The role of CD40+ fibrocytes in thyroid associated ophthalmopathy

CD40纤维细胞在甲状腺相关性眼病中的作用

• 批准号: 8436241
• 负责人: RAYMOND S DOUGLAS
• 金额: $ 36.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436241
• 关键词: Affect; Autoantigens; Autoimmune Diseases; Autoimmune Process; Biological Markers; Blindness; Blood; Bone Marrow; CCL2 gene; Cells; Clinical; Data; Development; Disease; Eye; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Frequencies; Goals; Immune; Infiltration; Inflammation; Inflammatory; Interferon Type II; Knowledge; Lead; Mediating; Ocular orbit; Outcome; Pathologic; Patients; Play; Process; Production; Research; Role; Severities; Severity of illness; Signal Transduction; Signal Transduction Pathway; Strabismus; Surrogate Markers; Swelling; Syndrome; TNFRSF5 gene; TRAF6 gene; Testing; Therapeutic; Thyroid Gland; Time; Tissues; Ursidae Family; Vision; Work; abstracting; base; cell type; cytokine; insight; novel; orbit muscle; peripheral blood; prevent; research study; response; therapy development; thyroid associated ophthalmopathies

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.

抽象的 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。轨道 称为甲状腺相关眼病（TAO）的表现是异质的，但可以包括 眼外肌和眼眶脂肪扩张导致斜视和视力丧失。目前，有 目前尚无治疗方法能够预防、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。这 TAO 免疫浸润的机制尚不清楚，但提出成纤维细胞作为眼眶细胞 目标。细胞因子的过度表达似乎也在炎症和炎症反应中发挥着关键作用。 疾病的纤维化表现。我们的长期目标是了解统一机制 GD 中甲状腺和眼眶受累的基础。这些见解应该为以下方面提供生物标志物： 评估疾病活动性并促进针对性治疗的发展。 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，我们发现外周血和眼眶组织中纤维细胞的水平增加 TAO 患者与健康对照者进行比较。我们还证明这些细胞 表型和功能与 TAO 成纤维细胞相似，并且组成型表达 CD40。而且， 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， 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 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，我们确定 TAO 患者病情严重 与稳定 TAO 的患者相比，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/或治疗期间发生改变。 我们还建议确定 CD40 介导的纤维细胞表达的机制和作用 TAO 中涉及的细胞因子。我们首次证明了纤维细胞表达 CD40 该提议，因此信号机制尚未探索。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 TAO 生物标志物的开发和新疗法的引入。