KIR- Ligand Interactions in Hypertensive Disorders in Pregnancy

Abstract

HypothesisThe activity of natural killer (NK) cells is considered an important factor for the tolerance of the fetus during pregnancy. The complications of pregnancy, such as hypertensive disorders (HDP), may be therefore associated with this immune compartment.MethodsThe current study included 41 pregnant women diagnosed with HDPs (Gestational Hypertension; GH or Preeclampsia; PE) and 21 healthy women. All the patients were under continuous obstetric care during the pregnancy and labour. The number of mother-child mismatches within killer immunoglobulin-like receptors (KIRs), their ligands [MM], and missing KIR ligands [MSLs] was assessed. KIRs and their ligands were assessed with Next Generation Sequencing (NGS) and Polymerase Chain Reaction Sequence-Specific Oligonucleotide (PCR-SSO) typing. The subsets of NK cells were assessed with multicolor flow cytometry and correlated to the number of MSLs.ResultsThe number of MSLs was significantly higher in HDP patients when compared to healthy non-complicated pregnancy patients. Some MSLs, such as those with 2DS2 activating KIR, were present only in HDP patients. The percentage of CD56+CD16-CD94+ NK cells and CD56+CD16-CD279+ NK cells correlated with the number of MSLs with inhibiting KIRs only in healthy patients. In HDP patients, there was a correlation between the percentage of CD56-CD16+CD69+ NK cells and the number of MSLs with inhibiting and activating KIRs. As compared to the healthy group, the percentage of CD56+CD16-CD279+ NK cells and CD56-CD16+CD279+ NK cells were lower in HDP patients. HDP patients were also characterized by a higher percentage of CD56+CD16+perforin+ NK cells than their healthy counterparts.ConclusionsPatients with HDP were characterized by a higher number of MSLs within the KIRs receptors. It seemed that the number of MSLs in the healthy group was balanced by various receptors, such as CD94 or inhibitory CD279, expressed on NK cells. Conversely, in HDP patients the number of MSLs was associated with the activation detected as the increased level of CD69+ NK cells.

High maternal-fetal HLA eplet compatibility is associated with severe manifestation of preeclampsia

“…It has also been postulated that impaired placentation and PE in general result from insufficient maternal tolerance to fetal alloantigens. This is in accordance with altered proportions and function of NK cell subsets in peripheral blood (3,6,(13)(14)(15) and placentas of women with PE (14,16). Similar changes were observed for decidual macrophages (17), dendritic cells (DC) (18), and T cells including an increased Th17/Treg ratio (19,20).…”

“…In some patients (~25% of GH cases; 3-7% of all pregnancies), GH progresses into PE, which is associated with endothelial dysfunction and changes in the coagulative system that may lead to end-organ injury. The clinical manifestation of PE is usually characterized by proteinuria, elevated levels of liver enzymes, and epigastric pain being the consequence of liver dysfunction, low platelet counts, and/or neurological symptoms (3,5,6). Thus, it may contribute to maternal morbidity including renal failure, liver rupture, stroke, eclampsia, and death.…”

“…Despite PE being annually responsible for more than 70,000 maternal deaths and 500,000 fetal deaths globally 5 , its pathogenesis remains unclear. Among several theories, defective placentation and incomplete remodeling of the spiral arteries in the placenta are the most accepted (6,(8)(9)(10)(11).…”

“…Decidual natural killer cells (dNKs) were shown to secrete cytokines and proangiogenic factors crucial for proper vascular remodeling and placentation (11). In addition, recently we and others showed an association between certain combinations of maternal killer cell immunoglobulin-like receptors (KIRs) and fetal/placental HLA-C antigens in the etiology of PE (6,11).…”

Global trends in research of immune cells associated with hypertensive disorders of pregnancy: A 20-year bibliometric analyses (from 2001 to 2021)

“…It has been proposed that the killer immunoglobulin-like receptor (KIR), expressed on NK cells, is a key regulator of NK cell function and modulates NK cell activity by recognizing with specific human leukocyte antigen (HLA) molecules in the fetus, affecting maternal immune tolerance in the fetus, which influences the development of HDP ( 53 ). It was found that the absolute number of KIR ligand mismatches is significantly elevated in HDP and the homeostatic activation of NK cells affects the invasion of trophoblast cells into the uterine spiral arteries, leading to inadequate placental perfusion, so that KIR receptor-based diagnostics can be detected and used as a predictive HDP risk marker ( 54 ). However, studies on the specific regulation of the number, phenotype and function of dNK cells involved in the development of HDP are still at the stage of inference rather than evidence, further validation studies are still needed.…”