Abstract
IntroductionIn pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance.MethodsGenotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309).ResultsIn uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies.ConclusionThe data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy.
Highlights
In pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus
Genotype and Allele Frequencies in Maternal-Fetal killer-cell immunoglobin-like receptor (KIR)/HLA-C Combinations. We investigated in both pregnancy cohorts whether certain combinations of maternal KIR and fetal HLA-C genotype were observed more frequently than what would be expected-bychance
As no significant differences were found in the amount of total maternalfetal and locus-specific HLA matches compared to expected-bychance, we conclude there is no selection for increased maternalfetal HLA compatibility in uncomplicated naturally conceived pregnancies
Summary
The mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. Encounter of cells and immunogenic molecules from the fetus mainly occurs at the fetal-maternal interface [1,2,3]. The expressed HLA molecules play a crucial role in placentation and pregnancy outcome, as these mediate contact between the extravillous trophoblast (EVT) and maternal decidual leukocytes [1]. The killer-cell immunoglobin-like receptor (KIR) on uNK cells can directly interact with HLA-C molecules expressed on the surface of EVTs to enhance these processes, mainly through the release of cytokines. The interaction of maternal KIR with fetal HLA-C is crucial for the success of the pregnancy, as specific combinations are associated with enhancement or disruption of placentation. The lack of uNK activation is associated with the risk of severe pregnancy complications such as preeclampsia [8]
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