How Does the Maternal Immune System Contribute to the Development of Pre-eclampsia?

KIR receptors and their HLA-C ligands. Both HLA-C1 and HLA-C2 groups have corresponding inhibitory and activating KIR receptors. Inhibitory receptors signal through intra-cellular ITIM motifs and activating receptors on association with the adaptor molecule DAP-12 which has ITAM motifs.

The A and B KIR haplotypes differ essentially by the number of activating receptors they possess. Both haplotypes may have inhibitory receptors for HLA-C1 and C2 but only B haplotypes have the corresponding activating receptors.

Certain combinations of maternal KIR and fetal HLA-C genotypes increase susceptibility to pre-eclampsia. A cross (×) indicates the increased risk of a poor clinical outcome.

The frequency of the maternal KIR AA genotype is significantly increased in pre-eclamptic pregnancies as compared to non-affected but only when the fetus has a HLA-C2 allele in homozygous or heterozygous state. There is no associated risk of pre-eclampsia when the fetus is a HLA-C1 homozygote.

KIR frequencies in control and affected pregnancies when HLA-C2 is present in the fetus. There is a significant lack of the closely-linked KIR genes at the telomeric end of the KIR B haplotype.

Model for the interaction of maternal uterine NK cell KIR with fetal HLA-C2 on the extravillous trophoblast.

Genetic predisposition to pre-eclampsia involves both maternal and paternal genes. However, the maternal genotype has a greater contribution to the risk. Odds ratios as published by Skjaerven et al. [17].

KIR AA genotype and HLA-C2 frequencies in different populations. Modified from Hiby et al. [23].