Autoantibodies to the IGF1 Receptor in Graves' Orbitopathy.Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Köhrle J, Eckstein A, Schomburg L. J Clin Endocrinol Metab. 2013 Feb;98(2):752-60. doi: 10.1210/jc.2012-1771
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: We tested for autoantibodies against the IGF1R (IGF1R-Abs) in sera of GD patients and controls and elucidated their possible implication in the disease.: 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.
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.
Ther data demonstrate the existence of IGF1R-Abs in an equal number of patients and control subjects, but do not support the hypothesis that the IGF1R-Abs contribute to GO pathogenesis. The antibodies appeared to be functional blocking antibodies
Circulating IgGs May Modulate IGF-I Receptor Stimulating Activity in a Subset of Patients With Graves' Ophthalmopathy.Varewijck AJ, Boelen A, Lamberts SW, Fliers E, Hofland LJ, Wiersinga WM, Janssen JA. J Clin Endocrinol Metab. 2013 Feb;98(2):769-76. doi: 10.1210/jc.2012-2270.
There is a close association between levels of TSH binding inhibitory immunoglobulins (TBIIs) and Graves' ophthalmopathy (GO). In addition to the TSH receptor, the IGF-I receptor (IGF-IR) has been proposed to be a second autoantigen that plays a role in the pathogenesis of GO.: The aim was to study relationships between TBII and serum IGF-IR stimulating activity in relationship to age in patients with GO.: We performed a prospective study of 70 patients with GO (26 euthyroid, 39 subclinical hyperthyroid, 5 hyperthyroid; 8 males, 62 females; age, 47.9 ± 1.0 y). Patients were graded according to clinical activity score. IGF-IR stimulating activity was determined by IGF-IR kinase receptor activation assay; TBIIs were measured by immunoassay (Trak). Protein G magnetic beads were used to deplete serum of IgGs.
TBII and clinical activity score were positively related (r = 0.30; P = .01). In subjects with TBII above mean +1 SD, IGF-IR stimulating activity was positively related to age (r = 0.43; P = .05), whereas such a relationship was absent for subjects with TBII below the mean +1 SD (r = -0.04; P = .81). Depletion of IgGs from sera of patients with both TBII above the mean +1 SD and IGF-IR stimulating activity above the mean -1 SD decreased IGF-IR stimulating activity, whereas depletion in patients with TBII above the mean +1 SD but IGF-IR stimulating activity below the mean -1 SD did not change IGF-IR stimulating activity
In subjects with TBII above the mean +1 SD, there was an increase of IGF-IR stimulating activity with age. In a subgroup of these patients, depletion of IgGs significantly decreased IGF-IR stimulating activity, suggesting that, in a subset of patients with GO, IgGs may have IGF-IR stimulating activities.
COMMENT-Both of these studies, using different assays,find IGF-1-R antibodies to be detectable in patients with GO. One study finds the antibodies equally present in controls, and apparrently having an inhibitory action on IGF-1 function. The second study finds increasing levels with patient’s age, and a correlation with TBII when TBII levels are high. Could this correlation reflect a generalized immune-stimulation of antibody formation in the presence of an active,on-going, immune response?. One may also question whether appropriate corrections were made for assessing significance when making multiple correlation
Together these two reports clearly indicate that anti-IGF-1-R antibodies can be present in GO patients, but do not indicate they play a causal role in the problem. L De Groot, MD
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