Autoantibodies to the IGF1 Receptor in Graves' Orbitopathy
Institute for Experimental Endocrinology (W.B.M., N.D., T.W., C.S., N.G.M., J.K., L.S.), Charité-Universitätsmedizin Berlin, D-13353 Berlin, GermanyThe Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 12/2012; 98(2). DOI: 10.1210/jc.2012-1771
Context:Graves' disease (GD) is maintained by stimulating antibodies against the TSH receptor. Graves' orbitopathy (GO) is the main extrathyroidal manifestation of GD, potentially involving autoimmunity against the IGF1 receptor (IGF1R).Objective:We tested for autoantibodies against the IGF1R (IGF1R-Abs) in sera of GD patients and controls and elucidated their possible implication in the disease.Design:A diagnostic assay for IGF1R-Ab was established with recombinant human IGF1R as autoantigen. Serum samples or purified Ig preparations were analyzed for IGF1R binding and modulation of IGF1 signaling in vitro. A total of 108 consecutive GO patients represented on average by 5.4 separate serum samples per individual along with 92 healthy controls were analyzed.Results:IGF1R-Ab were detected in 10 serum samples from control subjects (11%) and in 60 samples (10%) from the GO patient serum bank. The positive patient samples were derived from 15 individuals yielding an IGF1R-Ab prevalence of 14% in GO. More than three consecutive samples were available from 11 of the 15 positive GO patients spanning an average disease period of 2 years. IGF1R-Ab concentrations were constantly elevated in these patients demonstrating relatively stable IGF1R-Ab expression over time. IGF1R-Ab failed to stimulate IGF1R autophosphorylation but instead inhibited IGF1-induced signaling in hepatocarcinoma HepG2 cells. Similarly, growth of MCF7 breast cancer cells was inhibited by IGF1R-Ab, supporting their classification as IGF1 antagonists.Conclusions:Our data demonstrate the existence of IGF1R-Abs in humans but do not support the hypothesis that the IGF1R-Abs contribute to GO pathogenesis.
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- "The authors concluded that IGF-1R antibodies do not contribute to the pathogenesis of GO. Serum IGF-1, IGF-II and IGF-binding proteins are present at normal levels in GO patients . Therefore, one hypothesis is that local production of IGF-1, acting in autocrine or paracrine fashion , might be involved in the autoimmune reaction  . "
ABSTRACT: Although there are adequate therapies for Graves' hyperthyroidism, mild to moderate Graves' orbitopathy (GO) is usually treated symptomatically whereas definitive therapy is reserved for severe, vision-threatening GO. Importantly, none of the treatment regimens for Graves' disease used today are directed at the pathogenesis of the disease. Herein, we review some aspects of what is known about the pathogenesis of these 2 major components of Graves' disease, specifically the apparent important roles of the TSH and IGF-1 receptors, and thereafter describe future therapeutic approaches directed at these receptors. We propose that targeting these receptors will yield effective and better tolerated treatments for Graves' disease, especially for GO. © Georg Thieme Verlag KG Stuttgart · New York.
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ABSTRACT: Thyroid autoimmunity involves loss of tolerance to thyroid proteins in genetically susceptible individuals in association with environmental factors. In central-tolerance, intrathymic autoantigen presentation deletes immature T-cells with high affinity for autoantigen-derived peptides. Regulatory T-cells provide an alternative mechanism to silence autoimmune T-cells in the periphery. The thyrotropin-receptor (TSHR), thyroid peroxidase (TPO) and thyroglobulin (Tg) have unusual properties ("immunogenicity") that contribute to breaking tolerance including size, abundance, membrane-association, glycosylation and polymorphisms. Insight into loss of tolerance to thyroid proteins comes from spontaneous and induced animal models:- 1) Intrathymic expression controls self-tolerance to the TSHR, not TPO or Tg; 2) Regulatory T-cells are not involved in TSHR self-tolerance and instead control the balance between Graves' disease and thyroiditis; 3) Breaking TSHR-tolerance involves contributions from MHC molecules (humans and induced mouse models), TSHR polymorphism(s) (humans) and alternative splicing (mice); 4) Loss of tolerance to Tg before TPO indicates that greater Tg immunogenicity versus TPO dominates central tolerance expectations; 5) Tolerance is induced by thyroid autoantigen administration before autoimmunity is established; 6) Interferon-α therapy for hepatitis C infection enhances thyroid autoimmunity in patients with intact immunity; Graves' disease developing after T cell depletion reflects reconstitution autoimmunity; 7) Most environmental factors (including excess iodine) "reveal", but do not induce thyroid autoimmunity. Micro-organisms likely exert their effects via bystander stimulation. Finally, no single mechanism explains the loss of tolerance to thyroid proteins. The goal of inducing self-tolerance to prevent autoimmune thyroid disease will require accurate prediction of at-risk individuals together with an antigen-specific, not blanket, therapeutic approach.
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