THYROID STATUS AND ITS CORRELATION WITH THE FUNCTIONAL ACTIVITY OF IMMUNOCYTES

Pathogenesis studies in thyroid autoimmune diseases take a specific place among endocrine disorders, due to high prevalence of these pathologies, thus representing an urgent problem of the modern medicine. Their triggering mechanisms of their are still unknown. Changes of thyroid status in cases of nonthyroid pathology, e.g., during development of «nonthyroidal syndrome», may launch synthesis of some functionally opposite cytokines by immunocytes, with subsequent loss of tolerance to thyroid autoantigens. One may suggest that mast cells may potentially influence secretory activity of thyrocytes via Toll-like receptors, and, therefore, induce synthesis of opposite cytokines, with subsequent loss of auto-tolerance. The mast cells found in thyroid gland affected by an autoimmune disorder may also regulate functional activity of immunocytes and hormone-secreting cells due to molecular effects of secretable substances. The mechanisms prevailing in autoimmune thyroid disease are, however, widely unknown. These effects may involve either primary activation of mast cells by thyroid hormones, or secondary changes of thyroid status. To address these issues, we studied some features of mast cells response and production of functionally opposite cytokines (IL-1β, IL-10, IFNγ, TNFα) in experimental thyrotoxicosis and hypothyroidism. To boost the immune response, a subgroup of experimental animals with thyrotoxicosis was treated with recombinant interleukin-2. Specific changes of IFNγ/IL-10 ratio depending on thyroid status confirmed a role of opposite cytokine balance for development of different pathological variants. A significant increase in the Th1-marker cytokines revealed at the organ level in cases of thyrotoxicosis argued for direct involvement of thyroid hormones into the immune regulation, as confirmed by a focal infiltration of a thyroid gland with mast cells, along with significant increase in pro-inflammatory cytokines at systemic and organ levels. A hypothesis on possible reception of thyroid hormones by immune cells is in accordance with intensive correlations between the levels of opposite cytokines in target organ and contents of thyroid hormones in peripheral blood. A regulatory role of interleukin-2 was suggested as a factor of keeping balance for opposite cytokines and changing vector of immune response in case of altered thyroid status. The results of our study presume an important role of mast cells and balance of opposite cytokines in pathogenesis of thyroid dysfunction. Further studies are required, in order to clarify the mechanisms of interaction between thyroid hormones and immune cells.

1. Здор В.В., Тихонов Я.Н. Иммунные и гистологические изменения в железах внутренней секреции при экс- периментальном тиреотоксикозе и гипотиреозе // Клиническая и экспериментальная тиреоидология, 2014. Т. 10, № 1. C. 55-60. [Zdor V.V., Tikhonov Ya.N. Immune and histological changes in the endocrines glands in experimental thyrotoxicosis and hypothyroidism. Klinicheskaya i eksperimental`naya tireoidologiya = Clinical and Exeperimental Thyroidology, 2014, Vol. 10, no. 1, pp. 55-60. (In Russ.)]

2. Микроскопическая техника: Руководство / Под ред. Саркисова Д.С., Перова Ю.Л. М.: Медицина, 1996. 554 с. [Microscopic technique: Manual (Ed. by D.S. Sarkisov, Yu.L. Perova)]. Moscow: Medicine, 1996. 554 p.

3. Хмельницкий О.К. Цитологическая и гистологическая диагностика заболеваний щитовидной железы. СПб.: СО- ТИС, 2002. 288 с. [Khmelnitsky O.K. Cytological and histological diagnosis of thyroid diseases]. St. Petersburg: SOTIS, 2002. 288 p.

4. Яглова Н.В., Березов Т.Т. Роль тиреотропного гормона в изменении гормонального и цитокинового профиля при экспериментальном синдроме нетиреоидных заболеваний // Иммунология, 2010. № 3. С. 146-151. [Yaglova N.V., Berezov T.T. The role of thyroid-stimulating hormone in the changing hormonal and cytokine profile in experimental syndrome nonthyroidal diseases. Immunologiya = Immunology, 2010, no. 3, pp. 146-151. (In Russ.)]

5. Яглова Н.В., Яглов В.В. Ультраструктурные проявления молекулярного способа выделения секреторного материала тучными клетками щитовидной железы при воздействии липополисахарида // Бюллетень экспериментальной биологии и медицины, 2013. T. 155, № 2. С. 260-263. [Yaglova N.V., Yaglov V.V. Ultrastructural characteristics of molecular release of secretory products from thyroid mast cells induced by lipopolysaccharide. Byulleten` eksperimental`noy biologii i meditsiny = Bulletin of Experimental Biology and Medicine, 2013, Vol. 155, no. 2, pp. 260-263. (In Russ.)]

