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MiR-346 regulates CD4+CXCR5+ T cells in the pathogenesis of Graves’ disease

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Abstract

Follicular helper T (Tfh) cells are increasingly recognized as participants in various autoimmune diseases, including Graves’ disease. Although many transcription factors and cytokines are known to regulate Tfh cells, the role of noncoding RNA in Tfh cells development and function is poorly understood. Twenty-three patients with GD, eleven patients with remitting GD, and twenty-four healthy controls were enrolled in the current study. The interaction of miRNA and target gene was predicted through software analysis and then validated by luciferase assay and Western blot. The levels of miR-346 in circulating CD4+ T cells and plasma were measured by qRT-PCR. The correlation of miR-346 levels with the percentages of CD4+CXCR5+T cells and autoantibody levels were also analyzed. Up-regulation of Bcl-6 and down-regulation of miR-346 in GD patients were observed, and miR-346 could inhibit Bcl-6 at both transcriptional and translational levels. Overexpression of miR-346 led to attenuating CD4+CXCR5+ T cells. The abnormal expression of miR-346 restored in GD patients after treatment. A negative correlation between levels of miR-346 and percentages of CD4+CXCR5+ T cells was confirmed in GD patients. Additionally, negative correlations between the levels of miR-346 in circulating CD4+ T cells and serum concentrations of TR-Ab, TG-Ab, and TPO-Ab were also revealed in GD patients. MiR-346 regulates CD4+CXCR5+ T cells by targeting Bcl-6, a positive regulator of Tfh cells, and might play an important role in the pathogenesis of Graves’ disease.

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References

  1. S. Crotty, Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011)

    Article  CAS  PubMed  Google Scholar 

  2. J. Rolf, S.E. Bell, D. Kovesdi, M.L. Janas, D.R. Soond, L.M. Webb, S. Santinelli, T. Saunders, B. Hebeis, N. Killeen, K. Okkenhaug, M. Turner, Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol. 185(7), 4042–4052 (2010)

    Article  CAS  PubMed  Google Scholar 

  3. J. Ma, C. Zhu, B. Ma, J. Tian, S.E. Baidoo, C. Mao, W. Wu, J. Chen, J. Tong, M. Yang, Z. Jiao, H. Xu, L. Lu, S. Wang, Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin. Dev. Immunol. 2012, 827480 (2012)

    PubMed Central  PubMed  Google Scholar 

  4. S. Crotty, R.J. Johnston, S.P. Schoenberger, Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11(2), 114–120 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. R.J. Johnston, A.C. Poholek, D. DiToro, I. Yusuf, D. Eto, B. Barnett, A.L. Dent, J. Craft, S. Crotty, Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325(5943), 1006–1010 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. R.I. Nurieva, Y. Chung, G.J. Martinez, X.O. Yang, S. Tanaka, T.D. Matskevitch, Y.H. Wang, C. Dong, Bcl6 mediates the development of T follicular helper cells. Science 325(5943), 1001–1005 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. D. Yu, S. Rao, L.M. Tsai, S.K. Lee, Y. He, E.L. Sutcliffe, M. Srivastava, M. Linterman, L. Zheng, N. Simpson, J.I. Ellyard, I.A. Parish, C.S. Ma, Q.J. Li, C.R. Parish, C.R. Mackay, C.G. Vinuesa, The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31(3), 457–468 (2009)

    Article  CAS  PubMed  Google Scholar 

  8. M. Rotondi, L. Chiovato, Vitamin D deficiency in patients with Graves’ disease: probably something more than a casual association. Endocrine 43(1), 3–5 (2013)

    Article  CAS  PubMed  Google Scholar 

  9. A.P. Weetman, Autoimmune thyroid disease. Autoimmunity 37(4), 337–340 (2004)

    Article  CAS  PubMed  Google Scholar 

  10. E. Szczepanek-Parulska, M. Ruchala, A. Hernik, Unexpected conversion from hypothyroidism to an euthyroid state due to Graves’ disease in a patient with an ectopic thyroid. Endocrine 46(3), 684–685 (2014)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. J. Zhang, H. Zeng, M. Ren, H. Yan, M. Xu, Z. Feng, W. Liang, C. Yang, H. Cheng, H. Ding, L. Yan, Interleukin-21 is associated with disease activity in patients with Graves’ disease. Endocrine 46(3), 539–548 (2014)

