title: Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors?
abstract: BACKGROUND
  The immunopathogenesis of Graves' ophthalmopathy (GO) is still incompletely understood. Attention has shifted from the TSH receptor (TSHR) to the IGF-I receptor (IGF-1R) as a major autoantigen. This review on the pathophysiology of GO focused on orbital fibroblasts and the question whether autoimmunity against TSHR or IGF-1R is primarily involved.
  
  
  METHODS
  Relevant papers on GO were identified by a search on PubMed and scrutiny of their reference lists. In addition, abstracts presented on GO at the 14th International Thyroid Congress in 2010 in Paris, France, were read.
  
  
  RESULTS
  Orbital fibroblasts (OF) are recognized as the prime target cells of the autoimmune attack in GO. In early stages OF are undifferentiated with low TSHR expression and are stimulated to produce hyaluronan by cytokines (released by activated infiltrating T cells) and not by Graves' IgG. OF lacking the surface glycoprotein Thy-1 (not present in the muscle compartment) may differentiate into adipocytes, associated with increased TSHR expression. Graves IgG stimulate hyaluronan in differentiated OF mostly via non-cAMP signaling pathways for growth, which can also be activated via TSHR. The existence of IGF-1R stimulating antibodies in serum remains dubious. Autoimmunity against IGF-1R is also observed in rheumatoid arthritis and is not specific for Graves' disease. Expression of IGF-1R on T and B lymphocytes may contribute to autoimmunity against fibroblasts.
  
  
  CONCLUSIONS
  Autoimmunity against TSHR is most likely initiating the immune response in GO. Autoimmunity against IGF-1R is not specific for Graves' DISEASE but may contribute to ongoing immune reactions.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands. w.m.wiersinga@amc.uva.nl
authors.forename: Wilmar M
authors.initials: WM
authors.lastname: Wiersinga
mesh_terms: D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000502:physiology*; D049970:Graves Ophthalmopathy / Q000276:immunology* / Q000503:physiopathology*; D006801:Humans; D017526:Receptor, IGF Type 1 / Q000276:immunology*; D011989:Receptors, Thyrotropin / Q000276:immunology*
chemical_list: D001324:Autoantigens; D011989:Receptors, Thyrotropin; D017526:Receptor, IGF Type 1