Evidence for an Association between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors: A Tale of Two Antigens Implicated in Graves’ Disease

Abstract

Thyroid-stimulating hormone receptor (TSHR) plays a central role in regulating thyroid function and is targeted by IgGs in Graves’ disease (GD-IgG). Whether TSHR is involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO), the orbital manifestation of GD, remains uncertain. TSHR signaling overlaps with that of insulin-like grow factor 1 receptor (IGF-1R). GD-IgG can activate fibroblasts derived from donors with GD to synthesize T cell chemoattractants and hyaluronan, actions mediated through IGF-1R. In this study, we compare levels of IGF-1R and TSHR on the surfaces of TAO and control orbital fibroblasts and thyrocytes and explore the physical and functional relationship between the two receptors. TSHR levels are 11-fold higher on thyrocytes than on TAO or control fibroblasts. In contrast, IGF-1R levels are 3-fold higher on TAO vs control fibroblasts. In pull-down studies using fibroblasts, thyrocytes, and thyroid tissue, Abs directed specifically against either IGF-1Rβ or TSHR bring both proteins out of solution. Moreover, IGF-1Rβ and TSHR colocalize to the perinuclear and cytoplasmic compartments in fibroblasts and thyrocytes by confocal microscopy. Examination of orbital tissue from patients with TAO reveals similar colocalization to cell membranes. Treatment of primary thyrocytes with recombinant human TSH results in rapid ERK phosphorylation which can be blocked by an IGF-1R-blocking mAb. Our findings suggest that IGF-1R might mediate some TSH-provoked signaling. Furthermore, they indicate that TSHR levels on orbital fibroblasts are considerably lower than those on thyrocytes and that this receptor associates with IGF-1R in situ and together may comprise a functional complex in thyroid and orbital tissue.

IgG4-related Ocular Adnexal Disease Mimicking Thyroid-associated Orbitopathy

“…Notably, in patients with TAO, alpha fodrin may be one of the autoantigens involved in both the salivary glands and orbit (16) and thus may have been responsible for the symptoms observed in our patient. In addition, calsequestrin, collagen XIII, IGF-1 receptor and TSH receptor have been proposed to be antigens involved in the pathogenesis of TAO (17,18). Further investigations are warranted to identify common autoantigens among autoimmune thyroid diseases, ocular adnexal diseases and IgG4-RD.…”

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

“…Moreover, these investigators found that both IGF-IR␤ and TSHR could be pulled down by antibodies specific for either protein. It is noteworthy that that report also suggested that interrupting IGF-IR signaling by incubating cells with a blocking monoclonal antibody directed against IGF-IR␣ (1H7) could attenuate the activation of Erk provoked by TSH (Tsui et al, 2008). Those findings imply a functional complex comprising TSHR and IGF-IR and that IGF-IR transactivation could mediate at least some aspects of TSHR signaling.…”

“…Specifically, TSHR and IGF-IR seem to act in concert to regulate discrete metabolic activities within the thyroid, including cellular proliferation and apoptosis. Recently, a report suggested that TSHR and IGF-IR colocalize in orbital fibroblasts and in human thyroid epithelial cells in culture (Tsui et al, 2008). Moreover, these investigators found that both IGF-IR␤ and TSHR could be pulled down by antibodies specific for either protein.…”

Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves’ ophthalmopathy: evidence that oxidative stress has a role in this disorder

“…[4][5][6][7][8][9] It may represent a complex interplay among orbital fibroblasts, immune cells, cytokines, autoantibodies, genetics, and environmental factors. [9][10][11][12][13] Recently, there is growing evidence that a change of reactive oxygen species (ROS) metabolism has been implicated in the aetiopathogenesis of several autoimmune disorders including Graves' disease and GO. [14][15][16] Bednarek et al 17,18 reported that the ROS and antioxidant enzymes were increased in peripheral blood of hyperthyroid patients and euthyroid patients with infiltrative ophthalmopathy.…”