Placental immunology and maternal alloimmune responses

During pregnancy, women are tolerant of their semi-allogeneic fetus whilst not being immunosuppressed and indeed readily form alloantibodies. This 'Immunological Paradox of Pregnancy' may be explained by an understanding of placental anatomy and immunology. Trophoblast cells form the interface between the fetus and maternal tissues and blood and escape allorecognition because they lack classical human leucocyte antigen (HLA) class I and II molecules. Local immunoregulation, or tolerance, in the decidua is mediated partly by HLA-G(+) extravillous trophoblasts (EVT) that invade the tissue and prevent killing by maternal natural killer cells, cytotoxic T cells and macrophages. Placental hormones orchestrate the composition and regulatory function of maternal immune cells. In contrast, syncytiotrophoblast cells at the surface of chorionic villi, in contact with maternal blood, maintain a state of mild maternal systemic immunity via activation of innate immunity and skewing towards humoral immunity. This enables maintenance of a healthy immune system in pregnant women and robust protective antibody responses to pathogens whilst enabling survival of the fetus. However, this has the unfortunate consequence that pregnant women readily form alloantibodies to incompatible alloantigens on fetal red cells, platelets and leucocytes if fetomaternal haemorrhage (FMH) occurs. The antibodies are initially low affinity but after re-immunization with further FMH become functionally effective, high-titre IgG.