Skip to main content
    • Aa
    • Aa

Immunology of pregnancy: cellular mechanisms allowing fetal survival within the maternal uterus

  • Ana Claudia Zenclussen (a1), Anne Schumacher (a1), Maria Laura Zenclussen (a1), Paul Wafula (a1) and Hans-Dieter Volk (a1)...

Pregnancy success remains a fascinating phenomenon to immunologists as it defies the immunological rules of rejection. Although it was previously thought that the maternal immune system does not see the fetus, it is now well documented that fetal cells reach the maternal body and encounter host immune cells. Natural tolerance mechanisms following this interaction remain to be fully elucidated. This article reviews the current literature on mechanisms of adaptive immunity, with emphasis on regulatory T cells and heme oxygenase 1 (HO-1). We propose a scenario in which regulatory T cells create a tolerant microenvironment at the fetal–maternal interface characterised by the presence of tolerance-associated molecules such as HO-1, which has been shown to be of vital importance for fetal survival.

Corresponding author
*Corresponding author: Ana Claudia Zenclussen, AG Reproduktionsimmunologie, Institut für Medizinische Immunologie, Charite, Medizinische Universität zu Berlin, CVK, Biomedizinisches Forschungszentrum, Raum 2.0534, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49 30 450 559886; Fax: +49 30 450 559986; E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2 W.D. Billington (1992) The normal fetomaternal immune relationship. Baillieres Clin Obstet Gynaecol 6, 417-438

3 J. Andrassy (2003) Tolerance to noninherited maternal MHC antigens in mice. J Immunol 171, 5554-5561

4 Z. Yan (2005) Male microchimerism in women without sons: quantitative assessment and correlation with pregnancy history. Am J Med 118, 899-906

5 K. Khoshrotehran (2005) Natural history of fetal cell microchimerism during and following murine pregnancy. J Reprod Immunol 66, 1-12

7 G. Chaouat , J.P. Kolb and T.G. Wegmann (1983) The murine placenta as an immunological barrier between the mother and the fetus. Immunol Rev 75, 31-60

8 T.G. Wegmann (1987) Placental immunotrophism: maternal T cells enhance placental growth and function. Am J Reprod Immunol Microbiol 15, 67-69

9 A. Elbe-Burger (2000) Major histocompatibility complex class II- fetal skin dendritic cells are potent accessory cells of polyclonal T-cell responses. Immunology 101, 242-253

10 A. Tafuri (1995) T cell awareness of paternal alloantigens during pregnancy. Science 270, 630-633

16 P. Le Bouteiller and F. Lenfant (1996) Antigen-presenting function(s) of the nonclassical HLA-E, -F and -G class I molecules: the beginning of a story. Res Immunol 147, 301-313

17 L. Gardner and A. Moffett (2003) Dendritic cells in the human decidua. Biol Reprod 69, 1438-1446

18 Y. Sasaki (2004) Decidual and peripheral blood CD4+ CD25+  regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod 10, 347-353

19 M. Shiroishi (2006) Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proc Natl Acad Sci U S A 103, 16412-16417

20 C.C. Chang (2002) Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 3, 237-243

21 F.W. Velten (2004) A gene signature of inhibitory MHC receptors identifies a BDCA3(+) subset of IL-10-induced dendritic cells with reduced allostimulatory capacity in vitro. Eur J Immunol 34, 2800-2811

23 D.H. Munn (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191-1193

24 I. Guleria (2005) A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 202, 231-237

25 X.Y. Zhu (2005) Blockade of CD86 signaling facilitates a Th2 bias at the maternalfetal interface and expands peripheral CD4+ CD25+  regulatory T cells to rescue abortion-prone fetuses. Biol Reprod 72, 338-345

26 I. Malan Borel (1991) IgG asymmetric molecules with anti-paternal activity isolated from sera and placental of pregnant human. J Reprod Immunol 20, 129-140

28 S. Tangri and R. Raghupathy (1993) Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorption. Biol Reprod 49, 850-856

30 A.C. Zenclussen (2005) Abnormal T cell reactivity against paternal antigens in spontaneous abortion: Adoptive transfer of pregnancy-induced CD4+ CD25+  T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol 166, 811-822

31 C.L. Stewart (1992) Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359, 76-79

32 M.L. Zenclussen (2006) Overexpression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a murine model of abortion. J Reprod Immunol 69, 35-52

33 V.M. Abrahams (2005) A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol 175, 8096-8104

34 S. Fest (2007) Trophoblast–macrophage interactions: a regulatory network for the protection of pregnancy. Am J Reprod Immunol 57, 55-66

35 B. Baban (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J Reprod Immunol 61, 67-77

36 L. Svensson (2001) The Th2 cytokines IL-4 and IL-10 are not crucial for the completion of allogeneic pregnancy in mice. J Reprod Immunol 51, 3-7

37 P.G. Fallon (2002) IL-4 induces characteristic Th2 even in the combined absence of IL-5, IL-9 and IL-13. Immunity 17, 7-17

38 R. Raghupathy (1997) Th1-type immunity is incompatible with successful pregnancy. Immunol Today 18, 478-482

39 S. Saito (2001) Cytokine network at the feto-maternal interface. J Reprod Immunol 47, 87-103

40 M.P. Piccinni (1998) Defective production of both, leukemia inhibitor factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 4, 1020-1024

41 A.C. Zenclussen (2003) Murine abortion is associated with enhanced interleukin-6 levels at the feto-maternal interface. Cytokine 24, 150-160

44 G. Dealtry , M. O'Farrell and N. Fernandez (2000) The Th2 cytokine environment of the placenta. Int Arch Allergy Immunol 123, 107-119

46 C.A. White (2004) Effect of interleukin-10 null mutation on maternal immune response and reproductive outcome in mice. Biol Reprod 70, 123-131

47 A. Kruse (1999) Evidence of specialized leukocyte-vascular homing interactions at the maternal/foetal interface. Eur J Immunol 29, 1116-1126

48 D. Austrup (1997) P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissue. Nature 385, 81-83

49 A.Z. Bertoja (2005) Anti-P and E-selectin therapy prevents abortion in the CBA/J x DBA/2J combination by blocking the migration of Th1 lymphocytes into the foetal-maternal interface. Cell Immunol 238, 97-102

50 A.C. Zenclussen (2001) Upregulation of decidual P-selectin expression is associated with an increased number of Th1 cell populations in patients suffering from spontaneous abortion. Cell Immunol 213, 94-103

51 A.C. Zenclussen (2004) Introducing a mouse model for pre-eclampsia: adoptive transfer of activated Th1 cells leads to pre-eclampsia-like symptoms exclusively in pregnant mice. Eur J Immunol 34, 377-387

52 R. Pijnenborg (1996) Attachment and differentiation in vitro of trophoblast from normal and preeclamptic human placentas. Am J Obstet Gynecol 175, 30-36

53 M.M. Faas (1994) A new animal model for human preeclampsia: ultralow dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol 171, 158-164

54 S. Akira , T. Taga and T. Kishimoto (1993) Interleukin-6 in biology and medicine. Adv Immunol 54, 1-78

55 E. Nishino (1990) Trophoblast-derived interleukin-6 (IL-6) regulates human chorionic gonadotropin release through IL-6 receptor on human trophoblasts. J Clin Endocrinol Metab 71, 436-441

56 M.Y. Wu (2001) Mouse embryo toxicity of IL-6 in peritoneal fluids from women with or without endometriosis. Acta Obstet Gynecol Scand 80, 7-11

59 A. Meisser (1999) Effects of interleukin-6 (IL-6) on cytotrophoblastic cells. Mol Hum Reprod 5, 1055-1058

60 R.A. Margni and A.C. Zenclussen (2001) During pregnancy, in the context of a Th2 type cytokine prolife, serum IL-6 levels might condition the quality of the synthesized antibodies. Am J Reprod Immunol 46, 181-187

61 R.A. Margni and I. Malan Borel (1998) Paradoxical behavior of asymmetric IgG antibodies. Immunol Rev 163, 77-87

62 A.C. Zenclussen (2001) Asymmetric antibodies and pregnancy. Am J Reprod Immunol 45, 289-294

63 A.C. Zenclussen (2000) Interleukin-6 and soluble interleukin-6 receptor serum levels in recurrent spontaneous abortion women immunized with paternal white cells. Am J Reprod Immunol 44, 22-29

64 E. Bettelli (2006) Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441, 235-238

65 S. Sakaguchi (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22, 531-562

66 H. Waldmann (2004) Regulatory T cells and organ transplantation. Semin Immunol 16, 119-126

68 G. Chaouat and G.A. Voisin (1981) Regulatory T cells in pregnancy. V. Allopregnancy-induced T-cell-suppressor factor is H-2 restricted and bears Ia determinants. Cell Immunol 62, 186-95

69 D.A. Somerset (2004) Normal human pregnancy is associated with an elevation in the immune suppressive CD25+  CD4+  regulatory T-cell subset. Immunology 112, 38-43

71 M. Karim (2004) Alloantigen-induced CD25+ CD4+  regulatory T cells can develop in vivo from CD25-CD4+  precursors in a thymus-independent process. J Immunol 172, 923-928

72 A.C. Zenclussen (2006) Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface. Eur J Immunol 36, 82-94

73 A. Sollwedel (2005) Protection from abortion by HO-1 up-regulation is associated with increased levels of Bag-1 and neuropilin-1 at the fetal-maternal interface. J Immunol 175, 4875-4885

74 S.M. Metcalfe and S De P.A. Muthukumarana (2005) Transplantation tolerance: gene expression profiles comparing allotolerance vs. allorejection. Int Immunopharmacol 5, 33-39

76 N.G. Abraham (1988) The physiological significance of heme oxygenase. Int J Biochem 20, 543-558

77 R. Beri and R. Chandra (1993) Chemistry and biology of heme. Effect of metal salts, organometals and metalloporphyrins on heme synthesis and catabolism, with special reference to clinical implications and interactions with cytochrome P-450. Drug Metab Rev 25, 49-152

78 S. Sassa and T. Nagai (1996) The role of heme in gene expression. Int J Hematol 63, 167-178

79 P. Ponka (1999) Cell biology of heme. Am J Med Sci 318, 241-256

80 G.M. Vercellotti (1994) Heme and the vasculature: an oxidative hazard that induces antioxidant defenses in the endothelium. Artif Cells Blood Substit Immobil Biotechnol 22, 207-213

81 V. Jeney (2002) Pro-oxidant and cytotoxic effects of circulating heme. Blood 100, 879-887

82 G. Balla (1991) Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb 11, 1700-1711

83 S.W. Ryter and R.M. Tyrrell (2000) The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med 28, 289-309

85 A. Yesilkaya , R. Altinayak and D.K. Korgun (2000) The antioxidant effect of free bilirubin on cumene-hydroperoxide treated human leukocytes. Gen Pharmacol 35, 17-20

87 S.W. Ryter and A.M. Choi (2002) Heme oxygenase-1: molecular mechanisms of gene expression in oxygen-related stress. Antioxid Redox Signal 4, 625-632

88 M.D. Maines (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37, 517-554

89 P.R. Montellano (2000) The mechanism of heme oxygenase. Curr Opin Chem Biol 4, 221-227

90 D. Morse and A.M. Choi (2002) Heme oxygenase-1. The “emerging molecule” has arrived. Am J Respir Cell Mol Biol 27, 8-16

91 X. Li and J.D. Clark (2000) Chronic morphine exposure and the expression of heme oxygenase type 2. Brain Res Mol Brain Res 75, 179-184

92 N. Liu (2000) Developmentally regulated expression of two transcripts for heme oxygenase-2 with a first exon unique to rat testis: control by corticosterone of the oxygenase protein expression. Gene 241, 175-183

93 M.D. Maines and N. Panahian (2001) The heme oxygenase system and cellular defense mechanisms. Do HO-1 and HO-2 have different functions? Adv Exp Med Biol 502, 249-272

94 W.K. McCoubrey Jr., T.J. Huang and M.D. Maines (1997) Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 247, 725-732

95 J. Woo (2000) Alleviation of graft-versus-host disease after conditioning with cobalt-protoporphyrin, an inducer of heme oxygenase-1. Transplantation 69, 623-633

96 C. Chauveau (2002) Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection. Am J Transplant 2, 581-592

97 M.P. Soares (1998) Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med 4, 1073-1077

98 A.C. Zenclussen (2005) Heme oxygenase as a therapeutic target in immunological pregnancy complications. Int Immunopharmacol 5, 41-51

