Comparing the Frequency of CD4+T Cells in Recurrent Spontaneous Abortion Women with and without Anti-thyroid Peroxidase (TPO)
Thyroid autoimmunity, being recognized by the presence of auto-antibodies against thyroid peroxidase (TPO) and thyroglobulin, has known to be associated with increased risk of recurrent spontaneous abortion (RSA), even in euthyroid subjects. There was no robust evidence regarding T cell deviations in anti-TPO positive RSA patients. The aim of this study was to investigate if the numbers of different CD4+T subsets were different in women who experienced RSA and have an anti-TPO antibody from those without autoantibody and normal fertile women or not. In this study, peripheral blood samples were obtained from three groups of women (age: 20-35 years) including RSA anti-TPO positive (n=17), RSA anti-TPO negative (n=27), and fertile (n=29) groups. The frequency of T helper (Th) 1, Th2, Th17, and regulatory T cells (Tregs) and also, the proportions of Th1/Th2 and Th17/Treg were measured by flow cytometry and compared between groups in different menstrual phases. The findings indicated elevated levels of Th1 in anti-TPO+ RSA in comparison with those without anti-TPO (p-value: 0.004), exclusively in the luteal phase. Other T cell subsets were different only between RSA and control groups. Also, the Th1/Th2 and Th17/Treg ratios were increased in both RSA groups compared to fertile women. The only subset of CD4+ T cell different between RSA groups (i.e. with and without anti-TPO) was Th1 cells. Other CD4+ T cells’ deviations including Th2, Th17, and Treg cells could be related to the presence of abortion, regardless of the underlying thyroid autoimmunity state.
2. Kuon RJ, Strowitzki T, Sohn C, Daniel V, Toth B. Immune profiling in patients with recurrent miscarriage. J Reprod Immunol 2015; 108:136-41.
3. De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. Lancet Diabetes Endocrinol 2017; 6(7):575-86.
4. Crawford NM, Steiner AZ. Thyroid Autoimmunity and Reproductive Function. Semin Reprod Med 2016; 34(6):343-50.
5. Twig G, Shina A, Amital H, Shoenfeld Y. Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity. J Autoimmun2012; 38(2-3):J275-81.
6. Lee SK, Kim JY, Lee M, Gilman-Sachs A, Kwak-Kim J. Th17 and regulatory T cells in women with recurrent pregnancy loss. Am J Reprod Immunol 2012; 67(4):311-8.
7. Liu YS, Wu L, Tong XH, Wu LM, He GP, Zhou GX, et al. Study on the relationship between Th17 cells and unexplained recurrent spontaneous abortion. Am J Reprod Immunol 2011; 65(5):503-11.
8. Saifi B, Rezaee SA, Tajik N, Ahmadpour ME, Ashrafi M, Vakili R, et al. Th17 cells and related cytokines in unexplained recurrent spontaneous miscarriage at the implantation window. Reprod Biomed Online 2014; 29(4):481-9.
9. Saito S, Nakashima A, Shima T, Ito M. REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T-Cell Paradigm in Pregnancy. Am J Reprod Immunol 2010; 63(6):601-10.
10. Wu L, Luo LH, Zhang YX, Li Q, Xu B, Zhou GX, et al. Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy. Reprod Biol Endocrinol 2014; 12:74.
11. Zhu L, Chen H, Liu M, Yuan Y, Wang Z, Chen Y, et al. Treg/Th17 Cell Imbalance and IL-6 Profile in Patients With Unexplained Recurrent Spontaneous Abortion. Reprod Sci2017; 24(6):882-90.
12. Phenekos C, Vryonidou A, Gritzapis AD, Baxevanis CN, Goula M, Papamichail M. Th1 and Th2 Serum Cytokine Profiles Characterize Patients with Hashimoto’s Thyroiditis (Th1) and Graves’ Disease (Th2). Neuroimmunomodulation2004; 11(4):209-13.
13. Ehlers M, Jordan AL, Feldkamp J, Fritzen R, Quadbeck B, Haase M, et al. Anti-Thyroperoxidase Antibody Levels >500 IU/ml Indicate a Moderately Increased Risk for Developing Hypothyroidism in Autoimmune Thyroiditis. Horm Metab Res2016; 48(10):623-9.
14. Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015; 14(2):174-80.
15. Figueroa-Vega N, Alfonso-Perez M, Benedicto I, Sanchez-Madrid F, Gonzalez-Amaro R, Marazuela M. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis. J Clin Endocrinol Metab 2010; 95(2):953-62.
16. De Leo S, Pearce EN. Autoimmune thyroid disease during pregnancy. Lancet Diabetes Endocrinol 2018; 6(7):575-86.
17. Turhan Iyidir O, Konca Degertekin C, Sonmez C, Atak Yucel A, Erdem M, Akturk M, et al. The effect of thyroid autoimmunity on T-cell responses in early pregnancy. J Reprod Immunol2015; 110:61-6.
18. Shi Y, Wang H, Su Z, Chen J, Xue Y, Wang S, et al. Differentiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto's thyroiditis. Scand J Immunol 2010; 72(3):250-5.
