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The possible role of CD4+CD25highFoxp3+/CD4+IL-17A+ cell imbalance in the autoimmunity of patients with Hashimoto thyroiditis

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Abstract

Hashimoto thyroiditis (HT) is a prototypic organ-specific autoimmune thyroid disease, for which the exact etiology remains unclear. The aim of this study was to investigate dynamic changes in regulatory T cell (Treg) and T helper 17 cell (Th17) populations in patients with HT at different stages of thyroid dysfunction, as well as to analyze the possible correlation between the Treg/Th17 cell axis and autoimmune status in HT. We assessed thyroid function and autoantibody serology both in HT patients and in healthy controls (HCs) and divided HT patients into three subgroups according to thyroid function. We then determined the percentages of Treg and Th17 cells in peripheral blood mononuclear cells and analyzed mRNA expression of the Treg and Th17 cell-defining transcription factors Foxp3 and RORγt. In addition, serum levels of TGF-β and IL-17A were assessed. We found that the percentage of Treg cells, Foxp3 mRNA levels, and the ratio of Treg/Th17 cells were all significantly lower in HT patients, while Th17 cell percentages and RORγt mRNA levels were significantly higher. Interestingly, we also observed significant differences in these measurements between HT patient subgroups. Serum IL-17A levels were markedly increased in HT patients, while serum concentrations of TGF-β were lower, compared to HCs. The ratio of Treg/Th17 cells was negatively correlated with the levels of serum thyroperoxidase antibody, thyroglobulin antibody, and thyrotropin (TSH) in HT patients. Taken together, our data suggest that the balance between Treg and Th17 cells shifts in favor of Th17 cells during clinical progression of HT, which is negatively correlated with levels of thyroid-specific autoantibodies and TSH, implying that Treg/Th17 cell imbalance may contribute to thyroid damage in HT.

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References

  1. S.H. Golden, K.A. Robinson, I. Saldanha et al., Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J. Clin. Endocrinol. Metab. 94(6), 1853–1878 (2009)

    Article  CAS  PubMed  Google Scholar 

  2. M. Rizzo, R.T. Rossi, O. Bonaffini et al., Increased annual frequency of Hashimoto’s thyroiditis between years 1988 and 2007 at a cytological unit of Sicily. Ann. Endocrinol. (Paris) 71(6), 525–534 (2010)

    Article  CAS  Google Scholar 

  3. B. Delemer, J.P. Aubert, P. Nys et al., An observational study of the initial 3212 management of hypothyroidism in France: the ORCHIDEE study. Eur. J. Endocrinol. 167(6), 817–823 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. M.P. Vanderpump, The epidemiology of thyroid disease. Br. Med. Bull. 99(1), 39–51 (2011)

    Article  PubMed  Google Scholar 

  5. E.N. Pearce, A.P. Farwell, L.E. Braverman, Thyroiditis. N. Engl. J. Med. 348(26), 2646–2655 (2003)

    Article  PubMed  Google Scholar 

  6. D.S. McLeod, D.S. Cooper, The incidence and prevalence of thyroid autoimmunity. Endocrine 42(2), 252–265 (2012)

    Article  CAS  PubMed  Google Scholar 

  7. S. Yu, G.C. Sharp, H. Braley-Mullen, Thyrocytes responding to IFN-gamma are essential for development of lymphocytic spontaneous autoimmune thyroiditis and inhibition of thyrocyte hyperplasia. J. Immunol. 176(2), 1259–1265 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. S. Koida, K. Tsukasaki, T. Tsuchiya et al., Primary T-cell lymphoma of the thyroid gland with chemokine receptors of Th1 phenotype complicating autoimmune thyroiditis. Haematologica 92(3), e37–40 (2007)

    Article  PubMed  Google Scholar 

  9. H. Qiu, W. Tang, P. Yin et al., Cytotoxic T-lymphocyte associated antigen 4 polymorphism and Hashimoto’s thyroiditis susceptibility: a meta-analysis. Endocrine 45(2), 198–205 (2014)

