Fetal–Maternal Immunological Relationships

Abstract

Despite inheriting half of its genetic material from its father, the fetoplacental unit is not rejected by the maternal immune system because of a unique immunological relationship with the mother. Despite maternal immune recognition of the conceptus as evidenced by alloantibodies, unlike for conventional allografts, the immune response is spared, cytotoxic effectors being downregulated or suppressed, whereas several cytokinic responses, including inflammatory ones, are used or even provoked for their preimplantation or later on ‘immunotrophic’ effects. This unique relationship is partly due to the peculiar antigen expression in the placenta, culminating in humans with the sole expression of human leucocyte antigen C (HLA‐C) and monomorphic HLA‐G on invading cytotrophoblasts and also many immunoregulatory pathways, with special emphasis presently put on regulatory T cells. Moreover, uterine natural killer (uNK) cells are a distinct, specialised NK subset, endowed with immunoregulatory and angiogenic properties, necessary for local (spiral) arteries development. Consequences for abortion eclampsia are discussed, as well as antibody‐induced fetal haemolytic disease.

Key Concepts:

  • The fetus is usually seen as an allograft in mother's womb, which should be rejected by the maternal immune system.

  • Pregnancy induces systemic modifications in the maternal immune system but these do not really account for fetal survival.

  • Recognition of the ‘foreign’ nature of the fetus is good and even sometimes required for successful pregnancy.

  • Placenta acts as a barrier between the fetus and maternal cells.

  • Uterine natural killer cells are not endowed with the same properties as the ones found in peripheral blood.

  • One of the keys to fetal survival is the peculiar expression of MHC antigens in the placenta, including in human the expression of a nonpolymorphic antigen, HLA‐G, in membrane bound and soluble forms both endowed with immunoregulatory properties.

  • Uterine natural killer cells control local uterine angiogenesis.

  • The placenta bathes in/secretes immunotregulatory materials.

  • Regulatory T cells mitigate the effects of allorecognition by maternal immune system in placental mammals.

  • Allopregnancy is a Th2 phenomenon.

  • In variance with MHC antigens, red blood cells antigens can induce maternal antibodies which can cross the placenta, and destroy in utero fetal red blood cells.

Keywords: placenta; graft; antigen expression; rejection; tolerance; abortion; eclampsia; tregs; uNK; angiogenesis; RH haemolytic disease

Figure 1.

(a) Activated NK cells are very abundant at implantatioin site (murine implantation site) and (b) balance between inhibition of cytotoxicity (action on KIR, inhibitory Killer Ig like receptors, or Killer Inhibiting receptors) or KAR (activating Killer Ig‐like receptors, or Killer Activating receptors).

Figure 2.

Successful allopregnancy is a Th2 phenomenon: predominance of Th2 cytokine leads to fetal survival, whereas unbalance towards Th1 leads to fetal demise.

Figure 3.

The CBA×DBA/2 model. CBA/J female (brown mice, centre, H‐2k) shows a high rate of fetal resorbtion when mated with DBA/2 mice (grey, left, H‐2d), but not when mated with BALB/c mice (right, white; also H‐2d). Anti BALB/c immunisation of the female prior to DBA/2 mating prevents resorption. Syngeneic matings do not abort /resorb.

Figure 4.

Accumulation of Tregs (see above) in grey, and transient influx of T cells and macrophages (red).

close

References

Ahmed A, Singh J, Khan Y, Seshan SV and Girardi G (2010) A new mouse model to explore therapies for preeclampsia. PLoS One 5(10): e13663.

Allen WR, Kydd JH and Antczack DF (1986) Successful application of immunotherapy to a model of pregnancy failure in equids. In: Clark DA and Croy BA (eds) Reproductive Immunology, pp. 253–261. Amsterdam: Elsevier.

Avril T, Jarousseau AC, Watier H, Bardos P and Thibault G (1999) Trophoblastic resistance to NK lysis mainly involves an HLA‐G dependent mechanisms. Journal of Immunology 162: 5902–5909.

Baines MG and Gendron RL (1993) Natural and experimental animal models of reproductive failure. In: Chaouat G (ed.) Immunology of Pregnancy pp. 173–203. Florida, USA: CRC Press Boca Raton.

Bayraktar M, Peltier M, Vetrano A et al. (2009) IL‐10 modulates placental responses to TLR ligands. American Journal of Reproductive Immunology 62(6): 390–399.

Bazer FW, Spencer TE and Ott TL (1997) Interferons tau: a novel pregnancy recognition signal. American Journal of Reproductive Immunology 37(6): 412–421.

