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Immunology of placentation in eutherian mammals

Key Points

  • The anatomical relationship between the placenta and the uterus holds the key to our understanding of the 'immunological paradox' of pregnancy because this is where direct tissue contact occurs.

  • There is great diversity in placental structures in eutherian mammals. For immunologists, the most important feature is the extent to which the placental trophoblast cells invade the uterus. This ranges from no invasion at all (epitheliochorial placentation) to very extensive invasion (haemochorial placentation). The human placenta is the most invasive of all.

  • During pregnancy, in invasive forms of placentation, the uterine lining is transformed into decidual tissue. The most obvious feature of the decidua is the influx of a distinctive population of uterine natural killer (NK) cells.

  • Trophoblast cells express an array of MHC molecules some of which might be potential ligands for receptors expressed by the NK cells (CD94–NKG2A and KIRs (killer-cell immunoglobulin-like receptors)) and expressed by myelomonocytic cells (LILRB1 (leukocyte immunoglobulin-like receptor B1) and LILRB2) in the uterus. Interaction between HLA-C expressed by trophoblast cells and KIRs on maternal NK cells influences reproductive performance. Binding of HLA-G to LILRB molecules might induce tolerance in maternal T cells, thereby allowing cooperation between the innate and adaptive immune systems in mammalian reproduction.

  • It is proposed that the function of uterine NK cells is to alter the structure of the uterine spiral arteries that supply the feto-placental unit. This effect could be mediated directly by affecting the structure or function of the vessel wall (as in mice) or indirectly through the influence on trophoblast-cell infiltration. The arterial modification is necessary to allow sufficient blood flow to the placenta and fetus. Inadequate arterial transformation results in pregnancy disorders (such as fetal growth restriction or pre-eclampsia).

Abstract

The traditional way to study the immunology of pregnancy follows the classical transplantation model, which views the fetus as an allograft. A more recent approach, which is the subject of this Review, focuses on the unique, local uterine immune response to the implanting placenta. This approach requires knowledge of placental structure and its variations in different species, as this greatly affects the type of immune response that is generated by the mother. At the implantation site, cells from the mother and the fetus intermingle during pregnancy. Unravelling what happens here is crucial to our understanding of why some human pregnancies are successful whereas others are not.

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Figure 1: Types of placentation.
Figure 2: Disorders of human pregnancy resulting from abnormal placentation.
Figure 3: Placentation in rhesus monkeys and mice.

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Acknowledgements

The authors thank D. Antczak, G. Burton, S. Ellis, S. Murphy, P. Parham, R. Pijneneborg, A. Sharkey and P. Wooding for helpful comments.

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Glossary

Trophoblast cells

Trophoblast cells are the earliest extra-embryonic cells to differentiate from the cells of the mammalian embryo. They surround the conceptus throughout gestation and are in direct contact with maternal tissues.

Blastocyst

After fertilization, the potential embryo undergoes mitotic division and, at the 128-cell stage in humans, two distinct cell lineages are present. Trophoblast cells are derived from the trophectoderm that surrounds the blastocyst and the inner cell mass gives rise to the embryo.

Eutherian placenta

Eutherian mammals include all mammalian species except marsupials and egg-laying monotremes. The eutherian placenta is well developed compared with the marsupial placenta and has a great diversity of forms.

Amniote egg

Eggs of amniote vertebrates provide an interface between the embryo and its immediate environment, therefore allowing increased respiratory and excretory capacity as well as nutrient provision.

Yolk sac

The first of the four extra-embryonic membranes of amniote eggs to form during embryogenesis. It surrounds the mass of yolk in reptile and bird eggs and is connected to the midgut by the yolk stalk. The yolk sac is also formed in mammals, despite the absence of yolk.

Amnion

The innermost membranous sac of amniote eggs. It is filled with a serous fluid and encloses the embryo of an amniote (reptile, bird or mammal).

Chorion

In birds and reptiles, the chorion adheres to the shell and is highly vascularized to function in gas exchange. In mammals, it forms the fetal contribution to the placenta, made by an outer layer of trophoblast cells and inner layer of extra-embryonic mesoderm, which contains blood vessels that allow exchange of materials with the maternal circulation.

Allantois

The extra-embryonic membrane that emerges as a sac from the posterior part of hindgut of the embryo. It fuses with the chorion to form the chorio-allantoic placenta. The connection it makes between the embryo and the placenta becomes the umbilical cord.

Retroposed elements

Retroposons randomly insert into the genomes with little likelihood of the same element integrating into the orthologous position in different species. Analysis of the patterns of presence or absence of retroposons is a reliable method for studying the evolutionary history of organisms.

Convergent evolution

The process whereby organisms that are not closely related independently acquire similar characteristics while evolving in separate and sometimes varying ecosystems.

Haemolytic disease of the newborn

If there is rhesus-blood-group incompatibility between the mother and her fetus, the mother makes an antibody response against fetal red blood cells that access the mother's circulation at delivery. These IgG antibodies cross the placenta during a subsequent pregnancy, which results in the destruction of fetal red blood cells, leading to haemolytic disease of the new born.

Maternal and fetal microchimerism

The presence of fetal cells in the mother or maternal cells in the fetus. Fetal or maternal cells generally cross the placenta at delivery and might persist for many years.

Systemic sclerosis

A chronic autoimmune disease that causes a hardening of the skin. The skin thickens because of increased deposits of collagen. Compared with the localized form of the disease (scleroderma), systemic sclerosis causes more widespread skin changes and can be associated with damage to the lungs, heart and kidneys.

Endometriotic foci

Foci of endometrial tissue outside the endometrium or myometrium (muscle wall) of the uterus. They are usually found in the peritoneum.

Tubal pregnancy

An ectopic pregnancy occurs when the blastocyst implants at a site outside the uterus. Most ectopic pregnancies occur in the fallopian tube so the terms ectopic pregnancy and tubal pregnancy are nearly synonymous.

Placenta creta

A condition when placental trophoblast cells invade deeply into the muscle coat (myometrium) of the uterus, usually because of the absence of decidua. This can lead to uterine rupture, torrential haemorrhage and failure of the placenta to separate after delivery.

Procrustean bed

In Greek mythology, Procrustes (whose name means he who stretches) was a host who adjusted his guests to their bed. If they were longer than the bed, he cut off the redundant part; if shorter, he stretched them till they fitted it. Any attempt to reduce men to one standard, one way of thinking or one way of acting, is called placing them on a Procrustean bed.

Pre-eclampsia

Eclampsia (in Greek meaning bolt from the blue) describes grand mal seizures (epileptic fits) occurring towards the end of pregnancy. Pre-eclampsia describes the symptoms that precede eclampsia, which include oedema, proteinuria and hypertension.

Inferior vena cava

The large vein that carries de-oxygenated blood from the lower half of the body to the heart.

Endometrial cups

A focal collection of trophoblast cells that penetrate the uterus of horses. These cells are responsible for secretion of equine chorionic gonadotrophin.

Ectoplacental cone

A core of rapidly dividing trophoblast cells with an outer layer of giant cells that is present in the developing mouse conceptus at 7.5 days post-coitum.

Syncytiotrophoblast

The outermost trophoblast-cell layer covering the chorionic villi that is formed by fusion of the underlying layer of mononuclear trophoblast cells to become a multinucleated syncytium, which forms a barrier between the fetus and the mother.

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Moffett, A., Loke, C. Immunology of placentation in eutherian mammals. Nat Rev Immunol 6, 584–594 (2006). https://doi.org/10.1038/nri1897

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