Autoantibodies to the IGF1 Receptor in Graves' Orbitopathy

ArticleinThe Journal of Clinical Endocrinology and Metabolism 98(2) · December 2012with21 Reads
DOI: 10.1210/jc.2012-1771 · Source: PubMed
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.
    • "Considerable data supporting cross-talk and interactions between TSHR and IGF-1R are available. The first deals with receptor cross talk between G-protein coupled receptors such as TSHR and tyrosine kinase receptors such as IGF-1R in the orbital fibroblasts [84]. Second, evidence has been provided on a closely linked physical relationship between TSHR and IGF-1R on the orbital fibroblast plasma membrane that may have a bearing on downstream signaling events mediated by each receptor [81]. "
    [Show abstract] [Hide abstract] ABSTRACT: Graves' orbitopathy (GO), also known as thyroid eye disease is an inflammatory disease of the orbital tissue of the eye that arises as a consequence of autoimmune thyroid disease. The central feature of the disease is the production of antibodies to the thyrotropin hormone receptor (TSHR) that modulate the function of the receptor leading to autoimmune hyperthyroidism and GO. Over the years, all viable preclinical models of Graves' disease have been incomplete and singularly failed to progress in the treatment of orbital complications. A new mouse model of GO based upon immunogenic presentation of human TSHR A-subunit plasmid by close field electroporation is shown to lead to induction of prolonged functional antibodies to TSHR resulting in chronic disease with subsequent progression to GO. The stable preclinical GO model exhibited pathologies reminiscent of human disease characterized by orbital remodeling by inflammation and adipogenesis. Inflammatory lesions characterized by CD3+ T cells and macrophages were localized in the orbital muscle tissue. This was accompanied by extensive adipogenesis of orbital fat in some immune animals. Surprisingly, other signs of orbital involvement were reminiscent of eyelid inflammation involving chemosis, with dilated and congested orbital blood vessels. More recently, the model is replicated in the author's independent laboratories. The pre-clinical model will provide the basis to study the pathogenic and regulatory roles of immune T and B cells and their subpopulations to understand the initiation, pathophysiology, and progression of GO. © Georg Thieme Verlag KG Stuttgart · New York.
    Full-text · Article · Aug 2015
    • "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 [61]. Therefore, one hypothesis is that local production of IGF-1, acting in autocrine or paracrine fashion , might be involved in the autoimmune reaction [10] . "
    [Show abstract] [Hide abstract] 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.
    Article · Jul 2015
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