Abstract

The pathogenesis of orbital Graves’ disease (GD), a process known as thyroid-associated ophthalmopathy (TAO), remains incompletely understood. The thyrotropin receptor (TSHR) represents the central autoantigen involved in GD and has been proposed as the thyroid antigen shared with the orbit that could explain the infiltration of immune cells into tissues surrounding the eye. Another cell surface protein, insulin-like growth factor-I receptor (IGF-IR), has recently been proposed as a second antigen that participates in TAO by virtue of its interactions with anti-IGF-IR antibodies generated in GD, its apparent physical and functional complex formation with TSHR, and its necessary involvement in TSHR post-receptor signaling. The proposal that IGF-IR is involved in TAO has provoked substantial debate. Furthermore, several studies from different laboratory groups, each using different experimental models, have yielded conflicting results. In this article, we attempt to summarize the biological characteristics of IGF-IR and TSHR. We also review the evidence supporting and refuting the postulate that IGF-IR is a self-antigen in GD and that it plays a potentially important role in TAO. The putative involvement of IGF-IR in disease pathogenesis carries substantial clinical implications. Specifically, blocking this receptor with monoclonal antibodies can dramatically attenuate the induction by TSH and pathogenic antibodies generated in GD of proinflammatory genes in cultured orbital fibroblasts and fibrocytes. These cell types appear critical to the development of TAO. These observations have led to the conduct of a now-completed multicenter therapeutic trial of a fully human monoclonal anti-IGF-IR blocking antibody in moderate to severe, active TAO.

Highlights

  • The mechanisms underlying Graves’ disease (GD) remain incompletely understood [1]

  • Factors underpinning the orbital manifestations of GD, a process known as thyroid-associated ophthalmopathy (TAO), are even less well understood

  • TSHR is the most likely candidate by virtue of its established central role in mediating the hyperthyroidism associated with GD

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Summary

INTRODUCTION

The mechanisms underlying Graves’ disease (GD) remain incompletely understood [1]. Among the open questions is the basis for loss of immunological tolerance to the thyrotropin receptor (TSHR). IGF-IR and the insulin receptor (IR) belong to the family of ligand-activated, plasma membrane-bound tyrosine kinase receptors Both receptors are widely expressed in many tissues [7]. Specificity of IGF-I and insulin in vivo may result from divergence in the levels of the respective receptors in target tissues coordinated with respective ligand concentration and availability [15] Hybrid receptors comprising both IGF-IR and IR may form in cells expressing both proteins [16]. By virtue of its catalytic domain, IGF-IR has traditionally been considered a member of the receptor tyrosine kinase family It appears that receptor autophosphorylation, at tyrosine residues 1131, 1135, and 1136, is critical to initiation of IGF-I-dependent signaling [20, 21]. The protein suppresses IGF-IR activity while promoting MAPK signaling [22, 27]

GENERAL CONCEPTS ABOUT THE TSHR
AUTHOR CONTRIBUTIONS

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