BACKGROUND Graves' disease (GD) patients experience two major issues: one is the severe hyperthyroidism associated with newly diagnosed GD, and the other involves the disfiguring and dysfunctional features of active Graves' orbitopathy (GO). Therefore, the aim of our study was to identify potential markers involved in the initial phase of GD dysfunction and the development of active GO. METHODS Seventy-eight subjects were recruited: 40 with newly diagnosed GD, 20 with inactive GO and 18 with active GO. GO activity was evaluated by the clinical activity score (CAS, active GO = CAS ≥ 3), and severity was assessed according to the NOSPECS classification. Plasma selenium concentrations were determined by dual channel hydride generation atomic fluorescence photometry. A liquid chip assay was used to measure plasma Th1 cytokines IFN-γ and TNF-α; Th2 cytokines IL4, IL5 and IL6; Th17 cytokine IL23; Treg cytokines IL10 and TGF-β; and two chemokines, CCL2 (Th2 chemokine) and CXCL10 (Th1 chemokine). RESULTS Among the three groups, newly diagnosed GD patients showed significantly elevated plasma levels of CXCL10 and IL-23 (all p < 0.05). Both CXCL10 and IL23 were significantly correlated with hyperthyroidism severity, specifically, increasing FT3 and FT4 and decreasing TSH. Notably, a very strong positive relationship between IL23 and CXCL10 was revealed (adjusted R square = 0.795; p < 0.001). Moreover, the selenium level was lower, while that of CCL2 was higher, in active GO than in inactive GO (p = 0.007, p < 0.001, respectively). Likewise, we also discovered that increasing CCL2 levels and decreasing selenium levels were associated with high CAS. Remarkably, after adjusting for potential confounding factors, selenium (OR, 0.919) and CCL2 (OR, 1.042) were still independent predictors for the diagnosis of active GO, and similar conclusions were drawn by receiver operating characteristic (ROC) curve analysis. CONCLUSION Pro-inflammatory cytokines, especially Th17-associated cytokines (e.g., IL23) and Th1 chemokines (e.g., CXCL10), appear to be involved in the initial phase of GD dysfunction. Moreover, we revealed for the first time that decreased plasma selenium levels and increased concentrations of Th2 chemokines (e.g., CCL2) may reflect GO disease activity, shedding light on the diagnosis and evaluation of active GO.

中文翻译：

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参与新诊断坟墓病和活动性坟墓眼眶病发展的潜在标志物

背景 Graves 病 (GD) 患者经历两个主要问题：一个是与新诊断的 GD 相关的严重甲状腺功能亢进症，另一个涉及活动性 Graves 眼眶病 (GO) 的毁容和功能障碍特征。因此，我们研究的目的是确定参与 GD 功能障碍初始阶段和活跃 GO 发展的潜在标志物。方法 招募了 78 名受试者：40 名新诊断的 GD，20 名非活动性 GO 和 18 名活动性 GO。通过临床活动评分（CAS，活动性GO=CAS≥3）评估GO活动，并根据NOSPECS分类评估严重程度。通过双通道氢化物发生原子荧光光度法测定血浆硒浓度。液体芯片检测用于测量血浆 Th1 细胞因子 IFN-γ 和 TNF-α；Th2 细胞因子 IL4、IL5 和 IL6；Th17 细胞因子 IL23; Treg 细胞因子 IL10 和 TGF-β；和两种趋化因子，CCL2（Th2 趋化因子）和 CXCL10（Th1 趋化因子）。结果三组中，新诊断的GD患者血浆CXCL10和IL-23水平显着升高（均p < 0.05）。CXCL10 和 IL23 均与甲亢严重程度显着相关，具体而言，增加 FT3 和 FT4 并降低 TSH。值得注意的是，IL23 和 CXCL10 之间显示出非常强的正相关关系（调整后的 R 平方 = 0.795；p < 0.001）。此外，活性 GO 的硒水平低于非活性 GO，而 CCL2 的硒水平高于非活性 GO（分别为 p = 0.007，p < 0.001）。同样，我们还发现增加 CCL2 水平和降低硒水平与高 CAS 相关。值得注意的是，调整潜在混杂因素后，硒（OR，0.919）和CCL2（OR，1.042）仍是诊断活动性GO的独立预测因子，受试者工作特征（ROC）曲线分析得出类似结论。结论 促炎细胞因子，尤其是 Th17 相关细胞因子（例如，IL23）和 Th1 趋化因子（例如，CXCL10），似乎参与了 GD 功能障碍的初始阶段。此外，我们首次发现血浆硒水平降低和 Th2 趋化因子（例如 CCL2）浓度增加可能反映了 GO 疾病的活动性，为活动性 GO 的诊断和评估提供了线索。并通过受试者工作特征（ROC）曲线分析得出了类似的结论。结论 促炎细胞因子，尤其是 Th17 相关细胞因子（例如，IL23）和 Th1 趋化因子（例如，CXCL10），似乎参与了 GD 功能障碍的初始阶段。此外，我们首次发现血浆硒水平降低和 Th2 趋化因子（例如 CCL2）浓度增加可能反映了 GO 疾病的活动性，为活动性 GO 的诊断和评估提供了线索。并通过受试者工作特征（ROC）曲线分析得出了类似的结论。结论 促炎细胞因子，尤其是 Th17 相关细胞因子（例如，IL23）和 Th1 趋化因子（例如，CXCL10），似乎参与了 GD 功能障碍的初始阶段。此外，我们首次发现血浆硒水平降低和 Th2 趋化因子（例如 CCL2）浓度增加可能反映了 GO 疾病的活动性，为活动性 GO 的诊断和评估提供了线索。