EYE IN GRAVES DISEASE--ROLE OF ORBITAL FIBROBLASTS

格雷夫斯眼病的后果包括疼痛、炎症、 毁容、复视和失明。目前，治疗方案 对于这种虚弱的情况，充其量也只是治标不治本。更好的方法 不太可能发展到管理和改善临床结果 直到对发病机制有了更好的了解。组织学 组织化学证据表明成纤维细胞是靶细胞 在格雷夫斯眼病(GO)和相关的皮肤状况下， 胫前皮病(PTD)。在这些条件下，积累了 病变组织中的糖胺多聚糖导致了这种特征 临床异常。原资金来源的中心前提 有人认为，GO和PTD是由于对 眼眶和胫前皮肤成纤维细胞合成糖胺多糖，以及 这种异常是通过免疫事件来调节的。研究 在过去三年时间内进行的表演支持这一前提，以及 有助于阐明导致这些连接的效应器途径 Graves病的组织表现。然而，启动此操作的事件 眼眶和胫前皮肤中的自身免疫反应未知；研究 旨在阐明这些启蒙事件构成了这项拨款的基础 更新。 众所周知，TSH受体(TSH-R0是甲状腺抗原 在Graves病中循环中的自身抗体是针对这些抗体的。 我们的初步数据表明，TSH-r也表达在 成纤维细胞。拟议中的实验要检验的假设是 提示TSH-r是围棋重要的成纤维细胞抗原。我们打算 确定1)眼后结缔组织中的成纤维细胞 眼外肌周组织、胫前皮肤和腹部皮肤不同 彼此在数量上或表达上的调节 TSH-r RNA或TSH-r蛋白；2)成纤维细胞TSH-r是否被识别 由GO患者眼眶中的淋巴细胞检测；GO中的频率为30 TSH-r密码子52第一位的突变，并评估 Tahe突变的免疫和功能后果；以及4) 体外白介素1刺激成纤维细胞糖胺多聚糖 特异蛋白的合成、细胞增殖和表达 免疫调节蛋白可被特异性抗IL-1药物抑制。 我们希望这些拟议的研究将增进对 在围棋的发病机制中引发事件，并将奠定基础 在未来的临床试验中使用抗细胞因子药物治疗或 预防围棋。我们认为，对发病机制有更好的理解 将导致改进管理策略的发展，以帮助我们的 患有这种衰弱状况的患者。

The consequences of Graves' ophthalmopathy include pain, inflammation, disfigurement, diplopia and loss of vision. At present, treatment options for this debilitating condition are palliative at best. Better approaches to management and improved clinical outcome will not likely be developed until there is a better understanding of the pathogenesis. Histological and histochemical evidence suggests that the fibroblast is the target cell in both Graves' ophthalmopathy (GO) and in the associated skin condition, pretibial dermopathy (PTD). In these conditions, an accumulation of glycosaminoglycans in the affected tissues results in the characteristic clinical abnormalities. The central premise of the original funded proposal was that GO and PTD result from disordered regulation of glycosaminoglycan synthesis by orbital and pretibial skin fibroblasts, and that this abnormality is mediated through immunologic events. Studies performed in the past three years' time have supported this premise, and have helped to elucidate the effector pathway leading to these connective tissue manifestations of Graves' disease. However, events initiating this autoimmune reaction in the orbit and pretibial skin are unknown; studies aimed at elucidating these initiating events form the basis of this grant renewal. it is well known that the TSH receptor (TSH-r0 is the thyroid antigen against which circulating autoantibodies are directed in Graves' disease. Our preliminary data suggests that the TSH-r is also expressed on fibroblasts. The hypothesis to be tested y the proposed experiments is that the TSH-r is an important fibroblast antigen in GO. We intend to determine 1) whether fibroblasts from retroocular connective tissue extraocular perimysial tissue, pretibial skin and abdominal skin differ from each other in the quantity or the modulation of their expression of TSH-r RNA or TSH-r protein; 2) whether the fibroblast TSH-r is recognized by lymphocytes from the orbits of patients with GO; 30 the frequency in GO of a mutation in the first position of codon 52 of the TSH-r, and to assess the immunologic and functional consequences of tahe mutation; and 4) whether in vitro interleukin-1-stimulated fibroblast glycosaminoglycan synthesis, cellular proliferation and expression of particular immunomodulatory proteins can be inhibited by specific anti-IL-1 agents. We intend that these proposed studies will enhance the understanding of initiating events in the pathogenesis of GO, and will lay the groundwork for future clinical trials using anti-cytokine agents in the treatment or prevention of GO. We believe that a better understanding of pathogenesis will lead to the development of improved management strategies to help our patients with this debilitating condition.