Beer AE, Quebbeman JF and Semprini AE (1983a) Immunological aspects of recurrent abortions in humans. In: Edelmann P and Sureau C (eds) Immunologie de la Reproduction Humaine, pp. 52–53. Paris: Sandoz Editions.

Beer AE, Quebbeman JF, Semprini AE, Smouse PE and Haines RF (1983b) Recurrent abortion: analysis of the role of parental sharing of histocompatibility antigens and maternal immunological responses to paternal antigens. In: Isojima S and Billington WD (eds) Reproductive Immunology, pp. 185–197. Amsterdam: Elsevier.

Beer AE, Scott JR and Billingham RE (1975) Histocompatibility and maternal immunological status as determinants of feto‐placental size and litter weight in rodents. Journal of Experimental Medicine 142: 180–198.

Bianchi DW, Mahr A, Zickwolf GK et al. (1992) Detection of foetal cells with 47,XY,+21 karyotype in maternal peripheral blood. Human Genetics 90: 368.

Boyon C, Collinet P, Boulanger L et al. (2011) Fetal microchimerism: benevolence or malevolence for the mother? European Journal of Obstetrics and Gynecology and Reproductive Biology 158(2): 148–152.

Brambell FW (1970) The Transmission of Passive Immunity from Mother to Young. Amsterdam: Elsevier North Holland.

Chaouat G, Clark DA and Wegmann TG (1988) Genetics aspects of the CBA/J_DBA/2J and B10_B10. A models of murine spontaneous abortions and prevention by leukocyte immunisation. In: Allen WR, Clark DA, Gill TJ III, Mowbray JF and Robertson WR (eds) Early Pregnancy Loss. Mechanisms and Treatment, 18th Royal College of Obstetricians and Gynaecologists Study Group, pp. 89–105. London: COG Press.

Clark DA, Lea RG, Denburg J et al. (1991) Transforming growth factor beta 2 related factor in mammalian pregnancy decidua: homologies between the mouse and human in successful pregnancy and in recurrent unexplained abortion. In: Chaouat G and Mowbray J (eds) Biologie Cellulaire et Moléculaire de la Relation Materno Fetale, Paris editions, pp. 171–181. Paris: INSERM John Libbey Eurotext.

Clark DA, McDermott M and Sczewzuk MR (1980) Impairment of host versus graft reaction in pregnant mice: (II) selective suppression of cytotoxic cell generation correlates with soluble suppressor activity foetal–maternal immunological relationships and successful allogeneic pregnancy. Cellular Immunology 52: 106–118.

Clark DA and McDermott MR (1981) Active suppression of host‐vs‐graft reaction in pregnant mice. III. Developmental kinetics, properties, and mechanism of induction of suppressor cells during first pregnancy. Journal of Immunology 127(4): 1267–1273.

Cooper JC, Fernandez N, Joly E and Dealtry GB (1998) Regulation of MHC complex and TAP gene products in pre implantation stage mouse embryos. American Journal of Reproductive Immunology 40: 165.

Coulam CB, Clark DA, Collins JA and The Recurrent Miscarriage Immunotherapy Trialist Group (1994) World wide collaborative observational study and meta analysis on allogeneic leukocyte therapy for recurrent spontaneous abortion. American Journal of Reproductive Immunology 32: 55–72.

Drake BL and Head JR (1989) Murine trophoblast can be killed by lymphokine‐activated killer cells. Journal of Immunology 143: 9–14.

Ellis SA (1990) HLA‐G: at the interface. American Journal of Reproductive Immunology 23: 84–86.

Faulk WP and McIntyre JA (1983) Immunological studies of trophoblast markers, subsets and functions. Immunological Reviews 75: 139–175.

Garlanda C, Maina V, Martinez de la Torre Y, Nebuloni M and Locati M (2008) Inflammatory reaction and implantation: the new entries PTX3 and D6. Placenta 29(Suppl. B): 129–134.

Gnainsky Y, Granot I, Aldo PB et al. (2010) Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertility and Sterility 94(6): 2030–2036.

Guimond MJ, Luross JA, Wang B et al. (1997) Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice. Biology of Reproduction 56: 169–179.

Guimond MJ, Wang B and Croy BA (1998) Engraftment of bone marrow from severe combined immunodeficiency (SCID) mice reverses the reproductive deficit in natural killer cell deficient Tge26 mice. Journal of Experimental Medicine 187: 217–223.

Hiby SE, Walker JJ, O'shaughnessy KM et al. (2004) Combinations of maternal KIR and foetal HLA‐C genes influence the risk of preeclampsia and reproductive success. Journal of Experimental Medicine 200(8): 957–965.

