For immunologists, ruminations about the immune sys-tem during pregnancy are mostly centred on the acqui-sition of maternal tolerance to the allogeneic fetus1,2. This view is probably too simplistic because it does not take into consideration the anatomical fact that it is the maternal relationship with the placenta rather than with the fetus that holds the key to our understanding of the ‘immunological paradox’ of pregnancy. In particular, the focus should be on the intermingling of placental and maternal cells in the uterine wall, as this is where direct tissue contact occurs during placentation. Failure to dis-tinguish between the local uterine immune response to the placenta and the systemic immune response to fetal cells (which usually cross to the mother at delivery) has led to a great deal of confusion.To understand maternal uterine immune responses to the placenta requires knowledge of the sequen-tial anatomical and physiological events that occur during placentation. Herein lies a difficulty, in that each species has developed its own strategy and this results in a great divergence of types of placentation in mammals3–5. One of the most obvious differences is the extent of invasion into the uterus by placental trophoblast cells. This can range from no invasion at all (as in epitheliochorial placentation) to very extensive invasion (as in haemo chorial placentation), whereby trophoblast cells penetrate through uterine blood ves-sels to come into direct contact with maternal blood. Humans have haemochorial placentae, as do many laboratory animals, such as mice, rats, guinea pigs and rabbits, but even among this group, the human placenta is particularly invasive.Comparison of divergent placental strategies must also encompass the maternal reaction that each placental type evokes. Here there is also much diversity. In haemo-chorial placentation, the uterine mucosa is transformed into a highly specialized tissue known as the decidua (a process referred to as decidualization). This does not occur in species with non-invasive epithelio chorial placentae. In primates, decidualization correlates closely with the degree of invasion, so the most marked decidual change is seen in those species with the most invasive placentae. A conspicuous feature of the decidua is the influx of a distinctive lymphocyte population of maternal uterine natural killer (NK) cells6. NK cells are emerging as important players in the uterine immune response to invasive forms of placentation, although the precise role they have is still unclear.The cells that define the boundary between the mother and fetus are trophoblast cells7. These cells are derived from the outer layer of the blastocyst and have many unusual characteristics that tend to be ignored by immunologists8 (BOX 1). Because trophoblast cells are freed from the developmental constraints that affect the rest of the embryo, they have a unique pattern of pater-nal and maternal gene expression. Of most relevance to immunologists is the expression of MHC and MHC-like genes by trophoblast cells, which would be the poten-tial ligands for immune receptors on uterine NK cells, lympho cytes and myelomonocytic cells. Human tropho-blast cells have been studied extensively and express a unique and intriguing array of HLA class I molecules, the functions of which might hold the key to the successful temporary coexistence of two individuals.King’s College, Cambridge CB2 1ST, UK.Correspondence to A.M. e-mail: [email protected]:10.1038/nri1897Trophoblast cellsTrophoblast 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.BlastocystAfter 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.Immunology of placentation in eutherian mammalsAshley Moffett and Charlie LokeAbstract | 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.REVIEWS584 | AUGUST 2006 | VOLUME 6 www.nature.com/reviews/immunol© 2006 Nature Publishing GroupEutherian placentaEutherian 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 eggEggs 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 sacThe 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.AmnionThe innermost membranous sac of amniote eggs. It is filled with a serous fluid and encloses the embryo of an amniote (reptile, bird or mammal).It is therefore clear that a detailed knowledge of the anatomical and molecular interactions between the pla-centa and the uterus at the implantation site is necessary if we are to understand nature’s allograft. The starting point of this Review will be the eutherian placenta. The evolution from the extra-embryonic membranes of amniote eggs to the formation of the definitive placenta is traced and the diverse characteristics of placentae that are seen in extant mammalian species is emphasized. The unique characteristics of trophoblast cells and the adaptation of the uterine mucosa by transformation into decidua are described. Also, the immunological implica-tions of these divergent placental forms are
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