Helper T Cell 17 and Regulatory T Cell Levels in Peripheral Blood of Newly Diagnosed Patients with Autoimmune Thyroid Disease: A Meta-Analysis

Abstract

This article aims to explore associated immune indicators of autoimmune thyroid disease (AITD) through a meta-analysis of published case-control studies on newly diagnosed AITD patients, intending to provide some suggestions for research on the mechanisms of AITD. Six electronic databases were searched for case-control studies on newly diagnosed AITD patients from inception to August 15, 2022. A random-effects model was used to calculate the standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (95% CI). A total of 26 articles were included in this meta-analysis. Patients with newly diagnosed AITD had higher levels of helper T cell 17 (Th17) (Hashimoto’s disease (HT): SMD=2.35, 95% CI: 1.98, 2.72; Graves’ disease (GD): SMD=1.61, 95% CI: 1.23, 1.98), lower levels of regulatory T cell (Treg) (HT: SMD=–2.04, 95% CI: –2.67, –1.42; GD: SMD=–1.35, 95% CI: –2.11, –0.58), and lower levels of forkhead box P3 (FoxP3) mRNA (HT: SMD=–2.58, 95% CI: –3.12, –2.05; GD: SMD=–2.13, 95% CI: –2.56, –1.70), compared to the healthy population. In addition, the single nucleotide polymorphism rs3761548 and rs3761549 in the promoter region of FoxP3 showed a higher frequency in the comparison of genotype “CT” only in HT patients than in the healthy population (OR=1.66, 95%CI: 1.18, 2.34). In patients with newly diagnosed AITD, the Th17/Treg ratio imbalance may develop AITD. Monitoring Th17 and Treg levels may become an essential tool to assess the organism’s immune homeostasis and hopefully guide clinical diagnosis and treatment.

Key words

Hashimoto’s disease - Graves’ disease - helper T cell 17 - regulatory T cell - meta-analysis

