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Immune Factors in Recurrent Implantation Failure

  • Diana Alecsandru
  • Juan A. Garcia-Velasco
Chapter

Abstract

The immune system’s role in recurrent reproductive failure is a controversial issue in assisted reproduction. Most of the previous studies about immune system implication in reproduction were focused on finding markers on peripheral blood and less on uterine environment. Maternofetal tolerance begins at the uterine level, so successful adaptation to the fetus happens after a complicated process. Insufficient invasion of the uterine lining by invading extravillous trophoblast is the primary defect in pregnancy disorders such as recurrent miscarriage, and this process is regulated by interaction between maternal killer immunoglobulin-like receptors (KIRs) expressed by the uterine natural killer (uNK) cells and their ligand human leukocyte antigen-C (HLA-C) expressed by extravillous trophoblast. Pregnancies are an increased risk of disorders in mothers with KIR AA when the fetus has paternal HLA-C2. Recently, it has been reported that the expression of more than one paternal HLA-C by extravillous trophoblast in assisted reproduction may affect placentation in mothers with KIR AA.

The chapter provides insight about the immune tolerance process and the role of the uterine NK cells on this complex process and RIF. These insights could have an impact on the selection of single embryo transfer and/or oocyte/sperm donor according to HLA-C in patients with recurrent implantation failure and recurrent miscarriage by their KIR haplotype.

Keywords

Human leukocyte antigen-C (HLA-C) Killer immunoglobulin-like receptor (KIR) Maternofetal immune tolerance Uterine natural killer cells 

