@2024 Afarand., IRAN
ISSN: 2251-8215 Sarem Journal of Reproductive Medicine 2018;2(3):93-97
ISSN: 2251-8215 Sarem Journal of Reproductive Medicine 2018;2(3):93-97
Comparison of Cytokines Levels Released from Th17 and Regulatory T Cells in Patients with Recurrent Spontaneous Abortions and Healthy Women
ARTICLE INFO
Article Type
Original ResearchAuthors
Roumandeh N. (1)Saremi A.T. (2)
Sanaye Naderi M. ()
Younesi B. (4)
Arasteh J. (5)
Zare A. (*)
() Sarem Fertility & Infertility Research Center (SAFIR), Sarem Women’s Hospital, Tehran, Iran
(*) “Sarem Fertility & Infertility Research Center (SAFIR)” and “Sarem Cell Research Center (SCRC)” , Shahid Beheshti Medical University, Tehran, Iran
(1) ”Sarem Cell Research Center (SCRC), Sarem Women’s Hospital, Tehran” and “Immunology Department, Medicine Faculty, Semnan University of Medical Sciences, Semnan, Iran
(2) “Sarem Fertility & Infertility Research Center (SAFIR)” and “Sarem Cell Research Center (SCRC)” , Sarem Women’s Hospital, Tehran, Iran
(4) Sarem Women’s Hospital, Tehran, Iran
(5) Biology Department, Basic Sciences Faculty, Central Tehran Branch, Islamic Azad University, Tehran, Iran
Correspondence
Article History
Received: February 9, 2017Accepted: June 27, 2017
ePublished: August 15, 2018
ABSTRACT
Aims
Unexplained recurrent spontaneous abortion (URSA) might be caused by an immunological rejection of fetus due to the immune dysregulation during pregnancy. It is supposed that the balance between Th17 and regulatory T cells (Treg) is one of the immune system regulatory mechanisms for pregnancy. The objective of the present study was to evaluate the Treg and Th17 cytokines in the women with URSA compared to healthy women.
Materials & Methods This case-control study was carried out on 30 women with a history of three or more URSA (case group) and 28 normal healthy women with at least one successful delivery (control group) in Sarem women hospital (Tehran, Iran). The levels of IL-17, IL-21, IL-10 and TGF-β were measured in the serum samples by ELISA method and compared between two groups. The data were analyzed by Mann-Whitney U test and Spearman's rank correlation coefficient using SPSS 22 software.
Findings The level of IL-17 in the case group was significantly higher than the control group (p<0.001). Also, the level of TGF-β in the control group was significantly higher than URSA patients (p=0.001). The serum level of IL-17 showed a positive correlation with TGF-β in URSA group (r=0.554; p=0.002). There were no significant differences in IL-21 and IL-10 levels between two groups (p>0.05).
Conclusion The level of IL-17 in patients with URSA is higher than normal healthy women, however, the concentration of TGF-β in women with URSA is lower than healthy women; these findings show that Th17 immunity and regulatory T cell-mediated immune regulation are involved in the pathogenesis of URSA.
Materials & Methods This case-control study was carried out on 30 women with a history of three or more URSA (case group) and 28 normal healthy women with at least one successful delivery (control group) in Sarem women hospital (Tehran, Iran). The levels of IL-17, IL-21, IL-10 and TGF-β were measured in the serum samples by ELISA method and compared between two groups. The data were analyzed by Mann-Whitney U test and Spearman's rank correlation coefficient using SPSS 22 software.
Findings The level of IL-17 in the case group was significantly higher than the control group (p<0.001). Also, the level of TGF-β in the control group was significantly higher than URSA patients (p=0.001). The serum level of IL-17 showed a positive correlation with TGF-β in URSA group (r=0.554; p=0.002). There were no significant differences in IL-21 and IL-10 levels between two groups (p>0.05).
Conclusion The level of IL-17 in patients with URSA is higher than normal healthy women, however, the concentration of TGF-β in women with URSA is lower than healthy women; these findings show that Th17 immunity and regulatory T cell-mediated immune regulation are involved in the pathogenesis of URSA.
Keywords:
Abortion, Habitual ,
Unexplained Recurrent Spontaneous Abortion ,
Regulatory T Cells ,
Th17 Cells ,
CITATION LINKS
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[19]Wang WJ, Hao CF, Qu QL, Wang X, Qiu LH, Lin QD. The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage. Hum Reprod. 2010;25(10):2591-6.
[20]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.
[21]Arruvito L, Sotelo AI, Billordo A, Fainboim L. A physiological role for inducible FOXP3(+) Treg cells. Lessons from women with reproductive failure. Clin Immunol. 2010;136(3):432-41.
[22]Lee SK, Kim JY, Hur SE, Kim CJ, Na BJ, Lee M, et al. An imbalance in interleukin-17-producing T and Foxp3(+) regulatory T cells in women with idiopathic recurrent pregnancy loss. Hum Reprod. 2011;26(11):2964-71.
