The role of CD40+ fibrocytes in thyroid associated ophthalmopathy

摘要 Graves病(GD)是一种影响甲状腺和眼眶的常见自身免疫综合征。轨道 甲状腺相关眼病(TAO)的表现是不同的，但可以包括 由于眼外肌和眼眶脂肪扩张而导致的斜视和视力丧失。目前，有 是否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性的替代标记物来指导治疗。这个 TAO的免疫渗透机制尚不清楚，但成纤维细胞被认为是眼眶细胞。 目标。细胞因子的过度表达似乎也在炎症性和非炎症性疾病中发挥关键作用。 疾病的纤维性表现。我们的长期目标是了解统一机制 GD的甲状腺和眼眶受累的潜在原因。这些洞察力应该为 评估疾病活跃度，推动开展靶向治疗。 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，我们确定了外周血和眼眶组织中纤维细胞水平的增加。 TAO患者与健康对照组比较。我们还证明了这些细胞是 在表型和功能上与TAO成纤维细胞相似，表达CD40。此外， CD40激活成纤维细胞可产生多种与TAO发病相关的细胞因子。我们 假设高度丰富的循环纤维细胞优先渗透到TAO眼眶组织和 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。 病人。根据我们的初步数据，我们已经确定了TAO患者病情严重 与稳定的TAO患者相比，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/或治疗过程中会发生变化。 我们还建议确定CD40介导的纤维细胞表达SELECT的机制和作用。 与TAO有关的细胞因子。我们首次证实了CD40在纤维细胞中的表达 因此，这一提议的信号机制尚未得到探索。然而，我们假设 CD40激活纤维细胞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。 CD40介导的纤维细胞细胞因子产生机制。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。

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.