Maternal-Fetal HLA Compatibility in Uncomplicated and Preeclamptic Naturally Conceived Pregnancies

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.

Human Leukocyte Antigens in Pregnancy and Preeclampsia

“…Retrospective analysis of oocyte donation pregnancies found pregnancy losses and preeclampsia were associated with increased numbers of HLA gene mismatches between maternal-fetal pairs ( Lashley, et al, 2015 ; van Bentem, et al, 2020 ). However, studies on HLA mismatches and preeclampsia in spontaneously conceived pregnancies have yielded varied and sometimes contradictory findings with no clear evidence for an association between HLA dissimilarity between the mother and fetus and the incidence of preeclampsia ( Hoff, et al, 1992 ; Biggar, et al, 2010 ; Triche, et al, 2014 ; Van’t Hof et al, 2021 ).…”

“…A lack of clear association between HLA mismatches and preeclampsia may reflect limitations in the analyses performed. Separation of the effects of individual HLA genes on preeclampsia has similarly mixed results, with demonstration of selective influence by either HLA class I ( Lashley, et al, 2015 ; van’t Hoff, et al, 2021 ) or HLA class II ( Triche, et al, 2014 ; van Bentem, et al, 2020 ; van’t Hoff, et al, 2021 ) genes. Of the class I genes, only HLA-C has been demonstrated to have statistically confident influence independent from other HLA mismatches ( van’t Hoff, et al, 2021 ).…”

“…Separation of the effects of individual HLA genes on preeclampsia has similarly mixed results, with demonstration of selective influence by either HLA class I ( Lashley, et al, 2015 ; van’t Hoff, et al, 2021 ) or HLA class II ( Triche, et al, 2014 ; van Bentem, et al, 2020 ; van’t Hoff, et al, 2021 ) genes. Of the class I genes, only HLA-C has been demonstrated to have statistically confident influence independent from other HLA mismatches ( van’t Hoff, et al, 2021 ). This likely reflects the fact that fetal trophoblast cells do not express HLA-A or HLA-B , but do express HLA-C , making it the only classical HLA class I molecule available to interact with maternal immune cells.…”

“…This likely reflects the fact that fetal trophoblast cells do not express HLA-A or HLA-B , but do express HLA-C , making it the only classical HLA class I molecule available to interact with maternal immune cells. Dissection of the effect of HLA-C mismatches indicates that fetal expression of paternal alleles in the C2 group are associated with increased risk for preeclampsia and placental immune lesions ( Hiby, et al, 2004 ; Hiby, et al, 2010 ; Schonkeren, et al, 2012 ; Larsen, et al, 2019 ; van’t Hoff, et al, 2021 ). Presumably, this association is driven by differential interaction of C2 group molecules with either activating or inhibitory KIR molecules.…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…KIR expression is crucial in protecting the fetus and may play a pivotal role also with preeclampsia associated with the inflammatory response generated by the pathogen [82][83][84][85][86]. An association between KIR/HLA class I mismatch and preeclampsia suggest that there may be more than one mechanism involved between NK cell activation upon pathogeninduced local inflammatory response and preeclampsia [85,86]. Future analysis should be directed towards understanding the phenomenon, and probably using small HLA inhibitory molecules HLA E/G could decrease the inflammatory burden.…”