Skip to main content

Advertisement

SpringerLink
Log in

Assessment of the levels of interleukin-17 and interleukin-38 in thyroid-associated ophthalmopathy patients

  • Original Paper
  • Published:
International Ophthalmology Aims and scope Submit manuscript

A Correction to this article was published on 29 April 2024

This article has been updated

Abstract

Purpose

The objective of the study was to analyse the levels of IL-17 and IL-38 in the samples of unstimulated tears, orbital adipose tissues, and sera of patients diagnosed with active forms of TAO. The correlation of the levels of IL-17 and IL-38 with clinical activity score (CAS) was scrutinized.

Methods

A study was conducted at the Kazakhstan Scientific Research Institute of Eye Diseases (Almaty city, Kazakhstan). Study participants (n = 70) were sub-divided into 3 groups: (1) a group of patients diagnosed with active TAO (n = 25), (2) a group of patients with an inactive form of TAO (n = 28), and (3) a “control group” (patients diagnosed with orbital fat prolapse, n = 17). All patients underwent a clinical assessment and diagnostics. The activity of the disease and its severity were assessed using the CAS and NOSPECS scales. Thyroid function tests were performed, including the study of the levels of thyroid-stimulating hormone, triiodothyronine, free thyroxine, and antibodies to the thyroid-stimulating hormone receptor. IL-17 and IL-38 levels in non-stimulated tear samples, orbital tissue, and patients’ sera were measured using commercial ELISA kits.

Results

The results showed that the number of former smokers prevailed among patients with active TAO (48%) in comparison with patients with inactive TAO (15.4%), p = 0.001. The concentration of IL-17 significantly increased in the samples of non-stimulated tears, adipose tissues of the orbit and sera of patients with active forms of TAO. The level of IL-38 was reduced in all types of samples (p ≤ 0.05). The results of a histological study of orbital adipose tissues in the group of patients with an active form of TAO showed the presence of focal infiltration with lymphocytes, histiocytes, plasma cells, severe sclerosis and vascular plethora. We observed an association between the CAS of patients with active TAO and the level of IL-17 in sera (r = 0.885; p = 0.001). On the contrary, a negative correlation was detected for the level of IL-38 in sera.

Conclusions

The results highlighted the systemic effect of IL-17 and the local effect of IL-38 in TAO. We observed a significant increase in the production of IL-17, and a decrease in IL-38 in samples of sera and unstimulated tears (the active form of TAO). Our data indicate a correlation of IL-17 and IL-38 levels with the clinical activity of TAO.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All available data were included to the manuscript text.

Change history

References

  1. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC (2015) Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol 2015:249125

    Article  PubMed  PubMed Central  Google Scholar 

  2. Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM et al (2020) New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol 16(2):104–116

    Article  CAS  PubMed  Google Scholar 

  3. Hiromatsu Y, Kaku H, Miyake I, Murayama S, Soejima E (2002) Role of cytokines in the pathogenesis of thyroid-associated ophthalmopathy. Thyroid 12(3):217–221

    Article  CAS  PubMed  Google Scholar 

  4. Antonelli A, Fallahi P, Elia G, Ragusa F, Paparo SR, Ruffilli I et al (2020) Graves’ disease: clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy. Best Pract Res Clin Endocrinol Metab 34(1):101388

    Article  CAS  PubMed  Google Scholar 

  5. Wiersinga WM (2017) Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy. Lancet Diabetes Endocrinol 5(2):134–142

    Article  CAS  PubMed  Google Scholar 

  6. Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF (2000) Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol 52(3):267–271

    Article  CAS  Google Scholar 

  7. Huang Y, Fang S, Li D, Zhou H, Li B, Fan X (2019) The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye 33(2):176–182

    Article  CAS  PubMed  Google Scholar 

  8. Gianoukakis AG, Khadavi N, Smith TJ (2008) Cytokines, Graves’ disease, and thyroid-associated ophthalmopathy. Thyroid Off J Am Thyroid Assoc 18(9):953–958

