Fibrosis in dysthyroid eye disease

Abstract

Dysthyroid eye disease is a rare condition, mainly found in people with Graves’ hyperthyroidism. Autoimmune responses to thyroid/orbit shared antigens drive extensive tissue remodelling. This includes excess adipogenesis and over-production of extra-cellular matrix, which both tend to occur in the earlier ‘active’ inflammatory stages of disease. With time these give way to fibrosis, which has a profound impact on eye motility and may be life-long. Progress has been made in identifying the shared autoantigen(s) and the role of specific T cells and autoantibodies in remodelling, which have facilitated development of novel therapies. However relatively little is known of the autoimmune processes under-pinning fibrosis and currently there are no adequate medical treatments.

摘要

甲状腺功能异常性眼病为罕见疾病, 主要见于 Graves甲状腺功能亢进的患者。由于甲状腺组织与眼眶组织存在共同抗原, 自身免疫反应可导致组织重塑。此过程包括过多的脂肪生成和细胞外基质的过度产生, 这两种情况均易发生在疾病活跃的炎症早期。随着疾病进展为组织纤维化阶段, 会对眼球的运动造成影响, 甚至影响终身。关于Graves眼病的在识别共同的自身免疫性抗原、特异性T细胞、自身抗体在组织重塑中的作用的研究已经取得了进展, 从而有助于研发新的治疗方法。然而, 在纤维化中自身免疫的在整个过程的作用机制还不清楚, 目前缺乏有效的药物治疗。

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Perros P, Hegedüs L, Bartalena L, Marcocci C, Kahaly GJ, Baldeschi L, et al. Graves’ orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement. Orphanet J Rare Dis. 2017;12:72. https://doi.org/10.1186/s13023-017-0625-1.

  2. 2.

    Draman MS, Ludgate M. Thyroid eye disease an update. Expert Rev Ophthalmol. 2016. https://doi.org/10.1080/17469899.2016.1202113.

  3. 3.

    Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velazquez-Villoria A, Galofre JC. Graves’ Ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015;2015:249125 https://doi.org/10.1155/2015/249125.

  4. 4.

    Wiersinga WM, Kahaly GJ. Graves’ orbitopathy: a multidisciplinary approach. 3rd ed. Karger; Basel; 2017.

  5. 5.

    Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM. Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br J Ophthalmol. 1998;82:773–9.

  6. 6.

    Wiersinga WM. Smoking and thyroid. Clin Endocrinol. 2013;79:145–51. https://doi.org/10.1111/cen.12222.

  7. 7.

    Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362:726–38. https://doi.org/10.1056/NEJMra0905750.

  8. 8.

    Rotondo Dottore G, Torregrossa L, Caturegli PP, Ionni I, Sframeli A, Sabini E, et al. Association of T and B cells infiltrating orbital tissues with clinical features of Graves’ orbitopathy. JAMA Ophthalmol. 2018;136:613–9. https://doi.org/10.1001/jamaophthalmol.2018.0806.

  9. 9.

    Virakul S, van Steensel L, Dalm VA, Paridaens D, van Hagen PM, Dik WA. Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves’ ophthalmopathy. J Clin Endocrinol Metab. 2012;97:E400–408. https://doi.org/10.1210/jc.2011-2697.

  10. 10.

    Paschke R, Ludgate M. The thyrotropin receptor in thyroid disease. N Engl J Med. 1997;337:1675–81.

  11. 11.

    Marcocci C, Bartalena L, Bogazzi F, Panicucci M, Pinchera A. Studies on the occurrence of ophthalmopathy in Graves’ disease. Acta Endocrinol. 1989;120:473–8.

  12. 12.

    Metcalfe R, Jordan N, Watson P, Gullu S, Wiltshire M, Crisp M, et al. Demonstration of IgG, IgA and IgE autoantibodies to the human thyrotropin receptor using flow cytometry. J Clin Endocrinol Metab. 2002;87:1754–61.

  13. 13.

    Crisp M, Lane C, Halliwell M, Wynford-Thomas D, Ludgate M. Thyrotropin receptor transcripts in human adipose tissue. J Clin Endocrinol Metab. 1997;82:2003–5.

  14. 14.

    Starkey KJ, Heufelder A, Baker G, Joba W, Evans M, Davies S, et al. Adipose thyrotrophin receptor expression is elevated in Graves’ and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. J Mol Endocrinol. 2003;30:369–80.

  15. 15.

