Evaluation of Th1/Th2 Lymphocyte Balance in Peripheral Blood Mononuclear Cells of Patients with Hashimoto’s Thyroiditis
Abstract
Background: The role of T cells in the pathogenesis of Hashimoto’s thyroiditis is well established, whereas the precise and likely the overlapping contributions of different T-cell subpopulations to thyroid injury are less understood. The purpose of this study was to assess the expression pattern of two lineage determining transcription factors, T-bet and GATA-3 that regulate differentiation of T cells into Th1 or Th2 cell fates, respectively. Moreover, the mRNA expression and plasma concentration of Th1(IFN-γ) and Th2(IL-4) cytokineswere analyzed.
Methods: In this case-control study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression patterns of various transcripts in 20 patients (in Endocrinology Clinic, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran, in 2015) with Hashimoto’s thyroiditis (HT) and 22 healthy controls. Plasma IL-4 and IFN-γ concentrations were also measured using enzyme-linked immunosorbent assay.
Results: T-bet gene expression was significantly lower in patients compared to healthy controls (P=0.014). The expression of IL-4 mRNAs was significantly increased in the
peripheral blood mononuclear cells from patients as compared to normal controls (P=0.001). In addition, a marked increase in plasma IL-4 levels were observed in patient group compared to controls (P=0.043).
Conclusion: Altered balance between Th1 and Th2 related transcription factors and cytokines may be implicated in the pathogenesis of Hashimoto’s thyroiditis.
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2. Marinkovic T, Garin A, Yokota Y et al (2006). Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of ter-tiary lymphoid structures in the thy-roid. J Clin Invest, 116(10):2622-32.
3. Rose NR, Molotchnikoff MF, Twarog FJ(1973). Factors affecting transfer of experimental autoimmune thyroiditis in rats. Immunology, 24(5):859-70.
4. Ohashi H, Okugawa T, Itoh M(1991). Circulating activated T cell subsets in autoimmune thyroid diseases: differ-ences between untreated and treated patients. Acta Endocrinol (Copenh), 125(5):502-9.
5. Stassi G, De Maria R(2002). Autoim-mune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol, 2(3):195-204.
6. Agnello D, Lankford CS, Bream J et al(2003). Cytokines and transcription factors that regulate T helper cell dif-ferentiation: new players and new in-sights. J Clin Immunol, 23(3):147-61.
7. Vaseghi H, Sanati MH, Jadali Z(2016). T-helper Cell Type-1 Transcription Fac-tor T-Bet Is Down-regulated in Type 1 Diabetes. Iran J Allergy Asthma Immunol, 15(5):386-393.
8. Lin ZW, Wu LX, Xie Y et al (2015). The expression levels of transcription factors T-bet, GATA-3, RORγt and FOXP3 in peripheral blood lymphocyte (PBL) of patients with liver cancer and their significance. Int J Med Sci, 12(1):7-16.
9. Shi Y, Wang H, Su Z et al(2010). Differ-entiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto's thyroiditis. Scand J Immu-nol, 72(3):250-5.
10. Figueroa-Vega N, Alfonso-Pérez M, Benedicto I et al (2010). Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis. J Clin Endocrinol Metab, 95(2):953-62.
11. Zaletel K, Gaberšček S (2011). Hash-imoto's Thyroiditis: From Genes to the Disease. Curr Genomics, 12(8):576-88.
12. Safdari V, Alijani E, Nemati M, Jafarza-deh A (2017). Imbalances in T cell-related transcription factors among pa-tients with Hashimoto's thyroiditis. Sultan Qaboos Univ Med J, 17(2):e174-e180.
13. Heuer M, Aust G, Ode-Hakim S, Scherbaum WA(1996). Different cy-tokine mRNA profiles in Graves' dis-ease, Hashimoto's thyroiditis, and nonautoimmune thyroid disorders de-termined by quantitative reverse tran-scriptase polymerase chain reaction (RT-PCR). Thyroid, 6(2):97-106.
14. Ajjan RA, Watson PF, McIntosh RS, Weetman AP (1996). Intrathyroidal cytokine gene expression in Hashimo-to's thyroiditis. Clin Exp Immunol, 105(3):523-8.
15. Sakatsume Y, Matsubayashi S, Kasuga Y, Volpé R(1990). Lack of response of peripheral blood mononuclear cells to thyroid microsomal antigen in non-toxic nodular goiters. Reg Immunol, 3(1):42-5.
16. Schuetz M, Duan H, Wahl K et al (2006). T lymphocyte cytokine pro-duction patterns in hashimoto patients with elevated calcitonin levels and their relationship to tumor initiation. Anticancer Res, 26(6B):4591-6.