    Article  PubMed  Google Scholar 

  12. T. Kocjan, B. Wraber, U. Repnik, S. Hojker, Changes in Th1/Th2 cytokine balance in Graves’ disease. Pflugers Arch. 440(5 Suppl), R94–95 (2000)

    Article  CAS  PubMed  Google Scholar 

  13. Y. Nagayama, K. Watanabe, M. Niwa, S.M. McLachlan, B. Rapoport, Schistosoma mansoni and alpha-galactosylceramide: prophylactic effect of Th1 Immune suppression in a mouse model of Graves’ hyperthyroidism. J Immunol 173(3), 2167–2173 (2004)

    Article  CAS  PubMed  Google Scholar 

  14. T. Nanba, M. Watanabe, N. Inoue, Y. Iwatani, Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease. Thyroid 19(5), 495–501 (2009)

    Article  CAS  PubMed  Google Scholar 

  15. S. Wang, S.E. Baidoo, Y. Liu, C. Zhu, J. Tian, J. Ma, J. Tong, J. Chen, X. Tang, H. Xu, L. Lu, T cell-derived leptin contributes to increased frequency of T helper type 17 cells in female patients with Hashimoto’s thyroiditis. Clin. Exp. Immunol. 171(1), 63–68 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. C. Zhu, J. Ma, Y. Liu, J. Tong, J. Tian, J. Chen, X. Tang, H. Xu, L. Lu, S. Wang, Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 97(3), 943–950 (2012)

    Article  CAS  PubMed  Google Scholar 

  17. D. Breitfeld, L. Ohl, E. Kremmer, J. Ellwart, F. Sallusto, M. Lipp, R. Forster, Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192(11), 1545–1552 (2000)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. C.H. Kim, L.S. Rott, I. Clark-Lewis, D.J. Campbell, L. Wu, E.C. Butcher, Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193(12), 1373–1381 (2001)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. P. Schaerli, K. Willimann, A.B. Lang, M. Lipp, P. Loetscher, B. Moser, CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192(11), 1553–1562 (2000)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. N. Fazilleau, L. Mark, L.J. McHeyzer-Williams, M.G. McHeyzer-Williams, Follicular helper T cells: lineage and location. Immunity 30(3), 324–335 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. D.P. Bartel, MicroRNAs: target recognition and regulatory functions. Cell 136(2), 215–233 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. J. Tian, K. Rui, S. Wang, Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Med. Hypotheses 83(2), 151–153 (2014)

    Article  CAS  PubMed  Google Scholar 

  23. J. Lu, G. Getz, E.A. Miska, E. Alvarez-Saavedra, J. Lamb, D. Peck, A. Sweet-Cordero, B.L. Ebert, R.H. Mak, A.A. Ferrando, J.R. Downing, T. Jacks, H.R. Horvitz, T.R. Golub, MicroRNA expression profiles classify human cancers. Nature 435(7043), 834–838 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. X. Tang, X. Tian, Y. Zhang, W. Wu, J. Tian, K. Rui, J. Tong, L. Lu, H. Xu, S. Wang, Correlation between the frequency of Th17 cell and the expression of MicroRNA-206 in patients with dermatomyositis. Clin. Dev. Immunol. 2013, 7 (2013)

    Google Scholar 

  25. T. Thum, C. Gross, J. Fiedler, T. Fischer, S. Kissler, M. Bussen, P. Galuppo, S. Just, W. Rottbauer, S. Frantz, M. Castoldi, J. Soutschek, V. Koteliansky, A. Rosenwald, M.A. Basson, J.D. Licht, J.T. Pena, S.H. Rouhanifard, M.U. Muckenthaler, T. Tuschl, G.R. Martin, J. Bauersachs, S. Engelhardt, MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456(7224), 980–984 (2008)

    Article  CAS  PubMed  Google Scholar 

  26. K.M. Pauley, M. Satoh, A.L. Chan, M.R. Bubb, W.H. Reeves, E.K. Chan, Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthr. Res. Ther. 10(4), R101 (2008)

    Article  Google Scholar 

  27. E. Stagakis, G. Bertsias, P. Verginis, M. Nakou, M. Hatziapostolou, H. Kritikos, D. Iliopoulos, D.T. Boumpas, Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann. Rheum. Dis. 70(8), 1496–1506 (2011)