99 N. Ihara (1998) Developmental changes of gene expression in heme metabolic enzymes in rat placenta. FEBS Lett 439, 163-167

100 A.C. Zenclussen (2002) Heme oxygenase is downregulated in stress-triggered and IL-12 mediated murine abortion. Scand J Immunol 55, 560-569

101 A. Barber (2001) Heme oxygenase expression in human placenta and placental bed: reduced expression of placenta endothelial HO-2 in preeclampsia and fetal growth restriction. FASEB J 15, 1158-1168

102 A.C. Zenclussen (2003) Heme oxygenases in pregnancy II: HO-2 is downregulated in human pathological pregnancies. Am J Reprod Immunol 50, 66-76

103 D. Denschlag (2004) The size of a microsatellite polymorphism of the haem oxygenase 1 gene is associated with idiopathic recurrent miscarriage. Mol Hum Reprod 10, 211-214

104 K. Poss and S. Tonegawa (1997) Reduced stress defense in heme oxygenase-1 deficient cells. Proc Natl Acad Sci U S A 94, 10925-10930

106 B.M. Choi (2005) Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression. Biochem Biophys Res Commun 327, 1066-1071

107 R. Jaffe , A. Dorgan and J.S. Abramowicz (1995) Color Doppler imaging of the uteroplacental circulation in the first trimester: value in predicting pregnancy failure or complication. Am J Roentgenol 164, 1255-1258

108 B.J. Trudinger , W.B. Giles and C.M. Cook (1985) Uteroplacental blood flow velocitytime waveforms in normal and complicated pregnancy. Br J Obstet Gynaecol 92, 39-45

109 S.D. Appleton (2002) Heme oxygenase activity in placenta: direct dependence on oxygen availability. Am J Physiol Heart Circ Physiol 282, 2055-2059

110 Y. Zhou , C.H. Damsky and S.J. Fisher (1997) Pre-eclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 99, 2152-2164

111 G.S. Marks (1991) Does carbon monoxide have a physiological function? Trends Pharmacol Sci 12, 185-188

112 A. Verma (1993) Carbon monoxide: a putative neural messenger. Science 259, 381-384

114 J.C. Khoury (2004) Consequences of smoking and caffeine consumption during pregnancy in women with type 1 diabetes. J Matern Fetal Neonatal Med 15, 44-50

116 T. Takeshita (2004) Diagnosis and treatment of recurrent miscarriage associated with immunological disorders: is paternal lymphocyte immunization a relic of the past? J Nippon Med Sch 71, 308-313

117 J.A. Hill (1997) Immunotherapy for recurrent pregnancy loss: “standard of care or buyer beware”. J Soc Gynecol Invest 4, 267-273

118 O.B. Christiansen , H.S. Nielsen and A.M. Kolte (2006) Future directions of failed implantation and recurrent miscarriage research. Reprod Biomed Online 13, 71-83

I. Guleria and M. Sayegh (2007) Maternal acceptance of the fetus: true human tolerance. J Immunol 178, 3345-3351An excellent review on mechanisms of tolerance towards the allogeneic fetus.

J. Hunt (2006) Stranger in a strange land. Immunol Rev 213, 36-47A review focusing primarily on the role of HLA-G in tolerance maintenance.

A. Moffett and C. Loke (2006) Immunology of placentation in eutherian mammals. Nat Rev Immunol 6, 584-594A beautiful review comparing the immunology of implantation and placentation among species.

C. Kling (2006) Transfusion related risks of intradermal allogeneic lymphocyte immunotherapy: single cases in a large cohort and review of the literature. Am J Reprod Immunol 56, 157-171A critical review of the side effects of immunotherapy with paternal lymphocytes.

V.M. Abrahams and G. Mor (2005) Toll-like receptors and their role in the trophoblast. Placenta 26, 540-547A review on mechanisms of innate immunity in the placenta.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Altmetric attention score

Full text views

Total number of HTML views: 2
Total number of PDF views: 19 *
Loading metrics...

Abstract views

Total abstract views: 174 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 27th June 2017. This data will be updated every 24 hours.