Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2
Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2
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DOI：
10.1172/jci43998
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Moffett, Ashley
中科院分区：
文献类型：
--
作者：
Hiby, Susan E.;Apps, Richard;Moffett, Ashley
许多常见的妊娠疾病归因于滋养细胞对子宫内层的侵袭不足，滋养细胞是胎盘的主要细胞类型。胎儿滋养层细胞和母体子宫NK(Unk)细胞之间的相互作用--特别是胎儿滋养层细胞表达的人类白细胞抗原-C分子与母体Unk细胞上的杀伤Ig样受体(KIRS)之间的相互作用--影响着人类妊娠期间的胎盘形成。与此一致的是，KIR单倍型A(KIR AA)纯合子母亲的妊娠先兆子痫风险增加。在这项研究中，我们证明了滋养层细胞表达父系和母系遗传的人类白细胞抗原-C表面蛋白，并且只有当胎儿比母亲具有更多的第二组人类白细胞抗原-C基因(C2)时，母体KIR AA频率才会在受影响的妊娠中增加。这些数据增加了父亲C2产生有害的同种异体效应的可能性。我们发现，这种效应也发生在其他妊娠障碍(胎儿生长受限和反复流产)中，表明这些受体/配体对在妊娠早期在生殖失败的发病机制中发挥了作用。值得注意的是，在拥有KIR B单倍型端粒末端的母亲中，妊娠障碍较少发生，KIR B单倍型含有激活的KIR2DS1。此外，Unk细胞表达KIR2DS1，与C2(+)滋养层细胞特异性结合。这些发现突出了在母胎免疫相互作用中激活KIR和HLA-C的特定组合的复杂性和核心重要性，这些相互作用决定了生殖成功。
Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells - specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells - influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2(+) trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success.