THYROID EYE DISEASE (TED) RESOURCES

Chapter 1: Pathophysiology of Thyroid Eye Disease (TED)

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

Chapter 2: Inflammatory Cascade and Potential Consequences of TED

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

Damage can include:

• Proptosis
• Strabismus
• Corneal ulceration
• Optic nerve compression
• 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.
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.
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.