AUTOANTIBODIES TO IGF-1 BINDING-SITES IN THYROID-ASSOCIATED OPHTHALMOPATHY

Graves' disease is an autoimmune disorder but the nature of the associ ation between hyperthyroidism and ophthalmopathy is not yet understood . Serum autoantibodies to orbital tissues have previously been identif ied and the cross-reactivity with orbital and thyroid antigens has bee n implicated in the development of thyroid-associated ophthalmopathy ( TAO). The ophthalmopathy of Graves' disease is remarkable for the hype rtrophy of extraocular muscles and proliferation of fibroblasts within the orbit; features which suggest a possible involvement of growth fa ctors. The present study was therefore undertaken to investigate the i nteraction of IgGs extracted from the sera of patients with Graves' di sease, with or without overt ophthalmopathy, with respect to IGF-1 rec eptor binding sites on fibroblasts from human orbital tissue. IGF-1 bi nding sites were demonstrated on human orbital fibroblast monolayers g rown from eye muscle explants. These cells exhibited a population of h igh affinity IGF-1 binding sites (Kd, 0.5nM SEM +/- 0.05). IgG prepare d from sera taken from patients with Graves' disease (n = 23) signific antly inhibited [I-125]IGF-1 binding to orbital fibroblasts when compa red to IgGs prepared from normal volunteers (n = 13, p < 0.002). It wa s found that 12 of 23 (52%) patients' IgG samples gave rise to signifi cant levels of inhibition of [I-125]IGF-l binding to orbital fibroblas ts. The IgG preparations did not bind directly to IGF-1.This study dem onstrates that IgG prepared from patients with Graves' disease with or without overt ophthalmopathy interact with IGF-1 binding sites on orb ital fibroblasts whereas IgG from normal subjects had no significant e ffect. 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 muscle s which characterise TAO.