Best Practice & Research Clinical Endocrinology & Metabolism
5Immunopathogenesis of Graves’ ophthalmopathy: The role of the TSH receptor
Introduction
Graves’ orbitopathy (GO) is an inflammatory autoimmune disorder of the orbit.1 The immune basis of the disease is suggested by a perivascular and diffuse infiltration of CD4+ and CD8 + T cells, B cells, plasma cells and macrophages.2 In addition, the connective tissues are extensively remodeled with enlargement of the extra-ocular muscles and orbital adipose tissues.3, 4, 5, 6 Underlying these changes are excessive production of hyaluronic acid (HA) and new fat cell development. While GO affects primarily patients with a history of Graves’ hyperthyroidism, it is also encountered in euthyroid and hypothyroid individuals with laboratory evidence of autoimmune thyroid disease. While the onset of GO occasionally precedes or follows that of hyperthyroidism by several years, these conditions most commonly occur simultaneously or within 18 months of each other.7 Owing to the close clinical and temporal relationships between Graves’ hyperthyroidism and GO, investigators have long hypothesized that both autoimmune conditions derive from a single systemic process and share the thyrotropin receptor (TSHR) as a common autoantigen. In this review, we will explore current evidence that autoimmunity directed against TSHR on orbital cells sets in motion the connective tissue changes within the orbit that lead to the clinical disease.
Section snippets
The target cell in GO
Evidence from several laboratories suggests that orbital fibroblasts are the autoimmune target cells in GO.8, 9, 10, *11 Early studies found that orbital-infiltrating CD8 + T cells recognize orbital fibroblasts and not eye muscle extracts, and that they respond by proliferation via major histocompatibility complex (MHC) class II and CD40 signaling.9 Unlike eye muscle cells, orbital fibroblasts express human leukocyte antigen (HLA)-DR, suggesting that they may act as antigen-presenting cells.12
TSHR as autoantigen in GO
TSHR on thyroid follicular cells serves as the autoimmune target in Graves’ hyperthyroidism and antibodies directed against this cell surface receptor stimulate the over-production of thyroid hormones.16 Clinical observations suggesting that the same receptor may be the primary target in GO include that TSHR-directed autoantibodies (TRAb) can be detected in essentially all patients with GO, including euthyroid patients,17 that levels of TRAb correlate with the severity and clinical activity of
TSHR structure and function
TSHR is a glycoprotein hormone receptor which, along with luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR), is a member of the G protein-coupled receptor (GPCR) family.16 TSHR contains a large extracellular domain (ectodomain) that is mainly responsible for recognition and binding to the ligand, a seven-transmembrane domain, and an intracellular domain (endodomain) bound to G-protein subunits, mainly the Gαs and Gαq. Upon stimulation, both subunits trigger
TSHR antibodies
Sera from individual patients with Graves’ disease contain a mixture of TRAb.*34, 38 The ultimate clinical expression of the disease appears to be influenced by the particular varieties and affinities of TRAb present. The production of specific human, mouse and hamster monoclonal TSHR antibodies has allowed their use as probes to better understand TRAb binding sites and signaling pathways. TRAb can be classified as stimulating (TSAb), blocking (TBAb), or neutral depending on their respective
The potential role of TRAb in orbital tissue remodeling
Signs and symptoms experienced by patients with GO include proptosis (forward protrusion of the eyes), conjunctival and eyelid swelling and erythema, diplopia, and ocular pain. These features derive from expansion of the orbital adipose tissues and extra-ocular muscle bodies within the inflexible bony orbit. The resulting increase in orbital pressure displaces the orbit forward and hinders venous drainage, facilitating the accumulation of inflammatory mediators.1 Orbital inflammation in GO
Possible interactions between TSHR and IGF-1R
The IGF-1R, as well as the structurally related insulin receptor (IR), contains two α- and 2 β-chains that form a heterotetrameric structure linked by covalent disulphide bridges.59, 60 These receptors may also exist as hybrid dimers consisting of one α- β-dimer of each receptor type. Binding of either IGF-1 or insulin initiates dimerization, autophosphorylation, and activation of the receptor complex. Subsequent phosphorylation of tyrosine substrates leads to binding and activation of the
Novel TSHR-directed therapy for GO
Recent information concerning the structure of TSHR and its similarities to LHR and FSHR has led to the development of a generation of small molecule ligands (SML) of TSHR. Drs. Susanne Neumann and Marvin Gershengorn (Clinical Endocrinology Branch, National Institutes of Health, Bethesda, Maryland) have used molecular modeling, high-throughput screening and functional experiments to identify SML that inhibit TSH- and TSAb-stimulated signaling, as well as constitutive signaling of thyrocyte TSHR.
Summary
We present evidence that autoimmunity directed against TSHR on orbital cells sets in motion connective tissue remodeling within the orbit that leads to the various clinical expressions of GO. HA accumulation, expansion of orbital adipose tissues and local inflammation appear to be the salient histologic features of the disease. Orbital fibroblasts express functional TSHR and are considered to be the target cells. Several laboratories have explored the impact of TSHR activation in these cells on
Acknowledgments
This work was supported in part by the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (grant number DK77814 to RSB).
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