Clinical and Experimental Reproductive Medicine

The Korean Society for Reproductive Medicine (대한생식의학회)
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T helper cell subsets and related cytokines in infertile women undergoing in vitro fertilization before and after seminal plasma exposure

  • Azad, Marziyeh (Department of Immunology, Shiraz University of Medical Sciences) ;
  • Keshtgar, Sara (Department of Physiology, Shiraz University of Medical Sciences) ;
  • Jahromi, Bahia Namavar (Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences) ;
  • Kanannejad, Zahra (Department of Immunology, Shiraz University of Medical Sciences) ;
  • Gharesi-Fard, Behrouz (Department of Immunology, Shiraz University of Medical Sciences)
  • Received : 2017.06.07
  • Accepted : 2017.10.05
  • Published : 2017.12.31
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Abstract

Objective: In vitro fertilization (IVF) is a well-known method for the treatment of infertility. The present study aimed to compare the differences between infertile women with successful and unsuccessful IVF outcomes regarding the expression of T helper (Th) cell transcription factors and a group of related cytokines before and after exposure to their husbands' seminal plasma. Methods: This study was performed on 19 couples with unexplained infertility undergoing IVF treatment. Among the studied group, nine and 10 couples had successful and unsuccessful IVF outcomes, respectively. This study was carried out using real-time polymerase chain reaction. Results: Before seminal plasma exposure, the expression levels of T-bet (p< 0.007), $interferon-{\gamma}$ (p= 0.013), and tumor necrosis factor $(TNF)-{\alpha}$ (p= 0.017) were higher in the infertile women with IVF failure than in those with successful IVF outcomes, while those of GATA3 (p< 0.001), Foxp3 (p= 0.001), and interleukin (IL)-35 (p< 0.003) were lower. After seminal exposure, the expression of T-bet (p= 0.02), Rorc (p< 0.001), $TNF-{\alpha}$ (p= 0.001), Foxp3 (p= 0.02), and $interferon-{\gamma}$ (p= 0.001) increased in the unsuccessful IVF group, while the expression of Foxp3 (p= 0.02), Rorc (p< 0.001), IL-23 (p= 0.04), IL-17 (p= 0.02), IL-6 (p< 0.001), transforming growth $factor-{\beta}$ (p= 0.01), and IL-35 (p< 0.001) increased in the successful IVF group. Conclusion: In summary, IVF failure was associated with imbalanced Th1/Th2/Th17/Treg responses. Moreover, our results show that seminal plasma might have a positive effect on IVF outcomes via changes in peripheral blood T cell subsets.