Publikationsverlauf

Eingereicht: 12. Juli 2022

Angenommen nach Revision: 04. November 2022

Accepted Manuscript online:
04. November 2022

Artikel online veröffentlicht:
09. Dezember 2022

• References

• 1 Luty J, Ruckemann-Dziurdzińska K, Witkowski JM. et al. Immunological aspects of autoimmune thyroid disease – complex interplay between cells and cytokines. Cytokine 2019; 116: 128-133
• 2 Inoue Y, Watanabe M, Inoue N. et al. Associations of single nucleotide polymorphisms in precursor-microRNA (miR)-125a and the expression of mature miR-125a with the development and prognosis of autoimmune thyroid diseases. Clin Exp Immunol 2014; 178: 229-235
• 3 Cogni G, Chiovato L. An overview of the pathogenesis of thyroid autoimmunity. Hormones (Athens) 2013; 12: 19-29
• 4 Guo Y, Zynat J, Xing S. et al. Immunological changes of T helper cells in flow cytometer-sorted CD4+T cells from patients with Hashimoto’s thyroiditis. Exp Ther Med 2018; 15: 3596-3602
• 5 Gerenova J, Manolova I, Stanilova S. Serum levels of interleukin – 23 and interleukin – 17 in Hashimoto’s thyroiditis. Acta Endocrinol (Buchar) 2019; 5: 74-79
• 6 Zhang N, Wang Q, Tian Y. et al. Expressions of IL-17 and TNF-α in patients with Hashimoto’s disease combined with thyroid cancer before and after surgery and their relationship with prognosis. Clin Transl Oncol 2020; 22: 1280-1287
• 7 Esfahanian F, Ghelich R, Rashidian H. et al. Increased levels of serum interleukin-17 in patients with Hashimoto’s thyroiditis. Indian J Endocrinol Metab 2017; 21: 551-554
• 8 Safdari V, Alijani E, Nemati M. et al. Imbalances in T cell-related transcription factors among patients with Hashimoto’s thyroiditis. Sultan Qaboos Univ Med J 2017; 17: e174-e180
• 9 Fang S, Zhang S, Huang Y. et al. Evidence for associations between Th1/Th17 “Hybrid” phenotype and altered lipometabolism in very severe Graves orbitopathy. J Clin Endocrinol Metab 2020; 105 dgaa124
• 10 Li C, Yuan J, Zhu YF. et al. Imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases. Cell Physiol Biochem 2016; 40: 245-252
• 11 Zhang D, Qiu X, Li J. et al. MiR-23a-3p-regulated abnormal acetylation of FOXP3 induces regulatory T cell function defect in Graves’ disease. Biol Chem 2019; 400: 639-650
• 12 Kalantar K, Khansalar S, Eshkevar Vakili M. et al. Association of foxp3 gene variants with risk of Hashimoto’s thyroiditis and correlation with anti-TPO antibody levels. Acta Endocrinol (Buchar) 2019; 15: 423-429
• 13 Fathima N, Narne P, Ishaq M. Association and gene-gene interaction analyses for polymorphic variants in CTLA-4 and FOXP3 genes: role in susceptibility to autoimmune thyroid disease. Endocrine 2019; 64: 591-560.
• 14 González-Amaro R, Marazuela M. T regulatory (Treg) and T helper 17 (Th17) lymphocytes in thyroid autoimmunity. Endocrine 2016; 52: 30-38
• 15 Wells GA, Shea B, O’Connell D et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
• 16 Harris RJ, Deeks JJ, Altman DG. et al. Metan: fixed- and random-effects meta-analysis. Stata J 2008; 8: 3-28
• 17 Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Archiv Pub Health 2014; 72: 39
• 18 Higgins JPT, Thomas J, Chandler J. et al. Cochrane handbook for systematic reviews of interventions version 6.0 (updated July 2019). 2019
• 19 Egger M, Davey Smith G, Schneider M. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629-634
• 20 Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455-463
• 21 Song JZ, Wu HN, Qian W. Significance of the alternation of Th17 cells in patients with chronic lymphocytic thyroiditis. Chin J Cell Mol Immunol 2009; 25: 927-931
• 22 Jin X, Shang XM, Chen HB. et al. Study on dynamic changes and significance of the peripheral blood regulatory T cells ( Treg) and Th17 cells in patients with Hashimoto’s thyroiditis. J Clin Exp Med 2018; 17: 2092-2094
• 23 Li XJ, Zhang L. Th3, Th17 and its related influential factors in autoimmune thyroid diseases and its significance. J North Pharm 2016; 13: 129-130
• 24 Gao ST, Zhu TN, Zhang YN. et al. The frequency and function of CD4+CD25+regulatory T cells in autoimmune thyroid diseases. Chin J Immunol 2011; 27: 269-273
• 25 Xue HB, Ma L, Li YB. et al. Correlation between Treg/Th17 cells imbalance and autoimmunity in Hashimoto thyroiditis. Chin J Modern Med 2012; 22: 67-71
