Abstract
Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves’ disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves’ disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.
Highlights
Division of Metabolism, Department of Internal Medicine, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA
The original hypothesis was challenged by several important observations in liverspecific Insulin-Like Growth Factor (IGF)-I gene knock-out (KO) mice (Liver IGF-I−/−) [49,51]. Those IGF-I−/− animals grew normally compared to wild-type littermates, despite circulating IGF-I level reductions to less than 25% of those in intact animals [49]
IGF-I regulates several aspects of immune activities in myeloid, lymphoid and hematopoietic cell types through endocrine, autocrine and paracrine actions [65]. Both innate and adaptive immune systems are affected by IGF-I, insulin and IGFBPs [66]
Summary
Growth hormone (GH) can directly stimulate tissue growth in many organs, such as muscle, bone, and cartilage; many actions by GH are mediated indirectly through those of IGF-I. The original hypothesis was challenged by several important observations in liverspecific IGF-I gene knock-out (KO) mice (Liver IGF-I−/−) [49,51] Those IGF-I−/− animals grew normally compared to wild-type littermates (body weight, body length, and femoral length), despite circulating IGF-I level reductions to less than 25% of those in intact animals [49]. The growth-promoting effects of IGF-I via actions through IGF-IR include stimulation of DNA synthesis, cell proliferation, differentiation, and migration of many cell types [1,58] It inhibits apoptosis (programmed cell death) and repair (maintenance) of many tissues [59,60]. Diminished head circumference and underdeveloped facial structures characterize these patients These individuals represent a unique model for the roles of IGF-I in development of the human orbit [61] and the eye [62]. Growth of individual organs might be uncoupled from that of overall body growth, a divergence potentially involving IGF-IR [63]
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