    Article  CAS  Google Scholar 

  9. Łacheta D, Miśkiewicz P, Głuszko A, Nowicka G, Struga M, Kantor I et al (2019) Immunological aspects of Graves’ ophthalmopathy. Biomed Res Int 2019:7453260

    Article  PubMed  PubMed Central  Google Scholar 

  10. Huang D, Luo Q, Yang H, Mao Y (2014) Changes of lacrimal gland and tear inflammatory cytokines in thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 55(8):4935–4943

    Article  CAS  PubMed  Google Scholar 

  11. Kim SE, Yoon JS, Kim KH, Lee SY (2012) Increased serum interleukin-17 in Graves’ ophthalmopathy. Graefe’s Arch Clin Exp Ophthalmol. 250(10):1521–1526

    Article  CAS  Google Scholar 

  12. Zheng L, Ye P, Liu C (2013) The role of the IL-23/IL-17 axis in the pathogenesis of Graves’ disease. Endocr J 60(5):591–597

    Article  CAS  PubMed  Google Scholar 

  13. Shi L, Ye H, Huang J, Li Y, Wang X, Xu Z et al (2021) IL-38 Exerts anti-inflammatory and antifibrotic effects in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 106(8):e3125–e3142

    Article  PubMed  Google Scholar 

  14. Lin H, Ho AS, Haley-Vicente D, Zhang J, Bernal-Fussell J, Pace AM et al (2001) Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J Biol Chem 276(23):20597–20602

    Article  CAS  PubMed  Google Scholar 

  15. Bensen JT, Dawson PA, Mychaleckyj JC, Bowden DW (2001) Identification of a novel human cytokine gene in the interleukin gene cluster on chromosome 2q12-14. J Interferon Cytokine Res 21(11):899–904

    Article  CAS  PubMed  Google Scholar 

  16. van de Veerdonk FL, Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG et al (2012) IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proc Natl Acad Sci U S A 109(8):3001–3005

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pan Y, Wang M, Chen X, Chen Y, Ai S, Su W et al (2021) Elevated IL-38 inhibits IL-23R expression and IL-17A production in thyroid-associated ophthalmopathy. Int Immunopharmacol 91:107300

    Article  CAS  PubMed  Google Scholar 

  18. Xu WD, Su LC, He CS, Huang AF (2018) Plasma interleukin-38 in patients with rheumatoid arthritis. Int Immunopharmacol 65:1–7

    Article  CAS  PubMed  Google Scholar 

  19. Garraud T, Harel M, Boutet MA, Le Goff B, Blanchard F (2018) The enigmatic role of IL-38 in inflammatory diseases. Cytokine Growth Factor Rev 39:26–35

    Article  CAS  PubMed  Google Scholar 

  20. Mercurio L, Morelli M, Scarponi C, Eisenmesser EZ, Doti N, Pagnanelli G et al (2018) IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment. Cell Death Dis 9(11):1104

    Article  PubMed  PubMed Central  Google Scholar 

  21. Xu J, Huang G, Weng L, Gong L, Mao Y, Li Y et al (2022) Low serum interleukin-38 levels in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Lab Anal 36(1):e24101

    Article  CAS  PubMed  Google Scholar 

  22. Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C et al (2008) Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 158(3):273–285

    Article  CAS  PubMed  Google Scholar 

  23. Salvi M, Campi I (2015) Medical treatment of Graves’ orbitopathy. Horm Metab Res 47(10):779–788

    Article  CAS  PubMed  Google Scholar 

  24. Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA et al (2017) Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 376(18):1748–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S et al (2006) Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 91(9):3464–3470

    Article  CAS  PubMed  Google Scholar 

  26. Smith LD, Moscato EE, Seiff SR (2022) Tocilizumab for the management of thyroid-associated orbitopathy. Ophthalmic Plast Reconstr Surg 38(2):188–192

    Article  PubMed  Google Scholar 

  27. Dagi LR, Zoumalan CI, Konrad H, Trokel SL, Kazim M (2011) Correlation between extraocular muscle size and motility restriction in thyroid eye disease. Ophthalmic Plast Reconstr Surg 27(2):102–110

