Immunoregulatory proteins and cytokines in the blood of patients with Graves’ disease

Background. Immunoregulatory proteins (alpha-2-macroglobulin, lactoferrin) actively participate in inflammatory and autoimmune processes, affect synthesis and transport of hormones and cytokines, and control cell proliferation and apoptosis. However, the role of these proteins in the pathogenesis of Graves’ disease (GD) is poorly understood.

Objective — the study objective was to determine blood levels of alpha-2-macroglobulin (α2-MG), lactoferrin (LF), and cytokines (TNF-α, IL-6, IL-8, and IFN-γ) in GD.

Material and methods. We determined blood levels of TSH, free T4, TSH receptor antibodies, TNF-α, IL-6, IL-8, IFN-γ, and LF by ELISA as well as α2-MG by quantitative rocket immunoelectrophoresis in 50 patients with decompensated and compensated (4―6 months and 1.5―2 years after treatment onset) GD and 25 healthy females (control group).

Results. GD clinically manifested by body weight l in 84% of patients, sinus tachycardia in almost all patients, paroxysmal atrial fibrillation in 18% of cases, endocrine ophthalmopathy in 12% of patients, and neurological changes. In decompensated GD, there was a statistically significant increase in levels of IFN-γ, IL-6, and α2-MG and an especially significant increase in levels of IL-8 and LF. At 4―6 months after treatment onset, clinical manifestations were stopped in all patients, levels of IL-6 and α2-MG decreased, but the concentrations of TSH receptor antibodies (TSHR-Abs), IL-8, IFN-γ, and LF remained elevated. At 1.5―2 years, levels of the studied proteins and cytokines did not differ from those in the control group.

Conclusion. An increase in blood levels of IL-8, LF, IL-6, and α2-MG in incident or recurrent GD and a decrease in the levels during treatment confirm involvement of immunoregulatory proteins in pathogenesis of the disease.

Graves’ disease, alpha-2-macroglobulin, lactoferrin, cytokines

1. Лазанович В.В., Маркелова Е.В. Показатели цитокинового статуса, тиреоидных аутоантител и их динамические изменения на фоне лечения болезни Грейвса. // Клиническая экспериментальная тиреоидология. — 2008. — Т. 4. — №3. — С. 28-35. [Lazanovich VV, Markelova EV. Cytokine status, thyroid autoantibodies and their dynamic changes during the treatment of graves’ disease. Clinical and Experimental Thyroidology. 2008; 4(3):28-35. (In Russ.)]. doi: https://doi.org/10.14341/ket20084328-35

2. Ganesh BB, Bhattacharya P, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res. 2011;31(10):721-731. doi: https://doi.org/10.1089/jir.2011.0049

3. Кандрор В.И. Механизмы развития болезни Грейвса и действия тиреоидных гормонов. // Клиническая и экспериментальная тиреоидология. — 2008. — Т. 4. — №1. — С. 26-34. [Kandror VI. Pathogenesis of graves disease and mechanism of action of thiroid hormones. Clinical and Experimental Thyroidology. 2008;4(1):26-34. (In Russ.)]. doi: https://doi.org/10.14341/ket20084126-34

4. Здор В.В., Маркелова Е.В. Уровень сывороточных цитокинов, трансформирующего фактора роста-Β, IL-17, IL-10, IL-1α и ILl-1β в дебюте аутоиммунного тиреотоксикоза при болезни Грейвса—Базедова. // Медицинская Иммунология. — 2011. — Т. 13. — №4-5. — С. 366. [Zdor VV, Markelova EV. Uroven’ syvorotochnykh tsitokinov, transformiruyushchego faktora rosta-Β, IL-17, IL-10, IL-1α and IL-1β v debyute autoimmunnogo tireotoksikoza pri bolezni Greyvsa—Bazedova. Meditsinskaya Immunologiya. 2011;13(4-5):366. (In Russ.)].

5. Eshaghkhani Y, Sanati MH, Nakhjavani M, et al. Disturbed Th1 and Th2 balance in patients with graves’ disease. Minerva Endocrinol. 2016;41(1):28-36.