• 26 Zheng LT, Yu SP, Wang N. et al. The role of regulatory T cells and TGF-β1 in autoimmune thyroid disease. Shandong Med J 2012; 52: 81-83
• 27 Chen Q, Niu J, Zheng BJ. et al. Application of regulatory T cells and thyroid autoantibody detection in autoimmune thyroid diseases. Curr Immunol 2012; 32: 144-147
• 28 Zhao JY, Wen Y, Wang Q. Detection and significance of the alteration of Th17 cells in patients with Hashimoto’s thyroiditis and Graves’ disease. Chin J Lab Diagn 2012; 16: 637-640
• 29 Huang GY, Xuan WT, He LJ. Tregs role of CD4+CD25+Foxp3+Tregs in autoimmune thyroid diseases. Med Innov China 2017; 23: 16-20
• 30 Hu Y, Zhang L, Chen H. et al. Analysis of regulatory T cell subsets and their expression of helios and PD-1 in patients with Hashimoto thyroiditis. Int J Endocrinol. 2019 5368473.
• 31 Mao C, Wang S, Xiao Y. et al. Impairment of regulatory capacity of CD4+CD25+regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves’ disease. J Immunol 2011; 186: 4734-4743
• 32 Qin J, Zhou J, Fan C. et al. Increased circulating Th17 but decreased CD4+Foxp3+Treg and CD19+CD1dhiCD5+Breg subsets in new-onset Graves’ disease. Biomed Res Int 2017; 8431838
• 33 Xue HB, Yang Y, Zhang Y. et al. Macrophage migration inhibitory factor interacting with Th17 cells may be involved in the pathogenesis of autoimmune damage in Hashimoto’s thyroiditis. Mediators Inflamm 2015; 621072
• 34 Şıklar Z, Karataş D, Doğu F. et al. Regulatory T cells and vitamin D status in children with chronic autoimmune thyroiditis. J Clin Res Pediatr Endocrinol 2016; 8: 276-281
• 35 Yang X, Lun Y, Jiang H. et al. SIRT1-regulated abnormal acetylation of FOXP3 induces regulatory T-cell function defect in Hashimoto’s thyroiditis. Thyroid 2018; 28: 246-256
• 36 Klatka M, Grywalska E, Partyka M. et al. Th17 and Treg cells in adolescents with Graves’ disease. Impact of treatment with methimazole on these cell subsets. Autoimmunity 2014; 47: 201-211
• 37 Rydzewska M, Góralczyk A, Gościk J. et al. Analysis of chosen polymorphisms rs2476601 a/G – PTPN22, rs1990760 C/T – IFIH1, rs179247 a/G – TSHR in pathogenesis of autoimmune thyroid diseases in children. Autoimmunity 2018; 51: 183-190
• 38 Inoue N, Watanabe M, Morita M. et al. Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases. Clin Exp Immunol 2010; 162: 402-406
• 39 Zheng L, Wang X, Xu L. et al. Foxp3 gene polymorphisms and haplotypes associate with susceptibility of Graves’ disease in Chinese Han population. Int Immunopharmacol 2015; 25: 425-431
• 40 Safdari V, Alijani E, Nemati M. et al. Imbalances in T cell-related transcription factors among patients with Hashimoto’s thyroiditis. Sultan Qaboos Univ Med J 2017; 17: e174-e180
• 41 Xue H, Yu X, Ma L. et al. The possible role of CD4⁺CD25(high)Foxp3⁺/CD4+IL-17A⁺ cell imbalance in the autoimmunity of patients with Hashimoto thyroiditis. Endocrine 2015; 50: 665-673
• 42 Tan Y, Chen W, Liu C. et al. Effect of IL-21 on the balance of Th17 cells/Treg cells in the pathogenesis of Graves’ disease. Endocr Res 2019; 44: 138-147
• 43 Ren X, Chen H. Changes in Th9 and Th17 lymphocytes and functional cytokines and their relationship with thyroid-stimulating hormone receptor antibodies at different stages of graves’ disease. Front Immunol 2022; 13: 919681
• 44 Li Q, Wang B, Mu K. et al. The pathogenesis of thyroid autoimmune diseases: New T lymphocytes – Cytokines circuits beyond the Th1-Th2 paradigm. J Cell Physiol 2019; 234: 2204-2216
• 45 Zake T, Skuja S, Kalere I. et al. Upregulated tissue expression of T helper (Th) 17 pathogenic interleukin (IL)-23 and IL-1β in Hashimoto’s thyroiditis but not in Graves’ disease. Endocr J 2019; 66: 423-430
• 46 Zhao N, Liu X, Wu C. et al. Changes in Treg numbers and activity in papillary thyroid carcinoma with and without Hashimoto’s thyroiditis. J Int Med Res 2020; 48 300060520919222
• 47 Lee DJ. The relationship between TIGIT+regulatory T cells and autoimmune disease. Int Immunopharmacol 2020; 83: 106378
• 48 Cao Y, Jin X, Sun Y. et al. Therapeutic effect of mesenchymal stem cell on Hashimoto’s thyroiditis in a rat model by modulating Th17/Treg cell balance. Autoimmunity 2020; 53: 35-45
• 49 Zhang D, Qiu X, Li J. et al. MiR-23a-3p-regulated abnormal acetylation of FOXP3 induces regulatory T cell function defect in Graves’ disease. Biol Chem 2019; 400: 639-650