Advertisement

Der Gynäkologe

, Volume 51, Issue 4, pp 274–285 | Cite as

Pathophysiologie der Frühschwangerschaft, Plazentation und Immunologie

  • Udo R. Markert
  • Johanna Seitz
  • Theresa Wagner
  • Juliane Götze
  • Sebastian Schamberger
  • Julia I. Heger
  • Jana Pastuschek
Leitthema
  • 169 Downloads

Zusammenfassung

Die Schwangerschaft stellt die einzigartige Situation dar, in der 2 allogene Organismen, Mutter und Fetus, ohne Abstoßungsreaktionen in Symbiose zusammenleben. Die Plazenta bildet dabei den größten Teil der Grenzfläche und ist somit von besonderer immunologischer Bedeutung. Verschiedenste plazentare Faktoren, großenteils von Trophoblastzellen produziert und sezerniert, induzieren eine weitgehend spezifische Toleranz gegenüber dem Embryo oder Fetus, ohne dabei die eigentlichen Funktionen des Immunsystems grundlegend zu verändern. Störungen dieser Toleranz können zu allen Zeitpunkten den Schwangerschaftsverlauf beeinträchtigen oder eine Schwangerschaft gar nicht erst zustande kommen lassen. Immunologische Parameter im Endometrium haben daher das Potenzial, als diagnostische Marker und für neue Behandlungsstrategien bei Kinderwunschpatientinnen genutzt zu werden. Die vorliegende Übersichtsarbeit soll einen groben Eindruck in die komplexe Thematik vermitteln.

Schlüsselwörter

Trophoblasten Symbiose Embryoimplantation Endometrium Immunsystem 

Pathophysiology of early pregnancy, placentation, and immunology

Abstract

Pregnancy is the unique situation in which two allogeneic organisms, mother and fetus, live in symbiosis without rejection. The placenta forms the major part of the interface, and therefore, plays a special immunological role. Very different placental factors, mainly produced and secreted by trophoblast cells, induce a widely specific tolerance towards the embryo and fetus without major alterations of the principle functions of the immune system. At any time, disorders of this tolerance may harm pregnancy or even inhibit its initiation by disturbing implantation and placentation. Immunological parameters in the endometrium have the potential of serving as diagnostic markers or for developing novel treatment strategies in infertile patients. The present review aims to provide a rough overview on this complex topic.

Keywords

Trophoblasts Symbiosis Embryo implantation Endometrium Immune system 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