    Eckstein A, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ opthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab. 2006;91:3464–70. https://doi.org/10.1210/jc.2005-2813

  16. 16.

    Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves’ orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation. Endocrinology. 2013;154:3008–15. https://doi.org/10.1210/en.2013-1576.

  17. 17.

    Berchner-Pfannschmidt U, Moshkelgosha S, Diaz-Cano S, Edelmann B, Görtz G-E, Horstmann M, et al. Comparative assessment of female mouse model of Graves’ orbitopathy under different environments, accompanied by proinflammatory cytokine and T-cell responses to thyrotropin hormone receptor antigen. Endocrinology. 2016;157:1673–82. https://doi.org/10.1210/en.2015-1829.

  18. 18.

    Smith TJ, Janssen J. Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy. Endocr Rev. 2018; https://doi.org/10.1210/er.2018-00066.

  19. 19.

    Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Köhrle J, et al. Autoantibodies to the IGF1 receptor in Graves’ orbitopathy. J Clin Endocrinol Metab. 2013;98:752–60. https://doi.org/10.1210/jc.2012-1771.

  20. 20.

    Marino M, Rotondo Dottore G, Ionni I, Lanzolla G, Sabini E, Ricci D, et al. Serum antibodies against the insulin-like growth factor-1 receptor (IGF-1R) in Graves’ disease and Graves’ orbitopathy. J Endocrinol Investig. 2019;42:471–80. https://doi.org/10.1007/s40618-018-0943-8.

  21. 21.

    Krieger CC, Neumann S, Place RF, Marcus-Samuels B, Gershengorn MC. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobins. J Clin Endocrinol Metab. 2015;100:1071–7.

  22. 22.

    Smith TJ, George J, Kahaly MD, Daniel G, Ezra MD, James C, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. 2007;376:1748–61. https://doi.org/10.1056/NEJMoa1614949.

  23. 23.

    Taylor P, Zhang L, Lee R, Muller I, Ezra D, Dayan M, et al. New Insights into the pathogenesis and non-surgical management of Graves’ orbitopathy. Nat Rev Endocrinol. Accepted for publication.

  24. 24.

    Kozdon K, Fitchett C, Rose GE, Ezra DG, Bailly M. Mesenchymal stem cell-like properties of orbital fibroblasts in Graves’ orbitopathy. Investig Ophthalmol Vis Sci. 2015;56:5743–50. https://doi.org/10.1167/iovs.15-16580.

  25. 25.

    Brandau S, Bruderek K, Hestermann K, Görtz GE, Horstmann M, Mattheis S, et al. Orbital fibroblasts from Graves’ orbitopathy patients share functional and immunophenotypic properties with mesenchymal stem/stromal. Cells Investig Ophthalmol Vis Sci. 2015;56:6549–57. https://doi.org/10.1167/iovs.15-16610.

  26. 26.

    Smith TJ. Insights into the role of fibroblasts in human autoimmune diseases. Clin Exp Immunol. 2005;141:388–97. https://doi.org/10.1111/j.1365-2249.2005.02824.x.

  27. 27.

    Alonso-Merino E, Martín-Orozco R, Ruíz-Llorente L, Martínez-Iglesias O, Velasco-Martín J, Montero-Pedrazuela A, et al. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses. PNAS. 2016;113:E3451–E3460. https://doi.org/10.1073/pnas.1506113113.

  28. 28.

    Zhang L, Baker G, Janus D, Paddon C, Fuhrer D, Ludgate M. Biological effects of thyrotropin receptor activation on human orbital preadipocytes. Investig Ophthalmol Vis Sci. 2006;47:5197–203. https://doi.org/10.1167/iovs.06-0596.

  29. 29.

    Kumar S, Nadeem S, Stan MN, Coenen M, Bahn RS. A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves’ ophthalmopathy. J Mol Endocrinol. 2011;46:155–63. https://doi.org/10.1530/jme-11-0006.

  30. 30.

    Zhang L, Bowen T, Grennan-Jones F, Paddon C, Giles P, Webber J, et al. Thyrotropin receptor activation increases hyaluronan production in preadipocyte-fibroblasts; contributory role in hyaluronan accumulation in thyroid dysfunction. J Biol Chem. 2009;284:26447–55.

  31. 31.

    Hagood JS. Thy-1 as an integrator of diverse extracellular signals. Front Cell Dev Biol. 2019. https://doi.org/10.3389/fcell.2019.00026.

  32. 32.

    Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol. 2003 ;163:1291–300.

  33. 33.

    Hu P, Barker TH. Thy-1 in integrin mediated mechanotransduction front. Cell Dev Biol. 2019. https://doi.org/10.3389/fcell.2019.00022.

  34. 34.

    Li H, Fitchett C, Kozdon K, Jayaram H, Rose GE, Bailly M, et al. Independent adipogenic and contractile properties of fibroblasts in Graves’ orbitopathy: an in vitro model for the evaluation of treatments. PLoS ONE. 2014;9:e95586. https://doi.org/10.1371/journal.pone.0095586.

  35. 35.

    Yang IH, Rose GE, Ezra DG, Bailly M. Macrophages promote a profibrotic phenotype in orbital fibroblasts through increased hyaluronic acid production and cell contractility. Sci Rep. 2019;9:9622 https://doi.org/10.1038/s41598-019-46075-1.

  36. 36.

    Shin MS, Lee N, Kang I. Effector T cell subsets in systemic lupus erythematosus: update focusing on Th17 cells. Curr Opin Rheumatol. 2011;23:444–8. https://doi.org/10.1097/BOR.0b013e328349a255.

  37. 37.

    Fang S, Huang Y, Wang S, Zhang Y, Luo X, Liu L, et al. IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO. J Clin Endocrinol Metab. 2016;101:jc.2016-1882.

  38. 38.

    Fang S, Huang Y, Zhong S, Li Y, Zhang Y, Li Y, et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in Graves orbitopathy. J Clin Endocrinol Metab. 2017;102:4273–83. https://doi.org/10.1210/jc.2017-01349.

  39. 39.

    Lee GR. The balance of Th17 versus treg cells in autoimmunity. Int J Mol Sci. 2018;19:730. https://doi.org/10.3390/ijms19030730.

  40. 40.

    Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Investig. 2001;108:1097–104. https://doi.org/10.1172/JCI14235.

  41. 41.

    Köhling H, Plummer SF, Marchesi JR, Davidge KS, Ludgate M. The microbiota and autoimmunity: their role in thyroid autoimmune diseases. Clin Immunol. 2017;183:63–74. https://doi.org/10.1016/j.clim.2017.07.001.

  42. 42.

    Covelli D, Ludgate M. The thyroid, the eyes and the gut: a possible connection. J Endocrinol Investig. 2017. https://doi.org/10.1007/s40618-016-0594-6.

  43. 43.

    Many M-C, Costagliola S, Detrait M, Denef J-F, Vassart G, Ludgate M. Development of an animal model of autoimmune thyroid eye disease. J Immunol. 1999;162:4966–74.

  44. 44.

    Baker G, Mazziotti G, von Ruhland C, Ludgate M. Re-evaluating thyrotropin receptor induced mouse models of Graves’ disease & ophthalmopathy. Endocrinology. 2005;146:835–44.

  45. 45.

    Masetti G, Moshkelgosha S, Köhling H-L, Covelli D, Banga JP, Berchner-Pfannschmidt U, et al. Gut microbiota in experimental murine model of Graves’ orbitopathy established in different environments may modulate clinical presentation of disease. Microbiome. 2018;6:97. https://doi.org/10.1186/s40168-018-0478-4; https://microbiomejournal.biomedcentral.com/track/pdf/10.1186/s40168-018-0478-4.

  46. 46.

    Ohtani N, Kawada N. Role of the gut–liver axis in liver inflammation, fibrosis, and cancer: a special focus on the gut microbiota relationship. Hepatol Commun. 2019;3:456–70. https://doi.org/10.1002/hep4.1331.

  47. 47.

    Savin Z, Kivity S, Yonath H, Yehuda S. Smoking and the intestinal microbiome. Arch Microbiol. 2018;200:677–84.

  48. 48.

    Liu X, Wong SS, Taype CA, Kim J, Shentu TP, Espinoza CR, et al. Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution. Lab Investig. 2017;97:256–67.

Download references

Acknowledgements

I am sincerely grateful to the Cambridge Ophthalmological Society and organizers of the symposium for inviting me to participate once again in this excellent meeting; special thanks of course to Louise.

Author information

Correspondence to Marian Ludgate.

Ethics declarations

Conflict of interest

The author declares that she has no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ludgate, M. Fibrosis in dysthyroid eye disease. Eye 34, 279–284 (2020). https://doi.org/10.1038/s41433-019-0731-5

Download citation