背景:甲状腺眼病(TED)涉及几种致病途径和一系列浸润单核细胞,细胞因子,和轨道上的趋化因子。揭示主要分子,在TED的发病机制中起着重要作用,将有助于开发新的治疗策略。方法:在多中心,单盲,病例对照研究,在眼眶减压术(44名TED患者)或非TED相关的眼整形(16名对照)手术期间收集了60个组织样本。福尔马林固定和石蜡包埋保存的眼眶组织。通过微聚合物标记技术用18种抗体对组织切片进行免疫染色。通过PanoramicDesk扫描免疫染色载玻片,并通过独立于用户的查看器软件进行盲目评估。结果:在临床活跃的TED患者(n=22)的眼眶组织标本中观察到明显的淋巴细胞浸润,而在非活跃的病例中(n=22)的程度要小得多。而它在对照组中不存在。在所有样本中都注意到血管分布增加,临床活动性TED标本中的眼眶充血。组织纤维化存在于TED样品中,但不存在于对照中。眼眶组织的免疫组织化学在TED和对照组之间明显区分,以及活跃和不活跃的TED之间。与对照组相比,分化簇20(CD20)除外,18种抗体中有17种在TED患者的眼眶结缔组织中高表达。尤其是,促甲状腺激素受体(TSH-R),胰岛素样生长因子1受体(IGF-1R),CD40,分化簇40配体(CD40L),CD3,CD68,白细胞介素-17A(IL-17A),IL-23A,IL-1β,IL-4在激活时受到调节,正常T细胞表达和分泌(RANTES),巨噬细胞趋化蛋白1(MCP-1),IL-16和B细胞活化因子(BAFF)在临床活性TED中过表达(所有p<0.001)。此外,CD40L的表达,IL-17A,IL-23A,IL-6,IL-1β,RANTES,BAFF非常高(TED/对照比>3),中等(比例>2),活性低(p<0.001),不活动的TED和控件,分别。TSH-R的表达,IGF-1R,CD40,CD40L,CD3,CD68,CD20,IL-17A,IL-23A,RANTES,MCP-1和BAFF与血清TSH-R刺激性抗体浓度和临床活性评分呈正相关且显着相关,而与TED持续时间呈负相关。轨道照射降低TSH-R(p<0.001)和IGF-1R表达(p=0.012);相反,既不吸烟,年龄,性别也不影响免疫组织化学染色。结论:适应性和细胞介导的免疫,TSH-R/IGF-1R和CD40/CD40L的过表达是TED的相关病理机制。在疾病的活跃阶段针对这些关键参与者提供了特定和新颖的治疗方法。
Background: Thyroid eye disease (TED) involves several pathogenic pathways and a battery of infiltrating mononuclear cells, cytokines, and chemokines in the orbit. Revealing the main molecules, which play a major role in the pathogenesis of TED, will help developing novel treatment strategies. Methods: In a multicenter, single-blind, case-control
study, 60 tissue samples were collected during orbital decompression (44 TED patients) or non-TED related oculoplastic (16 controls) surgeries. Formalin-fixation and paraffin embedding preserved orbital tissue. Tissue sections were immunostained with 18 antibodies by the micro-polymer labeling technique. Immunostaining slides were scanned by Panoramic Desk and blindly evaluated by a user-independent viewer software. Results: Marked lymphocyte infiltration was observed in orbital tissue specimens of patients with clinically active TED (n = 22) and to a much lesser extent in inactive cases (n = 22), while it was absent in controls. Increased vascularity was noted in all samples, with orbital congestion in specimens of clinically active TED. Tissue fibrosis was present in TED samples but not in controls. Immunohistochemistry of orbital tissue clearly differentiated between TED and controls, as well as between active and inactive TED. In contrast to controls and with the exception of cluster of differentiation 20 (CD20), 17 out of 18 antibodies were highly expressed in orbital connective tissue of TED patients. Especially, thyrotropin receptor (TSH-R), insulin-like growth factor 1 receptor (IGF-1R), CD40, cluster of differentiation 40 ligand (CD40L), CD3, CD68, interleukin-17A (IL-17A), IL-23A, IL-1β, IL-4, regulated on activation, normal T cell expressed and secreted (RANTES), macrophage chemoattractant protein 1 (MCP-1), IL-16, and B cell activating factor (BAFF) were overexpressed in clinically active TED (all p < 0.001). Also, the expression of CD40L, IL-17A, IL-23A, IL-6, IL-1β, RANTES, and BAFF was very high (TED/control ratio >3), moderate (ratio >2), and low in active (p < 0.001), inactive TED and controls, respectively. The expression of TSH-R, IGF-1R, CD40, CD40L, CD3, CD68, CD20, IL-17A, IL-23A, RANTES, MCP-1, and BAFF positively and significantly correlated with both serum TSH-R stimulatory antibody concentrations and clinical activity scores while it negatively correlated with TED duration. Orbital irradiation decreased TSH-R (p < 0.001) and IGF-1R expression (p = 0.012); in contrast, neither smoking, age, nor gender did impact immunohistochemical staining. Conclusions: Adaptive and cell-mediated immunity, overexpression of TSH-R/IGF-1R and CD40/CD40L are the relevant pathomechanisms in TED. Targeting these key players in the active phase of the disease offers specific and novel treatment approaches.