The role of interleukins 17, 23 and antibodies to the thyroid-stimulating hormone receptor in the pathogenesis of endocrine ophthalmopathy

Background. Endocrine ophthalmopathy (EOP) is an autoimmune orbit disease characterized by soft retrobulbar tissues damage. The level of antibodies to the thyroid-stimulating hormone receptor (TSHRAbs) is considered as a laboratory marker of EOP activity. Interleukins 17 (IL-17) and 23 (IL-23) play an important role in the pathogenesis of some autoimmune diseases and directly correlate with clinical activity. At present, there is an open question about the role of these cytokines in EOP and their relationship with TSHRAbs.

Aims. To assess pathogenetic role of IL-17, IL-23 and TSHRAbs in patients with EOP.

Materials and methods. The study included 50 people (100 eyes) at the age of 43 [35; 50] years. Three study groups were formed: 32 patients with moderate severity of EOP (clinical group), 18 patients with thyroid pathology without EOP (comparison group) and 15 healthy subjects (control group). All groups were comparable in age and sex. The diagnosis was verified clinically, laboratory and instrumentally. A comprehensive ophthalmologic examination and blood sampling were performed to determine the concentrations of IL-17, IL-23 and TSHRAbs. Statistical processing of the data was carried out in the program “Statistica 10.0”, StatSoft, Inc.

Results. An increase in the level of TSHRAbs was observed in all phases of EOP activity in comparison with both comparison group and control (p < 0.05). But in the active phase TSHRAbs level reached the maximum values in 100% of patients. An increase in the IL-17 concentration in 5,3 times was found in the active EOP in comparison with the control group (p < 0.05). Concentration of TSHRAbs and IL-17 in blood serum directly correlates with EOP activity (p < 0.001). After carrying out pulse therapy with glucocorticosteroids, the consentration of IL-17 decreased almost to zero. There were no significant differences in the level of IL-23 in the groups (p = 0.56).

Conclusions. Determination of TSHRAbs and IL-17 levels in serum can be used as a laboratory diagnostic marker of EOP activity.

 

endocrine ophthalmopathy, thyroid eye disease, Graves’ ophthalmopathy, antibodies to thyroid-stimulating hormone receptor, interleukin 17, interleukin 23

1. Бровкина А.Ф. Эндокринная офтальмопатия. – М.: ГЭОТАР-Медиа; 2008. [Brovkina AF. Endokrinnaya oftal’mopatiya. Moscow: GEOTAR-Media; 2008. (In Russ.)]

2. Дедов И.И., Мельниченко Г.А., Свириденко Н.Ю., и др. Федеральные клинические рекомендации по диагностике и лечению эндокринной офтальмопатии при аутоиммунной патологии щитовидной железы. // Проблемы эндокринологии. – 2015. – Т. 61. – №1. – С. 61-74. [Dedov II, Melnichenko GA, Sviridenko NY, et al. Federal clinical recommendations on diagnostics and treatment of endocrine ophthalmopathy associated with autoimmune thyroid pathology. Problems of endocrinology. 2015;61(1):61-74. (In Russ.)] doi: 10.14341/probl201561161-74.

3. Cвириденко Н.Ю., Лиханцева В.Г., Беловалова И.М., и др. Антитела к рецептору ТТГ как предикторы тяжести и исходов эндокринной офтальмопатии у пациентов с болезнью Грейвса. // Проблемы эндокринологии. – 2011. – Т. 57. – №2. – С. 23-26. [Sviridenko NY, Likhantseva VG, Belovaloyava IM, et al. Anti-TSH receptor antibodies as predictors of the severity and outcome of endocrine ophthalmopathy in the patients presenting with Graves’ disease. Problems of endocrinology. 2011;57(2):23-26. (In Russ.)] doi: 10.14341/probl201157223-26.

4. Khong JJ, McNab AA, Ebeling PR, et al. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol. 2016;100(1):142-150. doi: 10.1136/bjophthalmol-2015-307399.

5. Weiler DL. Thyroid eye disease: a review. Clin Exp Optom. 2017;100(1):20-25. doi: 10.1111/cxo.12472.

6. Харинцев В.В., Серебрякова О.В., Серкин Д.М., и др. Роль некоторых про- и противовоспалительных цитокинов в течении эндокринной офтальмопатии. // Забайкальский медицинский вестник. – 2016. – №2. – С. 33-40. [Kharintsev VV, Serebryakova OV, Serkin DM, et al. The role of some pro-inflammatory and anti-inflammatory cytokines in the development of endocrine ophthalmopathy. Zabaykal’skiy meditsinskiy vestnik. 2016;(2):33-40. (In Russ.)]

