TED pathogenesis: A “complex” story of disordered signaling
Though the exact autoimmune triggers of thyroid eye disease are unknown, emerging evidence does identify two co-localized receptors expressed on orbital fibroblasts, acting together as a receptor signaling complex, as a key gatekeeper of the pro-inflammatory cascade and downstream effects.6
Watch how TED autoantibodies activate a receptor signaling complex
made up of the insulin-like growth factor 1 receptor (IGF‑1R) and the thyroid‑stimulating hormone receptor (TSHR) to mediate inflammation
cascade in actionDive deeper into orbital tissue changes
and their consequences
Thyroid eye disease, or TED, is a serious, progressive, and vision-threatening autoimmune disease. Emerging research demonstrates that the orbital fibroblast, a specialized cell responsible for tissue repair, is central to the pathophysiology of TED.1-4
Pathogenic orbital fibroblasts are believed to recruit fibrocytes and lymphocytes that infiltrate the orbit.4,5 Fibrocytes differentiate into orbital fibroblasts, which enhance T-cell proliferation and activation.2,4,6
T-cells and B-cells activate orbital fibroblasts and secrete cytokines, thyroid-stimulating hormone receptor, or TSHR, autoantibodies, and insulin-like growth factor-1 receptor, or IGF-1R, autoantibodies, which contribute to the inflammatory cascade.4,7
Two co-localized receptors reside on the surface of orbital fibroblasts: TSHR and IGF-1R, a gatekeeper of orbital fibroblast activation.2,4,8-10 Autoantibodies activate TSHR and IGF-1R, and cross talk mediated by beta-arrestin creates a receptor-signaling complex that stimulates orbital fibroblasts.4,11
Once activated, orbital fibroblasts proliferate and produce inflammatory cytokines and hydrophilic hyaluronan, which enlarges orbital tissue volume.1,4 Activated orbital fibroblasts differentiate into adipocytes and myofibroblasts, which contribute, respectively, to adipogenesis and fibrosis of the orbital tissues.4,12
The ensuing tissue expansion and remodeling leads to crowding in the fixed bony orbit, and this may have long-term sequelae.4 Potentially irreversible damage can include proptosis, strabismus, corneal ulceration, optic nerve compression and vision impairment, such as diplopia, optic neuropathy, or even blindness.13-15
Cross talk between TSHR and IGF-1R, as well as IGF-1R-mediated immune function, may play a critical role in the pathophysiology of TED. Understanding the cross talk may be vital to addressing this debilitating disease.4,10,16
References: 1. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726-738. 2. Shan SJ, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol. 2014;34(2):177-185. 3. Weiler DL. Thyroid eye disease: a review. Clin Exp Optom. 2017;100(1):20-25. 4. Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves’ ophthalmopathy. Exp Eye Res. 2016;142:83-91. 5. Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol. 2008;181(6):4397-4405. 6. Chesney J, Bacher M, Bender A, Bucala R. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci U S A. 1997;94(12):6307-6312. 7. Virakul S, van Steensel L, Dalm VA, Paridaens D, van Hagen PM, Dik WA. Platelet-derived growth factor: a key factor in the pathogenesis of Graves’ ophthalmopathy and potential target for treatment. Eur Thyroid J. 2014;3(4):217-226. 8. Smith TJ. Rationale for therapeutic targeting insulin-like growth factor-1 receptor and bone marrow-derived fibrocytes in thyroid-associated ophthalmopathy. Expert Rev Ophthalmol. 2016;11(2):77-79. 9. Gupta S, Douglas R. The pathophysiology of thyroid eye disease (TED): implications for immunotherapy. Curr Opin Ophthalmol. 2011;22(5):385-390. 10. Mohyi M, Smith TJ. IGF1 receptor and thyroid-associated ophthalmopathy. J Mol Endocrinol. 2018;61(1):T29-T43. 11. Krieger CC, Boutin A, Jang D, et al. Arrestin-β-1 physically scaffolds TSH and IGF1 receptors to enable crosstalk. Endocrinology. 2019;160(6):1468-1479. 12. Li H, Yuan Y, Zhang Y, Zhang X, Gao L, Xu R. Icariin inhibits AMPK-dependent autophagy and adipogenesis in adipocytes in vitro and in a model of Graves’ orbitopathy in vivo. Front Physiol. 2017;8. doi:10.3389/fphys.2017.00045. 13. Bruscolini A, Sacchetti M, La Cava M, et al. Quality of life and neuropsychiatric disorders in patients with Graves’ orbitopathy: current concepts. Autoimmun Rev. 2018;17(7):639-643. 14. Mamoojee Y, Pearce SHS. Natural history. In: Wiersinga WM, Kahaly GJ, eds. Graves’ Orbitopathy: A Multidisciplinary Approach—Questions and Answers. 3rd ed. Basel, Switzerland: Karger; 2017:93-104. 15. McAlinden C. An overview of thyroid disease. Eye Vis (Lond). 2014;1:9. doi:10.1186/s40662-014-0009-8. 16. Strianese D, Rossi F. Interruption of autoimmunity for thyroid eye disease: B-cell and T-cell strategy. Eye (Lond). 2019;33(2):191-199.