U.R. Markert, J. Seitz, T. Wagner, J. Götze, S. Schamberger, J.I. Heger und J. Pastuschek geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Medawar PB (1953) Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 7:320–328Google Scholar
  2. 2.
    Svensson-Arvelund J et al (2014) The placenta in toxicology. Part II: systemic and local immune adaptations in pregnancy. Toxicol Pathol 42(2):327–338CrossRefPubMedGoogle Scholar
  3. 3.
    Arck PC, Hecher K (2013) Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med 19(5):548–556CrossRefPubMedGoogle Scholar
  4. 4.
    Szekeres-Bartho J, Markert UR, Varla-Leftherioti M (2015) Immunology in reproduction. J Reprod Immunol 108:1CrossRefPubMedGoogle Scholar
  5. 5.
    Filippini A et al (2001) Control and impairment of immune privilege in the testis and in semen. Hum Reprod Update 7(5):444–449CrossRefPubMedGoogle Scholar
  6. 6.
    Kammerer U, von Wolff M, Markert UR (2004) Immunology of human endometrium. Immunobiology 209(7):569–574CrossRefPubMedGoogle Scholar
  7. 7.
    Bulmer JN, Williams PJ, Lash GE (2010) Immune cells in the placental bed. Int J Dev Biol 54(2–3):281–294CrossRefPubMedGoogle Scholar
  8. 8.
    Tuckerman E et al (2010) Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF. J Reprod Immunol 87(1–2):60–66CrossRefPubMedGoogle Scholar
  9. 9.
    Farag SS, Caligiuri MA (2006) Human natural killer cell development and biology. Blood Rev 20(3):123–137CrossRefPubMedGoogle Scholar
  10. 10.
    Russell P et al (2013) The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. III: Further observations and reference ranges. Pathology 45(4):393–401CrossRefPubMedGoogle Scholar
  11. 11.
    Kuon RJ et al (2017) Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol.  https://doi.org/10.1111/aji.12721 PubMedGoogle Scholar
  12. 12.
    Chen X et al (2017) Measurement of uterine natural killer cell percentage in the periimplantation endometrium from fertile women and women with recurrent reproductive failure: establishment of a reference range. Am J Obstet Gynecol 217(6):680e1–680e6CrossRefGoogle Scholar
  13. 13.
    Giuliani E et al (2014) Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis. Am J Reprod Immunol 72(3):262–269CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Aksu S, Caliskan E, Cakiroglu Y (2016) Evaluation of endometrial natural killer cell expression of CD4, CD103, and CD16 cells in women with unexplained infertility. J Reprod Immunol 117:70–75CrossRefPubMedGoogle Scholar
  15. 15.
    Kofod L et al (2017) Endometrial immune markers are potential predictors of normal fertility and pregnancy after in vitro fertilization. Am J Reprod Immunol.  https://doi.org/10.1111/aji.12684 PubMedGoogle Scholar
  16. 16.
    Ledee N et al (2017) Uterine immune profiling for increasing live birth rate: a one-to-one matched cohort study. J Reprod Immunol 119:23–30CrossRefPubMedGoogle Scholar
  17. 17.
    Seshadri S, Sunkara SK (2014) Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update 20(3):429–438CrossRefPubMedGoogle Scholar
  18. 18.
    McQueen DB et al (2015) Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril 104(4):927–931CrossRefPubMedGoogle Scholar
  19. 19.
    Bayer-Garner IB, Nickell JA, Korourian S (2004) Routine syndecan-1 immunohistochemistry aids in the diagnosis of chronic endometritis. Arch Pathol Lab Med 128(9):1000–1003PubMedGoogle Scholar
  20. 20.
    Mitchell CM et al (2015) Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. Am J Obstet Gynecol 212(5): 611e1– 611e9CrossRefGoogle Scholar
  21. 21.
    Moreno I et al (2016) Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol 215(6):684–703CrossRefPubMedGoogle Scholar
  22. 22.
    Kitaya K et al (2016) Chronic endometritis: potential cause of infertility and obstetric and neonatal complications. Am J Reprod Immunol 75(1):13–22CrossRefPubMedGoogle Scholar
  23. 23.
    Cicinelli E et al (2015) Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 30(2):323–330CrossRefPubMedGoogle Scholar
  24. 24.
    Kitaya K (2011) Prevalence of chronic endometritis in recurrent miscarriages. Fertil Steril 95(3):1156–1158CrossRefPubMedGoogle Scholar
  25. 25.
