The role of CD40+ fibrocytes in thyroid associated ophthalmopathy

描述（由申请人提供）：格雷夫斯病（GD）是一种影响甲状腺和眼眶的常见自身免疫综合征。被称为甲状腺相关性眼病 (TAO) 的眼眶表现是多种多样的，但可能包括斜视以及因眼外肌和眼眶脂肪扩张而导致的视力丧失。目前，尚无任何疗法可以预防、减缓或逆转 TAO 的渐进性和永久性影响。此外，没有疾病活动性或严重程度的替代标记来指导治疗。 TAO 的免疫浸润机制尚不清楚，但提出成纤维细胞作为眼眶细胞靶标。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志物，并促进靶向治疗的发展。我们最近发现 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相比，TAO 患者外周血和眼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，并且组成型表达 CD40。此外，通过 CD40 激活纤维细胞会引发多种与 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浸润 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，我们发现，与稳定的 TAO 患者相比，患有严重疾病的 TAO 患者的纤维细胞水平有所增加。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 相关的选定细胞因子的机制和作用。在本提案中，我们首次证明了纤维细胞表达 CD40，因此信号传导机制尚未探索。然而，我们假设纤维细胞的 CD40 激活是由经典信号转导途径介导的。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 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志物的开发和 TAO 新疗法的推出。 公共卫生相关性：格雷夫斯病是一种自身免疫性疾病，会影响甲状腺，并可能导致眼睛周围的组织肿胀、发炎以及眼睛凸出。我们发现这种疾病患者体内存在一种独特的细胞类型（纤维细胞）。我们提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出的信号。我们认为这些实验将为该疾病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.