TED damage begins behind the eye
Inflammatory changes behind the eye
Before erythema or proptosis is visible, TED autoantibodies are targeting the orbital fibroblasts, the specialized cells responsible for tissue and cell repair, via the IGF-1R/TSHR signaling complex.1,6 The resulting inflammatory cascade causes muscle tissue within the orbit to swell.7 Adipose tissue at the back of the orbit also expands.7 These tissue changes within the rigid, bony space of the orbit force the eye forward (exophthalmos) and put dangerous pressure on the optic nerve.7
MRI studies can provide objective confirmation of the substantial inflammatory changes in and around the orbit and show the involvement of individual muscles, including early in the course of disease.8 In one study, MRI revealed extraocular muscular swelling in 70% of patients who had Graves’ disease but no visible signs of TED.9,10
The swelling of muscle and expansion of orbital fat seen on these types of imaging studies can cause ocular tenderness, pain, and pressure.7 As TED progresses, the increased intraorbital volume puts pressure on the eye and optic nerve as more pronounced signs begin to appear, such as proptosis/exophthalmos, vision changes, and signs of corneal exposure.7
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- Bahn RS. Graves' ophthalmopathy. N Engl J Med. 2010;362:726-738.
- Mamoojee Y, Pearce SHS. Natural History. In: Wiersinga WM, Kahaly GJ (eds): Graves’ Orbitopathy: A Multidisciplinary Approach – Questions and Answers. Basel, Karger. 2017:93-104.
- Bartley GB. The epidemiological characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Tr Am Ophth Soc. 1994;92:477-588.
- Laurberg P, Berman DC, Pedersen IB, Andersen S, Carlé A. J Clin Endocrinol Metab. 2012;92(7):2325-2332.
- Perros P, Crombie AL, Matthews JN, Kendall-Taylor P. Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol (Oxf). 1993;38(4):367-372.
- Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol. 2008;181:4397-4405.
- Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves' ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015;2015:249125.
- Kilicarsan R, Alkan A, Ilhan MM, et al. Graves’ ophthalmopathy: the role of diffusion-weighted imaging in detecting involvement of extraocular muscles in early period of disease. Br J Radiol. 2015;88(1047):20140677.
- Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375:1552-1665.
- Villadolid MC, Yokoyama N, Isumi M, et al. Untreated Graves’ disease patients without clinical ophthalmopathy demonstrate a high frequency of extraocular muscle (EOM) enlargement by magnetic resonance. J Clin Endocrinol Metab. 1995;80(9):2830-2833.
- Rootman DB, Golan S, Pavlovich P, Rootman J. Postoperative changes in strabismus, ductions, exophthalmometry, and eyelid retraction after orbital decompression for thyroid orbitopathy. Ophthal Plast Reconstr Surg. 2017;33:289-293.
- Ponto KA, Merkesdal S, Hommel G, Pitz S, Pfeiffer N, Kahaly GJ. Public health relevance of Graves’ orbitopathy. J Clin Endocrinol Metab. 2013;98:145-152.
- Bruscolini A, Sacchetti M, La Cava M, et al. Quality of life and neuropsychiatric disorders in patients with Graves' orbitopathy: current concepts. Autoimmun Rev. 2018;17:639-643.
- Vardizer Y, Berendschot TTJM, Mourits MP. Effect of exophthalmometer design on its accuracy. Ophthal Plast Reconstr Surg. 2005;21(6):427-430.
- Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J Ophthal. 2011;60(2):88-93.
- Dolman PH. Grading severity and activity in thyroid eye disease. Ophthal Plast Reconstr Surg. 2018;34:S34-S40.
- Bartley GB, Fatourechi V, Kadrmas EF, et al. Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology. 1996;103:958-962.
- Mitchell AL, Goss L, Mathiopoulou L, et al. Diagnosis of Graves' orbitopathy (DiaGO): Results of a pilot study to assess the utility of an office tool for practicing endocrinologists. J Clin Endocrinol Metab. 2015;100(3):E458-E462.
- Ponto KA, Pitz S, Pfeiffer N, Hommel G, Weber MM, Kahaly GJ. Quality of life and occupational disability in endocrine orbitopathy. Dtsch Arztebl Int. 2009;106:283-299.
- Park JJ, Sullivan TJ, Mortimer RH, Wagenaar M, Perry-Keene DA. Assessing quality of life in Australian patients with Graves' ophthalmopathy. Br J Ophthalmol. 2004;88:75-78.
- Kahaly GJ, Petrak F, Hardt J, Pitz S, Egle UT. Psychosocial morbidity of Graves’ orbitopathy. Clin Endocrinol. 2005;63:395-402.
- Yang DD, Gonzalez MO, Durairaj VD. Medical management of thyroid eye disease. Saudi J Ophthalmol. 2011;25:3-13.
- Strianese D, Iuliano A, Ferrara M, et al. Methotrexate for the treatment of thyroid eye disease. J Ophthalmol. 2014;2014:128903.
- Yakopson VS, Carrasco JR, Sharma P, Rabinowitz MP, Stefanyszyn MA. Effect of intraorbital steroid injections on intraocular pressure in thyroid eye disease. Thyroid Disorders Ther. 2015;4(1):1000173.
- Gillespie EF, Smith TJ, Douglas RS. Thyroid eye disease: Towards an evidence base for treatment in the 21st century. Curr Neurol Neurosci Rep. 2012;12(3):318-324.
- Phelps P, Williams K. Thyroid eye disease for the primary care physician. Disease-a-Month. 2014;60:292-298.