The role of CD40+ fibrocytes in thyroid associated ophthalmopathy

描述（由申请人提供）：Graves病（GD）是一种常见的影响甲状腺和眼眶的自身免疫性综合征。眼眶表现称为甲状腺相关性眼病（TAO），是异质性的，但可包括斜视和眼外肌和眼眶脂肪扩张引起的视力丧失。目前，没有任何治疗方法可以预防、减缓或逆转TAO的进行性和永久性影响。此外，没有疾病活动性或严重程度的替代标志物来指导治疗。TAO的免疫浸润机制尚不清楚，但成纤维细胞被认为是眼眶细胞的靶点。细胞因子的过度表达似乎也在疾病的炎症和纤维化表现中发挥关键作用。我们的长期目标是了解GD中甲状腺和眶部受累的统一机制。这些发现将为疾病活动性评估提供生物标志物，并促进靶向治疗的发展。我们最近在TAO中涉及骨髓来源的成纤维细胞前体，称为纤维细胞。具体来说，我们发现与健康对照组相比，TAO患者外周血和眶组织中的纤维细胞水平升高。我们还证明这些细胞在表型和功能上与TAO成纤维细胞相似，并组成性地表达CD40。此外，通过CD40激活纤维细胞可引发几种与TAO具有病理相关性的细胞因子。我们假设高度丰富的循环纤维细胞优先渗入TAO眼眶组织，并通过激活CD40，通过局部产生细胞因子介导炎症和纤维化。我们建议确定与TAO患者纤维细胞水平升高相关的临床参数。根据我们的初步数据，我们已经确定，与病情稳定的TAO患者相比，病情严重的TAO患者的纤维细胞水平增加。我们的工作假设是纤维细胞水平在疾病过程和/或治疗过程中发生改变。我们还建议确定cd40介导的纤维细胞表达与TAO相关的选择细胞因子的机制和作用。在本研究中，我们首次在纤维细胞中证实了CD40的表达，因此其信号机制尚不清楚。然而，我们假设纤维细胞的CD40活化是由典型信号转导途径介导的。提出的研究将确定与纤维细胞水平升高相关的临床表现和cd40介导的纤维细胞细胞因子产生的机制。我们预计这些发现将导致生物标志物的开发和新的TAO治疗方法的引入。

DESCRIPTION (provided by applicant): Graves' disease (GD) is a common autoimmune syndrome affecting the thyroid and orbit. The orbital manifestations, termed thyroid associated ophthalmopathy (TAO), are heterogeneous, but can include strabismus and loss of vision from expansion of the extraocular muscles and orbital fat. Currently, there are no therapies shown to prevent, slow or reverse the progressive and permanent effects of TAO. Furthermore, there are no surrogate markers of disease activity or severity to guide treatment. The mechanisms of immune infiltration of TAO are unclear, but fibroblasts are proposed as the orbital cell targets. Over-representation of cytokines also appears to play a critical role in both the inflammatory and fibrotic manifestations of disease. Our long-term goal is to understand the unifying mechanisms underlying the thyroidal and orbital involvement in GD. These insights should provide biomarkers for assessment of disease activity and promote the development of targeted treatment. We have recently implicated bone marrow-derived fibroblast precursors, called fibrocytes in TAO. Specifically, we identified increased levels of fibrocytes in the peripheral blood and orbital tissue of patients with TAO compared to healthy controls. We also demonstrate that these cells are phenotypically and functionally similar to TAO fibroblasts and constitutively express CD40. Moreover, fibrocyte activation via CD40 elicits several cytokines which bear pathologic relevance to TAO. We hypothesize that highly abundant circulating fibrocytes preferentially infiltrate the TAO orbital tissue and through activation of CD40, mediate inflammation and fibrosis through local production of cytokines. We propose to identify the clinical parameters associated with increased fibrocyte levels from TAO patients. Based upon our preliminary data, we have identified that TAO patients with severe disease have increased fibrocytes levels compared to patients with stable TAO. Our working hypothesis is that fibrocyte level is altered during the disease process and/or treatment. We also propose to determine the mechanism and role of CD40-mediated fibrocyte expression of select cytokines implicated in TAO. We have demonstrated CD40 expression by fibrocytes for the first time in this proposal, therefore the signaling mechanisms are yet unexplored. However, we hypothesize that CD40 activation of fibrocytes is mediated by canonical signal transduction pathways. The studies proposed will identify the clinical manifestations associated with increased fibrocyte levels and the CD40-mediated mechanisms of fibrocyte cytokine production. We anticipate these findings will lead to biomarker development and the introduction of novel therapies for TAO. PUBLIC HEALTH RELEVANCE: Graves' disease is an autoimmune disease which affects the thyroid and can cause the tissue around the eye to become swollen and inflamed and for the eyes to bulge. We have found a unique cell type (fibrocyte) which is present in patients with the disease. We are proposing to investigate whether the number of fibrocytes in the blood predicts the severity of disease or response to treatment. We are also proposing to identify the signals these cells use to cause the eyes to bulge. We feel these experiments will lead to better treatment for patients with the disease.