6. Ярилин А.А. Иммунология. М.: ГЭОТАР-Медиа, 2010. 752 с. [Yarilin A.A. Immunology]. Moscow: GEOTAR-Media, 2010. 752 p.

7. Antonelli A., Ferrari S.M., Corrado A., Di Domenicantonio A., Fallahi P. Autoimmune thyroid disorders. Autoimmun. Rev., 2015, Vol. 14, no. 2, pp. 174-180.

8. Benoist C., Mathis D. Mast cells in autoimmune disease. Nature, 2002, Vol. 420, pp. 875-878.

9. Brown M.A., Tanzola M.B., Robbie-Ryan M. Mechanisms underlying mast cell influence on EAE disease course. Mol. Immunol., 2002, Vol. 38, pp. 1373-1378.

10. Csaba G., Pallinger E. Thyrotropic hormone (TSH) regulation of triiodothyronine (T(3)) concentration in immune cells. Inflamm. Res., 2009, Vol. 58, no. 3, pp. 151-154.

11. Gregory G.D., Brown M.A. Mast cells in allergy and autoimmunity: implications for adaptive immunity. Methods in Molecular Biology, 2006, Vol. 315, pp. 35-50.

12. Kristensen B. Regulatory B and T cell responses in patients with autoimmune thyroid disease and healthy controls. Dan. Med. J., 2016, Vol. 63, no. 2, pii: B5177.

13. Marazuela M., Garcia-Lopez M.A., Figueroa-Vega N., de la Fuente H., Alvarado-Sánchez B., Monsiváis-Urenda A., Sánchez-Madrid F., González-Amaro R. Regulatory T cells in human autoimmune thyroid disease. J. Clin. Endocrinol. Metab., 2006, Vol. 91, no. 9, pp. 3639-3646.

14. Nagayama Y., Saiton O., McLachlan S.M., Rapoport B., Kano H., Kumazawa Y. TSH receptor-adenovirus-induced Graves’ hyperthyroidism is attenuated in both interferon-γ and interleukin-4 knockout mice; implications for the Th1/Th2 paradigm. Clin. Exp. Immunol., 2004, Vol. 138, no. 3, pp. 417-422.

15. Piconese S., Gri G., Tripodo C. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/ OX40L axis toward Th17-cell differentiation. Blood, 2009, Vol. 114, no. 13, pp. 2639-2648.

16. Rao K.N., Brown M.A. Mast cells: multifaceted immune cells with diverse roles in health and disease. Annals of the New York Academy of Sciences, 2008, Vol. 1143, pp. 83-104.

17. Rocchi R., Kimura H., Shey-Cherng Tzou, Suzuki K., Rose N.R., Pinchera A., Ladenson P.W., Caturegli P. Toll-like receptor-MyD88 and Fc receptor pathways of mast cells mediate the thyroid dysfunctions observed during nonthyroidal illness. Proc. Natl. Acad. Sci. USA, 2007, Vol. 104, no. 14, pp. 6019-6024.

18. Sayed B.A., Christy A., Quirion M.R., Brown M.A. The master switch: the role of mast cells in autoimmunity and tolerance. Annual Review of Immunology, 2008, Vol. 26, pp.705-739.

19. Steiner D.R., Gonzalez N.C., Wood J.G. Mast cells mediate the microvascular inflammatory response to systemic hypoxia. J. Appl. Physiol. (1985), 2003, Vol. 94, no. 1, pp. 325-334.

20. Sun L., Zhang X., Dai F., Shen J., Ren C., Zuo C., Zhang Q. Elevated interleukin-1β in peripheral blood mononuclear cells contributes to the pathogenesis of autoimmunethyroid diseases, especially of Hashimoto thyroiditis. Endocr. Res., 2016, Vol. 41, no. 3, pp. 185-192.

21. Yaglova N.V. Disorders in the secretory cycle of follicular thyrocytes and their correction with thyrotropic hormone in experimental non-thyroidal illness syndrome. Bull. Exp. Biol. Med., 2011, Vol. 152, no. 2, pp. 253-257.

22. Yunzhi Xu, Guangjie Chen. Mast cell and autoimmune diseases. Mediators Inflamm., 2015, Vol. 1, pp. 1-8.

23. Zheng J.M., Yao G.H., Cheng Z., Wang R., Liu Z.H. Pathogenic role of mast cells in the development of diabetic nephropathy: a study of patients at different stages of the disease. Diabetologia, 2012, Vol. 55, no. 3, pp. 801-811.