6. Antonelli A, Ferrari SM, Corrado A, et al. Increase of interferon-gamma inducible CXCl9 and CXCl11 serum levels in patients with active graves’ disease and modulation by methimazole therapy. Thyroid. 2013;23(11):1461-1469. doi: https://doi.org/10.1089/thy.2012.0485

7. Gu LQ, Jia HY, Zhao YJ, et al. Association studies of Interleukin-8 gene in graves’ disease and graves’ ophthalmopathy. Endocrine. 2009;36(3):452-456. doi: https://doi.org/10.1007/s12020-009-9240-9

8. Зорин Н.А., Зорина В.Н. Сигнальная система макроглобулинов. (Обзор литературы). // Биомедицинская химия. — 2012. — Т. 58. — №4. — С. 400-410. [Zorin NA, Zorina VN. Signal’naya sistema makroglobulinov. Obzor Literatury. Biomeditsinskaya khimiya. 2012;58(4):400-410. (In Russ.)]. doi: https://doi.org/10.18097/pbmc20125804400

9. Legrand D, Elass E, Carpentier M, Mazurier J. Lactoferrin: a modulator of immune and inflammatory responses. Cell Mol Life Sci. 2005;62(22):2549-2559. doi: https://doi.org/10.1007/s00018-005-5370-2

10. Трошина Е.А., Свириденко Н.Ю., Ванушко В.Е., и др. Федеральные клинические рекомендации по диагностике и лечению токсического зоба. // Проблемы эндокринологии. — 2014. — Т. 60. — №6.— С. 67-77. [Troshina EA, Sviridenko NYu, Vanushko VE, et al. The Federal clinical recommendations on diagnostics and treatment of toxic goiter. Problems of Endocrinology. 2014;60(6):67-77. (In Russ.)]. doi: https://doi.org/10.14341/probl201460667-77

11. Ajjan RA, Weetman AP. Cytokines in thyroid autoimmunity. Autoimmunity. 2009;36(6-7):351-359. doi: https://doi.org/10.1080/08916930310001603046

12. Weetman AP. Cellular immune responses in autoimmune thyroid isease. Clin Endocrinol (Oxf). 2004;61(4):405-413. doi: https://doi.org/10.1111/j.1365-2265.2004.02085.x

13. Gianoukakis AG, Khadavi N, Smith TJ. Cytokines, graves’ disease, and thyroid-associated ophthalmopathy. Thyroid. 2008;18(9):953-958. doi: https://doi.org/10.1089/thy.2007.0405

14. Саприна Т.В., Прохоренко Т.С., Новицкий В.В. Аутоиммунные тиреопатии. Молекулярные подходы к дифференциальной диагностике. — Томск: Издательство СибГМУ; 2017. [Saprina TV, Prokhorenko TS, Novitskiy VV. Autoimmunnye tireopatii. Molekulyarnye podkhody k differentsial’noy diagnostike. Tomsk: Izdatel’stvo SibGMU; 2017. (In Russ.)].

15. Шарипова З.Ф., Фархутдинова Л.M. Взаимосвязь иммунологического статуса и микроэлементного профиля организма при тиреопатиях. // Врач. — 2007. — №S. — С. 51-52. [Sharipova ZF, Farkhutdinova LM. Vzaimosvyaz’ immunologicheskogo statusa I mikroelementnogo profilya organizma pri tireopatiyakh. Vrach. 2007;(S):51-52. (In Russ.)].

16. Wu SM, Patel DD, Pizzo SV. Oxidized alpha2-Macroglobulin (Alpha2m) differentially regulates receptor binding by cytokines/growth factors: implications for tissue injury and repair mechanisms in inflammation. J Immunol. 1998;161(8):4356-4365.

17. Lamarre J, Wolf BB, Kittler EL, et al. Regulation of macrophage alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma. J Clin Invest. 1993;91(3):1219-1224. doi: https://doi.org/10.1172/jci116283