Smith Terry J
Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, Ann Arbor, Michigan, USA.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Thyroid. 2025 Mar;35(3):232-244. doi: 10.1089/thy.2024.0606. Epub 2025 Feb 5.
Thyroid-associated ophthalmopathy (TAO, aka thyroid eye disease [TED], Graves' orbitopathy) remains poorly understood and inadequately treated since its initial description. It is disfiguring, can threaten vision, and represents an autoimmune process closely associated with thyroid disease. Unambiguous connections linking TAO to the glandular maladies of Graves' disease (GD) remain incompletely clarified. Detecting the thyrotropin receptor (TSHR) in periocular tissues suggests that this cell-surface protein represents a shared autoantigen with the thyroid gland, but we now know that its expression is ubiquitous. Most patients with TAO have relatively high circulating levels of activating anti-TSHR autoantibodies. Emerging more recently is the importance of insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of TAO. The TSHR/IGF-IR signaling complex apparently drives circulating fibrocytes and the unique phenotypes of fibroblasts inhabiting the TAO orbit (GD-OF). The PubMed database was scanned for articles dating back to the earliest time periods covered. Keywords used for primary searches included thyroid-associated ophthalmopathy, Graves' orbitopathy, TED, orbit, TSH receptor, IGF-I receptor, and autoimmune thyroid disease. Secondary searches used numerous other search terms. GD-OF have been characterized extensively as being particularly responsive to the immunological factors and key effectors in TAO pathogenesis. Both TSHR and IGF-IR are overexpressed by GD-OF and CD34 fibrocytes and form a signaling complex. They are activated through this TSHR/IGF-IR complex to produce large amounts of hyaluronan and express multiple cytokines. This complex mediates cellular responses to pathogenic IgGs in TAO. CD34 fibrocytes and CD34 OF also express relatively high levels of multiple thyroid autoantigens. Identifying IGF-IR as a key component of a receptor complex and its intertwining signaling activities with those of TSHR has led to a targeted medical therapy for TAO. This therapy involves the selective systemic inhibition of IGF-IR. Much has been learned over the preceding decades about the pathogenesis of TAO. Among these is the identification of IGF-IR as a pivotal component underpinning the disease. This has led directly to development of an effective targeted therapy. Important gaps in our understanding persist, and current therapies have limitations. Thus, despite these advancements, considerably more remains to be achieved.
自首次被描述以来，甲状腺相关性眼病（TAO，又称甲状腺眼病 [TED]、格雷夫斯眼眶病）一直未得到充分理解和有效治疗。它会损毁容貌，可威胁视力，是一种与甲状腺疾病密切相关的自身免疫过程。将TAO与格雷夫斯病（GD）的腺体疾病明确联系起来的研究仍未完全阐明。在眼周组织中检测到促甲状腺激素受体（TSHR），这表明这种细胞表面蛋白是甲状腺的一种共同自身抗原，但我们现在知道它在全身普遍表达。大多数TAO患者循环中具有较高水平的激活型抗TSHR自身抗体。最近，胰岛素样生长因子I受体（IGF-IR）在TAO发病机制中的重要性日益凸显。TSHR/IGF-IR信号复合物显然驱动循环中的纤维细胞以及居住在TAO眼眶（GD-OF）中的成纤维细胞的独特表型。对PubMed数据库进行扫描，查找最早涵盖时间段的文章。用于初步搜索的关键词包括甲状腺相关性眼病、格雷夫斯眼眶病、TED、眼眶、TSH受体、IGF-I受体和自身免疫性甲状腺疾病。二次搜索使用了许多其他搜索词。GD-OF已被广泛描述为对TAO发病机制中的免疫因素和关键效应器特别敏感。TSHR和IGF-IR在GD-OF和CD34纤维细胞中均过度表达，并形成信号复合物。它们通过这种TSHR/IGF-IR复合物被激活，从而产生大量透明质酸并表达多种细胞因子。该复合物介导TAO中细胞对致病性IgG的反应。CD34纤维细胞和CD34 OF也表达相对高水平的多种甲状腺自身抗原。将IGF-IR确定为受体复合物的关键组成部分以及它与TSHR相互交织的信号活动，促成了针对TAO的靶向药物治疗。这种治疗方法包括对IGF-IR的选择性全身抑制。在过去几十年里，人们对TAO的发病机制有了很多了解。其中包括确定IGF-IR是该疾病的关键组成部分。这直接促成了一种有效的靶向治疗方法的开发。我们的理解仍存在重要差距，当前的治疗方法也有局限性。因此，尽管取得了这些进展，但仍有相当多的工作有待完成。