Kahn DA and Baltimore D (2010) Pregnancy induces a fetal antigen‐specific maternal T regulatory cell response that contributes to tolerance. Proceeding of the National Academy of Sciences of the USA 107(20): 9299–9304.

Kallikourdis M and Betz AG (2007) Periodic accumulation of regulatory T cells in the uterus: preparation for the implantation of a semi‐allogeneic foetus? PLoS ONE 2: e382.

Kammerer U, Kruse A, Barrientos G, Arck PC and Blois SM (2008) Role of dendritic cells in the regulation of maternal immune responses to the foetus during mammalian gestation. Immunological Investigations 37(5): 499–533.

Krishnan L, Guilbert LJ, Russell AS et al. (1996b) Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigenspecific IFN‐g response and increased production of T helper 2 cytokines. Journal of Immunology 156: 644.

Krishnan L, Guilbert LJ, Wegmann TG, Belosevic M and Mossman TR (1996a) Helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and foetal resorption: correlation with increased IFN‐g and TNF and reduced IL‐10 production by placental cells. Journal of Immunology 156: 653.

Koopman LA, Kopcow HD, Rybalov B et al. (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. Journal of Experimental Medicine 198(8): 1201–1212.

Kumasawa K, Ikawa M, Kidoya H et al. (2011) Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proceeding of the National Academy of Sciences of the USA 108(4): 1451–1455.

Kvirkvelia N, Vojnovic I and Warner TD (2002) Placentally derived prostaglandin E2 acts via the EP4 receptor to inhibit IL‐2‐dependent proliferation of CTLL‐2T cells. Clinical and Experimental Immunology 127: 263–269.

Le Bouteiller P, Legrand‐Abravanel F and Solier C (2003) Soluble HLA‐G1 at the materno–foetal interface – a review. Placenta 24(Suppl. A): S10–S15.

Leach JL, Sedmak DD, Osborne JM et al. (1996) Isolation from human placenta of the IgG transporter FcRn and localisation to the syncytiotrophoblast. Journal of Immunology 157: 3317–3322.

Lédée‐Bataille N, Bonnet‐Chea K, Hosny G et al. (2005) Role of the endometrial tripod interleukin‐18, ‐15, and ‐12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization‐embryo transfer failure. Fertility and Sterility 83(3): 598–605.

Lee SK, Kim JY, Hur SE et al. (2011) An imbalance in interleukin‐17‐producing T and Foxp3+ regulatory T cells in women with idiopathic recurrent pregnancy loss. Human Reproduction 26(11): 2964–2971.

Leonard S, Murrant C, Tayade C et al. (2006) Mechanisms regulating immune cell contributions to spiral artery modification ‐facts and hypotheses – a review. Placenta 27(Suppl. A): S40–S46.

Loi P, Modlinski JA and Ptak G (2011) Inter species somatic cell nuclear transfer: a salvage tool seeking first aid. Theriogenology 76(2): 217–228.

Manaster I and Mandelboim O (2010) The unique properties of uterine NK cells. American Journal of Reproductive Immunology 63(6): 434–444.

Matzinger P (1994) Tolerance, danger, and the extended family. Annual Review of Immunology 12: 991–1045.

Medawar PB (1953) Some immunological and endocrinological problems raised by the evolution of viviparity invertebrates. Symposia of the Society for Experimental Biology 7: 320–338.

Moffett A and Hiby S (2009) Influence of activating and inhibitory killer immunoglobulin‐like receptors on predisposition to recurrent miscarriages. Human Reproduction 24(8): 2048–2949.

Moffet A and Loke YW (2006) Immunology of placentation in eutherian mammals. Nature Reviews Immunology 6: 584–594.

Moldenhauer LM, Diener KR, Thring DM et al. (2009) Cross‐presentation of male seminal fluid antigens elicits T cell activation to initiate the female immune response to pregnancy. Journal of Immunology 182(12): 8080–8093.

Mor G, Cardenas I, Abrahams V and Guller S (2011) Inflammation and pregnancy: the role of the immune system at the implantation site. Annals of the New York Academy of Sciences 1221: 80–87.

Mowbray JF, Gibbings C, Liddell H et al. (1985) Controlled trial of treatment of recurrent spontaneous abortions by immunisation with paternal cells. Lancet 1: 941–943.

Munn DH, Zhou M, Attwood JT et al. (1998) Prevention of allogeneic foetal rejection by tryptophan catabolism. Science 281: 1191–1193.

Petroff MG and Perchellet A (2010) B7 family molecules as regulators of the maternal immune system in pregnancy. American Journal of Reproductive Immunology 63(6): 506–519.

