Current Concepts in the Molecular Pathogenesis of Thyroid-Associated Ophthalmopathy

Abstract

Graves' disease (GD) is a common autoimmune condition. At its core, stimulatory autoantibodies are directed at the thyroid-stimulating hormone receptor (TSHR), resulting in dysregulated thyroid gland activity and growth. Closely associated with GD is the ocular condition known as thyroid-associated ophthalmopathy (TAO). The pathogenesis of TAO remains enigmatic as do the connections between the thyroid and orbit. This review highlights the putative molecular mechanisms involved in TAO and suggests how these insights provide future directions for identifying therapeutic targets. Genetic, epigenetic, and environmental factors have been suggested as contributory to the development of GD and TAO. Thyroid-stimulating hormone receptor and insulin-like growth factor receptor (IGF-1R) are expressed at higher levels in the orbital connective tissue from individuals with TAO than in healthy tissues. Together, they form a functional complex and appear to promote signaling relevant to GD and TAO. Orbital fibroblasts display an array of cell surface receptors and generate a host of inflammatory molecules that may participate in T and B cell infiltration. Recently, a population of orbital fibroblasts has been putatively traced to bone marrow-derived progenitor cells, known as fibrocytes, as they express CD45, CD34, CXCR4, collagen I, functional TSHR, and thyroglobulin (Tg). Fibrocytes become more numerous in GD and we believe traffic to the orbit in TAO. Numerous attempts at developing complete animal models of GD have been largely unsuccessful, because they lack fidelity with the ocular manifestations seen in TAO. Better understanding of the pathogenesis of TAO and development of improved animal models should greatly accelerate the identification of medical therapy for this vexing medical problem.

An update on thyroid-associated ophthalmopathy in children and adolescents

“…In early stages of the disease, connective tissue, orbital fat and muscles are infiltrated by T lymphocytes, mast cells and plasmatic cells. It was found that orbital fibroblasts are the main target of the autoagression process [16]. Activation of fibroblasts leads to their proliferation and differentiation into myofibroblasts and adipocytes and secondary production of glycosaminoglycans, chemokines and cytokines, which enhance inflammatory reaction in the orbital tissues [17,18].…”

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

“…Graves' orbitopathy (GO) is the extrathyroidal manifestation of Graves' disease characterized by an autoimmune inflammation resulting in an increased volume of the orbital connective tissue and enlargement of the extraocular muscles (Bahn 2010, Wang & Smith 2014. Orbital fibroblasts (OFs) are the main target cells in GO due to their expression of autoantigens specific to GO (Otto et al 1996, Bahn 2010, Wang & Smith 2014.…”

“…Orbital fibroblasts (OFs) are the main target cells in GO due to their expression of autoantigens specific to GO (Otto et al 1996, Bahn 2010, Wang & Smith 2014. Macrophages, T and B lymphocytes, and mast cells infiltrate the orbit and activate the OFs (Bahn 2010).…”

Thyrotropin and CD40L Stimulate Interleukin-12 Expression in Fibrocytes: Implications for Pathogenesis of Thyroid-Associated Ophthalmopathy

“…Activating autoantibodies targeting the TSHR and infiltrating lymphocytes cause thyroid gland dysfunction by driving overproduction of thyroid hormone and potentiating inflammation. Despite progress in understanding the endocrine manifestations of GD, the pathogenesis of thyroidassociated ophthalmopathy (TAO) and the role of the TSHR remain largely unknown (3). Orbital tissues from patients with TAO express several putative autoantigens, including the TSHR (4), which may mediate immune activation.…”