ANALYSIS OF FOLLICULAR TH-SUBSETS IN PATIENTS WITH HASHIMOTO THYROIDITIS ASSOCIATED WITH MENTAL DISORDERS

DOI: 10.22138/2500-0918-2024-21-4-446-466

P.A. Sobolevskaia¹, A.N. Gvozdeckii², I.V. Kudryavtsev³,
V.A. Chereshnev⁴, L.P. Churilov¹

 

¹FSBEI HPE «Saint-Petersburg State University», Saint-Petersburg, Russian Federation;
²North-Western State Medical University named after I.I. Mechnikov,
Saint-Petersburg, Russian Federation;
³Federal State Budgetary Scientific Institution «Institute of Experimental Medicine»,
Saint-Petersburg, Russian Federation;
⁴Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation

Abstract: This study presents an analysis of T-follicular helpers (Tfh) subsets in patients with Hashimoto’s chronic autoimmune thyroiditis (AIT) and examines their relationships with various clinical and laboratory parameters. Objective. To analyze Tfh-subsets in peripheral blood in patients with AIT, as well as in patients with AIT combined with mental disorders (MD). Materials and Methods. The study involved 80 participants aged 18 to 75 years, divided into three groups: the AIT+MD group (14 patients with AIT combined with various MD, mean age 54.3±11.4 years); the AIT group (46 patients with AIT without MD, mean age 48.6±12.5 years); and the control group HC (20 mentally and physically healthy individuals, mean age 45.6±13.1 years). Methods included multiparametric fluorescent analysis of cytokine concentrations, enzyme-linked immunosorbent assay (ELISA) for hormone and antibody concentrations, and flow cytometry for lymphocyte subpopulation analysis. Results. The study demonstrated elevated levels of CXCR3 expression on the surface of Tfh in patients with AIT and MD, which correlated with signs of thyroid gland involvement and may be pathogenetically significant for lymphocyte migration to the central nervous system (CNS) and thyroid gland. It was also shown that the proportion of Tfh in the blood was higher in the group of patients with MD than in other groups, and the level of IL-21 synthesized by Tfh was statistically significantly different in both groups of AIT patients compared to the control group. Conclusions. The study indicated that patients with MD exhibit an imbalance in the subpopulation composition of Tfh: a decrease in the Tfh2 subpopulation, which likely migrates to the lymph nodes and thyroid gland, which in AIT undergoes pronounced lymphoid infiltration and even forms lymphoid follicles, where these lymphocytes likely express IL-5 and IL-13, the systemic concentrations of which were elevated in patients with AIT and MD.

Keywords: autoimmune thyroiditis, mental disorders, cytokines, follicular T-helpers

There is no conflict of interest.
Contact details of the corresponding author:
Polina A. Sobolevskaia
dr.polinasobolevskaia@bk.ru
Received: 01.09.2024
For citation: Sobolevskaia P.A., Gvozdeckii A.N., Kudryavtsev I.V., Chereshnev V.A., Churilov L.P. Analysis of follicular Th-subsets in patients with Hashimoto thyroiditis associated with mental disorders. [Online] Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2024, Vol. 21, no. 4, pp. 446–466. DOI: 10.22138/2500-0918-2024-21-4-446-466 (In Russ)

REFERENCES
1. Khaitov M.R. Immunology: Structure and functions of the immune system [Immunologija: Struktura i funkcii immunnoj sistemy]. 2nd ed. Moscow: GEOTAR-Media=Moskva: GJeOTAR-Media, 2019. (In Russ).
2. Abbas A.K., Lichtman A.H., Pillai S. Cellular and Molecular Immunology E-Book: Cellular and Molecular Immunology E-Book. Elsevier Health Sciences, 2021.
3. Ragusa F., Fallahi P., Elia G., Gonnella D., Paparo S.R., Giusti C., Churilov L.P., Ferrari S.M., Antonelli A. Hashimotos’ thyroiditis: Epidemiology, pathogenesis, clinic and therapy. Best Pract Res Clin Endocrinol Metab. 2019; 33(6):101367. doi:10.1016/j.beem.2019.101367.
4. Nanba T., Watanabe M., Inoue N., Iwatani Y. Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease. Thyroid 2009; 19(5):495-501. doi:10.1210/jc.2011-1900.
5. Li Q., Wang B., Mu K., Zhang J.A. The pathogenesis of thyroid autoimmune diseases: New T-lymphocytes — Cytokines circuits beyond the Th1-Th2 paradigm. J Cell Physiol 2019; 234(3):2204-16. doi:10.1002/eji.201970107.
6. Bedoya S.K., Lam B., Lau K., Larkin J. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013; 2013:986789. doi:10.1016/j.jaut.2019.01.012.
7. Hashimoto H. Zur kenntniss der lymphomatosen veranderung der Schilddruse (Struma lymphomatosa). Arch Klin Chir; 97:219-48.
8. Pearce J.M. Sir William Withey Gull (1816-1890). Eur Neurol. 2006; 55(1):53-6. doi:10.1159/000091430.
9. Stroev Yu.I., Utekhin V.I., Churilov L.P. Hashimoto’s autoimmune thyroiditis, its consequences and comorbidity [Autoimmunnyj tiroidit Hasimoto, ego posledstvija i komorbidnost’]. In: A Guide to autoimmune diseases for general practitioners [Rukovodstvo po autoimmunnym zabolevanijam dlja vrachej obshhej praktiki]. Edited by I.Schoenfeld, P.L.Meroni, L.P.Churilov. St. Petersburg: ALBI-Medkniga=Sankt-Peterburg: JeLBI-Medkniga, 2017; 298-325. (In Russ).
10. Shi Y., Wang H., Su Z., Chen J., Xue Y., Wang S., Xue Y., He Z., Yang H., Zhou C., Kong F., Liu Y., Yang P., Lu L., Shao Q., Huang X., Xu H. Differentiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto’s thyroiditis. Scand J Immunol. 2010; 72(3):250-5. doi:10.1111/j.1365-3083.2010.02425.x.
11. Guo Y., Zynat J., Xing S., Xin L., Li S., Mammat N., Chen Y., Zhao L., Zhao H., Wang X. Immunological changes of T helper cells in flow cytometer-sorted CD4⁺ T cells from patients with Hashimoto’s thyroiditis. Exp Ther Med. 2018; 15(4):3596-3602. doi:10.3892/etm.2018.5825.
12. Zhu C., Ma J., Liu Y., Tong J., Tian J., Chen J., Tang X., Xu H., Lu L., Wang S. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 2012; 97(3):943-50. doi:10.1210/jc.2011-2003.
13. Sánchez-Gutiérrez R., Martínez-Hernández R., Serrano-Somavilla A., Sampedro-Nuñez M., Mendoza-Pérez A., de Nova J.L.M., Vitales-Noyola M., González-Amaro R., Marazuela M. Analysis of T follicular and T peripheral helper lymphocytes in autoimmune thyroid disease. Endocrine. 2024; 15. doi:10.1007/s12020-024-03686-7.
14. Churilov L.P., Sobolevskaia P.A., Stroev Y.I. Thyroid gland and brain: Enigma of Hashimoto’s encephalopathy. Best Pract Res Clin Endocrinol Metab. 2019; 33(6):101364. doi:10.1016/j.beem.2019.101364.
15. Akamizu T., Amino N. Hashimoto’s Thyroiditis. In: Feingold K.R., Anawalt B., Blackman M.R., Boyce A., Chrousos G., Corpas E., de Herder W.W., Dhatariya K., Dungan K., Hofland J., Kalra S., Kaltsas G., Kapoor N., Koch C., Kopp P., Korbonits M., Kovacs C.S., Kuohung W., Laferrère B., Levy M., McGee E.A., McLachlan R., New M., Purnell J., Sahay R., Shah A.S., Singer F., Sperling M.A., Stratakis C.A., Trence D.L., Wilson D.P., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. PMID: 25905412.
16. Ramakrishna H.K. Medical Statistics. Singapore: Springer Singapore, 2017; 188.
17. Buri M., Curt A., Steeves J., Hothorn T. Baseline-adjusted proportional odds models for the quantification of treatment effects in trials with ordinal sum score outcomes. BMC Med Res Methodol. 2020; 20(1):104. doi:10.1186/s12874-020-00984-2.
18. Benjamini Y., Drai D., Elmer G., Kafkafi N., Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001; 125(1-2):279-84. doi:10.1016/s0166-4328(01)00297-2.
19. Kudryavtsev I.V. Memory T-cells: The main populations and stages of differentiation [T-kletki pamjati: Osnovnye populjacii i stadii differencirovki]. Russian Immunological Journal=Rossijskij immunologicheskij zhurnal. 2014; 8(4):947-64. (In Russ).
20. Brodie T., Brenna E., Sallusto F. OMIP-018: chemokine receptor expression on human T helper cells. Cytometry A. 2013; 83(6):530-2. doi:10.1002/cyto.a.22278.
21. Cossarizza A., Chang H.D., Radbruch A.et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur J Immunol. 2019; 49(10):1457-1973. doi:10.1002/eji.201970107.
22. Morita R., Schmitt N., Bentebibel S.E., Ranganathan R., Bourdery L., Zurawski G., Foucat E., Dullaers M., Oh S., Sabzghabaei N., Lavecchio E.M., Punaro M., Pascual V., Banchereau J., Ueno H. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011; 34(1):108-21. doi:10.1016/j.immuni.2010.12.012.
23. Lord G.M., Rao R.M., Choe H., Sullivan B.M., Lichtman A.H., Luscinskas F.W., Glimcher L.H. T-bet is required for optimal proinflammatory CD4⁺ T-cell trafficking. Blood. 2005; 106(10):3432-9. doi:10.1182/blood-2005-04-1393.
24. Breitfeld D., Ohl L., Kremmer E., Ellwart J., Sallusto F., Lipp M., Förster R. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med. 2000; 192(11):1545-52. doi:10.1084/jem.192.11.1545.
25. Long D., Chen Y., Wu H., Zhao M., Lu Q. Clinical significance and immunobiology of IL-21 in autoimmunity. J Autoimmun. 2019; 99:1-14. doi:10.1016/j.jaut.2019.01.013.
26. Ribeiro F., Romão V.C., Rosa S., Jesus K., Água-Doce A., Barreira S.C., Martins P., da Silva S.L., Nobre E., Bugalho M.J., Fonseca V.R., Eurico Fonseca J., Graca L. Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation. Sci Rep. 2022; 12(1):17638. doi:10.1038/s41598-022-21576-8.
27. Lechner M.G., Zhou Z., Hoang A.T., Huang N., Ortega J., Scott L.N., Chen H.C., Patel A.Y., Yakhshi-Tafti R., Kim K., Hugo W., Famini P., Drakaki A., Ribas A., Angell T.E., Su M.A. Clonally expanded, thyrotoxic effector CD8⁺ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis. Sci Transl Med. 2023; 15(696):eadg0675. doi:10.1126/scitranslmed.adg0675.
28. Zivancevic-Simonovic S., Mihaljevic O., Majstorovic I., Popovic S., Markovic S., Milosevic-Djordjevic O., Jovanovic Z., Mijatovic-Teodorovic L., Mihajlovic D., Colic M. Cytokine production in patients with papillary thyroid cancer and associated autoimmune Hashimoto thyroiditis. Cancer Immunol Immunother. 2015; 64(8):1011-9. doi:10.1007/s00262-015-1705-5.
29. Bednarczuk T., Placha G., Jazdzewski K., Kurylowicz A., Kloza M., Makowska U., Hiromatsu Y., Nauman J. Interleukin-13 gene polymorphisms in patients with Graves’ disease. Clin Endocrinol (Oxf). 2003; 59(4):519-25. doi:10.1046/j.1365-2265.2003.01880.x.
30. Ajjan R.A., Watson P.F., Weetman A.P. Detection of IL-12, IL-13, and IL-15 messenger ribonucleic acid in the thyroid of patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 1997; 82(2):666-9. doi:10.1210/jcem.82.2.3760.
31. Zhao J., Chen Y., Zhao Q., Shi J., Yang W., Zhu Z., Yu W., Guan J., Song Y., Wu H., Jin W., Zhou Y., Liu J. Increased circulating Tfh17 and PD-1+Tfh cells are associated with autoantibodies in Hashimoto’s thyroiditis. Autoimmunity. 2018; 51(7):352-359. doi:10.1080/08916934.2018.1516761.
Auhtors

Sobolevskaia Polina Anatolievna
Federal State Budgetary Educational Institution of Higher Professional Education «Saint-Petersburg State University» (Saint-Petersburg State University)
Researcher of the Laboratory of the Microangiopathic Mechanisms of Atherogenesis
St.Petersburg, Russian Federation
dr.polinasobolevskaia@bk.ru

Gvozdeckii Anton Nikolaevich
North-Western State Medical University named after I.I.Mechnikov
Ph.D. (Medicine), Assistant of the Department of Psychiatry and Narcology
St.Petersburg, Russian Federation
comisora@yandex.ru

Kudryavtsev Igor Vladimirovich
Federal State Budgetary Scientific Institution «Institute of Experimental Medicine» (FSBSI «IEM»)
Ph.D. (Biology), Head of the Laboratory of Cellular Immunology
St.Petersburg, Russian Federation
igorek1981@yandex.ru

Chereshnev Valerii Alexandrovich
Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences (IIP UB RAS)
MD, Academician of the Russian Academy of Sciences, Professor, Scientific Director
Yekaterinburg, Russian Federation
v.chereshnev@mail.ru

Сhurilov Leonid Pavlovich
Federal State Budgetary Educational Institution of Higher Professional Education «Saint-Petersburg State University» (Saint-Petersburg State University)
Ph.D. (Medicine), Academician of the Moldovan Academy of Medical Sciences, Associate Professor, Chairman of the of the Pathology Department
St.Petersburg, Russian Federation
elpach@mail.ru

 
 
 

Authorization