Pre-eclampsia is a complication of the second half of pregnancy, resulting in poor fetal growth and changes to the maternal systemic vasculature. About 5–10% of pregnancies are affected by pre-eclampsia, and it is a significant cause of pregnancy-associated mortality. The only cure is to deliver the fetus. Hiby and colleagues now report that a specific combination of maternal KIR (killer-cell immunoglobulin-like receptor) and fetal HLA-C genotypes is associated with an increased risk of pre-eclampsia.
In humans, placentation involves remodelling of the maternal blood vessels to provide the fetus with sufficient nutrients from the mother's blood supply. Maternal natural killer (NK) cells — which constitute 50–90% of the leukocytes in the decidua — have a role in remodelling the spiral arteries in the decidual layer. The activation of uterine NK cells, similar to all NK cells, is controlled by signals from both activating and inhibitory receptors. Previous studies have shown that maternal and paternal genes contribute to pre-eclampsia, and in this study, Hiby and colleagues chose to assess the maternal KIR genotype and the fetal HLA-C genotype because both gene families are polymorphic.
The authors analysed the frequency of maternal KIR and fetal HLA-C genotypes in 200 pregnant women with pre-eclampsia and 200 women with normal pregnancies. Pre-eclampsia was found to be more common in women homozygous for the KIR-A haplotype (denoted AA). This haplotype has seven KIR loci, only one of which is activating (KIR2DS4), and because the most common allele of KIR2DS4 has a deletion, women with an AA genotype generally have no activating KIRs. Each additional activating KIR decreased the risk of pre-eclampsia. When the combination of KIR and HLA-C genotypes in pre-eclampsia was assessed, the authors found that the combination of the KIR AA genotype with fetal HLA-C2 — whether hetero- or homozygous — was significant for the development of pre-eclampsia.
These results indicate that too much inhibition of uterine NK cells leads to inadequate remodelling of the maternal arteries and increases the likelihood of pre-eclampsia. So, this interaction between maternal KIR and trophoblast HLA-C2 supports a physiological function during placentation, rather than an immunological role in mounting a response to the allogeneic fetus.
ORIGINAL RESEARCH PAPER
Hiby, S. E. et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of pre-eclampsia and reproductive success. J. Exp. Med. 200, 957–965 (2004).
Moffett-King, A. Natural killer cells and pregnancy. Nature Rev. Immunol. 2, 656–663 (2002).
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Bell, E. A bad combination. Nat Rev Immunol 4, 927 (2004). https://doi.org/10.1038/nri1514