Maternal Killer-cell Immunoglobulin-like Receptors Research Articles

Uterine natural killer cells: from foe to friend in reproduction.

Recurrent miscarriage and pre-eclampsia are common reproductive disorders, but their causes are often unknown. Recent evidence has provided new insight into immune system influences in reproductive disorders. A subset of lymphocytes of the innate immune system known as uterine natural killer (uNK) cells are now recognized as fundamental to achieving embryo implantation and successful pregnancy, but were initially attributed a bad reputation. Indeed, immune therapies have been developed to treat the 'exaggerated' immune response from uNK cells. These treatments have been based on studies of peripheral blood natural killer (pbNK) cells. However, uNK cells and pbNK cells have different phenotypic and functional characteristics. The functions of uNK cells are closely related to their interactions with the extravillous trophoblast cells (EVTs) and spiral arteries, which underlie an essential role in regulating vascular function, controlling trophoblast invasion and promoting placental development. EVTs express MHC molecules of class I HLA-C/E/G/F, while uNK cells express, among other receptors, killer cell immunoglobulin-like receptors (KIRs) that bind to HLA-C or CD94/NKG2A inhibitory receptors, and then bind HLA-E. Associations of certain KIR/HLA-C combinations with recurrent miscarriage, pre-eclampsia, and foetal growth restriction and the interactions between uNK cells, trophoblasts and vascular cells have led to the hypothesis that uNK cells may play a role in embryo implantation. Our objective was to review the evolution of our understanding of uNK cells, their functions, and their increasingly relevant role in reproduction. Relevant literature through June 2020 was retrieved using Google Scholar and PubMed. Search terms comprised uNK cells, human pregnancy, reproductive failure, maternal KIR and HLA-C, HLA-E/G/F in EVT cells, angiogenic cytokines, CD56+ NK cells, spiral artery, oestrogen and progesterone receptors, KIR haplotype and paternal HLA-C2. This review provides key insights into the evolving conceptualization of uNK cells, from their not-so-promising beginnings to now, when they are considered allies in reproduction. We synthesized current knowledge about uNK cells, their involvement in reproduction and their main functions in placental vascular remodeling and trophoblast invasion. One of the issues that this review presents is the enormous complexity involved in studying the immune system in reproduction. The complexity in the immunology of the maternal-foetal interface lies in the great variety of participating molecules, the processes and interactions that occur at different levels (molecular, cellular, tissue, etc.) and the great diversity of genetic combinations that are translated into different types of responses. Insights into uNK cells could offer an important breakthrough for ART outcomes, since each patient could be assessed based on the combination of HLA and its receptors in their uNK cells, evaluating the critical interactions at the materno-foetal interface. However, owing to the technical challenges in studying uNK cells in vivo, there is still much knowledge to gain, particularly regarding their exact origin and functions. New studies using novel molecular and genetic approaches can facilitate the identification of mechanisms by which uNK cells interact with other cells at the materno-foetal interface, perhaps translating this knowledge into clinical applicability.

Polymorphism in killer cell immunoglobulin-like receptors and human leukocyte antigen-c and predisposition to preeclampsia in Ethiopian pregnant women population

IntroductionPreeclampsia (PE) is a human specific pregnancy-related syndrome of unknown etiology that affects 2–8 % of pregnancies. Polymorphism in maternal Killer Cell Immunoglobulin-like Receptors (KIRs) and the ligand fetal Human Leukocyte Antigen-C (HLA-C) may predispose pregnant mothers for PE due to defective trophoblast invasion into the maternal decidua. Our study aimed to investigate the association between maternal KIR and fetal HLA-C polymorphism and PE in Ethiopian pregnant women. MethodsWe included a total of 288 (157 controls and 131 PE cases) in a case-controls study at Adama Regional Referral Hospital, Ethiopia. The KIR and HLA-C genotyping was done using traditional polymerase chain reaction on genomic DNA extracted form maternal venous and cord blood followed by 2% agarose gel electrophoresis. ResultsThe statistical associations between variables were evaluated using Pearson’s Chi-square test. P < 0.05, with 95 % confidence interval was considered statistically significant. A significant association was observed between the KIR2DS1 and PE, with a higher frequency (60.5 %) of the gene in the control group. Similarly, a significant association was observed between KIR AA genotype and PE, with a higher frequency (38.2 %) of this genotype in the PE group. Ethiopians share the same risk genotype for PE as seen in previous African and European studies, namely homozygosity of a maternal KIR AA genotype. However, Ethiopians differ from other East African populations by sharing the same protective KIR2DS1 gene as Europeans.

Maternal killer-cell immunoglobulin-like receptors and paternal human leukocyte antigen ligands in recurrent pregnancy loss cases in Turkey.

