TOPIC: Potential role for the IGF-1 receptor on T cells in Graves- disease
Title: Aberrant expressions of the insulin-like growth factor-1 receptor by T cells from patients with Graves- disease may carry functional consequences for disease pathogenesis.
Authors: Douglas RS, Gianoukakis AG, Kamat S, & Smith TJ.
Reference: Journal of Immunology 178: 3281-3287, 2007
Thyroid-associated ophthalmopathy is clinically important yet still an inadequately understood complication of Graves- disease and, less commonly, of autoimmune thyroiditis. Considerable evidence points to a key role for orbital fibroblasts in the pathogenesis of the disease, not least through the production of excessive amounts of glycosaminoglycan which trap water and lead to edema. Smith and colleagues have previously reported that the insulin-like growth factor-1 receptor (IGF-1R) is expressed by a high percentage of fibroblasts in patients with Graves- disease and also that when treated with IGF-1 or with IgG from patients with Graves- disease, such fibroblasts (but not those from controls) synthesise high levels of interleukin-16 and RANTES. Both of these are T cell chemokines. Furthermore antibodies against the IGF-1R are detectable in almost all patients with Graves- disease but infrequently in those without.
The objective of this study was to examine whether the IGF-1R was also expressed on T cells in patients with Graves- disease. The authors have gone on to look at the role of IGF-1 and its receptor in T cells in patients with Graves- disease.
Initial studies were conducted using flow cytometry to identify expression of the IGF-1R. The authors also undertook cell proliferation assays and assays of apoptosis to determine the effects of IGF-1 and IgG from patients with Graves- disease (containing the putative IGF-1 receptor autoantibody). In addition, the authors were able to study T cells derived from the orbital tissue of patients with thyroid ophthalmopathy who were having a decompression as treatment.
There was considerable elevation of T cells expressing the IGF-1R in patients with Graves- disease compared to controls (mean values 48% versus 15%). The 33 patients with Graves- disease in this study were mostly euthyroid on treatment; most had stable ophthalmopathy but 8 had clinically active eye disease. In the small number of samples they were able to study, there was evidence that orbital T cells expressing the IGF-1R were increased in ophthalmopathy. Further analysis revealed the expression of IGF-1R was mainly on both CD4 and CD8 cells expressing CD45R0. IGF-1 was able to enhance T cell proliferation in the Graves- lymphocyte population but not in controls, and IgG from patients with Graves- disease was also able to enhance proliferation compared to control IgG. A similar dichotomy between Graves- samples and controls was found for the effect of IGF-1 inhibiting Fas mediated apoptosis.
The authors concluded that these findings suggest a potential role for the IGF-1R on T cells in Graves- disease, and suggest that the expansion of memory T cells in Graves- disease may be due in part to IGF-1 autoantibody effects.
A role for IGF-1 in thyroid-associated ophthalmopathy (TAO) was first suggested in 1986 when IGF-1 immunoreactivity was found in affected orbital tissues. IGF-1 is known to stimulate glycosaminoglycan production and collagen secretion by fibroblasts. The first description of IGF-1 receptor autoantibodies was by Weightman et al. in 1993, who found antibodies capable of displacing IGF-1 from its receptor in cultured orbital fibroblasts. As noted above, Smith et al. have gone on to use a number of methods to extend these earlier observations and have found good evidence for IGF-1 autoantibodies with functional and immunologically relevant effects.
The secretion of chemokines by fibroblasts in response to IGF-1 receptor antibodies could readily explain the predominant T cell infiltrate that occurs in the orbital muscles and the remainder of the orbital tissue in TAO. As always with such non-tissue specific autoantibodies, however, questions immediately come to mind concerning the localisation of the response to such a tightly defined anatomical site, and the failure of mothers with TAO to transmit eye disease to their offspring, whereas TSH receptor stimulating antibodies so readily causing neonatal thyrotoxicosis.
The present study shows a clear difference in T cell behavior in response to IGF-1 by Graves- samples compared to controls, and of course such differences would not be transmittable to a neonate. IGF-1 receptor expression is also up-regulated at a number of sites in different diseases, including fibroblasts and adipocytes in Crohn-s disease and fibroblasts and macrophages in inflammatory diseases of the lung. The present findings add to the evidence that IGF-1 has an important role in TAO and, more generally, in Graves- disease.
However, many questions remain. Although there was an effect in vitro of IgG from patients with Graves- disease on T cells, future studies should be undertaken to confirm that these effects are indeed due to autoantibodies directed against the IGF-1 receptor. Sequential studies in patients with Graves- disease would help to determine whether the T cell responses are primary, with autoantibody production against the IGF-1 receptor occurring secondarily. It would also be interesting to know whether there is any relationship between the severity of ophthalmopathy, IGF-1 receptor autoantibody levels, and the levels of the newly recognised excess of IGF-1 receptor expressing T cells. One might imagine that in patients with the most severe manifestations (with combined dermopathy & ophthalmopathy), there would be an even higher proportion of such T cells if they play a pathogenic role. Looking at time course of disease in response to treatment could also reveal fresh insights in this difficult disorder.
Summary and commentary prepared by Anthony Weetman (related to Chapter 12 of TDM) Access: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17312178&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum