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Licensed Unlicensed Requires Authentication Published by De Gruyter August 17, 2020

Clinical relevance of T lymphocyte subsets in pediatric Graves’ disease

  • Ting Chen ORCID logo EMAIL logo , Linqi Chen , Haojie Song , Xiuli Chen , Rongrong Xie , Qin Xia , Dandan Zhang , Haiying Wu , Hui Sun , Xiaoyan Wang and Fengyun Wang

Abstract

Objectives

Graves’ disease (GD) is an autoimmune disease involving intimate response of both T cells and B cells. Immunophenotyping of peripheral blood lymphocyte subsets in GD children with different clinical characteristics can provide further information of the pathogenesis of GD.

Methods

We studied the lymphocyte subsets in peripheral blood of 141 children with GD. We repeatedly divided the patients into two groups in accordance with different clinical characteristics (abnormal or normal alanine aminotransferase (ALT) levels, the presence or absence of Graves’ orbitopathy (GO), and the presence or absence of hematuria. Then we compared the lymphocyte subsets measurements between two paired groups.

Results

We found that serum ALT levels correlated positively with CD3+CD8+ T cell percentages in children with GD. Moreover, we detected higher percentages of CD3−CD19+ cells and higher ratio of CD4/CD8 in patients with GO. However, no correlation was found between GO status and lymphocyte subsets after excluding confounding effect of TRAb. No difference of lymphocyte subset percentages was found between groups with or without hematuria.

Conclusions

Serum ALT levels correlate positively with cytotoxic T cell percentages in the peripheral blood of children with GD. The cytotoxic T cell may play a role in the pathogenesis of hepatic dysfunction in children with GD.


Corresponding author: Ting Chen, MD, Department of Endocrinology, Children’s Hospital of Soochow University, Suzhou, Jiangsu, China. Phone: 86 0512 8069 8211, E-mail:

Ting Chen and Linqi Chen: contributed equally to this study.


Funding source: The Department of Pediatrics Clinical Center of Suzhou

Award Identifier / Grant number: Szzx201504

Funding source: Suzhou Personnel Planning Project

Award Identifier / Grant number: GSWS2019051

Award Identifier / Grant number: 81700793

  1. Research funding: This study was supported by a National Natural Science Foundation of China (project code 81700793) and a Suzhou Personnel Planning Project (project code GSWS2019051) awarded to Dr. Ting Chen. This study is also partially supported by Suzhou children’s medical center of internal medicine.

  2. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Informed consent was obtained from the patients and family members included in this study, following procedures specified by the Ethics Committee of Children’s Hospital of Soochow University and the guidelines of World Medical Association Declaration of Helsinki 2000.

References

1. NB SET, McArthur, JW, Crawford, JD. Functional endocrinology: from birth to adolescence. Harvard University Press: Cambridge, Mass; 1952.Search in Google Scholar

2. Wilkins, L. The diagnosis and treatment of endocrine disorders in childhood and adolescence. Blackwell Scientific Publications: Oxford; 1950.Search in Google Scholar

3. Léger, J, Carel, JC. Hyperthyroidism in childhood: causes, when and how to treat. J Clin Res Pediatr Endocrinol 2013;5:50–6. https://doi.org/10.4274/Jcrpe.854.Search in Google Scholar PubMed PubMed Central

4. Williamson, S, Greene, SA. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol 2010;72:358–63. https://doi.org/10.1111/j.1365-2265.2009.03717.x.Search in Google Scholar PubMed

5. Kjær, RH, Andersen, MS, Hansen, D. Increasing incidence of juvenile thyrotoxicosis in Denmark: a nationwide study, 1998-2012. Horm Res Paediatr 2015;84:102–7. https://doi.org/10.1159/000430985.Search in Google Scholar PubMed

6. Wong, GWK, Cheng, PS. Increasing incidence of childhood Graves’ disease in Hong Kong: a follow-up study. Clin Endocrinol 2001;54:547–50. https://doi.org/10.1046/j.1365-2265.2001.01252.x.Search in Google Scholar PubMed

7. Antonelli, A, Ferrari, SM, Corrado, A, Di Domenicantonio, A, Fallahi, P. Autoimmune thyroid disorders. Autoimmun Rev 2015;14:174–80. https://doi.org/10.1016/j.autrev.2014.10.016.Search in Google Scholar PubMed

8. Glick, AB, Wodzinski, A, Fu, P, Levine, AD, Wald, DN. Impairment of regulatory T-cell function in autoimmune thyroid disease. Thyroid 2013;23:871–8. https://doi.org/10.1089/thy.2012.0514.Search in Google Scholar PubMed PubMed Central

9. Vitales-Noyola, M, Serrano-Somavilla, A, Martínez-Hernández, R, Sampedro-Nuñez, M, Ramos-Levi, AM, González-Amaro, R, et al.. Patients with autoimmune thyroiditis show diminished levels and defective suppressive function of Tr1 regulatory lymphocytes. J Clin Endocrinol Metab 2018;103:3359–67. https://doi.org/10.1210/jc.2018-00498.Search in Google Scholar PubMed

10. Ben-Skowronek, I, Szewczyk, L, Kulik-Rechberger, B, Korobowicz, E. The differences in T and B cell subsets in thyroid of children with Graves’ disease and Hashimoto’s thyroiditis. World J Pediatr 2013;9:245–50. https://doi.org/10.1007/s12519-013-0398-0.Search in Google Scholar PubMed

11. Van der Weerd, K, Van Hagen, PM, Schrijver, B, Kwekkeboom, DJ, De Herder, WW, Ten Broek, MRJ, et al.. The peripheral blood compartment in patients with G raves’ disease: activated T lymphocytes and increased transitional and pre-naive mature B lymphocytes. Clin Exp Immunol 2013;174:256–64. https://doi.org/10.1111/cei.12183.Search in Google Scholar PubMed PubMed Central

12. Ben-Skowronek, I, Sierocinska-Sawa, J, Korobowicz ESzewczyk, L. Lymphocytes in peripheral blood and thyroid tissue in children with Graves’ disease. World J Pediatr 2008;4:274–82. https://doi.org/10.1007/s12519-008-0050-6.Search in Google Scholar PubMed

13. Bartalena, L, Baldeschi, L, Dickinson, AJ, Eckstein, A, Kendall-Taylor, P, Marcocci, C, et al.. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 2008;18:333–46. https://doi.org/10.1089/thy.2007.0315.Search in Google Scholar PubMed

14. Wiersinga, WM, Perros, P, Kahaly, GJ, Mourits, MP, Baldeschi, L, Boboridis, K, et al.. Clinical assessment of patients with Graves’ orbitopathy: the European Group on Graves’ Orbitopathy recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol 2006;155:387–9. https://doi.org/10.1530/eje.1.02230.Search in Google Scholar PubMed

15. Bussler, S, Vogel, M, Pietzner, D, Harms, K, Buzek, T, Penke, M, et al.. New pediatric percentiles of liver enzyme serum levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase): effects of age, sex, body mass index, and pubertal stage. Hepatology 2018;68:1319–30. https://doi.org/10.1002/hep.29542.Search in Google Scholar PubMed

16. An, Q, Wang, Y, Hu, S, Fang, D, Xuan, C, Xu, S, et al.. Clinical significance of lymphocyte subset changes in hemophagocytic lymphohistiocytosis of children. Exp Ther Med 2016;12:3549–52. https://doi.org/10.3892/etm.2016.3809.Search in Google Scholar PubMed PubMed Central

17. Wang, F, Li, X, Zhu, X, Chen, Q, Jiang, L, Zhu, Z. Renal tubular complement 3 deposition in children with primary nephrotic syndrome. BioMed Res Int 2018;2018:1–5. https://doi.org/10.1155/2018/4386438.Search in Google Scholar PubMed PubMed Central

18. Ding, Y, Zhou, L, Xia, Y, Wang, W, Wang, Y, Li, L, et al.. Reference values for peripheral blood lymphocyte subsets of healthy children in China. J Allergy Clin Immunol 2018;142:970–3. https://doi.org/10.1016/j.jaci.2018.04.022.Search in Google Scholar PubMed

19. Eckstein, A, Esser, J, Mann, K, Schott, M. Clinical value of TSH receptor antibodies measurement in patients with Graves’ orbitopathy. Pediatr Endocrinol Rev 2010;7(Suppl 2):198–203.Search in Google Scholar

20. Ashkar, F, Miller, R, Smoak, W, Gilson, A. Liver disease in hyperthyroidism. South Med J 1971;64:462–5. https://doi.org/10.1097/00007611-197104000-00016.Search in Google Scholar PubMed

21. Huang, M, Liaw, Y. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 1995;10:344–50. https://doi.org/10.1111/j.1440-1746.1995.tb01106.x.Search in Google Scholar PubMed

22. Biscoveanu, M, Hasinski, S. Abnormal results of liver function tests in patients with Graves’disease. Endocr Pract 2000;6:367–9. https://doi.org/10.4158/EP.6.5.367.Search in Google Scholar PubMed

23. Lin, TY, Shekar, AO, Li, N, Yeh, MW, Saab, S, Wilson, M, et al.. Incidence of abnormal liver biochemical tests in hyperthyroidism. Clin Endocrinol 2017;86:755–9. https://doi.org/10.1111/cen.13312.Search in Google Scholar PubMed PubMed Central

24. He, K, Hu, Y, Xu, X-H, Mao, X-M. Hepatic dysfunction related to thyrotropin receptor antibody in patients with Graves’ disease. Exp Clin Endocrinol Diabetes 2014;122:368–72. https://doi.org/10.1055/s-0034-1375667.Search in Google Scholar PubMed

25. Zhang, R, Tian, X, Qin, L, Wei, X, Wang, J, Shen, J. Factors predicting abnormal liver function tests induced by Graves’ disease alone. Baltimore: a retrospective cohort study. Medicine; 2015:p. 94.10.1097/MD.0000000000000839Search in Google Scholar PubMed PubMed Central

26. Upadhyay, G, Singh, R, Kumar, A, Kumar, S, Kapoor, A, Godbole, MM. Severe hyperthyroidism induces mitochondria-mediated apoptosis in rat liver. Hepatology 2004;39:1120–30. https://doi.org/10.1002/hep.20085.Search in Google Scholar PubMed

27. Myers, JD, Brannon, ES, Holland, BC. A correlative study of the cardiac output and the hepatic circulation in hyperthyroidism. J Clin Invest 1950;29:1069–77. https://doi.org/10.1172/jci102338.Search in Google Scholar PubMed PubMed Central

28. Hong, SE, Choo, JW, Lim, SK, Lee, SJ, Park, JW, Kim, SE, et al.. A Case of Graves’ disease Accompanied with acute hepatitis A virus infection. Korean J Gastroenterol 2018;71:354–8. https://doi.org/10.4166/kjg.2018.71.6.354.Search in Google Scholar PubMed

29. Friedman, LS, Chopra, S, Travis, AC. Approach to the patient with abnormal liver biochemical and function tests. UpToDate, Post TW, editor, UpToDate Waltham, MA. [Accessed 10 June, 2020].Search in Google Scholar

30. Czaja, AJ. Autoimmune hepatitis. Liver pathophysiol. Elsevier: Salt Lake City; 2017:pp. 61–85.10.1016/B978-0-12-804274-8.00004-7Search in Google Scholar

31. Piantanida, E, Tanda, ML, Lai, A, Sassi, L, Bartalena, L. Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 2013;36:444–9. https://doi.org/10.3275/8937.Search in Google Scholar PubMed

32. Rotondo Dottore, G, Torregrossa, L, Caturegli, P, Ionni, I, Sframeli, A, Sabini, E, et al.. Association of T and B cells infiltrating orbital tissues with clinical features of Graves orbitopathy. JAMA Ophthalmol 2018;136:613–9. https://doi.org/10.1001/jamaophthalmol.2018.0806.Search in Google Scholar PubMed PubMed Central

33. Bahn, RS. Current insights into the pathogenesis of Graves’ ophthalmopathy. Horm Metab Res 2015;47:773–8. https://doi.org/10.1055/s-0035-1555762.Search in Google Scholar PubMed

34. de Carli, M, D’Elios, MM, Mariotti, S, Marcocci, C, Pinchera, A, Ricci, M, et al.. Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves’ ophthalmopathy. J Clin Endocrinol Metab 1993;77:1120–4. https://doi.org/10.1210/jc.77.5.1120.Search in Google Scholar

35. Huang, Y, Fang, S, Li, D, Zhou, H, Li, B, Fan, X. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye 2019;33:176–82. https://doi.org/10.1038/s41433-018-0279-9.Search in Google Scholar

36. Tan, Y, Chen, W, Liu, C, Zheng, X, Guo, A, Long, J. Effect of IL-21 on the balance of Th17 cells/Treg cells in the pathogenesis of Graves’ disease. Endocr Res 2019;44:138–47. https://doi.org/10.1080/07435800.2019.1600535.Search in Google Scholar

37. Rydzewska, M, Jaromin, M, Pasierowska, IE, Stozek, K, Bossowski, A. Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases. Thyroid Res 2018;11:2. https://doi.org/10.1186/s13044-018-0046-9.Search in Google Scholar

38. Park, YK, Yun, YW, Sung, SS, Park, US, Park, SH, Woo, JH, et al.. Propylthiouracil-associated p-ANCA positive vasculitis with focal segmental glomerulosclerosis. Korean J Nephrol 2004;23:997.Search in Google Scholar

39. Minamitani, K, Sato, H, Ohye, H, Harada, S, Arisaka, O. Guidelines for the treatment of childhood-onset Graves’ disease in Japan. Clin Pediatr Endocrinol 2016;2017:29–62. https://doi.org/10.1297/cpe.26.29.Search in Google Scholar

40. Vehaskari, VM, Rapola, J, Koskimies, O, Savilahti, E, Vilska, J, Hallman, N. Microscopic hematuria in schoolchildren: epidemiology and clinicopathologic evaluation. J Pediatr 1979;95:676–84. https://doi.org/10.1016/s0022-3476(79)80710-6.Search in Google Scholar


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0158).


Received: 2020-03-30
Accepted: 2020-07-20
Published Online: 2020-08-17
Published in Print: 2020-11-26

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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