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The immunological interaction between the mother and fetus has classically been thought of as one between paternal antigen and maternal T cells. However, the MHC antigen expression on human trophoblast and the immune cell populations present in the decidua suggest that this interaction primarily involves decidual NK cells rather than T cells, and this is supported by new functional studies. It is becoming apparent also that the maternal systemic immune response in pregnancy (Th1/Th2 shift) primarily involves NK cells. Aberrant NK cell activation both locally in the decidua and systemically in the maternal blood may be the cause of pre-eclampsia.

For several years, reproductive immunology has been dominated by the 'Th1/Th2' hypothesis, in which the fetus avoids maternal T-cell rejection through a bias towards T-helper (Th)2 cytokine production. The discovery that normal pregnancy is a controlled state of inflammation, at an early stage at the implantation site and also later systemically, has challenged this concept, as has the finding that the predominant immune interactions in the decidua are between the placental trophoblast and maternal natural killer (NK) cells instead of T cells. Here, we extend this concept to the interaction between the trophoblast and NK cells in the maternal circulation. We suggest novel ways in which the trophoblast might stimulate the maternal systemic inflammatory response, and how dysfunctional NK-cell activation could result in the maternal syndrome of pre-eclampsia.

A bias of T cell immunity towards type 2 (Th2) is thought to be critical for normal pregnancy. Pathological pregnancies, such as pre-eclampsia, are characterised by cell-mediated (Th1) immune dominance. The Th1/Th2 paradigm, however, is too simplistic. Normal pregnancy is associated with a systemic inflammatory response which increases throughout gestation. This inflammatory response is exaggerated in pre-eclampsia, a syndrome of the third trimester. T helper (Th) cells are considered the primary mediators of these altered immune responses, and other T cells, i.e. T cytotoxic (Tc) cells, and lymphocytes of the innate immune system, i.e. natural killer (NK) and NKT cells, have been largely disregarded. In this study, we have used novel pan type 1 (IL-18 receptor) and pan type 2 (ST2L) lymphocyte function markers in four-colour flow cytometry to broadly characterise peripheral blood lymphocyte populations from non-pregnant, normal pregnant and pre-eclamptic women. There were no changes in the Th1/Th2 or Tc1/Tc2 cell ratios between the three groups; however, the NK1/NK2 and NKT1/NKT2 cell ratios were significantly decreased in normal pregnancy compared with non-pregnant (p

Pre-eclampsia is a major disorder of human pregnancy, which may have an immunological basis. It is a disease of two stages. The first stage concerns the relative failure of early trophoblast invasion and remodelling of the spiral arteries, leading to a poor blood supply to the placenta, exposing it to oxidative stress. The inadequate trophoblast invasion may result from decreased expression of human leukocyte antigen-G (HLA-G) leading to an abnormal interaction with decidual natural killer (NK) cells, which are believed to play a major role in these processes through the production of immunoregulatory cytokines and angiogenic factors. Recent evidence suggests that the interaction between trophoblast human leukocyte antigen-C (HLA-C) molecules and decidual NK cell receptors may be the point at which the apparent partner specificity of the disease originates. The second stage is the maternal syndrome, which is characterized by a generalized systemic inflammatory response involving both leukocytes and endothelium. The inflammatory stimulus is believed to come from the placenta. In pre-eclampsia, placental oxidative stress may lead to increased shedding of apoptotic and/or necrotic syncytiotrophoblast debris into the maternal circulation. There is evidence that such trophoblast debris interacts with maternal leukocytes and endothelial cells to stimulate the release of proinflammatory cytokines, which could then trigger the maternal disease.

Pre-eclampsia is a common and potentially dangerous disorder of human pregnancy. The maternal syndrome of hypertension, proteinuria and oedema is part of a severe systemic inflammatory response that includes leukocyte and endothelial cell activation. Although the origins of pre-eclampsia remain unclear, a major cause is the failure to develop an adequate blood supply to the placenta, leading to placental oxidative stress. This results in the excess release of placental factors, such as syncytiotrophoblast debris or soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF), into the maternal circulation, where they trigger an inflammatory response and endothelial dysfunction. Alternatively, pre-eclampsia can develop in the presence of a normal placenta in women that are susceptible to systemic inflammation, such as with chronic cardiovascular disease or diabetes. While clinical management of pre-eclampsia does not currently include anti-inflammatory agents, current research is focusing on ways to reduce inflammation and oxidative stress.