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Graves' orbitopathy (GO) is an inflammatory autoimmune disorder of the orbit. 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. In addition, the connective tissues are extensively remodeled with enlargement of the extra-ocular muscles and orbital adipose tissues. 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. 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. Moreover, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role in the pathogenesis of Graves’ ophthalmopathy.
Role of the TSHR in the immunopathogenesis of GO
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. 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. 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, that levels of TRAb correlate with the severity and clinical activity of the disease and with disease prevalence in untreated patients with Graves’ hyperthyroidism. Several laboratories have explored the impact of TSHR activation in these cells on signaling and cellular functions relevant to the orbital tissue changes. Both HA synthesis and new fat cell development appear to be enhanced by activation of orbital fibroblast TSHR, whether effected through ligation of the receptor by TSH or monoclonal TRAb, or by the introduction of an activating mutant TSHR. The phosphoinositide 3-kinase/Akt signaling cascade appears to be the primary effector of the processes, with input from adenylyl cyclase/cAMP and other signaling pathways. Circulating TRAb in patients with Graves’ hyperthyroidism is heterogeneous with differing potency and affinities. These antibodies activate various TSHR signaling cascades in thyrocytes, resulting in the overproduction of thyroid hormones. It appears likely that they similarly activate orbital fibroblast TSHR to modulate HA synthesis and adipogenesis (Figure 1).
Figure 1. Role of the TSHR in the immunopathogenesis of GO.
Thyrotropin/IGF-1 receptor crosstalk in GO pathogenesis
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. It has been reported that antibodies engineered to inhibit binding to and activation of IGF-1Rs, one of which is in a clinical trial as therapy for GO, and a specific IGF-1R kinase inhibitor partially inhibit stimulation of GOFs by TSH and by a monoclonal TSAb, M22, which exhibited a biphasic dose-response of GOF stimulation. As neither TSH nor M22 activates IGF-1R auto-phosphorylation, the major initiating step in the mechanism of IGF-1R signaling, some researches postulated that crosstalk between TSHR and IGF-1R is involved in GOF activation by GO-Igs (Figure 2). In recent studies have demonstrated that IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk after binding to TSHR, not by direct binding to/activation of IGF-1R, and that this crosstalk is important in the pathogenesis of GO.
Figure 2. IGF1R-dependent vs. IGF1R-independent TSHR stimulation of HA secretion in GOFs
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 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. Functioning as allosteric modulators, these molecules position themselves within the transmembrane helices binding pocket and prevent contact with deeper residues essential for agonist activity. Thus, their action does not involve competition for extracellular TSH or TRAb binding sites. These SML have been shown to inhibit cAMP production in human thyrocytes stimulated either by TSH or IgG from each of 30 patients with Graves’ hyperthyroidism. Whether these SML are also capable of inhibiting TSHR signaling pathways, HA synthesis, cytokine secretion or adipogenesis in human orbital fibroblasts is at present unknown. Because SML can be produced in large quantities and are not degraded in the GI tract, they may represent potential novel oral therapy for Graves’ hyperthyroidism and/or GO.
Evidences have showed 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. Moreover, inhibition of IGF-1R signaling partially inhibits GO-Ig stimulation of HA secretion by inhibiting crosstalk and this may be the mechanism of action of the antiIGF-1R antibody in clinical trials at present, which is likely acting like 1H7. Some researches suggest that a more effective medical approach to the treatment of GO would be by inhibiting TSHR signaling or by a combination therapy with antagonists to both TSHR and IGF-1R that might allow for lower doses of each and thereby decrease the likelihood of adverse effects. Until the day when these technologies fulfill their potential in creating a broadly applicable and permanent GO cure.
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