It Takes Two to Tango: IGF-I and TSH Receptors in Thyroid Eye Disease

Abstract Context Thyroid eye disease (TED) is a complex autoimmune disease process. Orbital fibroblasts represent the central orbital immune target. Involvement of the TSH receptor (TSHR) in TED is not fully understood. IGF-I receptor (IGF-IR) is overexpressed in several cell types in TED, including fibrocytes and orbital fibroblasts. IGF-IR may form a physical and functional complex with TSHR. Objective Review literature relevant to autoantibody generation in TED and whether these induce orbital fibroblast responses directly through TSHR, IGF-IR, or both. Evidence IGF-IR has traditionally been considered a typical tyrosine kinase receptor in which tyrosine residues become phosphorylated following IGF-I binding. Evidence has emerged that IGF-IR possesses kinase-independent activities and can be considered a functional receptor tyrosine kinase/G-protein-coupled receptor hybrid, using the G-protein receptor kinase/β-arrestin system. Teprotumumab, a monoclonal IGF-IR antibody, effectively reduces TED disease activity, proptosis, and diplopia. In addition, the drug attenuates in vitro actions of both IGF-I and TSH in fibrocytes and orbital fibroblasts, including induction of proinflammatory cytokines by TSH and TED IgGs. Conclusions Although teprotumumab has been proven effective and relatively safe in the treatment of TED, many questions remain pertaining to IGF-IR, its relationship with TSHR, and how the drug might be disrupting these receptor protein/protein interactions. Here, we propose 4 possible IGF-IR activation models that could underlie clinical responses to teprotumumab observed in patients with TED. Teprotumumab is associated with several adverse events, including hyperglycemia and hearing abnormalities. Underpinning mechanisms of these are being investigated. Patients undergoing treatment with drug must be monitored for these and managed with best medical practices.