Engineering a Soluble Human Thyroid-Stimulating Hormone Receptor Protein

Abstract

Graves’ orbital disease (GOD) or thyroid eye disease (TED) or thyroid ophthalmopathy (TO) is an inflammatory condition of the orbit, etiologically poorly characterized, that occurs in patients with autoimmune thyroid disease (1,2). It occurs in about 50% of patients with clinically evident Graves’ disease (3). Severe TED occurs in about 3% to 5% of all cases (3). Soft tissues and extraocular muscles of the orbit are involved in the pathogenesis of the disease, which is characterized by enlargement of the extraocular muscles and increase of retrobulbar fat that cause exophthalmos, the main clinical manifestation of the disease. Involvement of cornea, optic nerve and orbital soft tissues may occur during the natural history of the disease (2). During the early stages of the eye condition termed variously Graves’ orbital disease, thyroid eye disease, and thyroid ophthalmopathy (1-4), macrophages, highly specialized T cells, mast cells, and occasional plasma cells infiltrate the orbital connective, adipose, and muscle tissues (5,6). Several cytokines (interferon-γ [IFN-γ] (7), tumor necrosis factor-α [TNF-α], interleukin-1 [IL-1], and transforming growth factor-β [TGF-β] (8,9), as well as growth factors including insulin-like growth factor-1 (IGF-1) and platelet-derived growth factor (PDGF) (10,11), have been detected within the orbital tissues in TED and are now known to be produced both by infiltrating immunocompetent cells and by residential fibroblasts, adipocytes, myocytes, and microvascular endothelial cells. These cytokines and growth factors stimulate cell proliferation, glucosaminoglycan (GAG) synthesis, and expression of immunomodulatory molecules in orbital fibroblasts and microvascular endothelial cells (1,12-14).