Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage

Hiby, Susan E.; Regan, Lesley; Lo, Winnie; Farrell, Lydia; Carrington, Mary; Moffett, Ashley

doi:10.1093/humrep/den011

Cited by 292 publications

(255 citation statements)

References 34 publications

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“…Our results show that there is a consistent relationship between particular combinations of maternal KIR and fetal HLA-C ligands and birthweight [3,35,37,38]. We compared maternal KIR and fetal HLA-C genotypes from a large number of first pregnancies selected from the Norwegian Mother -Baby cohort (MoBa) with known birthweight corrected for gestational age and fetal sex.…”

Section: Combinations Of Maternal Kir and Paternal Hla-c Genotypes Rementioning

confidence: 94%

“…In common with low birthweight, obstetric syndromes such as pre-eclampsia and recurrent miscarriage are associated with reduced uterine invasion by trophoblast [44]. Mothers at highest risk of these diseases are homozygous for the KIR A haplotype, and carry a fetus that has inherited HLA-C2 from the father [35,37,38]. Women with a HLA-C2 fetus are protected from these disorders by the KIR B haplotype that contributes to protection in two possible ways.…”

Section: Functions Of Uterine Natural Killer Cells During Placentationmentioning

confidence: 99%

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The role of the maternal immune system in the regulation of human birthweight

Moffett

Hiby

Sharkey

2015

Phil. Trans. R. Soc. B

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Human birthweight is subject to stabilizing selection. Large babies are at risk of obstetric complications such as obstructed labour, which endangers both mother and child. Small babies are also at risk with reduced survival. Fetal growth requires remodelling of maternal spiral arteries to provide an adequate maternal blood supply to the placenta. This arterial transformation is achieved by placental trophoblast cells, which invade into the uterine wall. Underinvasion is associated with fetal growth restriction; but if invasion is excessive large babies can result. A growing body of evidence suggests that this process is controlled by interactions between killer-cell immunoglobulin-like receptors (KIRs) expressed on maternal uterine natural killer cells (uNK) and their corresponding human leukocyte antigen-C (HLA-C) ligands on invading trophoblast. Mothers with the KIR AA genotype and a fetus with a paternal HLA-C2 allele tend to have small babies, because this combination inhibits cytokine secretion by uNK. Mothers with the activating KIR2DS1 gene and an HLA-C2 fetus are more likely to have large babies. When KIR2DS1 binds to HLA-C2 this increases secretion of cytokines that enhance trophoblast invasion. We conclude that specific combinations of the highly polymorphic gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birthweight between two extremes.

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Section: Combinations Of Maternal Kir and Paternal Hla-c Genotypes Rementioning

confidence: 94%

Section: Functions Of Uterine Natural Killer Cells During Placentationmentioning

confidence: 99%

The role of the maternal immune system in the regulation of human birthweight

Moffett

Hiby

Sharkey

2015

Phil. Trans. R. Soc. B

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“…Although group A KIR haplotypes protect against HCV infection, they are risk factors for the pregnancy syndromes preeclampsia (43) and recurrent miscarriage (44). Preeclampsia and eclampsia are leading causes of death for women of child-bearing age, especially in undeveloped countries (45).…”

Section: A Model In Which a And B Kir Haplotypes Diversified Under Sementioning

confidence: 99%

“…Preeclampsia and eclampsia are leading causes of death for women of child-bearing age, especially in undeveloped countries (45). At risk are pregnancies in which C2-expressing fetuses are carried by group A KIR homozygous mothers; conversely, maternal group B KIR haplotypes and fetal C1 homozygosity are protective (43,44). The inverse correlation between C2 and group A KIR haplotype frequencies in human populations worldwide, argues for the importance of selection by diseases of pregnancy (43).…”

Section: A Model In Which a And B Kir Haplotypes Diversified Under Sementioning

confidence: 99%

Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands

Gendzekhadze

Norman

Abi-Rached

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

109

178

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Natural killer (NK) cells contribute to immunity and reproduction.Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.Amerindian ͉ immune diversity ͉ natural selection ͉ NK cells ͉ reproduction

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“…This would result in trophoblast that expressed more HLA-C2 than did the maternal tissues. Later this hypothesis was extended to explain a paternal contribution to recurrent miscarriage (Hiby et al 2008). A new study (Hiby et al 2010) has elaborated on previous work concerning interactions between HLA-C epitopes and their receptors.…”

Section: Implication Of Hla-c Ligands In Pregnancy Diseasementioning

confidence: 99%

Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep trophoblast invasion and an explanation for human pregnancy disorders

Carter

2011

Reproduction

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Deep trophoblast invasion in the placental bed has been considered the hallmark of human pregnancy. It occurs by two routes, interstitial and endovascular, and results in transformation of the walls of the spiral arteries as they traverse the decidua and the inner third of the myometrium. Disturbances in this process are associated with reproductive disorders such preeclampsia. In contrast, trophoblast invasion in Old World monkeys occurs only by the endovascular route and seldom reaches the myometrium. Recently, it was shown that this pattern is maintained in gibbons, but that the human arrangement also occurs in chimpanzee and gorilla. There is an interesting parallel with results from placental immunology regarding the evolution of the major histocompatability complex class I antigen HLA-C and its cognate receptors. HLA-C is not present in Old World monkeys or gibbons. It emerged in the orangutan and became polymorphic in the lineage leading to gorilla, bonobo, chimpanzee, and human. Interaction between HLA-C1 and HLA-C2 on the surface of trophoblast and killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer cells are important regulators of trophoblast invasion. Evolution of this system in great apes may have been one prerequisite for deep trophoblast invasion but seems to have come at a price. The evidence now suggests that certain combinations of maternal genotype for KIRs and fetal genotype for HLA-C imply an increased risk of preeclampsia, fetal growth restriction, and recurrent abortion. The fetal genotype is in part derived from the father providing an explanation for the paternal contribution to reproductive disorders.

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Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage

Abstract: This is the first report to identify a genetic male factor that confers risk in RM. These findings support the idea that successful placentation depends on the correct balance of NK cell inhibition and activation in response to trophoblast.

Cited by 292 publications

References 34 publications

The role of the maternal immune system in the regulation of human birthweight

The role of the maternal immune system in the regulation of human birthweight

Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands

Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep trophoblast invasion and an explanation for human pregnancy disorders

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