    Johnston-MacAnanny EB et al (2010) Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril 93(2):437–441CrossRefPubMedGoogle Scholar
  26. 26.
    Cicinelli E et al (2018) Chronic endometritis in patients with unexplained infertility: prevalence and effects of antibiotic treatment on spontaneous conception. Am J Reprod Immunol.  https://doi.org/10.1111/aji.12782 PubMedGoogle Scholar
  27. 27.
    Kitaya K et al (2017) Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol.  https://doi.org/10.1111/aji.12719 PubMedGoogle Scholar
  28. 28.
    Mor G (2008) Inflammation and pregnancy: the role of toll-like receptors in trophoblast-immune interaction. Ann N Y Acad Sci 1127:121–128CrossRefPubMedGoogle Scholar
  29. 29.
    Trundley A, Moffett A (2004) Human uterine leukocytes and pregnancy. Tissue Antigens 63(1):1–12CrossRefPubMedGoogle Scholar
  30. 30.
    Redman CW, Sacks GP, Sargent IL (1999) Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 180(2 Pt 1):499–506CrossRefPubMedGoogle Scholar
  31. 31.
    Mor G, Cardenas I (2010) The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 63(6):425–433CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Schamberger S et al (2013) Establishment of a one-sided ex vivo human placenta perfusion model to assess adhesion and invasion behavior of T cell leukemia cell lines. Leuk Lymphoma 54(8):1811–1813CrossRefPubMedGoogle Scholar
  33. 33.
    Faas MM, de Vos P (2017) Uterine NK cells and macrophages in pregnancy. Placenta 56:44–52CrossRefPubMedGoogle Scholar
  34. 34.
    Smith SD et al (2009) Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 174(5):1959–1971CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Silini AR et al (2017) Is immune modulation the mechanism underlying the beneficial effects of amniotic cells and their derivatives in regenerative medicine? Cell Transplant 26(4):531–539CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Schmorl CG (1893) Pathologisch-anatomische Untersuchungen über Puerperal-Eklampsie. Vogel, LeipzigGoogle Scholar
  37. 37.
    Foster BP et al (2016) Extracellular vesicles in blood, milk and body fluids of the female and male urogenital tract and with special regard to reproduction. Crit Rev Clin Lab Sci 53(6):379–395CrossRefPubMedGoogle Scholar
  38. 38.
    Wegmann TG et al (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14(7):353–356CrossRefPubMedGoogle Scholar
  39. 39.
    Chaouat G (2013) Inflammation, NK cells and implantation: friend and foe (the good, the bad and the ugly?): replacing placental viviparity in an evolutionary perspective. J Reprod Immunol 97(1):2–13CrossRefPubMedGoogle Scholar
  40. 40.
    Moore KL, Persaud TVN (2007) Embryologie: Entwicklungsstadien, Frühentwicklung, Organogenese, Klinik, 5. Aufl. Elsevier, Urban & Fischer, MünchenGoogle Scholar
  41. 41.
    Saito S, Sasaki Y, Sakai M (2005) CD4(+)CD25high regulatory T cells in human pregnancy. J Reprod Immunol 65(2):111–120CrossRefPubMedGoogle Scholar
  42. 42.
    Guerin LR, Prins JR, Robertson SA (2009) Regulatory T‑cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update 15(5):517–535CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Steinborn A et al (2012) Pregnancy-associated diseases are characterized by the composition of the systemic regulatory T cell (Treg) pool with distinct subsets of Tregs. Clin Exp Immunol 167(1):84–98CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mincheva-Nilsson L (2003) Pregnancy and gamma/delta T cells: taking on the hard questions. Reprod Biol Endocrinol 1:120CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Barakonyi A et al (2002) Recognition of nonclassical HLA class I antigens by gamma delta T cells during pregnancy. J Immunol 168(6):2683–2688CrossRefPubMedGoogle Scholar
  46. 46.
    Colucci F, Caligiuri MA, Di Santo JP (2003) What does it take to make a natural killer? Nat Rev Immunol 3(5):413–425CrossRefPubMedGoogle Scholar
  47. 47.
    Caligiuri MA (2008) Human natural killer cells. Blood 112(3):461–469CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Vacca P, Mingari MC, Moretta L (2013) Natural killer cells in human pregnancy. J Reprod Immunol 97(1):14–19CrossRefPubMedGoogle Scholar