19. Li C, Yuan J, Zhu YF, Yang XJ, Wang Q, Xu J, et al. Imbalance of Th17/Treg in Different Subtypes of Autoimmune Thyroid Diseases. Cell Physiol Biochem 2016; 40(1-2):245-52.
20. Qin Q, Liu P, Liu L, Wang R, Yan N, Yang J, et al. The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto's thyroiditis but not in Graves' disease. Braz J Med Biol Res 2012; 45(12):1202-8.
21. Nanba T, Watanabe M, Inoue N, Iwatani Y. Increases of the Th1/Th2 cell ratio in severe Hashimoto's disease and in the proportion of Th17 cells in intractable Graves' disease. Thyroid 2009; 19(5):495-501.
22. Yang X, Lun Y, Jiang H, Liu X, Duan Z, Xin S, et al. SIRT1-regualted abnormal acetylation of FOXP3 induces Treg function defect in Hashimoto's thyroiditis. Thyroid 2018; 28(2):246-56.
23. Bossowski A, Moniuszko M, Idzkowska E, Grubczak K, Singh P, Bossowska A, et al. Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127- and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3+ T cells in children with autoimmune thyroid diseases. Autoimmunity 2016; 49(5):320-8.
24. Ho H-N, Chao K-H, Chen H-F, Chen S-U, Wu M-Y, Yang Y-S. Distribution of Th1 and Th2 cell populations in human peripheral and decidual T cells from normal and anembryonic pregnancies.Fertil Steril 2001; 76(4):797-803.
25. Doria A, Iaccarino L, Arienti S, Ghirardello A, Zampieri S, Rampudda ME, et al. Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases. Reprod Toxicol 2006; 22(2):234-41.
26. Marron K, Harrity C. Endometrial lymphocyte concentrations in adverse reproductive outcome populations. J Assist Reprod Genet 2019; 36(5.
27. Abdolmohammadi Vahid S, Ghaebi M, Ahmadi M, Nouri M, Danaei S, Aghebati-Maleki L, et al. Altered T-cell subpopulations in recurrent pregnancy loss patients with cellular immune abnormalities. J Cell Physiol 2019; 234(4):4924-33.
28. Hosseini S, Shokri F, Ansari Pour S, Jeddi-Tehrani M, Nikoo S, Yousefi M, et al. A shift in the balance of T17 and Treg cells in menstrual blood of women with unexplained recurrent spontaneous abortion. J Reprod Immunol 2016; 116:13-22.
29. Sereshki N, Gharagozloo M, Ostadi V, Ghahiri A, Roghaei MA, Mehrabian F, et al. Variations in T-helper 17 and Regulatory T Cells during The Menstrual Cycle in Peripheral Blood of Women with Recurrent Spontaneous Abortion. Int J Fertil Steril 2014; 8(1):59-66.
30. Wang WJ, Hao CF, Yi L, Yin GJ, Bao SH, Qiu LH, et al. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J Reprod Immunol 2010; 84(2):164-70.
31. Mei S, Tan J, Chen H, Chen Y, Zhang J. Changes of CD4+CD25high regulatory T cells and FOXP3 expression in unexplained recurrent spontaneous abortion patients. Fertil Steril 2010; 94(6):2244-7.
32. Yang H, Qiu L, Chen G, Ye Z, Lu C, Lin Q. Proportional change of CD4+CD25+ regulatory T cells in decidua and peripheral blood in unexplained recurrent spontaneous abortion patients. Fertil Steril2008; 89(3):656-61.
33. Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod 2004; 10(5):347-53.
34. Dong P, Wen X, Liu J, Yan CY, Yuan J, Luo LR, et al. Simultaneous detection of decidual Th1/Th2 and NK1/NK2 immunophenotyping in unknown recurrent miscarriage using 8-color flow cytometry with FSC/Vt extended strategy. Biosci Rep 2017; 37(3).
35. Gao Y, Wang PL. Increased CD56(+) NK cells and enhanced Th1 responses in human unexplained recurrent spontaneous abortion. Genet Mol Res 2015; 14(4):18103-9.
36. Kwak-Kim J, Lee SK, Gilman-Sachs A. Elevated Th1/Th2 cell ratios in a pregnant woman with a history of RSA, secondary Sjogren's syndrome and rheumatoid arthritis complicated with one fetal demise of twin pregnancy. Am J Reprod Immunol 2007; 58(4):325-9.
37. Chaouat G, Ledee-Bataille N, Dubanchet S, Zourbas S, Sandra O, Martal J. TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm. Int Arch Allergy Immunol 2004; 134(2):93-119.
38. Makhseed M, Raghupathy R, Azizieh F, Omu A, Al-Shamali E, Ashkanani L. Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod 2001; 16(10):2219-26.
39. Guo J, Rapoport B, McLachlan SM. Balance of Th1/Th2 cytokines in thyroid autoantibody synthesis in vitro. Autoimmunity 1999; 30(1):1-9.
40. Tavakoli M, Jeddi-Tehrani M, Salek-Moghaddam A, Rajaei S, Mohammadzadeh A, Sheikhhasani S, et al. Effects of 1,25(OH)2 vitamin D3 on cytokine production by endometrial cells of women with recurrent spontaneous abortion. Fertil Steril 2011; 96(3):751-7.