Fetal–Maternal Immunological Relationships


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).



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Further Reading

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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.

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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]