    Article  CAS  PubMed  Google Scholar 

  10. M. Feng, F.B. Zhang, H.R. Deng, The CTLA4 +49A/G polymorphism is associated with an increased risk of Hashimoto’s thyroiditis in Asian but not Caucasian populations: an updated meta-analysis. Endocrine 44(2), 350–358 (2013)

    Article  CAS  PubMed  Google Scholar 

  11. S. Alfadhli, Q. Almutawa, J.M. Abbas et al., Association of Hashimoto’s thyroiditis with cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and inducible co-stimulator (ICOS) genes in a Kuwaiti population. Endocrine 43(3), 666–677 (2013)

    Article  CAS  PubMed  Google Scholar 

  12. J. Yang, Q. Qin, N. Yan et al., CD40 C/T(-1) and CTLA-4 A/G(49) SNPs are associated with autoimmune thyroid diseases in the Chinese population. Endocrine 41(1), 111–115 (2012)

    Article  CAS  PubMed  Google Scholar 

  13. S. Sakaguchi, M. Ono, R. Setoguchi et al., Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006)

    Article  CAS  PubMed  Google Scholar 

  14. Q. Tang, J.A. Bluestone, The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat. Immunol. 9(3), 239–244 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. J. Zhu, W.E. Paul, CD4 T cells: fates, functions, and faults. Blood 112(5), 1557–1569 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. A.B. Glick, A. Wodzinski, P. Fu, A.D. Levine, D.N. Wald, Impairment of regulatory T-cell function in autoimmune thyroid disease. Thyroid 23(7), 871–878 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. C.T. Weaver, R.D. Hatton, P.R. Mangan, L.E. Harrington, IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007)

    Article  CAS  PubMed  Google Scholar 

  18. E. Bettelli, M. Oukka, V.K. Kuchroo, T(H)-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8(4), 345–350 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. J. Furuzawa-Carballeda, M.I. Vargas-Rojas, A.R. Cabral, Autoimmune inflammation from the Th17 perspective. Autoimmun. Rev. 6(3), 169–175 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. P. Miossec, T. Korn, V.K. Kuchroo, Interleukin-17 and type 17 helper T cells. N. Engl. J. Med. 361(9), 888–898 (2009)

    Article  CAS  PubMed  Google Scholar 

  21. T. Korn, E. Bettelli, M. Oukka, V.K. Kuchroo, IL-17 and Th17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009)

    Article  CAS  PubMed  Google Scholar 

  22. Y. Shi, H. Wang, Z. Su et al., Differentiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto’s thyroiditis. Scand. J. Immunol. 72(3), 250–255 (2010)

    Article  CAS  PubMed  Google Scholar 

  23. J.T. Dunn, H.E. Crutchfield, R. Gutekunst, A.D. Dunn, Methods for measuring iodine in urine (International Council for the Control of Deficiency Disorders, Wageningen, 1993)

    Google Scholar 

  24. W. Teng, Z. Shan, X. Teng et al., Effect of iodine intake on thyroid diseases in China. N. Engl. J. Med. 354(26), 2783–2793 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. I. Raphael, S. Nalawade, T.N. Eagar, T.G. Forsthuber, T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine (2014). doi:10.1016/j.cyto.2014.09.011

    PubMed  Google Scholar 

  26. N. Figueroa-Vega, M. Alfonso-Perez, I. Benedicto et al., Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis. J. Clin. Endocrinol. Metab. 95(2), 953–962 (2010)

    Article  CAS  PubMed  Google Scholar 

  27. D. Peng, B. Xu, Y. Wang, H. Guo, Y. Jiang, A high frequency of circulating Th22 and Th17 cells in patients with new onset Graves’ disease. PLoS ONE 8(7), e68446 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. G.P. Morris, N.K. Brown, Y.C. Kong, Naturally-existing CD4+CD25+Foxp3+ regulatory T cells are required for tolerance to experimental autoimmune thyroiditis induced by either exogenous or endogenous autoantigen. J. Autoimmun. 33(1), 68–76 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. S. Yu, P.K. Maiti, M. Dyson et al., B cell-deficient NOD.H-2h4 mice have CD4+CD25+T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis. J. Exp. Med. 203(2), 349–358 (2006)