  49. 49.
    Jabrane-Ferrat N, Siewiera J (2014) The up side of decidual natural killer cells: new developments in immunology of pregnancy. Immunology 141(4):490–497CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Tao Y et al (2015) CD56(bright)CD25+ NK cells are preferentially recruited to the maternal/fetal interface in early human pregnancy. Cell Mol Immunol 12(1):77–86CrossRefPubMedGoogle Scholar
  51. 51.
    Santoni A, Carlino C, Gismondi A (2008) Uterine NK cell development, migration and function. Reprod Biomed Online 16(2):202–210CrossRefPubMedGoogle Scholar
  52. 52.
    Carlino C et al (2012) Chemerin regulates NK cell accumulation and endothelial cell morphogenesis in the decidua during early pregnancy. J Clin Endocrinol Metab 97(10):3603–3612CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964CrossRefPubMedGoogle Scholar
  54. 54.
    Heikkinen J et al (2003) Phenotypic characterization of human decidual macrophages. Clin Exp Immunol 131(3):498–505CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Singh U et al (2005) Immunological properties of human decidual macrophages—a possible role in intrauterine immunity. Reproduction 129(5):631–637CrossRefPubMedGoogle Scholar
  56. 56.
    Mor G, Abrahams VM (2003) Potential role of macrophages as immunoregulators of pregnancy. Reprod Biol Endocrinol 1:119CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Reister F et al (2001) Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab Invest 81(8):1143–1152CrossRefPubMedGoogle Scholar
  58. 58.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35CrossRefPubMedGoogle Scholar
  59. 59.
    Gustafsson C et al (2008) Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS ONE 3(4):e2078CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Martinez FO et al (2006) Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 177(10):7303–7311CrossRefPubMedGoogle Scholar
  61. 61.
    Svensson J et al (2011) Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M‑CSF and IL-10. J Immunol 187(7):3671–3682CrossRefPubMedGoogle Scholar
  62. 62.
    McIntire RH, Ganacias KG, Hunt JS (2008) Programming of human monocytes by the uteroplacental environment. Reprod Sci 15(5):437–447CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Porcheray F et al (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142(3):481–489PubMedPubMedCentralGoogle Scholar
  64. 64.
    Aldo PB et al (2014) Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol 72(3):270–284CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Reyes L, Wolfe B, Golos T (2017) Hofbauer cells: placental macrophages of fetal origin. Results Probl Cell Differ 62:45–60CrossRefPubMedGoogle Scholar
  66. 66.
    Persson G et al (2017) HLA class Ib in pregnancy and pregnancy-related disorders. Immunogenetics 69(8–9):581–595CrossRefPubMedGoogle Scholar
  67. 67.
    Poehlmann TG et al (2006) Inhibition of term decidual NK cell cytotoxicity by soluble HLA-G1. Am J Reprod Immunol 56(5–6):275–285CrossRefPubMedGoogle Scholar
  68. 68.
    Koc S et al (2003) Enhancement of immunogenicity of Jeg3 cells by ectopic expression of HLA-A*0201 and CD80. Am J Reprod Immunol 50(3):243–253CrossRefPubMedGoogle Scholar
  69. 69.
    Blaschitz A et al (2011) Vascular endothelial expression of indoleamine 2,3-dioxygenase 1 forms a positive gradient towards the feto-maternal interface. PLoS ONE 6(7):e21774CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762–774CrossRefPubMedGoogle Scholar
  71. 71.
    Terness P et al (2007) Tolerance signaling molecules and pregnancy: IDO, galectins, and the renaissance of regulatory T cells. Am J Reprod Immunol 58(3):238–254CrossRefPubMedGoogle Scholar
  72. 72.
    Chen W et al (2008) The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol 181(8):5396–5404CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Robinson DP, Klein SL (2012) Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 62(3):263–271CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Jones LA et al (2010) Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J Immunol 185(8):4525–4534CrossRefPubMedGoogle Scholar
  75. 75.
