The role of KIR and HLA-C in reproductive success. (360G-Wellcome-085992_Z_08_Z)

Our aim is to unravel the complexities underlying our previous finding that particular maternal KIR with fetal HLA-C combinations (in essence KIR AA and fetal C2) are associated with pre-eclampsia. Successful pregnancy and fetal growth depends on trophoblast infiltration into the uterus and this is most severely deficient in women who have pre-eclampsia and the baby also has FGR. We have access to 100,000 Norwegian samples and can select adequate numbers of these severely abnormal pregnancies to compare with normal controls. We will determine individual KIR gene frequencies and type HLA-C alleles on mother and baby. For the first time we will address how the mother s HLA-C status affects the response of uNK to the fetal trophoblast. We will also focus on one particular KIR, KIR2DL1 and address how polymorphism of this gene encoding the receptor for HLA-C2 alleles influences pregnancy outcome and uNK function. Finally, we aim to translate the genetic studies into functional outcomes usi ng primary uterine NK cells and normal trophoblast. These studies will reveal how the complex system of interacting maternal KIR receptors and fetal HLA-C ligands are critical determinants of clinical outcomes during pregnancy.