[23]Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol. 2007;179(8):5571-5.
[24]Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet. 2014; 290(4): 757–62.
[25]Areia AL, Fonseca E, Areia M, Moura P. Low-molecular-weight heparin plus aspirin versus aspirin alone in pregnant women with hereditary thrombophilia to improve live birth rate: Meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2016 Jan;293(1):81-6.
[26]Yuksel H, Kayatas S, Boza AT, Api M, Ertekin AA, Cam C. Low molecular weight heparin use in unexplained recurrent miscarriage. Pak J Med Sci. 2014; 30(6): 1232–7.
[27]Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: A randomized placebo-controlled study. Arch Gynecol Obstet. 2008;278(1):33-8.
[28]Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586-96.
[29]Hussain M, El-Hakim S, Cahill DJ. Progesterone supplementation in women with otherwise unexplained recurrent miscarriages. J Hum Reprod Sci. 2012;5(3):248-51.
[30]Bansal AS, Bajardeen B, Thum MY. The basis and value of currently used immunomodulatory therapies in recurrent miscarriage. J Reprod Immunol. 2012;93(1):41-51.
[31]Practice Committee of the American Society for Reproductive Medicine. Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss. Fertil Steril. 2004;82 Suppl 1:s199-200.
[32]Egerup P, Lindschou J, Gluud C, Christiansen OB. The effects of immunotherapy with intravenous immunoglobulins versus no intervention, placebo, or usual care in patients with recurrent miscarriages: A protocol for a systematic review with meta-analyses, trial sequential analyses, and individual patient data meta-analyses of randomised clinical trials. Syst Rev. 2014;3:89.
[33]Takeshita T. Diagnosis and treatment of recurrent miscarriage associated with immunologic disorders: Is paternal lymphocyte immunization a relic of the past?. J Nippon Med Sch. 2004;71(5):308-13.
[34]Mowbray JF, Gibbings C, Liddell H, Reginald PW, Underwood JL, Beard RW. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet. 1985;1(8435):941-3.
[35]Pandey MK, Thakur S, Agrawal S. Lymphocyte immunotherapy and its probable mechanism in the maintenance of pregnancy in women with recurrent spontaneous abortion. Arch Gynecol Obstet. 2004;269(3):161-72.
[36]Kano T, Mori T, Furudono M, Ishikawa H, Watanabe H, Kikkawa E, et al. Human leukocyte antigen may predict outcome of primary recurrent spontaneous abortion treated with paternal lymphocyte alloimmunization therapy. Am J Reprod Immunol. 2007;58(4):383-7.
[37]Ito K, Tanaka T, Tsutsumi N, Obata F, Kashiwagi N. Possible mechanisms of immunotherapy for maintaining pregnancy in recurrent spontaneous aborters: Analysis of anti-idiotypic antibodies directed against autologous T-cell receptors. Hum Reprod. 1999;14(3):650-5.
[2]Hogge WA, Byrnes AL, Lanasa MC, Surti U. The clinical use of karyotyping spontaneous abortions. Am J Obstet Gynecol. 2003;189(2):397-400.
[3]Christiansen OB, Nielsen HS, Kolte AM. Future directions of failed implantation and recurrent miscarriage research. Reprod Biomed Online. 2006;13(1):71-83.
[4]Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet. 2005;272(2):95-108.
[5]Beaman KD, Ntrivalas E, Mallers TM, Jaiswal MK, Kwak-Kim J, Gilman-Sachs A. Immune etiology of recurrent pregnancy loss and its diagnosis. Am J Reprod Immunol. 2012;67(4):319-25.
[6]Hanidziar D, Koulmanda M. Inflammation and the balance of Treg and Th17 cells in transplant rejection and tolerance. Curr Opin Organ Transplant. 2010;15(4):411-5.
[7]Sharma S. Natural killer cells and regulatory T cells in early pregnancy loss. Int J Dev Biol. 2014;58(2-4):219-29.
[8]Christiansen OB. Reproductive immunology. Mol Immunol. 2013;55(1):8-15.
[9]Kuon RJ, Strowitzki T, Sohn C, Daniel V, Toth B. Immune profiling in patients with recurrent miscarriage. J Reprod Immunol. 2015;108:136-41.
[10]Shoenfeld Y, Carp HJ, Molina V, Blank M, Cervera R, Balasch J, et al. Autoantibodies and prediction of reproductive failure. Am J Reprod Immunol. 2006;56(5-6):337-44.
[11]Cervera R, Balasch J. Autoimmunity and recurrent pregnancy losses. Clin Rev Allergy Immunol. 2010;39(3):148-52.
[12]Khonina NA, Broitman EV, Shevela EY, Pasman NM, Chernykh ER. Mixed lymphocyte reaction blocking factors (MLR-Bf) as potential biomarker for indication and efficacy of paternal lymphocyte immunization in recurrent spontaneous abortion. Arch Gynecol Obstet. 2013;288(4):933-7
[13]Bansal AS. Joining the immunological dots in recurrent miscarriage. Am J Reprod Immunol. 2010;64(5):307-15.