17. Shen X, Yan X, Xie B et al(2015). Ge-netic variants of interleukin-4 gene in autoimmune thyroid diseases: An up-dated meta-analysis. Autoimmunity, 48(2):129-35.
18. Ito C, Watanabe M, Okuda N et al (2006). Association between the se-verity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene. Endocr J, 53(4):473-8.
19. Romagnani S (2006). Regulation of the T cell response. Clin Exp Allergy, 36(11):1357-66.
20. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P(2007). Role of chemokines in endocrine autoimmune diseases. Endocr Rev, 28(5): 492-520.
21. Romagnani S (2006). Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders? Allergy, 61(1):3-14.
22. Wen JT, Zhang DH, Fang PF et al (2017). Role of Th1/Th2 cytokines in the diag-nosis and prognostic evaluation of anky-losing spondylitis. Genet Mol Res,16;16(1).
23. Seddon B, Mason D(1999). Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thy-roiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes. J Exp Med, 189(2):279-88.
24. Tang H, Sharp GC, Peterson KE, Braley-Mullen H(1998). Induction of granu-lomatous experimental autoimmune thyroiditis in IL-4 gene-disrupted mice. J Immunol, 160(1):155-62.
25. Yamauchi K, Yamada T, Sato A, Inaza-wa K, Aizawa T(2010). Elevation of serum immunoglobulin G in Hashimo-to's thyroiditis and decrease after treatment with L-thyroxine in hypo-thyroid patients. Intern Med, 49(4):267-71.
26. Romaldini JH, Biancalana MM, Figueire-do DI et al (1996). Effect of L-thyroxine administration on antithy-roid antibody levels, lipid profile, and thyroid volume in patients with Hash-imoto's thyroiditis. Thyroid, 6(3):183-8.
27. Stasiolek M, Dedecjus M, Adamczewski Z et al (2014). Effect of L-thyroxine treatment on peripheral blood dendrit-ic cell subpopulations in patients with Hashimoto's thyroiditis. Folia Histo-chem Cytobiol, 52(2):138-43.
28. Leskela S, Rodríguez-Muñoz A, de la Fuente H et al(2013). Plasmacytoid dendritic cells in patients with autoimmune thyroid dis-ease. J Clin Endocrinol Metab, 98(7):2822-33.
29. Guclu F, Ozmen B, Kirmaz C, et al (2009). Down-regulation of the auto-aggressive processes in patients with hypothyroid Hashimoto's thyroiditis following substitutive treatment with L-thyroxine. Eur Cytokine Netw, 20(1):27-32.
30. Kristensen B, Hegedüs L, Madsen HO, Smith TJ, Nielsen CH(2015). Altered balance between self-reactive T helper (Th)17 cells and Th10 cells and be-tween full-length forkhead box protein 3 (FoxP3) and FoxP3 splice variants in Hashimoto's thyroiditis. Clin Exp Immunol, 180(1):58-69.
2. Marinkovic T, Garin A, Yokota Y et al (2006). Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of ter-tiary lymphoid structures in the thy-roid. J Clin Invest, 116(10):2622-32.
3. Rose NR, Molotchnikoff MF, Twarog FJ(1973). Factors affecting transfer of experimental autoimmune thyroiditis in rats. Immunology, 24(5):859-70.
4. Ohashi H, Okugawa T, Itoh M(1991). Circulating activated T cell subsets in autoimmune thyroid diseases: differ-ences between untreated and treated patients. Acta Endocrinol (Copenh), 125(5):502-9.
5. Stassi G, De Maria R(2002). Autoim-mune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol, 2(3):195-204.
6. Agnello D, Lankford CS, Bream J et al(2003). Cytokines and transcription factors that regulate T helper cell dif-ferentiation: new players and new in-sights. J Clin Immunol, 23(3):147-61.
7. Vaseghi H, Sanati MH, Jadali Z(2016). T-helper Cell Type-1 Transcription Fac-tor T-Bet Is Down-regulated in Type 1 Diabetes. Iran J Allergy Asthma Immunol, 15(5):386-393.
8. Lin ZW, Wu LX, Xie Y et al (2015). The expression levels of transcription factors T-bet, GATA-3, RORγt and FOXP3 in peripheral blood lymphocyte (PBL) of patients with liver cancer and their significance. Int J Med Sci, 12(1):7-16.
9. Shi Y, Wang H, Su Z et al(2010). Differ-entiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto's thyroiditis. Scand J Immu-nol, 72(3):250-5.
10. Figueroa-Vega N, Alfonso-Pérez M, Benedicto I et al (2010). Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis. J Clin Endocrinol Metab, 95(2):953-62.
