Article

Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy.

Endocrine Unit, University of Newcastle Department of Medicine, Medical School, Newcastle-Upon-Tyne.
Autoimmunity (Impact Factor: 2.75). 01/1993; 16(4):251-7. DOI: 10.3109/08916939309014643
Source: PubMed

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.(ABSTRACT TRUNCATED AT 250 WORDS)

1 Bookmark
 · 
72 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The aim of this investigations was to study the effectiveness of anti-CD20 antibody therapy in Graves' orbitopathy (GO) resistant to glucocorticoids. Five patients were entered in the study. The protocol required no improvement of orbital status after a recent course of glucocorticoids. Activity of GO was confirmed by three independent techniques: clinical activity score (CAS), (99m)Tc-labeled diethylene triamine pentaacetic acid ((99m)Tc DTPA) single photon emission computed tomography and magnetic resonance imaging. Rituximab (RTX) was given as weekly infusions of 375 mg/m(2) body surface area for four weeks. The mean follow-up period was 67 (range 58-81) months. Improvement of GO has been observed in all patients: CAS before therapy was 6.5 ± 1.7 and decreased to 3.4 ± 1.6 by one month (p < 0.05) and remained unchanged (3.2 ± 1.7) at 12 months. No further CAS change, in either direction, was detected during the yearly follow-up visits. The mean DTPA uptake before therapy was 16.52 ± 4.51 MBq/cm(3) and decreased to 11.97 ± 2.36 MBq/cm(3) at one year (p < 0.002). The mean of T2 relaxation times before and one year after therapy were 96.91 ± 17.61 ms and 84.29 ± 9.41 ms, respectively (p < 0.001). The mean serum TSH receptor antibody (TRAb) levels before therapy, at the one month and one year control visits were 7.4 ± 3.4 U/L, 5.6 ± 4.5 U/L and 1.7 ± 1.5 U/L, respectively (p < 0.004). No correlation between changes of TRAb and activity parameters has been found. Anti-CD20 treatment seems to influence positively the clinical course of GO, and this effect seems to be stable for five years. To our knowledge, this is the longest published follow-up of RTX treatment in GO.
    Autoimmunity 07/2014; DOI:10.3109/08916934.2014.939266 · 2.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context: Graves' orbitopathy (GO) is caused by expansion of the orbital contents by excess adipogenesis and over-production of hyaluronan (HA). Immunosuppressive and anti-inflammatory treatments of GO are not always effective and can have side-effects, while targeting GO-associated tissue remodelling might be a more logical therapeutic strategy. Previously, we reported that signalling cascades through IGF1R and TSHR within orbital preadipocyte/fibroblasts drove adipogenesis and HA production. Our current study, combined stimulation of IGF1R and TSHR increase HA accumulation, which we hypothesize is by activation of PI3K1A/PI3K1B respectively. The central aim of this study was to investigate whether PI3K/mTORC1 inhibitors affected adipogenesis and/or HA production within orbital preadipocyte/fibroblasts. Methods: Human orbital preadipocytes were treated with/without inhibitors, LY294002 (PI3K-1A/mTORC1), AS-605240 (PI3K-1B) or PI103 (PI3K-1A/mTORC1) in serum-free medium for 24 h or cultured in adipogenic medium for 15 days. QPCR was used to measure HAS2 transcripts and the terminal adipogenesis differentiation marker LPL. HA accumulation in the medium was measured by ELISA. Results: Unlike AS-605240, both LY294002 (10 μM) and PI-103 (5 μM) significantly decreased HAS2 transcripts/HA-accumulation and adipogenesis. Since PI-103 and LY294002 are dual PI3K/mTOR inhibitors, we investigated inhibition of mTORC1 (rapamycin 100 nM), which significantly decreased adipogenesis but had no effect on HAS2 transcripts/HA, implicating PI3K-1A in the latter. Conclusions: Combined inhibition of PI3K-1A and mTORC1 signalling in vitro decreased both HA accumulation and adipogenesis. Since PI3K and mTOR inhibitors are clinically used to treat other conditions, they have potential to be repositioned to be used as an alternative non-immunosuppressive therapy of GO.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; 99(7):jc20134182. DOI:10.1210/jc.2013-4182 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: : The pathophysiology of thyroid eye disease (TED) is complex and incompletely understood. Orbital fibroblasts (OFs) seem to be the key effector cells that are responsible for the characteristic soft tissue enlargement seen in TED. They express potentially pathogenic autoantigens, such as thyrotropin receptor and insulin-like growth factor-1 receptor. An intricate interplay between these autoantigens and the autoantibodies found in Graves disease may lead to the activation of OFs, which then leads to increased hyaluronan production, proinflammatory cytokine synthesis, and enhanced differentiation into either myofibroblasts or adipocytes. Some of the OFs in TED patients seem to be derived from infiltrating fibrocytes. These cells originate from the bone marrow and exhibit both fibroblast and myeloid phenotype. In the TED orbit, they may mediate the orbital expansion and inflammatory infiltration. Last, lymphocytes and cytokines are intimately involved in the initiation, amplification, and maintenance of the autoimmune process in TED.
    Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society 06/2014; 34(2):177-85. DOI:10.1097/WNO.0000000000000132 · 1.09 Impact Factor