7. Hirota K, Hashimoto M, Ito Y, et al. Autoimmune Th17 cells induced synovial stromal and innate lymphoid cell secretion of the cytokine GM-CSF to initiate and augment autoimmune arthritis. Immunity. 2018;48(6):1220-1232 e1225. doi: 10.1016/j.immuni.2018.04.009.

8. Шилова Л.Н., Паньшина Н.Н., Чернов А.С., и др. Иммунологическое значение интерлейкина-17 при псориатическом артрите. // Современные проблемы науки и образования. – 2015. – №6. [Shilova LN, Panshina NN, Chernov AS, et al. Immunological significance of interleukin-17 in psoriatic arthritis. Modern problems of science and education. 2015;(6). (In Russ.)]

9. Бекетова Т.В., Александрова Е.Н., Никонорова Н.О. Интерлейкин 23 у больных системными васкулитами, ассоциированными с антинейтрофильными цитоплазматическими антителами: собственные результаты и обзор литературы. // Научно-практическая ревматология. – 2015. – T. 53. – №5. – C. 493-501. [Beketova TV, Aleksandrova EN, Nikonorova NO. Interleukin-23 in patients with antineutrophil cytoplasmic antibody-associated systemic vasculitides: The authors’ results and a review of literature. Rheumatology science and practice. 2015;53(5):493-501. (In Russ.)] doi: 10.14412/1995-4484-2015-493-501.

10. Shen J, Li Z, Li W, et al. Th1, Th2, and Th17 cytokine involvement in thyroid associated ophthalmopathy. Dis Markers. 2015;2015: 609593. doi: 10.1155/2015/609593.

11. Bartalena L, Baldeschi L, Boboridis K, et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J. 2016;5(1):9-26. doi: 10.1159/000443828.

12. Лихванцева В.Г., Афанасьев М.С., Руденко Е.А., и др. Поиск тканей-мишеней в орбите для аутоиммунной агрессии тиреоидных антител при эндокринной офтальмопатии. // Медицинская иммунология. – 2017. – Т. 19. – №5. – С. 557-566. [Likhvantseva VG, Afanasiev MS, Rudenko EA, et al. Search for target tissue in the eye orbit for autoimmune aggression of thyroid antibodies in endocrine ophthalmopathy. Medical Immunology. 2017;19(5):557-566. (In Russ.)] doi: 10.15789/1563-0625-2017-5-557-566.

13. 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. doi: 10.1016/j.exer.2015.02.007.

14. Fang S, Huang Y, Zhong S, et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in Graves orbitopathy. J Clin Endocrinol Metab. 2017;102(11):4273-4283. doi: 10.1210/jc.2017-01349.

15. Fitz L, Zhang W, Soderstrom C, et al. Association between serum interleukin-17A and clinical response to tofacitinib and etanercept in moderate to severe psoriasis. Clin Exp Dermatol. 2018. doi: 10.1111/ced.13561.

16. Wei H, Guan M, Qin Y, et al. Circulating levels of miR-146a and IL-17 are significantly correlated with the clinical activity of Graves’ ophthalmopathy. Endocr J. 2014;61(11):1087-1092. doi: 10.1507/endocrj.EJ14-0246.

17. Qian Y, Kang Z, Liu C, Li X. IL-17 signaling in host defense and inflammatory diseases. Cell Mol Immunol. 2010;7(5):328-333. doi: 10.1038/cmi.2010.27.

18. Zhang J, Qiao Q, Liu M, et al. IL-17 promotes scar formation by inducing macrophage infiltration. Am J Pathol. 2018;188(7): 1693-1702. doi: 10.1016/j.ajpath.2018.04.005.

19. Liu M, Yang J, Xing X, et al. Interleukin-17A promotes functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway. Arthritis Res Ther. 2014;16(6):4223. doi: 10.1186/s13075-014-0512-2.

20. Duvallet E, Semerano L, Assier E, et al. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. 2011;43(7):503-511. doi: 10.3109/07853890.2011.577093.