    Article  CAS  PubMed  Google Scholar 

  28. J. Tian, J. Ma, K. Ma, H. Guo, S.E. Baidoo, Y. Zhang, J. Yan, L. Lu, H. Xu, S. Wang, β-Glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid-derived suppressor cells. Eur. J. Immunol. 43(5), 1220–1230 (2013)

    Article  CAS  PubMed  Google Scholar 

  29. J.F. Chen, E.M. Mandel, J.M. Thomson, Q. Wu, T.E. Callis, S.M. Hammond, F.L. Conlon, D.Z. Wang, The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet. 38(2), 228–233 (2006)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. A.P. Weetman, Graves’ disease. N. Engl. J. Med. 343(17), 1236–1248 (2000)

    Article  CAS  PubMed  Google Scholar 

  31. C. Du, C. Liu, J. Kang, G. Zhao, Z. Ye, S. Huang, Z. Li, Z. Wu, G. Pei, MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 10(12), 1252–1259 (2009)

    Article  CAS  PubMed  Google Scholar 

  32. K.P. Hoefig, V. Heissmeyer, MicroRNAs grow up in the immune system. Curr. Opin. Immunol. 20(3), 281–287 (2008)

    Article  CAS  PubMed  Google Scholar 

  33. C. Xiao, K. Rajewsky, MicroRNA control in the immune system: basic principles. Cell 136(1), 26–36 (2009)

    Article  CAS  PubMed  Google Scholar 

  34. E. Sonkoly, P. Janson, M.L. Majuri, T. Savinko, N. Fyhrquist, L. Eidsmo, N. Xu, F. Meisgen, T. Wei, M. Bradley, J. Stenvang, S. Kauppinen, H. Alenius, A. Lauerma, B. Homey, O. Winqvist, M. Stahle, A. Pivarcsi, MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4. J Allergy Clin Immunol. 126(3), 581–589 (2010). e581–520

    Article  CAS  PubMed  Google Scholar 

  35. Z. Feng, Y. Xia, M. Zhang, J. Zheng, MicroRNA-155 regulates T cell proliferation through targeting GSK3beta in cardiac allograft rejection in a murine transplantation model. Cell. Immunol. 281(2), 141–149 (2013)

    Article  CAS  PubMed  Google Scholar 

  36. X. Huang, X. Zhou, Z. Wang, F. Li, F. Liu, L. Zhong, X. Li, X. Han, Z. Wu, S. Chen, T. Zhao, CD99 triggers upregulation of miR-9-modulated PRDM1/BLIMP1 in Hodgkin/Reed-Sternberg cells and induces redifferentiation. Int. J. Cancer 131(4), E382–394 (2012)

    Article  CAS  PubMed  Google Scholar 

  37. J. Lin, T. Lwin, J.J. Zhao, W. Tam, Y.S. Choi, L.C. Moscinski, W.S. Dalton, E.M. Sotomayor, K.L. Wright, J. Tao, Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin’s B-cell lymphomas. Leukemia 25(1), 145–152 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education (Grant No. 20133227110008), National Natural Science Foundation of China (Grant Nos. 31100648, 81072453), Specialized Project for Clinical Medicine of Jiangsu Province (Grant No. BL2014065), Health Department Foundation of Jiangsu Province (Grant No. Z201312), Science and technology support program (Social Development) of Zhenjiang (Grant Nos. SH2013040, SH2014039) Graduate Student Research and Innovation Program of Jiangsu Province (Grant Nos. CXZZ13_0700, KYLX_1074), Jiangsu Province “333” Project, and Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. Juan Chen

    Present address: Department of Clinical Laboratory, Qingdao Central Hospital, Qingdao, China

Authors and Affiliations

  1. Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, 212002, Jiangsu Province, China

    Juan Chen, Yingzhao Liu & Shengjun Wang

  2. Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, 212013, China

    Jie Tian, Xinyi Tang, Ke Rui, Jie Ma, Chaoming Mao, Huaxi Xu & Shengjun Wang

  3. Department of Pathology and Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China

    Liwei Lu

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Juan Chen, Jie Tian, and Xinyi Tang have contributed equally to this work.

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Chen, J., Tian, J., Tang, X. et al. MiR-346 regulates CD4+CXCR5+ T cells in the pathogenesis of Graves’ disease. Endocrine 49, 752–760 (2015). https://doi.org/10.1007/s12020-015-0546-5

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  • DOI: https://doi.org/10.1007/s12020-015-0546-5

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