Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
Department of Nuclear Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
Endocrine. 2024 Feb;83(2):432-441. doi: 10.1007/s12020-023-03490-9. Epub 2023 Aug 31.
This study aimed to explore the molecular pathogenesis of Graves' disease (GD).
The gene expression profile in CD4 T cells from GD patients and healthy controls were analyzed through mRNA-sequencing. The expression of NR4A2 was determined by quantitative real-time PCR and western blot. The levels of Th17 and Treg were determined by flow cytometry. ELISA was employed to detect the levels of IL-10, IL-17A, IL-17F and IL-22.
In the CD4 T cells from GD patients, there were 128 up-regulated and 510 down-regulated genes. Subsequently, we focused on the role of nuclear receptor 4 group A member 2 (NR4A2) in GD. NR4A2 was lowly expressed in the CD4 T cells from GD patients. Its expression was negatively correlated with free triiodothyronine and tetraiodothyronine, but positively correlated with thyroid stimulating hormone. NR4A2 knockdown decreased the percentage of Treg cells, with a decreased IL-10 level. While its over-expression augmented the Treg differentiation, with an elevated IL-10 level. In addition, knockdown or over-expression of NR4A2 showed no significant influence on Th17 differentiation.
These results indicate that the low level of NR4A2 in GD patients may suppress Treg differentiation, but have no influence on Th17 differentiation, leading to the imbalance of Th17/Treg and contributing to the development of GD. Revealing the role of NR4A2 in GD provides a novel insight for the treatment of GD.
本研究旨在探索格雷夫斯病（GD）的分子发病机制。
通过 mRNA 测序分析 GD 患者和健康对照者 CD4 T 细胞中的基因表达谱。通过定量实时 PCR 和 Western blot 测定 NR4A2 的表达。通过流式细胞术测定 Th17 和 Treg 的水平。采用 ELISA 检测 IL-10、IL-17A、IL-17F 和 IL-22 的水平。
在 GD 患者的 CD4 T 细胞中，有 128 个上调基因和 510 个下调基因。随后，我们重点研究了核受体 4 组 A 成员 2（NR4A2）在 GD 中的作用。NR4A2 在 GD 患者的 CD4 T 细胞中低表达。其表达与游离三碘甲状腺原氨酸和四碘甲状腺原氨酸呈负相关，与促甲状腺激素呈正相关。NR4A2 敲低降低了 Treg 细胞的百分比，IL-10 水平降低。而其过表达则增加了 Treg 分化，IL-10 水平升高。此外，NR4A2 的敲低或过表达对 Th17 分化没有显著影响。
这些结果表明，GD 患者 NR4A2 水平低可能抑制 Treg 分化，但对 Th17 分化没有影响，导致 Th17/Treg 失衡，促进 GD 的发生。揭示 NR4A2 在 GD 中的作用为 GD 的治疗提供了新的思路。
