The role of CD40+ fibrocytes in thyroid associated ophthalmopathy

摘要 Graves病（GD）是一种常见的累及甲状腺和眼眶的自身免疫综合征。轨道 甲状腺相关眼病（TAO）的临床表现多种多样，但可包括 斜视和由于眼外肌和眼眶脂肪的扩张而导致的视力丧失。目前 目前还没有显示出预防、减缓或逆转TAO的进行性和永久性作用的疗法。 此外，没有疾病活动或严重程度的替代标志物来指导治疗。的 TAO的免疫浸润机制尚不清楚，但成纤维细胞被认为是眶细胞。 目标的细胞因子的过度表达似乎也在炎症和炎症反应中起关键作用。 疾病的纤维化表现。我们的长期目标是了解 GD中甲状腺和眼眶受累的基础。这些见解应该提供生物标志物， 评估疾病活动性，促进靶向治疗的发展。 我们最近牵连骨髓来源的成纤维细胞前体，称为纤维细胞在TAO。 具体地说，我们确定了外周血和眼眶组织中纤维细胞水平的增加， 与健康对照组相比，TAO患者。我们还证明，这些细胞是 在表型和功能上与TAO成纤维细胞相似，并且组成型表达CD 40。此外，委员会认为， 通过CD 40激活纤维细胞激发了几种与TAO病理相关的细胞因子。我们 假设高度丰富循环纤维细胞优先浸润TAO眼眶组织， 通过激活CD 40，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纤维细胞水平增加相关的临床参数 患者根据我们的初步数据，我们已经确定，TAO患者的严重疾病， 与稳定性TAO患者相比，纤维细胞水平增加。我们的假设是 纤维细胞水平在疾病过程和/或治疗期间改变。 我们还建议确定CD 40介导的纤维细胞表达选择性 与TAO有关的细胞因子。我们首次证实了CD 40在纤维细胞中的表达， 该提议，因此信号机制尚未被探索。然而，我们假设， 纤维细胞的CD 40活化由经典信号转导途径介导。 拟议的研究将确定与纤维细胞水平增加相关的临床表现 以及CD 40介导的纤维细胞因子产生机制。我们预计这些发现将 导致生物标志物的开发和TAO新疗法的引入。

Abstract 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.