    Arck P et al (2007) Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol 58(3):268–279CrossRefPubMedGoogle Scholar
  76. 76.
    Szekeres-Bartho J, Halasz M, Palkovics T (2009) Progesterone in pregnancy; receptor-ligand interaction and signaling pathways. J Reprod Immunol 83(1–2):60–64CrossRefPubMedGoogle Scholar
  77. 77.
    Piccinni MP et al (2000) Role of hormone-controlled Th1- and Th2-type cytokines in successful pregnancy. J Neuroimmunol 109(1):30–33CrossRefPubMedGoogle Scholar
  78. 78.
    Saito S (2000) Cytokine network at the feto-maternal interface. J Reprod Immunol 47(2):87–103CrossRefPubMedGoogle Scholar
  79. 79.
    Szekeres-Bartho J, Wegmann TG (1996) A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J Reprod Immunol 31(1–2):81–95CrossRefPubMedGoogle Scholar
  80. 80.
    Szekeres-Bartho J et al (2005) Progesterone-dependent immunomodulation. Chem Immunol Allergy 89:118–125CrossRefPubMedGoogle Scholar
  81. 81.
    Szekeres-Bartho J et al (2001) Progesterone as an immunomodulatory molecule. Int Immunopharmacol 1(6):1037–1048CrossRefPubMedGoogle Scholar
  82. 82.
    Szekeres-Bartho J, Polgar B (2010) PIBF: the double edged sword. Pregnancy and tumor. Am J Reprod Immunol 64(2):77–86PubMedGoogle Scholar
  83. 83.
    Ermisch C, Markert UR (2011) PIBF – Progesterone-induced blocking factor. Z Geburtshilfe Neonatol 215(3):93–97CrossRefPubMedGoogle Scholar
  84. 84.
    Fournier T (2016) Human chorionic gonadotropin: different glycoforms and biological activity depending on its source of production. Ann Endocrinol (Paris) 77(2):75–81CrossRefGoogle Scholar
  85. 85.
    Bogovic Crncic T et al (2005) Perforin and Fas/FasL cytolytic pathways at the maternal-fetal interface. Am J Reprod Immunol 54(5):241–248CrossRefPubMedGoogle Scholar
  86. 86.
    Aluvihare VR, Kallikourdis M, Betz AG (2005) Tolerance, suppression and the fetal allograft. J Mol Med 83(2):88–96CrossRefPubMedGoogle Scholar
  87. 87.
    Uckan D et al (1997) Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion. Mol Hum Reprod 3(8):655–662CrossRefPubMedGoogle Scholar
  88. 88.
    Makrigiannakis A et al (2008) Fetomaternal immunotolerance. Am J Reprod Immunol 60(6):482–496CrossRefPubMedGoogle Scholar
  89. 89.
    Kopcow HD et al (2008) T cell apoptosis at the maternal-fetal interface in early human pregnancy, involvement of galectin-1. Proc Natl Acad Sci U S A 105(47):18472–18477CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Schmorl G (1893) Pathologisch-anatomische Untersuchungen über Puerperal-Eklampsie. Vogel, LeipzigGoogle Scholar
  91. 91.
    Chamley LW et al (2014) Review: where is the maternofetal interface? Placenta 35(Suppl):S74–S80CrossRefPubMedGoogle Scholar
  92. 92.
    Gohner C et al (2015) A new enzyme-linked Sorbent assay (ELSA) to quantify syncytiotrophoblast extracellular vesicles in biological fluids. Am J Reprod Immunol 73(6):582–588CrossRefPubMedGoogle Scholar
  93. 93.
    Delorme-Axford E et al (2013) Human placental trophoblasts confer viral resistance to recipient cells. Proc Natl Acad Sci U S A 110(29):12048–12053CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Ospina-Prieto S et al (2016) MicroRNA-141 is upregulated in preeclamptic placentae and regulates trophoblast invasion and intercellular communication. Transl Res 172:61–72.  https://doi.org/10.1016/j.trsl.2016.02.012 CrossRefPubMedGoogle Scholar
  95. 95.
    VanWijk MJ et al (2002) Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction? Am J Obstet Gynecol 187(2):450–456CrossRefPubMedGoogle Scholar
  96. 96.
    Morales-Prieto DM et al (2014) Elsevier trophoblast research award lecture: origin, evolution and future of placenta miRNas. Placenta 35(Suppl):S39–45CrossRefPubMedGoogle Scholar
  97. 97.
    Huppertz B, Schleußner E (2018) Die Plazenta Grundlagen und klinische Bedeutung Bd. XIX. Springer, Berlin HeidelbergGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  • Udo R. Markert
    • 1
  • Johanna Seitz
    • 1
  • Theresa Wagner
    • 1
  • Juliane Götze
    • 1
  • Sebastian Schamberger
    • 1
  • Julia I. Heger
    • 1
  • Jana Pastuschek
    • 1
  1. 1.Placenta Labor, Abteilung für GeburtsmedizinUniversitätsklinikum JenaJenaDeutschland

Personalised recommendations