Abbreviations

ART

Assisted reproductive treatments

DET

Double embryo transfer

EVT

Invading extravillous trophoblast

HLA

Human leukocyte antigen

IVF

In vitro fertilization

KIR

Killer immunoglobulin-like receptor

NK cells

Natural killer cells

Pb

Peripheral blood

RIF

Recurrent implantation failure

RM

Recurrent miscarriage

SET

Single embryo transfer

uNK cells

Uterine natural killer cells

References

  1. 1.
    Garrido N, Bellver J, Remohi J, Simon C, Pellicer A. Cumulative live-birth rates per total number of embryos needed to reach newborn in consecutive in vitro fertilization (IVF) cycles: a new approach to measuring the likelihood of IVF success. Fertil Steril. 2011;96(1):40–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Alecsandru D, Garcia-Velasco JA. Immune testing and treatment: still an open debate. Hum Reprod. 2015;30(8):1994.CrossRefPubMedGoogle Scholar
  3. 3.
    Sacks G. Enough! Stop the arguments and get on with the science of natural killer cell testing. Hum Reprod. 2015;30(7):1526–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Tang AW, Alfirevic Z, Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Hum Reprod. 2011;26(8):1971–80.CrossRefPubMedGoogle Scholar
  5. 5.
    Moffett A, Shreeve N. Reply: First do no harm: continuing the uterine NK cell debate. Hum Reprod. 2015;31(1):218–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Moffett A, Shreeve N. First do no harm: uterine natural killer (NK) cells in assisted reproduction. Hum Reprod. 2015;30(7):1519–25.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Alecsandru D, Garcia-Velasco JA. Immunology and human reproduction. Curr Opin Obstet Gynecol. 2015;27(3):231–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med. 2003;198(8):1201–12.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Moffett A, Colucci F. Uterine NK cells: active regulators at the maternal-fetal interface. J Clin Invest. 2014;124(5):1872–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    King A, Balendran N, Wooding P, Carter NP, Loke YW. CD3- leukocytes present in the human uterus during early placentation: phenotypic and morphologic characterization of the CD56++ population. Dev Immunol. 1991;1(3):169–90.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    King A, Birkby C, Loke YW. Early human decidual cells exhibit NK activity against the K562 cell line but not against first trimester trophoblast. Cell Immunol. 1989;118(2):337–44.CrossRefPubMedGoogle Scholar
  13. 13.
    Bulmer JN, Lash GE. Human uterine natural killer cells: a reappraisal. Mol Immunol. 2005;42(4):511–21.CrossRefPubMedGoogle Scholar
  14. 14.
    Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O, et al. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J Clin Invest. 2013;123(10):4264–72.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol. 2006;6(8):584–94.CrossRefPubMedGoogle Scholar
  16. 16.
    Moffett A, Loke C. Implantation, embryo-maternal interactions, immunology and modulation of the uterine environment – a workshop report. Placenta. 2006;27(Suppl A):S54–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Parham P. NK cells and trophoblasts: partners in pregnancy. J Exp Med. 2004;200(8):951–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. 2002;2(9):656–63.CrossRefPubMedGoogle Scholar
  19. 19.
    King A, Hiby SE, Gardner L, Joseph S, Bowen JM, Verma S, et al. Recognition of trophoblast HLA class I molecules by decidual NK cell receptors–a review. Placenta. 2000;21(Suppl A):S81–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Apps R, Murphy SP, Fernando R, Gardner L, Ahad T, Moffett A. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology. 2009;127(1):26–39.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Parham P, Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat Rev Immunol. 2013;13(2):133–44.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, et al. Human diversity in killer cell inhibitory receptor genes. Immunity. 1997;7(6):753–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Winter CC, Gumperz JE, Parham P, Long EO, Wagtmann N. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J Immunol. 1998;161(2):571–7.PubMedGoogle Scholar
  24. 24.
    Hiby SE, Apps R, Sharkey AM, Farrell LE, Gardner L, Mulder A, et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J Clin Invest. 2010;120(11):4102–10.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang S, Li YP, Ding B, Zhao YR, Chen ZJ, Xu CY, et al. Recurrent miscarriage is associated with a decline of decidual natural killer cells expressing killer cell immunoglobulin-like receptors specific for human leukocyte antigen C. J Obstet Gynaecol Res. 2014;40(5):1288–95.CrossRefPubMedGoogle Scholar
  26. 26.
    Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod. 2008;23(4):972–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Hiby SE, Walker JJ, O’Shaughnessy KM, Redman CW, Carrington M, Trowsdale J, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200(8):957–65.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hiby SE, Ashrafian-Bonab M, Farrell L, Single RM, Balloux F, Carrington M, et al. Distribution of killer cell immunoglobulin-like receptors (KIR) and their HLA-C ligands in two Iranian populations. Immunogenetics. 2010;62(2):65–73.CrossRefPubMedGoogle Scholar
  29. 29.
    Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013;19(5):548–56.CrossRefPubMedGoogle Scholar
  30. 30.
    Faridi RM, Agrawal S. Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Hum Reprod. 2011;26(2):491–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Hiby SE, Apps R, Chazara O, Farrell LE, Magnus P, Trogstad L, et al. Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. J Immunol. 2014;192(11):5069–73.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hiby SE, Ashrafian-Bonab M, Farrell L, Single RM, Balloux F, Carrington M, et al. Distribution of killer cell immunoglobulin-like receptors (KIR) and their HLA-C ligands in two Iranian populations. Immunogenetics. 2009;62(2):65–73.CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Adams EJ, Parham P. Species-specific evolution of MHC class I genes in the higher primates. Immunol Rev. 2001;183:41–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Rajalingam R, Parham P, Abi-Rached L. Domain shuffling has been the main mechanism forming new hominoid killer cell Ig-like receptors. J Immunol. 2004;172(1):356–69.CrossRefPubMedGoogle Scholar
  35. 35.
    Saito S, Takeda Y, Sakai M, Nakabayahi M, Hayakawa S. The incidence of pre-eclampsia among couples consisting of Japanese women and Caucasian men. J Reprod Immunol. 2006;70(1-2):93–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Savasi VM, Mandia L, Laoreti A, Cetin I. Maternal and fetal outcomes in oocyte donation pregnancies. Hum Reprod Update. 2016;22:620.CrossRefPubMedGoogle Scholar
  37. 37.
    Pecks U, Maass N, Neulen J. Oocyte donation: a risk factor for pregnancy-induced hypertension: a meta-analysis and case series. Dtsch Arztebl Int. 2011;108(3):23–31.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Masoudian P, Nasr A, de Nanassy J, Fung-Kee-Fung K, Bainbridge SA, El Demellawy D. Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am J Obstet Gynecol. 2015;214(3):328–39.CrossRefPubMedGoogle Scholar
  39. 39.
    Blazquez A, Garcia D, Rodriguez A, Vassena R, Figueras F, Vernaeve V. Is oocyte donation a risk factor for preeclampsia? A systematic review and meta-analysis. J Assist Reprod Genet. 2016;33(7):855–63.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jeve YB, Potdar N, Opoku A, Khare M. Three-arm age-matched retrospective cohort study of obstetric outcomes of donor oocyte pregnancies. Int J Gynaecol Obstet. 2016;133(2):156–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Alecsandru D, Garrido N, Vicario JL, Barrio A, Aparicio P, Requena A, et al. Maternal KIR haplotype influences live birth rate after double embryo transfer in IVF cycles in patients with recurrent miscarriages and implantation failure. Hum Reprod. 2014;29(12):2637–43.CrossRefPubMedGoogle Scholar
  42. 42.
    Alecsandru D, Barrio A, Aparicio P, Aparicio M, García-Velasco JA, editors. Maternal killer-cell immunoglobulin-like receptor (KIR) and fetal HLA-C compatibility in ART-oocyte donor influences live birth rate. ESHRE. 2016.Google Scholar
  43. 43.
    Skjaerven R, Vatten LJ, Wilcox AJ, Ronning T, Irgens LM, Lie RT. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ. 2005;331(7521):877.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Nancy P, Erlebacher A. T cell behavior at the maternal-fetal interface. Int J Dev Biol. 2014;58(2-4):189–98.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    James E, Chai JG, Dewchand H, Macchiarulo E, Dazzi F, Simpson E. Multiparity induces priming to male-specific minor histocompatibility antigen, HY, in mice and humans. Blood. 2003;102(1):388–93.CrossRefPubMedGoogle Scholar
  46. 46.
    van Kampen CA, Versteeg-vd Voort Maarschalk MF, Langerak-Langerak J, Roelen DL, Claas FH. Kinetics of the pregnancy-induced humoral and cellular immune response against the paternal HLA class I antigens of the child. Hum Immunol. 2002;63(6):452–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Apps R, Gardner L, Moffett A. A critical look at HLA-G. Trends Immunol. 2008;29(7):313–21.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Rey Juan Carlos University, IVI RMA-MadridMadridSpain

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