Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
J Clin Endocrinol Metab. 2020 Jun 1;105(6). doi: 10.1210/clinem/dgaa124.
The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development.
Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization.
In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ-producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ-producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro.
Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.
本文旨在研究 Th1 细胞和 Th17 细胞谱系在 Graves 眼病（GO）极度严重发病中的特征。
通过流式细胞术分析 GO 患者、Graves 病（GD）患者和健康对照者的血液样本，以探索效应 T 细胞表型。对极度严重 GO 患者接受糖皮质激素（GC）治疗前后的血清进行脂质组学分析。采用免疫组织化学和 Western blot 法检测眼眶浸润性 Th17 细胞或体外 Th17 极化模型。
在 GD 中，Th1 细胞在周围效应 T 细胞亚群中占优势，而在 GO 中，Th17 细胞谱系占优势。在中重度 GO 中，Th17.1 细胞独立表达维甲酸受体相关孤儿受体-γt（RORγt）并产生白细胞介素-17A（IL-17A），而在极度严重 GO 中，Th17.1 细胞同时表达 RORγt 和 Tbet 并产生干扰素-γ（IFN-γ）。产生 IFN-γ的 Th17.1 细胞的增加与 GO 活性呈正相关，且与极度严重 GO 的发生有关。此外，GC 治疗抑制了 Th1 细胞和 Th17 细胞谱系，并调节了由 79 种血清代谢物组成的脂质谱。然而，在 GC 耐药的极度严重 GO 中，产生 IFN-γ的 Th17.1 细胞仍保持高水平，与血清甘油三酯升高相关。进一步的研究显示，GC 耐药的极度严重 GO 的眶后组织浸润着表达 Tbet 和 STAT4 的 CXCR3+Th17 细胞，且富含甘油三酯，促进了体外 Th17 细胞中 Th1 表型的表达。
本研究结果阐明了 Th17.1 细胞在 GO 发病机制中的重要性，可能有助于我们理解 Th17 细胞可塑性与 GO 疾病严重程度之间的关系。
