Pregnancy immunology and maternal alloimmune responses

Pregnancy is an “immunological Paradox”. This is because pregnant women are tolerant of their semi‐allogeneic fetus but are not immunosuppressed and indeed make strong antibody responses. The immunological changes required are driven mainly by the placenta, an organ derived from cells of the blastocyst surrounding the embryo. Trophoblast cells on the surface of the placenta form the interface between the fetus and maternal tissues and blood. They differentiate into (a) villous syncytiotrophoblast (ST) that are in contact with maternal blood and transfer gases and nutrients between maternal and fetal blood and (b) extravillous trophoblast cells that invade into the maternal decidua lining the uterus. Trophoblast cells escape allorecognition because they lack classical HLA class I and II molecules. Local immunoregulation, or tolerance, in the decidua is mediated mainly by HLA‐G+ extravillous trophoblasts that prevent killing of fetal and placental cells by maternal natural killer cells, cytotoxic T cells and macrophages, thus ensuring the fetus is not rejected. Placental hormones orchestrate the composition and regulatory function of maternal immune cells in the decidua. ST at the surface of chorionic villi, together with ST debris that is shed into maternal blood, maintain a state of mild maternal systemic inflammation by enhancing innate immunity and skewing the immune response towards humoral (antibody) immunity. This enables a healthy immune system to be maintained in pregnant women, with robust protective antibody responses to pathogens whilst enabling survival of the fetus. However, this immunological skewing ensures that pregnant women readily form alloantibodies to incompatible fetal alloantigens. If fetomaternal haemorrhage (FMH) occurs, they can make antibodies to fetal red cells, platelets and leucocytes that are in her blood. The alloantibodies are initially of low affinity but after re‐immunisation of the woman with further FMH (most commonly at delivery), they become functionally effective, high titre IgG. Maternal IgG is transferred by the ST to the fetus, to give the baby protective immunity to survive infancy. This has the unfortunate consequence that alloantibodies to blood cells are also transported, leading to haemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT). Both HDFN and FNAIT may result in death or serious neurological damage to the baby. HDFN due to anti‐D can be prevented by administration of prophylactic anti‐D to the mother, destroying or clearing D‐positive fetal red cells in FMH from her circulation before they can become immunogenic.