11. Zaletel K, Gaberšček S (2011). Hash-imoto's Thyroiditis: From Genes to the Disease. Curr Genomics, 12(8):576-88.
12. Safdari V, Alijani E, Nemati M, Jafarza-deh A (2017). Imbalances in T cell-related transcription factors among pa-tients with Hashimoto's thyroiditis. Sultan Qaboos Univ Med J, 17(2):e174-e180.
13. Heuer M, Aust G, Ode-Hakim S, Scherbaum WA(1996). Different cy-tokine mRNA profiles in Graves' dis-ease, Hashimoto's thyroiditis, and nonautoimmune thyroid disorders de-termined by quantitative reverse tran-scriptase polymerase chain reaction (RT-PCR). Thyroid, 6(2):97-106.
14. Ajjan RA, Watson PF, McIntosh RS, Weetman AP (1996). Intrathyroidal cytokine gene expression in Hashimo-to's thyroiditis. Clin Exp Immunol, 105(3):523-8.
15. Sakatsume Y, Matsubayashi S, Kasuga Y, Volpé R(1990). Lack of response of peripheral blood mononuclear cells to thyroid microsomal antigen in non-toxic nodular goiters. Reg Immunol, 3(1):42-5.
16. Schuetz M, Duan H, Wahl K et al (2006). T lymphocyte cytokine pro-duction patterns in hashimoto patients with elevated calcitonin levels and their relationship to tumor initiation. Anticancer Res, 26(6B):4591-6.
17. Shen X, Yan X, Xie B et al(2015). Ge-netic variants of interleukin-4 gene in autoimmune thyroid diseases: An up-dated meta-analysis. Autoimmunity, 48(2):129-35.
18. Ito C, Watanabe M, Okuda N et al (2006). Association between the se-verity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene. Endocr J, 53(4):473-8.
19. Romagnani S (2006). Regulation of the T cell response. Clin Exp Allergy, 36(11):1357-66.
20. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P(2007). Role of chemokines in endocrine autoimmune diseases. Endocr Rev, 28(5): 492-520.
21. Romagnani S (2006). Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders? Allergy, 61(1):3-14.
22. Wen JT, Zhang DH, Fang PF et al (2017). Role of Th1/Th2 cytokines in the diag-nosis and prognostic evaluation of anky-losing spondylitis. Genet Mol Res,16;16(1).
23. Seddon B, Mason D(1999). Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thy-roiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes. J Exp Med, 189(2):279-88.
24. Tang H, Sharp GC, Peterson KE, Braley-Mullen H(1998). Induction of granu-lomatous experimental autoimmune thyroiditis in IL-4 gene-disrupted mice. J Immunol, 160(1):155-62.
25. Yamauchi K, Yamada T, Sato A, Inaza-wa K, Aizawa T(2010). Elevation of serum immunoglobulin G in Hashimo-to's thyroiditis and decrease after treatment with L-thyroxine in hypo-thyroid patients. Intern Med, 49(4):267-71.
26. Romaldini JH, Biancalana MM, Figueire-do DI et al (1996). Effect of L-thyroxine administration on antithy-roid antibody levels, lipid profile, and thyroid volume in patients with Hash-imoto's thyroiditis. Thyroid, 6(3):183-8.
27. Stasiolek M, Dedecjus M, Adamczewski Z et al (2014). Effect of L-thyroxine treatment on peripheral blood dendrit-ic cell subpopulations in patients with Hashimoto's thyroiditis. Folia Histo-chem Cytobiol, 52(2):138-43.
28. Leskela S, Rodríguez-Muñoz A, de la Fuente H et al(2013). Plasmacytoid dendritic cells in patients with autoimmune thyroid dis-ease. J Clin Endocrinol Metab, 98(7):2822-33.
29. Guclu F, Ozmen B, Kirmaz C, et al (2009). Down-regulation of the auto-aggressive processes in patients with hypothyroid Hashimoto's thyroiditis following substitutive treatment with L-thyroxine. Eur Cytokine Netw, 20(1):27-32.
30. Kristensen B, Hegedüs L, Madsen HO, Smith TJ, Nielsen CH(2015). Altered balance between self-reactive T helper (Th)17 cells and Th10 cells and be-tween full-length forkhead box protein 3 (FoxP3) and FoxP3 splice variants in Hashimoto's thyroiditis. Clin Exp Immunol, 180(1):58-69.
| Files | ||
| Issue | Vol 49 No 3 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v49i3.3152 | |
| Keywords | ||
| Hashimoto's thyroiditis T lymphocyte Autoimmunity Cytokine | ||
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How to Cite
1.
VASEGHI H, ESFAHANIAN F, JADALI Z. Evaluation of Th1/Th2 Lymphocyte Balance in Peripheral Blood Mononuclear Cells of Patients with Hashimoto’s Thyroiditis. Iran J Public Health. 2020;49(3):549-556.
