Wakelkamp I M M J, Bakker O, Baldeschi L, Wiersinga W M, Prummel M F
Department of Endocrinology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Clin Endocrinol (Oxf). 2003 Mar;58(3):280-7. doi: 10.1046/j.1365-2265.2003.01708.x.
From in vitro studies using cultures of orbital fibroblasts, it has become clear that cytokines play an important role in the orbital inflammation in Graves' ophthalmopathy (GO). Orbital fibroblasts seem to be the key target cells of the autoimmune attack, and they are able to express the TSH receptor (TSH-R). In vivo data on the presence of cytokines in orbital tissues are sparse, and mostly limited to samples obtained from patients with endstage, inactive GO; the same holds true for the presence of the TSH-R. The aim of the present study was to determine whether the cytokine profile and TSH-R expression differ in the active vs. the inactive stage of GO.
Orbital fat/connective tissue was obtained from six patients with active, untreated GO undergoing emergency orbital decompression, and from 11 patients with inactive GO subjected to rehabilitative decompressive surgery. The mRNA levels of various cytokines and the TSH-R were assessed by real-time polymerase chain reaction (PCR) using the LightCycler. Data are expressed as ratios (unknown mRNA/beta-actin mRNA).
Active GO patients had much higher TSH-R expression than inactive patients: 4/0-24 (median value/range) vs. 0/0-9, P = 0.01. TSH-R expression was related to the Clinical Activity Score (r = 0.595, P = 0.015). Patients with active GO compared to those with inactive GO had higher mRNA levels of the proinflammatory cytokines interleukin-1beta (IL-1beta) (445/153-877 vs. 0/0-455, P = 0.001), IL-6 (1583/968-18825 vs. 559/0-7181, P = 0.01), IL-8 (1422/38-7579 vs. 32/0-1081, P = 0.046) and IL-10 (145/58-318 vs. 27/0-189, P = 0.002). In active GO there also existed a trend towards a predominance of T helper 1 (Th1)-derived cytokines as evident from higher IL-2 (37/0-158 vs. 0/0-68, P = 0.043), interferon-gamma (IFN-gamma) (20/0-79 vs. 0/0-16, P = 0.12) and IL-12 (2.3/0-14.8 vs. 0/0-1.6, P = 0.10) mRNAs. IL-1 receptor agonist (IL-1RA), IL-2 receptor (IL-2R), IL-3, IL-4, IL-5, IL-13, IL-18 and tumour necrosis factor-alpha (TNF-alpha) mRNAs were similar in both groups.
These data show that at the mRNA level, TSH-R expression is largely present only during the active stages of GO. The active phase is characterized by the presence of proinflammatory and Th1-derived cytokines, whereas other cytokines, among them Th2-derived cytokines, do not seem to be linked to a specific stage of GO.
通过使用眼眶成纤维细胞培养物进行的体外研究，已明确细胞因子在格雷夫斯眼病（GO）的眼眶炎症中起重要作用。眼眶成纤维细胞似乎是自身免疫攻击的关键靶细胞，并且它们能够表达促甲状腺激素受体（TSH-R）。关于眼眶组织中细胞因子存在情况的体内数据稀少，且大多限于从终末期、非活动期GO患者获取的样本；促甲状腺激素受体的情况也是如此。本研究的目的是确定细胞因子谱和TSH-R表达在GO的活动期与非活动期是否存在差异。
从6例接受紧急眼眶减压的未经治疗的活动期GO患者以及11例接受康复性减压手术的非活动期GO患者获取眼眶脂肪/结缔组织。使用LightCycler通过实时聚合酶链反应（PCR）评估各种细胞因子和TSH-R的mRNA水平。数据以比率（未知mRNA/β-肌动蛋白mRNA）表示。
活动期GO患者的TSH-R表达远高于非活动期患者：4/0 - 24（中位数/范围）对0/0 - 9，P = 0.01。TSH-R表达与临床活动评分相关（r = 0.595，P = 0.015）。与非活动期GO患者相比，活动期GO患者的促炎细胞因子白细胞介素-1β（IL-1β）（445/153 - 877对0/0 - 455，P = 0.001）、IL-6（1583/968 - 18825对559/0 - 7181，P = 0.01）、IL-8（1422/38 - 7579对32/0 - 1081，P = 0.046）和IL-10（145/58 - 318对27/0 - 189，P = 0.002）的mRNA水平更高。在活动期GO中，也存在以Th1衍生细胞因子占优势的趋势，这从更高的IL-2（37/0 - 158对0/0 - 68，P = 0.043）、干扰素-γ（IFN-γ）（20/0 - 79对0/0 - 16，P = 0.12）和IL-12（2.3/0 - 14.8对0/0 - 1.6，P = 0.10）mRNA中可见。两组中IL-1受体激动剂（IL-1RA）、IL-2受体（IL-2R）、IL-3、IL-4、IL-5、IL-13、IL-18和肿瘤坏死因子-α（TNF-α）的mRNA相似。
这些数据表明，在mRNA水平上，TSH-R表达主要仅在GO的活动期存在。活动期的特征是存在促炎和Th1衍生的细胞因子，而其他细胞因子，包括Th2衍生的细胞因子，似乎与GO的特定阶段无关。
