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

TLDR

Preeclampsia is a severe pregnancy complication caused by inadequate trophoblast invasion and is thought to involve an immunological component centered on fetal HLA‑C antigens. The study examined whether maternal KIR recognition of fetal HLA‑C on trophoblast influences preeclampsia risk. Mothers with an AA KIR genotype carrying fetal HLA‑C2 had a markedly higher preeclampsia risk, indicating that maternal KIR–fetal HLA‑C interactions affect placental development rather than immune surveillance, and the reciprocal distribution of these alleles across populations suggests evolutionary selection for reproductive success.

Abstract

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.