Immunology of Pre-Eclampsia

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Abstract

Pre-eclampsia develops in stages, only the last being the clinical illness. This is generated by a non-specific, systemic (vascular), inflammatory response, secondary to placental oxidative stress and not by reactivity to fetal alloantigens. However, maternal adaptation to fetal (paternal alloantigens) is crucial in the earlier stages. A pre-conceptual phase involves maternal tolerization to paternal antigens by seminal plasma. After conception, regulatory T cells, interacting with indoleamine 2,3-dioxygenase, together with decidual NK cell recognition of fetal HLA-C on extravillous trophoblast may facilitate placental growth by immunoregulation. Complete failure of this mechanism would cause miscarriage, while partial failure would cause poor placentation and dysfunctional uteroplacental perfusion. The first pregnancy preponderance and partner specificity of pre-eclampsia can be explained by this model. For the first time, the pathogenesis of pre-eclampsia can be related to defined immune mechanisms that are appropriate to the fetomaternal frontier. Now, the challenge is to prove the detail.

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Rheological and Physiological Consequences of Conversion of the Maternal Spiral Arteries for Uteroplacental Blood Flow during Human Pregnancy

G.J. Burton, A.W. Woods, E. Jauniaux … (2009)

Physiological conversion of the maternal spiral arteries is key to a successful human pregnancy. It involves loss of smooth muscle and the elastic lamina from the vessel wall as far as the inner third of the myometrium, and is associated with a 5–10-fold dilation at the vessel mouth. Failure of conversion accompanies common complications of pregnancy, such as early-onset preeclampsia and fetal growth restriction. Here, we model the effects of terminal dilation on inflow of blood into the placental intervillous space at term, using dimensions in the literature derived from three-dimensional reconstructions. We observe that dilation slows the rate of flow from 2 to 3 m/s in the non-dilated part of an artery of 0.4–0.5 mm diameter to approximately 10 cm/s at the 2.5 mm diameter mouth, depending on the exact radius and viscosity. This rate predicts a transit time through the intervillous space of approximately 25 s, which matches observed times closely. The model shows that in the absence of conversion blood will enter the intervillous space as a turbulent jet at rates of 1–2 m/s. We speculate that the high momentum will damage villous architecture, rupturing anchoring villi and creating echogenic cystic lesions as evidenced by ultrasound. The retention of smooth muscle will also increase the risk of spontaneous vasoconstriction and ischaemia–reperfusion injury, generating oxidative stress. Dilation has a surprisingly modest impact on total blood flow, and so we suggest the placental pathology associated with deficient conversion is dominated by rheological consequences rather than chronic hypoxia.

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Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

Susan E. Hiby, James J. Walker, Kevin M. O'Shaughnessy … (2004)

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.