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)
"However, in GO, the extra-ocular muscles do not express TSHR (Paschke et al. 1993), but a number of other eye muscle antigens have been characterized with serum antibodies from patients with GO (Gopinath et al. 2006). In addition, insulin-like growth factor receptor 1 (IGF1R) has been recognized as a relevant antigen in the pathogenesis of GO, perhaps serving as a second autoantigen (Weightman et al. 1993, Pritchard et al. 2003, Drexhage 2006). Resident fibroblasts and adipose tissue express functional TSHR and IGF1R (Bell et al. 2000, Zhang et al. 2009) and represent the key participants in orbital tissue remodeling in GO (Smith 2003), Recently, bone marrow-derived CD34 C fibrocytes have been detected among the fibroblasts inhabiting the orbit in GO, which express both receptors (Douglas et al. 2010, Kahaly 2010). "
[Show abstract][Hide abstract] ABSTRACT: The TSH receptor (TSHR) is the critical target for antibody production in Graves' disease (GD). Insulin-like growth factor 1 receptor (IGF1R) has been proposed as a second autoantigen in complications of GD such as orbitopathy. We attempted to induce orbital tissue remodeling in mice undergoing immunizations with plasmids encoding TSHR and IGF1R delivered by in vivo skeletal muscle electroporation, a procedure known to give a sustained, long-term antibody response. Female BALB/c mice were challenged with TSHR A-subunit or IGF1Rα subunit plasmid by injection and electroporation. Mice challenged with TSHR A-subunit plasmid resulted in high frequency (75%) of hyperthyroidism and thyroid-stimulating antibodies. But strikingly, immunization with TSHR A-subunit plasmid also elicited antibody to IGF1Rα subunit. Mice challenged in the same manner with IGF1Rα subunit plasmid produced strong antibody responses to IGF1R, but did not undergo any changes in phenotype. Simultaneous challenge by double antigen immunization with the two plasmids in distant anatomical sites reduced the incidence of hyperthyroidism, potentially as a consequence of antigenic competition. Thyroid glands from the TSHR A-subunit plasmid-challenged group were enlarged with patchy microscopic infiltrates. Histological analysis of the orbital tissues demonstrated moderate connective tissue fibrosis and deposition of Masson's trichrome staining material. Our findings imply that immunization with TSHR A-subunit plasmid leads to generation of IGF1R antibodies, which together with thyroid-stimulating antibodies may precipitate remodeling of orbital tissue, raising our understanding of its close association with GD.
Journal of Endocrinology 06/2011; 210(3):369-77. DOI:10.1530/JOE-11-0162 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Graves’ ophthalmopathy [thyroid-associated ophthalmopathy (TAO)] and dermopathy [thyroid-associated dermopathy (TAD)] are
extrathyroidal manifestations of Graves’ disease, which should be viewed as a multisystem autoimmune disease involving thyrocytes
but also orbital and pretibial fibroblasts. Smoking is a risk factor for TAO, and cessation of smoking is useful in the primary,
secondary and tertiary prevention of TAO. The immunopathogenesis of TAO and TAD looks very similar. Fibroblasts expressing
functional thyroid-stimulating hormone (TSH) receptors have been identified as the target cells of the autoimmune attack.
T cells sensitized to thyroid antigens (or TSH receptor stimulating antibodies, TSAb, in later stages) may recognize shared
antigens on fibroblasts, inducing release of cytokines. This results in the production of hydrophylic glycosaminoglycans,
causing tissue swelling. Recent findings point to the insulin-like growth factor (IGF)-1 receptor on fibroblasts as another
likely autoantigen. TAO appears to be primarily a Th1-cell-mediated disease. Intravenous methylprednisolone pulses are now
recommended as the treatment of choice in severe active TAO and topical corticosteroids under occlusive dressings for TAD.
Rehabilitative surgery for TAO should wait until the disease has become inactive. Promising new but still experimental treatment
modalities involve monoclonal antibodies against particular cytokines or T-cell surface molecules.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine if immunoglobulin G preparations (IgGs) from patients with Graves' disease can increase intracellular calcium in thyroid cells, as has been reported for TSH. Both TSH and Graves' IgGs (prepared by protein G affinity chromatography) increased calcium in a range of thyroid cells; however, the response seen, using Fura-2-loaded coverslips of cell monolayers, varied considerably. Chinese hamster ovary (CHO/JPO9) cells transfected with a high number of human TSH receptors showed the greatest response: TSH (10 mU/ml) increased calcium in 46% of experiments and 18 out of 25 (72%) Graves' IgGs increased calcium at 0.1 mg/ml (significantly greater, P < 0.001, than for control IgGs where cells responded to 2 out of 13 preparations). Rat FRTL-5 cells only responded to TSH in 22% of experiments and to 2 out of 8 (25%) of Graves' IgGs. Similarly, human thyroid cells responded to TSH in 22% of experiments and to 2 out of 9 (22%) of Graves' IgGs. (When studying cyclic AMP responses in JPO9 cells, much higher concentrations of Graves' IgGs were required (1-3 mg/ml). However, higher concentrations (0.3 mg/ml) of both Graves' IgGs, and to a lesser extent of control IgGs, were capable of increasing calcium in cells both with and without TSH receptors (control CHO cells and normal human dermal fibroblasts). We conclude that relatively low concentrations of patient IgGs can be distinguished from control IgGs in JPO9 cells on the basis of their ability to increase calcium, but that additionally all IgG preparations possibly contain another factor which can increase calcium in a range of cells independent of the presence of the TSH receptor.
Journal of Endocrinology 12/1994; 143(3):527-40. DOI:10.1677/joe.0.1430527 · 3.72 Impact Factor
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