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 对于这种衰弱的情况最多只能起到缓解作用。 更好的方法 管理和改善临床结果将不太可能发展 直到对发病机制有更好的了解。 组织学 组织化学证据表明成纤维细胞是靶细胞 在Graves眼病（GO）和相关的皮肤病中， 胫前皮肤病（PTD）。 在这种情况下， 受影响的组织中的糖胺聚糖导致特征性 临床异常 最初资助的中心前提是 有人认为，GO和PTD是由于 眼眶和胫前皮肤成纤维细胞的糖胺聚糖合成，和 这种异常是通过免疫事件介导的。 研究 在过去三年进行的研究，均支持这个假设， 有助于阐明导致这些结缔组织的效应途径， Graves病的组织表现 然而，引发这一事件的事件 眼眶和胫前皮肤的自身免疫反应尚不清楚;研究 旨在阐明这些起始事件的形式的基础上，这一赠款 退款 众所周知，TSH受体（TSH-r 0是甲状腺抗原 格雷夫斯氏病中循环自身抗体针对的抗体。 我们的初步数据表明，促甲状腺激素受体也表达在 成纤维细胞 拟用实验检验的假设是 促甲状腺激素-r是GO中重要的成纤维细胞抗原。 我们打算 确定1）是否来自眼后结缔组织的成纤维细胞 眼外肌周组织、胫前皮肤和腹部皮肤不同 在数量上或在它们的表达的调制上彼此不同， TSH-r RNA或TSH-r蛋白; 2）成纤维细胞TSH-r是否被识别 来自GO患者眼眶的淋巴细胞; 30 GO中的频率 在第一位的突变密码子52的TSH-r，并评估 tahe突变的免疫学和功能后果;以及4） 体外白细胞介素-1刺激的成纤维细胞糖胺聚糖 合成、细胞增殖和特定 免疫调节蛋白可被特异性抗IL-1试剂抑制。 我们希望这些拟议的研究将提高对以下问题的认识： 启动事件的发病机制，并将奠定基础， 用于将来在治疗中使用抗细胞因子药物的临床试验，或 预防GO。 我们相信更好地理解发病机制 将导致制定更好的管理战略，以帮助我们的 患有这种衰弱疾病的患者。

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.