Autoantibodies to Igf-1 Binding Sites in Thyroid Associated Ophthalmopathy

Abstract

Graves' disease is an autoimmune disorder but the nature of the association between hyperthyroidism and ophthalmopathy is not yet understood. Serum autoantibodies to orbital tissues have previously been identified and the cross-reactivity with orbital and thyroid antigens has been implicated in the development of thyroid-associated ophthalmopathy (TAO). The ophthalmopathy of Graves' disease is remarkable for the hypertrophy of extraocular muscles and proliferation of fibroblasts within the orbit;features which suggest a possible involvement of growth factors. The present study was therefore undertaken to investigate the interaction of IgGs extracted from the sera of patients with Graves' disease, with or without overt ophthalmopathy, with respect to IGF-1 receptor binding sites on fibroblasts from human orbital tissue.

IGF-1 binding sites were demonstrated on human orbital fibroblast monolayers grown from eye muscle explants. These cells exhibited a population of high affinity IGF-1 binding sites (Kd, 0.5nM SEM ±0.05). IgG prepared from sera taken from patients with Graves' disease (n = 23) significantly inhibited [¹²⁵I] IGF-1 binding to orbital fibroblasts when compared to IgGs prepared from normal volunteers (n = 13, p <0.002). It was found that 12 of 23 (52%) patients' IgG samples gave rise to significant levels of inhibition of [¹²⁵I]IGF-1 binding to orbital fibroblasts. The IgG preparations did not bind directly to IGF-1.

This study demonstrates that IgG prepared from patients with Graves' disease with or without overt ophthalmopathy interact with IGF-1 binding sites on orbital fibroblasts whereas IgG from normal subjects had no significant effect. This suggests (a) that antibodies may occur in Graves' disease which bind to the IGF-1 receptor and (b) that, if such antibodies were biologically active, IGF-1 mediated pathways may be implicated in the proliferation of orbital fibroblasts and hypertrophy of ocular muscles which characterise TAO.

Key Words:

• Thyroid
• Eye disease
• Autoantibodies
• IGF-1