    Article  PubMed  Google Scholar 

  28. Lee JY, Bae K, Park KA, Lyu IJ, Oh SY (2016) Correlation between extraocular muscle size measured by computed tomography and the vertical angle of deviation in thyroid eye disease. PLoS ONE 11(1):e0148167

    Article  PubMed  PubMed Central  Google Scholar 

  29. Adesina OO, Patel BC (2022) Optic nerve decompression. StatPearls Publishing, StatPearls Treasure Island (FL)

    Google Scholar 

  30. Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL et al (2020) A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy. Ophthalmology 127(4s):S160–S171

    Article  PubMed  Google Scholar 

  31. Park HH, Chun YS, Moon NJ, Kim JT, Park SJ, Lee JK (2018) Change in eyelid parameters after orbital decompression in thyroid-associated orbitopathy. Eye 32(6):1036–1041

    Article  PubMed  PubMed Central  Google Scholar 

  32. Cevik Y, Taylan Sekeroglu H, Ozgen B, Erkan Turan K, Sanac AS (2021) Clinical and radiological findings in patients with newly diagnosed Graves’ ophthalmopathy. Int J Endocrinol 2021:5513008

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kwon J-W, Jee D (2018) Aqueous humor cytokine levels in patients with diabetic macular edema refractory to anti-VEGF treatment. PLoS ONE 13(9):e0203408

    Article  PubMed  PubMed Central  Google Scholar 

  34. Feng S, Yu H, Yu Y, Geng Y, Li D, Yang C et al (2018) Levels of inflammatory cytokines IL-1β, IL-6, IL-8, IL-17A, and TNF-α in aqueous humour of patients with diabetic retinopathy. J Diabetes Res 2018:8546423

    Article  PubMed  PubMed Central  Google Scholar 

  35. Drui D, Du Pasquier FL, Vignal Clermont C, Daumerie C (2018) Graves’ orbitopathy: diagnosis and treatment. Ann Endocrinol 79(6):656–664

    Article  Google Scholar 

  36. Cai K, Wei R (2013) Interleukin-7 expression in tears and orbital tissues of patients with Graves’ ophthalmopathy. Endocrine 44(1):140–144

    Article  CAS  PubMed  Google Scholar 

  37. Bartalena L, Piantanida E, Gallo D, Lai A, Tanda ML (2020) Epidemiology, natural history, risk factors, and prevention of graves’ orbitopathy. Front Endocrinol 11:615993

    Article  Google Scholar 

  38. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C et al (2016) The 2016 European thyroid association/European group on Graves’ orbitopathy guidelines for the management of Graves’ orbitopathy. Eur Thyroid J 5(1):9–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bartalena L, Piantanida E (2016) Cigarette smoking: number one enemy for Graves ophthalmopathy. Pol Arch Med Wewn 126(10):725–726

    PubMed  Google Scholar 

  40. Bartalena L (2012) Prevention of Graves’ ophthalmopathy. Best Pract Res Clin Endocrinol Metab 26(3):371–379

    Article  PubMed  Google Scholar 

  41. He JF, Wu ZY, Yang HS, Yan JH, Mao YX, Chen ZC et al (2004) Clinical analysis of 339 cases of thyroid-associated ophthalmopathy. Chin J Ophthalmol 40(6):368–372

    Google Scholar 

  42. Lat AM, Jauculan MC, Sanchez CA, Jimeno C, Sison-Peña CM, Pe-Yan MR et al (2017) Risk factors associated with the activity and severity of Graves’ ophthalmopathy among patients at the university of the Philippines manila-Philippine general hospital. J ASEAN Fed Endocr Soc 32(2):151–157