Rossant J, Mauro VM and Croy BA (1982) Importance of trophoblast genotype for survival of interspecific murine chimeras. Journal of Embryology and Experimental Morphology 69: 141–168.

Samstein RM, Josefowicz SZ, Arvey A, Treuting PM and Rudensky AY (2012) Extrathymic generation of regulatory T cells in placental mammals mitigates maternal–foetal conflict. Cell 150(1): 29–38.

Sipes SL, Medaglia MV, Stabley DL et al. (1996) A new major histocompatibility complex class Ib gene expressed in the mouse blastocyst and placenta. Immunogenetics 45: 108–120.

Sivori S, Parolini S, Marcenaro E et al. (2000) Triggering receptors involved in natural killer cell‐mediated cytotoxicity against choriocarcinoma cell lines. Human Immunology 61: 1055–1058.

Stewart CL, Kaspar P, Brunet LJ et al. (1992) Blastocyst implantation depends on maternal expression of leukemia inhibitory factor. Nature 359: 76–79.

Story C, Mikulska JE and Simister ME (1994) A major histocompatibility class I complex related class I like Fc receptor cloned from human placenta. A possible role in transfer of immunoglobulin G to the foetus. Journal of Experimental Medicine 180: 2377–2381.

Tafuri A, Alferink J, Möller P, Hämmerling GJ and Arnold B (1995) T cell awareness of paternal alloantigens during pregnancy. Science 270(5236): 630–633.

Than NG, Romero R, Kim CJ et al. (2012) Galectins: guardians of eutherian pregnancy at the maternal–fetal interface. Trends in Endocrinology and Metabolism 23(1): 23–31.

Voisin G and Chaouat GA (1974) Demonstration, nature and properties of antibodies eluted from the placenta and directed against paternal antigens. Journal of Reproduction and Fertility 21: 89–124.

Voisin GA (1971) Immunological facilitation. A broadening of the concept of the enhancement phenomenon. Progress in Allergy 15: 328–485.

Voluménie JL, Mognetti B, De Smedt D, Menu E and Chaouat G (1995) Induction of transient murine T cell anergy by a low molecular weight compound obtained from supernatants of human placental cultures is linked to defective phoshorylation of CD3 ζ chain. American Journal of Reproductive Immunology 38: 168–176.

Wegmann TG (1984) Foetal protection against abortion: is it immunosuppression or immunostimulation? Annales d'Immunologie de l'Institut Pasteur 135: D309.

Wegmann TG, Lin H, Guilbert L and Mossman TH (1993) Bidirectional cytokines interactions in the maternofoetal relationship: successful allopregnancy is a Th2 phenomenon. Immunology Today 14: 353–355.

Winger EE, Reed JL, Ashoush S, El‐Toukhy T and Taranissi M (2012) Die‐off ratio correlates with increased TNF‐α: IL‐10 ratio and decreased IVF success rates correctable with humira. American Journal of Reproductive Immunology 30 Jul 2012. doi: 10.1111/j.1600‐0897.2012.01179.x. (Epub ahead of print).

Xu C, Mao D, Holers VM et al. (2000) A critical role for complement regulatory Crry in feto maternal tolerance. Science 287: 498–499.

Further Reading

Chaouat G, Sandra O and Ledée N (2012) Immunology of Pregnancy 2012. Bentham Press, in press.

Coulam CB, Clark DA, Beer AE et al. (1997) Current clinical options for diagnosis and treatment of recurrent spontaneous abortions. American Journal of Reproductive Immunology 38: 57–74.

Loke YW and King A (1995) Human Implantation. Cell Biology and Immunology. Cambridge: Cambridge University Press.

Martal JL, Chêne NM, Huynh LP et al. (1998) IFN‐tau: a novel subtype I IFN1. Structural characteristics, non‐ubiquitous expression, structure‐function relationships, a pregnancy hormonal embryonic signal and cross‐species therapeutic potentialities. Biochimie 80(8–9): 755–777.

Mor G (2006) Immunology of Pregnancy. New York: Springer Science.

Möller G (1983) Immunology of Feto maternal relationship. Immunological Reviews 75: 5–230.

Redman CW, Sargent IL and Starkey PM (1993) The Human Placenta. Oxford: Blackwell Scientific.

Simmon C and Pellicer A (eds) (1995) Regulators of human implantation. In: Human Reproduction, vol. 10, suppl. 2, December 1995. Oxford, UK: Oxford University Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Chaouat, Gérard(Dec 2012) Fetal–Maternal Immunological Relationships. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000516.pub3]