    Article  PubMed Central  PubMed  Google Scholar 

  30. J.D. Fontenot, J.P. Rasmussen, L.M. Williams et al., Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22(3), 329–341 (2005)

    Article  CAS  PubMed  Google Scholar 

  31. J.C. Marie, J.J. Letterio, M. Gavin, A.Y. Rudensky, TGF-beta l maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201(7), 1061–1067 (2005)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. D. Li, W. Cai, R. Gu et al., Th17 cell plays a role in the pathogenesis of Hashimoto’s thyroiditis in patients. Clin. Immunol. 149(3), 411–420 (2013)

    Article  CAS  PubMed  Google Scholar 

  33. M. Klatka, E. Grywalska, M. Partyka et al., Th17 and Treg cells in adolescents with Graves’ disease. Impact of treatment with methimazole on these cell subsets. Autoimmunity 47(3), 201–211 (2014)

    Article  CAS  PubMed  Google Scholar 

  34. B. Kristensen, L. Hegedüs, H.O. Madsen et al., Altered balance between self-reactive Th17 cells and Th10 cells and between full-length Foxp3 and Foxp3 splice variants in Hashimoto’s thyroiditis. Clin. Exp. Immunol. (2014). doi:10.1111/cei.12557

    Google Scholar 

  35. H.G. Evans, T. Suddason, I. Jackson et al., Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes. Proc. Natl. Acad. Sci. USA 104(43), 17034–17039 (2007)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. E.V. Acosta-Rodriguez, G. Napolitani, A. Lanzavecchia, F. Sallusto, Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8(9), 942–949 (2007)

    Article  CAS  PubMed  Google Scholar 

  37. N.J. Wilson, K. Boniface, J.R. Chan et al., Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat. Immunol. 8(9), 950–957 (2007)

    Article  CAS  PubMed  Google Scholar 

  38. L. Zhou, J.E. Lopes, M.M. Chong et al., TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192), 236–240 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. K. Ichiyama, H. Yoshida, Y. Wakabayashi et al., Foxp3 inhibits ROR gammat-mediated IL-17 mRNA transcription through direct interaction with ROR gammat. J. Biol. Chem. 283(25), 17003–17008 (2008)

    Article  CAS  PubMed  Google Scholar 

  40. L. Shi, M. Bi, R. Yang et al., Defective expression of regulatory B cells in iodine-induced autoimmune thyroiditis in non-obese diabetic H-2(h4) mice. J. Endocrinol. Invest. 37(1), 43–50 (2014)

    Article  CAS  PubMed  Google Scholar 

  41. P.I. Spuls, L. Hooft, Brodalumab and ixekizumab, anti-interleukin-17-receptor antibodies for psoriasis: a critical appraisal. Br. J. Dermatol. 167(4), 710–713 (2012); discussion 714–715

    Article  PubMed  Google Scholar 

  42. W. Hueber, D.D. Patel, T. Dryja et al., Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. (2010). doi:10.1126/scitranslmed.3001107

    PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge Dr. Bradley N. Martin (Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, USA) for his excellent English-language-editing of the manuscript. This work was funded by the Shandong Province Higher Educational Science and Technology Program of China (No. J11LF66), Shandong Province Natural Science Foundation of China (No. ZR2013HM049), and Shandong Province Science and Technology Development Project of China (No. 2011YD18063).

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The authors of this study have no conflict of interest regarding this article.

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    Authors and Affiliations

    1. Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, China

      Haibo Xue, Shoujun Song, Li Zhang, Tingting Yang & Huan Liu

    2. International Office, Binzhou Medical University Hospital, Binzhou, China

      Xiurong Yu

    3. Department of Dermatology, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China

      Lei Ma

    4. Department of Endocrinology and Metabolism, Shanxi Dayi Hospital, Taiyuan, China

      Yuanbin Li

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    Haibo Xue, Xiurong Yu and Lei Ma have contributed equally to this work.

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    Xue, H., Yu, X., Ma, L. et al. The possible role of CD4+CD25highFoxp3+/CD4+IL-17A+ cell imbalance in the autoimmunity of patients with Hashimoto thyroiditis. Endocrine 50, 665–673 (2015). https://doi.org/10.1007/s12020-015-0569-y

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