The role of CD40+ fibrocytes in thyroid associated ophthalmopathy

描述(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综合征。眼眶表现称为甲状腺相关眼病(TAO)，是异质性的，但可包括斜视和由于眼外肌和眼眶脂肪扩张而导致的视力丧失。目前，还没有显示出可以预防、减缓或逆转TAO进行性和永久性影响的治疗方法。此外，没有疾病活动性或严重性的替代标记物来指导治疗。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在疾病的炎症和纤维化表现中都起着关键作用。我们的长期目标是了解GD中甲状腺和眼眶受累的统一机制。这些见解应该为评估疾病活动性提供生物标记物，并促进靶向治疗的发展。我们最近发现在TAO中存在骨髓源性成纤维细胞前体，称为成纤维细胞。具体地说，我们发现TAO患者外周血和眼眶组织中纤维细胞的水平与健康对照组相比增加。我们还证明了这些细胞在表型和功能上与TAO成纤维细胞相似，并且结构性地表达CD40。此外，通过CD40激活纤维细胞可产生多种细胞因子，这些细胞因子与TAO的发病机制有关。我们假设，高度丰富的循环纤维细胞优先渗透到TAO眼眶组织，并通过激活CD40，通过局部产生细胞因子来介导炎症和纤维化。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，我们已经确认，与稳定的TAO患者相比，病情严重的TAO患者的纤维细胞水平升高。我们的工作假设是，纤维细胞水平在疾病过程和/或治疗过程中发生变化。我们还建议确定CD40介导的纤维细胞表达与TAO有关的部分细胞因子的机制和作用。在这一方案中，我们首次证明了CD40在纤维细胞中的表达，因此其信号转导机制尚不清楚。然而，我们假设CD40对纤维细胞的激活是由典型的信号转导通路介导的。建议的研究将确定与纤维细胞水平升高相关的临床表现以及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记物的开发和TAO新疗法的引入。 与公共卫生相关：格雷夫斯病是一种自身免疫性疾病，会影响甲状腺，会导致眼睛周围的组织肿胀和发炎，并导致眼睛肿胀。我们发现了一种独特的细胞类型(纤维细胞)，这种细胞存在于这种疾病的患者中。我们建议研究血液中纤维细胞的数量是否可以预测疾病的严重程度或对治疗的反应。我们还提议识别这些细胞用来导致眼睛凸起的信号。我们认为这些实验将为患有这种疾病的患者带来更好的治疗。

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.