[14]Zhu LY, Chen X, Xu ZZ, Xu L, Mao T, Zhang H. Changes and clinical significance of peripheral blood helper T lymphocyte and natural killer (NK) cells in unexplained recurrent spontaneous abortion (URSA) patients after abortion and successful pregnancy. Clin Exp Obstet Gynecol. 2015;42(1):62-6.
[15]Yuan J, Li J, Huang SY, Sun X. Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. J Reprod Immunol. 2015;110:81-8.
[16]Li X, Wang B, Li Y, Wang L, Zhao X, Zhou X, et al. The Th1/Th2/Th17/Treg paradigm induced by stachydrine hydrochloride reduces uterine bleeding in RU486-induced abortion mice. J Ethnopharmacol. 2013;145(1):241-53.
[17]Xu W, Roos A, Schlagwein N, Woltman AM, Daha MR, van Kooten C. IL-10-producing macrophages preferentially clear early apoptotic cells. Blood. 2006;107(12):4930-7.
[18]Nakashima A, Shima T, Inada K, Ito M, Saito S. The balance of the immune system between T cells and NK cells in miscarriage. Am J Reprod Immunol. 2012;67(4):304-10.
[19]Wang WJ, Hao CF, Qu QL, Wang X, Qiu LH, Lin QD. The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage. Hum Reprod. 2010;25(10):2591-6.
[20]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.
[21]Arruvito L, Sotelo AI, Billordo A, Fainboim L. A physiological role for inducible FOXP3(+) Treg cells. Lessons from women with reproductive failure. Clin Immunol. 2010;136(3):432-41.
[22]Lee SK, Kim JY, Hur SE, Kim CJ, Na BJ, Lee M, et al. An imbalance in interleukin-17-producing T and Foxp3(+) regulatory T cells in women with idiopathic recurrent pregnancy loss. Hum Reprod. 2011;26(11):2964-71.
[23]Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol. 2007;179(8):5571-5.
[24]Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet. 2014; 290(4): 757–62.
[25]Areia AL, Fonseca E, Areia M, Moura P. Low-molecular-weight heparin plus aspirin versus aspirin alone in pregnant women with hereditary thrombophilia to improve live birth rate: Meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2016 Jan;293(1):81-6.
[26]Yuksel H, Kayatas S, Boza AT, Api M, Ertekin AA, Cam C. Low molecular weight heparin use in unexplained recurrent miscarriage. Pak J Med Sci. 2014; 30(6): 1232–7.
[27]Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: A randomized placebo-controlled study. Arch Gynecol Obstet. 2008;278(1):33-8.
[28]Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586-96.
[29]Hussain M, El-Hakim S, Cahill DJ. Progesterone supplementation in women with otherwise unexplained recurrent miscarriages. J Hum Reprod Sci. 2012;5(3):248-51.
[30]Bansal AS, Bajardeen B, Thum MY. The basis and value of currently used immunomodulatory therapies in recurrent miscarriage. J Reprod Immunol. 2012;93(1):41-51.
[31]Practice Committee of the American Society for Reproductive Medicine. Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss. Fertil Steril. 2004;82 Suppl 1:s199-200.
[32]Egerup P, Lindschou J, Gluud C, Christiansen OB. The effects of immunotherapy with intravenous immunoglobulins versus no intervention, placebo, or usual care in patients with recurrent miscarriages: A protocol for a systematic review with meta-analyses, trial sequential analyses, and individual patient data meta-analyses of randomised clinical trials. Syst Rev. 2014;3:89.
[33]Takeshita T. Diagnosis and treatment of recurrent miscarriage associated with immunologic disorders: Is paternal lymphocyte immunization a relic of the past?. J Nippon Med Sch. 2004;71(5):308-13.
[34]Mowbray JF, Gibbings C, Liddell H, Reginald PW, Underwood JL, Beard RW. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet. 1985;1(8435):941-3.
[35]Pandey MK, Thakur S, Agrawal S. Lymphocyte immunotherapy and its probable mechanism in the maintenance of pregnancy in women with recurrent spontaneous abortion. Arch Gynecol Obstet. 2004;269(3):161-72.
[36]Kano T, Mori T, Furudono M, Ishikawa H, Watanabe H, Kikkawa E, et al. Human leukocyte antigen may predict outcome of primary recurrent spontaneous abortion treated with paternal lymphocyte alloimmunization therapy. Am J Reprod Immunol. 2007;58(4):383-7.
[37]Ito K, Tanaka T, Tsutsumi N, Obata F, Kashiwagi N. Possible mechanisms of immunotherapy for maintaining pregnancy in recurrent spontaneous aborters: Analysis of anti-idiotypic antibodies directed against autologous T-cell receptors. Hum Reprod. 1999;14(3):650-5.