Keywords

References

  1. Montoya JM, Bernal A, Borrero C. Diagnostics in assisted human reproduction. Reprod Biomed Online 2002;5:198-210. https://doi.org/10.1016/S1472-6483(10)61624-0
  2. Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: an update and review of practice. Reprod Biomed Online 2012;24:591-602. https://doi.org/10.1016/j.rbmo.2012.02.021
  3. Akhter S, Alam H, Khanam NN, Zabin F. Characteristics of infertile couples. Mymensingh Med J 2011;20:121-7.
  4. Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med 2008;14:1197-213. https://doi.org/10.1038/nm.f.1895
  5. Anderson DJ, Hill JA. Cell-mediated immunity in infertility. Am J Reprod Immunol Microbiol 1988;17:22-30. https://doi.org/10.1111/j.1600-0897.1988.tb00197.x
  6. Carp HJ, Selmi C, Shoenfeld Y. The autoimmune bases of infertility and pregnancy loss. J Autoimmun 2012;38:J266-74. https://doi.org/10.1016/j.jaut.2011.11.016
  7. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 2010;63:601-10. https://doi.org/10.1111/j.1600-0897.2010.00852.x
  8. Chaouat G. The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 2007;29:95-113. https://doi.org/10.1007/s00281-007-0069-0
  9. Crome SQ, Wang AY, Levings MK. Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2010;159:109-19. https://doi.org/10.1111/j.1365-2249.2009.04037.x
  10. Nakashima A, Ito M, Yoneda S, Shiozaki A, Hidaka T, Saito S. Circulating and decidual Th17 cell levels in healthy pregnancy. Am J Reprod Immunol 2010;63:104-9.
  11. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467-76. https://doi.org/10.1016/j.immuni.2004.08.018
  12. Wang WJ, Hao CF, Yi-Lin, 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;84:164-70. https://doi.org/10.1016/j.jri.2009.12.003
  13. 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;26:2964-71. https://doi.org/10.1093/humrep/der301
  14. Saito S, Sasaki Y, Sakai M. CD4(+)CD25high regulatory T cells in human pregnancy. J Reprod Immunol 2005;65:111-20. https://doi.org/10.1016/j.jri.2005.01.004
  15. Robertson SA, Mau VJ, Hudson SN, Tremellen KP. Cytokine-leukocyte networks and the establishment of pregnancy. Am J Reprod Immunol 1997;37:438-42. https://doi.org/10.1111/j.1600-0897.1997.tb00257.x
  16. Black CA, Rohan LC, Cost M, Watkins SC, Draviam R, Alber S, et al. Vaginal mucosa serves as an inductive site for tolerance. J Immunol 2000;165:5077-83. https://doi.org/10.4049/jimmunol.165.9.5077
  17. Crawford G, Ray A, Gudi A, Shah A, Homburg R. The role of seminal plasma for improved outcomes during in vitro fertilization treatment: review of the literature and meta-analysis. Hum Reprod Update 2015;21:275-84. https://doi.org/10.1093/humupd/dmu052
  18. Maegawa M, Kamada M, Irahara M, Yamamoto S, Yoshikawa S, Kasai Y, et al. A repertoire of cytokines in human seminal plasma. J Reprod Immunol 2002;54:33-42. https://doi.org/10.1016/S0165-0378(01)00063-8
  19. Politch JA, Tucker L, Bowman FP, Anderson DJ. Concentrations and significance of cytokines and other immunologic factors in semen of healthy fertile men. Hum Reprod 2007;22:2928-35. https://doi.org/10.1093/humrep/dem281
  20. Jeremias J, Mockel S, Witkin SS. Human semen induces interleukin 10 and 70 kDa heat shock protein gene transcription and inhibits interferon-gamma messenger RNA production in peripheral blood mononuclear cells. Mol Hum Reprod 1998;4:1084-8. https://doi.org/10.1093/molehr/4.11.1084
  21. Robertson SA, Guerin LR, Bromfield JJ, Branson KM, Ahlstrom AC, Care AS. Seminal fluid drives expansion of the CD4+CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod 2009;80:1036-45. https://doi.org/10.1095/biolreprod.108.074658
  22. Guerin LR, Moldenhauer LM, Prins JR, Bromfield JJ, Hayball JD, Robertson SA. Seminal fluid regulates accumulation of FOXP3+ regulatory T cells in the preimplantation mouse uterus through expanding the FOXP3+ cell pool and CCL19-mediated recruitment. Biol Reprod 2011;85:397-408.
  23. Gutsche S, von Wolff M, Strowitzki T, Thaler CJ. Seminal plasma induces mRNA expression of IL-1beta, IL-6 and LIF in endometrial epithelial cells in vitro. Mol Hum Reprod 2003;9:785-91. https://doi.org/10.1093/molehr/gag095
  24. Johansson M, Bromfield JJ, Jasper MJ, Robertson SA. Semen activates the female immune response during early pregnancy in mice. Immunology 2004;112:290-300. https://doi.org/10.1111/j.1365-2567.2004.01876.x
  25. Tremellen KP, Valbuena D, Landeras J, Ballesteros A, Martinez J, Mendoza S, et al. The effect of intercourse on pregnancy rates during assisted human reproduction. Hum Reprod 2000;15:2653-8. https://doi.org/10.1093/humrep/15.12.2653
  26. Aflatoonian A, Ghandi S, Tabibnejad N. The effect of intercourse around embryo transfer on pregnancy rate in assisted reproductive technology cycles. Int J Fertil Steril 2009;4.
  27. Fishel S, Webster J, Jackson P, Faratian B. Evaluation of high vaginal insemination at oocyte recovery in patients undergoing in vitro fertilization. Fertil Steril 1989;51:135-8. https://doi.org/10.1016/S0015-0282(16)60442-9
  28. Kwak-Kim JY, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman KD, et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod 2003;18:767-73. https://doi.org/10.1093/humrep/deg156
  29. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478-82. https://doi.org/10.1016/S0167-5699(97)01127-4
  30. Ng SC, Gilman-Sachs A, Thaker P, Beaman KD, Beer AE, Kwak-Kim J. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol 2002;48:77-86. https://doi.org/10.1034/j.1600-0897.2002.01105.x
  31. Ginsburg ES, Xiao L, Gargiulo AR, Kung FT, Politch JA, Schust DJ, et al. T-helper 2 and 3 type immunity to trophoblast in successful in vitro fertilization-embryo transfer. Fertil Steril 2005;83:1659-64. https://doi.org/10.1016/j.fertnstert.2004.12.038
  32. 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;67:311-8. https://doi.org/10.1111/j.1600-0897.2012.01116.x
  33. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and nonself. Nat Immunol 2005;6:345-52.
  34. 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;10:347-53. https://doi.org/10.1093/molehr/gah044
  35. Yue CY, Zhang B, Ying CM. Elevated serum level of IL-35 associated with the maintenance of maternal-fetal immune tolerance in normal pregnancy. PLoS One 2015;10:e0128219. https://doi.org/10.1371/journal.pone.0128219
  36. Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol 2012;129:207-15.e1-5. https://doi.org/10.1016/j.jaci.2011.08.009
  37. Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 2007;37:3021-9. https://doi.org/10.1002/eji.200737810
  38. Ozkan ZS, Deveci D, Kumbak B, Simsek M, Ilhan F, Sekercioglu S, et al. What is the impact of Th1/Th2 ratio, SOCS3, IL17, and IL35 levels in unexplained infertility? J Reprod Immunol 2014;103:53-8. https://doi.org/10.1016/j.jri.2013.11.002
  39. Robertson SA, Sharkey DJ. Seminal fluid and fertility in women. Fertil Steril 2016;106:511-9. https://doi.org/10.1016/j.fertnstert.2016.07.1101
  40. Schjenken JE, Robertson SA. Seminal fluid signalling in the female reproductive tract: implications for reproductive success and offspring health. Adv Exp Med Biol 2015;868:127-58.
  41. Robertson SA, Prins JR, Sharkey DJ, Moldenhauer LM. Seminal fluid and the generation of regulatory T cells for embryo implantation. Am J Reprod Immunol 2013;69:315-30. https://doi.org/10.1111/aji.12107
  42. Sharkey DJ, Macpherson AM, Tremellen KP, Robertson SA. Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells. Mol Hum Reprod 2007;13:491-501. https://doi.org/10.1093/molehr/gam028
  43. Hyde KJ, Schust DJ. Immunologic challenges of human reproduction: an evolving story. Fertil Steril 2016;106:499-510. https://doi.org/10.1016/j.fertnstert.2016.07.1073
  44. Bromfield JJ, Schjenken JE, Chin PY, Care AS, Jasper MJ, Robertson SA. Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring. Proc Natl Acad Sci U S A 2014;111:2200-5. https://doi.org/10.1073/pnas.1305609111

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