Building the Case for Insulin-Like Growth Factor Receptor-I Involvement in Thyroid-Associated Ophthalmopathy

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.

Keywords: Graves’ disease; antibodies; autoantibodies; autoimmune; hybrid receptor; insulin-like growth factor I receptor; thyrotropin receptor.

Figure 1

Theoretical mechanisms involved in the crosstalk between insulin-like growth factor-I receptor (IGF-IR) and thyrotropin receptor (TSHR) pathways. (A) Binding of TSH-like agonists to TSHR activates the classical post-receptor pathway by inducing cAMP production, resulting in activation of protein kinase A, mitogen-activated ERK kinase (MEK), and mitogen-activated protein kinase (MAPK). Phosphorylated MAPK translocates to the nucleus where it stimulates several transcription factors regulating gene expression. In this scenario, TSHR activation of its post-receptor pathways is independent of IGF-IR activation. (B) Binding of IGF-I-like agonists to IGF-IR activates the classical post-receptor pathway by inducing receptor autophosphorylation leading to activation of the phosphoinositide 3-kinase pathway and phosphorylation of Akt. Phosphorylated Akt increases translocation of glucose and is essential for cell survival. Auto-phosphorylated IGF-IR may also activate Ras which stimulates RAF kinase activity and that of MEK, leading to stimulation of mitogen-activated protein kinase (MAPK). Phosphorylated MAPK translocates to the nucleus where it phosphorylates specific transcription factors regulating gene expression. In this scenario, stimulation of IGF-IR and its post-receptor pathways is independent of TSHR activation. (C) Bidirectional crosstalk between the two receptors can occur. IGF-IR agonists can enhance the effects of TSHR agonists. When IGF-IR agonists bind to IGF-IR and TSHR agonists bind to TSHR, additive/synergistic effects can result in higher amplitude stimulation and phosphorylation of MAPK than that resulting from TSHR agonists or IGF-IR agonists acting alone. (D) A specific antibody directly targeting IGF-IR might attenuate both IGF-IR- and TSHR-mediated events, thus inhibiting additive/synergistic actions of IGF-IR agonists mediated through TSHR. Blocking IGF-IR with an IGF-IR-specific antagonist may be equivalent to its knockdown. This situation is accompanied by relative TSHR insensitivity (55). (E) IGF-IR and TSHR appear to form a physical/functional tyrosine kinase/G protein-coupled receptor (RTK/GPCR) hybrid (57). Such hybrids utilize components of GPCR signaling and can thus activate conventional pathways used by both receptors. Importantly, IGF-IR stimulation by IGF-IR agonists may lead to non-canonical TSHR signaling. Thus, the identical pathways downstream from TSHR may be activated. In this model, signaling downstream from TSHR may occur independently of TSHR activation. Thus, functional IGF-IR/TSHR hybrids may result in bidirectional receptor crosstalk. (F) Formation of IGF-IR/TSHR hybrid receptors may underlie inhibitory anti-IGF-IR antibody attenuation of actions initiated at both receptors. Thus, blocking IGF-IR may inhibit both IGF-IR and TSHR-mediated effects. This situation may carry functional equivalence to knocking down IGF-IR, where relative insensitivity to TSH has been demonstrated (55).