    Article  PubMed  PubMed Central  Google Scholar 

  43. Pfeilschifter J, Ziegler R (1996) Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol 45(4):477–481

    Article  CAS  Google Scholar 

  44. Prummel MF, Wiersinga WM (1993) Smoking and risk of Graves’ disease. JAMA 269(4):479–482

    Article  CAS  PubMed  Google Scholar 

  45. Lim SL, Lim AK, Mumtaz M, Hussein E, Wan Bebakar WM, Khir AS (2008) Prevalence, risk factors, and clinical features of thyroid-associated ophthalmopathy in multiethnic Malaysian patients with Graves’ disease. Thyroid Off J Am Thyroid Assoc 18(12):1297–1301

    Article  Google Scholar 

  46. Gomes JP, Watad A, Shoenfeld Y (2018) Nicotine and autoimmunity: the lotus’ flower in tobacco. Pharmacol Res 128:101–109

    Article  PubMed  Google Scholar 

  47. Bartalena L, Martino E, Marcocci C, Bogazzi F, Panicucci M, Velluzzi F et al (1989) More on smoking habits and Graves’ ophthalmopathy. J Endocrinol Invest 12(10):733–737

    Article  CAS  PubMed  Google Scholar 

  48. Cawood TJ, Moriarty P, O’Farrelly C, O’Shea D (2007) Smoking and thyroid-associated ophthalmopathy: a novel explanation of the biological link. J Clin Endocrinol Metab 92(1):59–64

    Article  CAS  PubMed  Google Scholar 

  49. Wei H, Guan M, Qin Y, Xie C, Fu X, Gao F et al (2014) Circulating levels of miR-146a and IL-17 are significantly correlated with the clinical activity of Graves’ ophthalmopathy. Endocr J 61(11):1087–1092

    Article  CAS  PubMed  Google Scholar 

  50. Yuan XL, Li Y, Pan XH, Zhou M, Gao QY, Li MC (2016) Production of recombinant human interleukin-38 and its inhibitory effect on the expression of proinflammatory cytokines in THP-1 cells. Mol Biol (Mosk) 50(3):466–473

    Article  CAS  PubMed  Google Scholar 

  51. Shen J, Li Z, Li W, Ge Y, Xie M, Lv M et al (2015) Th1, Th2, and Th17 cytokine involvement in thyroid associated ophthalmopathy. Dis Markers 2015:609593

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP et al (2015) IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 16(4):354–365

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Author information

Authors and Affiliations

  1. S.D. Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan

    Ainura Mussakulova, Aigul Balmukhanova, Timur Saliev, Shynar Tanabayeva & Ildar Fakhradiyev

  2. Kazakh Eye Research Institute, Almaty, Kazakhstan

    Alua Aubakirova

  3. Institute of Genetics and Physiology, Almaty, Kazakhstan

    Gulnur Zhunusova

  4. Al-Farabi Kazakh National University, Almaty, Kazakhstan

    Altynay Balmukhanova

  5. Clinic “Oftalmo-Medical” Almaty, Almaty, Kazakhstan

    Jamilya Issakhanova

Authors
  1. Ainura Mussakulova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aigul Balmukhanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alua Aubakirova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gulnur Zhunusova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Altynay Balmukhanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jamilya Issakhanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Timur Saliev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shynar Tanabayeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ildar Fakhradiyev
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AM and AB designed and supervised the study and reviewed the manuscript. AM, GZ and JI were in charge of data acquisition, data collection. AM, AB, ST, TS and IF analysed and interpreted the data and prepared the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Ildar Fakhradiyev.

Ethics declarations

Conflict of interest

All the authors have no conflicts of interest.

Consent to participate

Informed consent was obtained from the patients.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the Local Ethics Committee of S.D. Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan (protocol of Local Ethics Committee No 3(94), dated 25.03.2020).

Additional information

Publisher's Note

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

One of the authors name is updated as Ainura Mussakulova.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mussakulova, A., Balmukhanova, A., Aubakirova, A. et al. Assessment of the levels of interleukin-17 and interleukin-38 in thyroid-associated ophthalmopathy patients. Int Ophthalmol 43, 2811–2824 (2023). https://doi.org/10.1007/s10792-023-02679-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-023-02679-1

Keywords

Search

Navigation