Thyrotropin Receptor Auto Antibodies in Graves' Ophthalmopathy

描述(申请人提供)：我们工作的长期目标是更好地了解Graves眼病(GO)的发病机制，以帮助开发治疗或预防这种疾病的新方法。这项实验室研究的目的是确定促甲状腺激素受体(TSHR)导向的自身抗体(TRAb)刺激GO眼眶前脂肪细胞脂肪生成的机制。翻译的目标是确定利妥昔单抗，一种阻断B细胞激活和分化的药物，是否在GO患者的试点研究中提供治疗益处。我们已经证明，GO患者眼眶组织中的成脂作用得到增强，TRAb可刺激GO眼眶前脂肪细胞的脂肪细胞发育。此外，我们还证实了患者眼眶组织标本中可溶性卷曲相关蛋白-1(SFRP-1)的表达增加，并提出了TRAb增强该蛋白在患者眼眶前脂肪细胞中表达的证据。SFRP-1是一种Wnt信号的抑制剂，作用于前脂肪细胞，逆转Wnt诱导的脂肪生成抑制，从而促进脂肪细胞的发育。类似于Graves病患者TRAb激活甲状腺TSHR并刺激甲状腺激素的过度分泌，我们推测这些自身抗体激活眼眶前脂肪细胞上的/TSHR刺激GO的脂肪生成。这项提议的三个具体目的是检验以下假设：1)TRAb诱导的脂肪生成是通过抑制Wnt信号介导的，GO患者的免疫球蛋白具有相似的功能；2)GO眼眶前脂肪细胞对TRAb的反应与其他部位的前脂肪细胞不同；以及3)利妥昔单抗对严重活动期GO患者的治疗有效。我们将招募30名患者参加随机、前瞻性、双盲临床试验，以确定该药对临床活动评分、特定数量眼参数和与健康相关的生活质量的影响。我们相信，我们的项目代表了围棋研究的一种新颖的、综合的、翻译的方法。我们的研究将提供有关疾病发展机制的信息，并将确定一种新的治疗方法的有效性。

DESCRIPTION (provided by applicant): The long term objective of our work is to better understand the pathogenesis of Graves' ophthalmopathy (GO) in order to aid in the development of new approaches to treatment or prevention of this disease. The goal of the laboratory investigations in this proposal is to determine mechanisms involved in the stimulation of adipogenesis by thyrotropin receptor (TSHR)-directed autoantibodies (TRAb) in GO orbital preadipocytes. The translational goal is to determine whether rituximab, an agent that blocks the activation and differentiation of B cells, confers therapeutic benefit in a pilot study of patients with GO. We have shown that adipogenesis is enhanced in orbital tissues from GO patients, and that TRAb act to stimulate fat cell development in GO orbital preadipocytes. Further, we have demonstrated elevated expression of soluble frizzled-related protein-1 (sFRP-1) in patients' orbital tissue specimens, and present evidence that TRAb enhance expression of this protein in their orbital preadipocytes. sFRP-1 is an inhibitor of Wnt signaling that acts in preadipocytes to reverse Wnt-induced inhibition of adipogenesis, thereby enhancing fat cell development. Analogous to TRAb activating thyroidal TSHR and stimulating over-production of thyroid hormone in Graves' disease, we postulate that these autoantibodies activate/TSHR on orbital preadipocytes to stimulate adipogenesis in GO. The 3 specific aims of this proposal are to test the hypotheses that: 1) TRAb-induced adipogenesis is mediated via inhibition of Wnt signaling, and that IgG from GO patients function similarly; 2) GO orbital preadipocytes differ from preadipocytes from other sites in their responses to TRAb; and 3) Rituximab is effective in the treatment of patients with severe, active GO. We will enroll 30 patients in a randomized, prospective, double-blind clinical trial to determine effects of this agent on clinical activity score, specific quantitative ocular parameters, and health-related quality of life. We believe that our program represents a novel, integrated, translational approach to the study of GO. Our studies will yield information concerning mechanisms involved in disease development, and will determine the effectiveness of a novel approach to therapy.