GITR were decreased in generalized MG (GMG) patients (n = 14), compared with HDs (n = 14) and ocular MG (OMG) patients (n = 16). Helios+Tregs possessed greater immunosuppressive capacity compared to Helios−Tregs. Further analysis indicates soluble GITR was negatively correlated with quantitative MG score and promoted Helios expression and enhanced function of Tregs independently of membrane GITRL.ConclusionThis work demonstrates abnormal changes in Helios+Tregs and soluble GITR in MG, as well as direct regulation of Helios by GITR in the context of Tregs. This work provides new insight into the role of GITR in the regulatory pathway of Helios and pathogenesis of MG.