Lombardi Amber E M, Habets Denise H J, Al-Nasiry Salwan, Spaanderman Marc E A, Wieten Lotte
GROW Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands.
Department of Transplantation Immunology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
Am J Reprod Immunol. 2025 Feb;93(2):e70045. doi: 10.1111/aji.70045.
Natural killer (NK) cells undergo education for full functionality via interactions between killer immunoglobulin-like receptors (KIRs) or NKG2A and human leukocyte antigen (HLA) ligands. Presumably, education is important during early pregnancy as insufficient education has been associated with impaired vascular remodeling and restricted fetal growth in mice. NK cell education is influenced by receptor co-expression patterns, human cytomegalovirus (CMV), the HLA-E107 dimorphism, and HLA-B leader peptide variants. We hypothesized altered NK cell education status and differences in frequencies of HLA-E genotypes and HLA-B leader peptide variants in women with recurrent pregnancy loss (RPL) compared to women with previously uncomplicated pregnancies, and between CMV seropositive and seronegative RPL women.
Peripheral blood mononuclear cells were analyzed by flow cytometry. HLA-ABC was typed by sequence-specific oligonucleotide PCR, and HLA-E by Sanger sequencing. CMV status was determined by anti-CMV IgG immunoassay. NK cells were considered "educated" if the HLA ligand to a KIR or NKG2A was present.
KIR/NKG2A co-expression patterns and percentages of educated NK cells were similar between RPL and controls, and between seropositive and seronegative RPL women. Frequencies of HLA-E genotypes and HLA-B leader peptide variants were comparable. RPL women with the HLA-B T/T variant had a lower percentage of NKG2A-educated NK cells (47.8%) compared to controls (66.4%) (p = 0.025).
HLA-B leader peptide variants might impact NKG2A-specific NK cell education in RPL, warranting validation in larger studies. Follow-up studies are needed to investigate the education status of uterine NK cells and their role in pregnancy.
自然杀伤（NK）细胞通过杀伤免疫球蛋白样受体（KIR）或NKG2A与人类白细胞抗原（HLA）配体之间的相互作用接受完全功能的教育。据推测，在妊娠早期，这种教育很重要，因为在小鼠中，教育不足与血管重塑受损和胎儿生长受限有关。NK细胞教育受受体共表达模式、人巨细胞病毒（CMV）、HLA-E107二态性和HLA-B前导肽变体的影响。我们假设，与既往妊娠无并发症的女性相比，复发性流产（RPL）女性以及CMV血清阳性和血清阴性的RPL女性中，NK细胞教育状态改变，且HLA-E基因型和HLA-B前导肽变体的频率存在差异。
采用流式细胞术分析外周血单个核细胞。通过序列特异性寡核苷酸PCR对HLA-ABC进行分型，通过桑格测序对HLA-E进行分型。通过抗CMV IgG免疫测定确定CMV状态。如果存在与KIR或NKG2A结合的HLA配体，则NK细胞被认为“受过教育”。
RPL女性与对照组之间以及血清阳性和血清阴性的RPL女性之间，KIR/NKG2A共表达模式和受过教育的NK细胞百分比相似。HLA-E基因型和HLA-B前导肽变体的频率相当。与对照组（66.4%）相比，携带HLA-B T/T变体的RPL女性中，接受NKG2A教育的NK细胞百分比更低（47.8%）（p = 0.025）。
HLA-B前导肽变体可能影响RPL中NKG2A特异性NK细胞教育，需要在更大规模研究中进行验证。需要进行后续研究以调查子宫NK细胞的教育状态及其在妊娠中的作用。
