Placental immunology and maternal alloimmune responses

Abstract

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.

A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy

“…Our previous study also featured patients (N 5 2) with anti-HPA-1a antibodies (normally observed in FNAIT patients) formed after transfusion, and they also did not display a skewing in core fucosylation. 32 Because other glycosylation patterns were affected as well, we hypothesize that this kind of IgG response must be governed by the very settings under which these antibodies are formed: either the T helper 2-dominant features of pregnancies, 39 the anti-platelet response, the anti-HPA-1a response, or a combination of these factors. We also investigated an FNAIT anti-HPA-1a sample, which also contained anti-HLA antibodies, with lowered Fc fucosylation for the anti-HPA-1a antibodies, but not for the anti-HLA antibodies.…”

Regulation of immunity and inflammation by hypoxia in immunological niches

“…The developing placenta is a key site of immunity that provides protection for the developing fetus while preventing the maternal immune system from attacking the semi-allogeneic trophoblasts of the fetus 93 . As a placenta grows, intra-placental oxygen gradients are established and HIF becomes activated, even under normal physiological conditions 94 .…”

Immunological Aspects of Pregnancy: A Literature Review

“…However, understanding the immunological mechanisms involved in the non-rejection of the placenta by the maternal immune system has been challenging. The placenta, for its embryonic origin, has both maternal and paternal genetic material and can potentially express paternal antigens, which are genetically foreign to the mother and therefore could induce an immune reaction that leads to rejection in a manner similar to that of other grafted tissues [2].…”

“…The immunological relationship between the mother and the fetus is a bi-directional communication determined on the one hand by fetal antigen presentation and on the other hand by recognition of and reaction to these antigens by the maternal immune system [2].…”