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.
- The Journal of Clinical Endocrinology and Metabolism 02/2013; 98(2):515-8. DOI:10.1210/jc.2013-1004 · 6.21 Impact Factor
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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.Endocrine reviews 10/2013; 35(1). DOI:10.1210/er.2013-1055 · 21.06 Impact Factor
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ABSTRACT: Graves' disease (GD) is a common autoimmune condition. At its core, stimulatory autoantibodies are directed at the thyroid-stimulating hormone receptor (TSHR), resulting in dysregulated thyroid gland activity and growth. Closely associated with GD is the ocular condition known as thyroid-associated ophthalmopathy (TAO). The pathogenesis of TAO remains enigmatic as do the connections between the thyroid and orbit. This review highlights the putative molecular mechanisms involved in TAO and suggests how these insights provide future directions for identifying therapeutic targets. Genetic, epigenetic, and environmental factors have been suggested as contributory to the development of GD and TAO. Thyroid-stimulating hormone receptor and insulin-like growth factor receptor (IGF-1R) are expressed at higher levels in the orbital connective tissue from individuals with TAO than in healthy tissues. Together, they form a functional complex and appear to promote signaling relevant to GD and TAO. Orbital fibroblasts display an array of cell surface receptors and generate a host of inflammatory molecules that may participate in T and B cell infiltration. Recently, a population of orbital fibroblasts has been putatively traced to bone marrow-derived progenitor cells, known as fibrocytes, as they express CD45, CD34, CXCR4, collagen I, functional TSHR, and thyroglobulin (Tg). Fibrocytes become more numerous in GD and we believe traffic to the orbit in TAO. Numerous attempts at developing complete animal models of GD have been largely unsuccessful, because they lack fidelity with the ocular manifestations seen in TAO. Better understanding of the pathogenesis of TAO and development of improved animal models should greatly accelerate the identification of medical therapy for this vexing medical problem.Investigative ophthalmology & visual science 03/2014; 55(3):1735-48. DOI:10.1167/iovs.14-14002 · 3.40 Impact Factor
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