Objective The survival of a semi-allogeneic fetus depends on several immunological mechanisms, and it has been suggested that recurrent pregnancy loss (RPL) could develop as a result of one or more immunological abnormalities.Methods Compatibility between partners for human leukocyte antigen (HLA) genotypes and the relationships between maternal killer-cell immunoglobulin-like receptor (KIR) and paternal HLA-Bw4/Bw6 and HLA-C1/C2 supra-groups were investigated in 25 couples with RPL in comparison to healthy couples with children. HLA and KIR genotyping was performed using polymerase chain reaction with sequence-specific primers and/or sequence-specific oligonucleotides.Results HLA class I incompatibility between partners, especially in HLA-B alleles, was more common in the RPL group (p= 0.01). HLA-C2 homozygosity was more frequent in the male partners of RPL couples than in other groups (p= 0.03). The KIR2DL5 gene frequency was significantly higher in both the female and male partners of RPL couples, whereas the KIR2DS3 gene frequency in male partners of RPL couples was significantly reduced (p= 0.03). The presence of KIR2DL3 in women with RPL was correlated with the presence of HLA-C2 alleles in their spouses (p= 0.03).Conclusion Our data from a Turkish population suggest that male HLA-C2 homozygosity may play an important role in RPL. Additionally, an incidental match between male HLA-C2 and female HLA-C1 ligand KIR receptors might perturb the balance between activatory and inhibitory KIR-ligand interactions during pregnancy in couples affected by RPL. The roles of orphan KIR2DL5 and orphan KIR2DS3 in RPL remain obscure.

Recurrent Spontaneous Abortion (RSA) and Maternal KIR Genes: A Comprehensive Meta-Analysis.

Natural killer cells (NKs) are the most important cells in the fetomaternal immune tolerance induced through interaction of maternal killer-cell immunoglobulin-like receptors (KIR) and fetal human leucocyte antigens (HLA). Hence, we intend to perform a meta-analysis on the role of maternal KIR genes diversity in recurrent spontaneous abortion (RSA). The present paper is a meta-analysis of previous genetic association studies and our previous original study. The results showed that KIR3DL1 was a significantly protecting factor for RSA (p=0.044; OR=0.833 [0.698-0.995]; fixed effect model). KIR2DS2 (p=0.034; OR=1.195 [1.013-1.408]; fixed effect model) and KIR2DS3 (p=0.013; OR=1.246 [1.047-1.483]; fixed effect model) were significantly risk factors for RSA. For KIR2DS1 there was a high heterogeneity and publication bias. Briefly, the inhibitory gene KIR3DL1 was a protecting factor, and the activating genes KIR2DS2 and KIR2DS3 were risk factors for RSA. However, the effect sizes were not suitable. We suggest further studies on different causes of pregnancy loss, to find the role of KIR2DS1.

Fetal human leukocyte antigen-C and maternal killer-cell immunoglobulin-like receptors in cases of severe preeclampsia

IntroductionThe pathogenesis of preeclampsia may involve inadequate trophoblast invasion caused by excessive inhibition of uterine natural killer cells (uNK) by extravillous trophoblast cells (EVT). This may be the result of a combination of maternal killer-cell immunoglobin-like receptor (KIR) AA genotype and fetal human leukocyte antigen-C2 (HLA-C2) genotype. A few studies have reported a significantly increased frequency of the maternal KIR AA/fetal HLA-C2 combination in cases of preeclampsia compared to controls. MethodsStudy subjects were 259 cases of severe preeclampsia/eclampsia and 259 matched pregnant women without preeclampsia or eclampsia. All pregnancies were singleton pregnancies, and mothers were preferentially primigravidae. Blood samples from women and their newborns were obtained from the Danish National Birth Cohort (DNBC) and the Danish Neonatal Screening Biobank. Significant differences in the frequencies of KIR AA and HLA-C2 between cases and controls were investigated. ResultsNo significant difference was observed between cases and controls in the frequency of maternal KIR AA (OR = 0.86, 95%CI = 0.60–1.23, P = 0.41), neither when the fetus carried an HLA-C2 allele (OR = 0.85, 95%CI = 0.52–1.38, P = 0.51), nor when the fetus carried an HLA-C2 allele more than its mother (OR = 0.75, 95%CI = 0.34–1.64, P = 0.47). ConclusionThe Results show no influence of HLA-C/KIR genetic variation on the risk of severe preeclampsia, contrary to what some previous studies have observed. An explanation could be that severe preeclampsia represents a separate pathological entity compared to mild preeclampsia.

Association of maternal KIR gene content polymorphisms with reduction in perinatal transmission of HIV-1.

The role of killer cell immunoglobulin-like receptors (KIRs) in the transmission of HIV-1 has not been extensively studied. Here, we investigated the association of KIR gene content polymorphisms with perinatal HIV-1 transmission. The KIR gene family comprising 16 genes was genotyped in 313 HIV-1 positive Kenyan mothers paired with their infants. Gene content polymorphisms were presented as presence of individual KIR genes, haplotypes, genotypes and KIR gene concordance. The genetic data were analyzed for associations with perinatal transmission of HIV. There was no association of infant KIR genes with perinatal HIV-1 transmission. After adjustment for gravidity, viral load, and CD4 cell count, there was evidence of an association between reduction in perinatal HIV-1 transmission and the maternal individual KIR genes KIR2DL2 (adjusted OR = 0.50; 95% CI: 0.24–1.02, P = 0.06), KIR2DL5 (adjusted OR = 0.47; 95% CI: 0.23–0.95, P = 0.04) and KIR2DS5 (adjusted OR = 0.39; 95% CI: 0.18–0.80, P = 0.01). Furthermore, these maternal KIR genes were only significantly associated with reduction in perinatal HIV transmission in women with CD4 cell count ≥ 350 cells/ μl and viral load <10000 copies/ml. Concordance analysis showed that when both mother and child had KIR2DS2, there was less likelihood of perinatal HIV-1 transmission (adjusted OR = 0.44; 95% CI: 0.20–0.96, P = 0.039). In conclusion, the maternal KIR genes KIR2DL2, KIR2DL5, KIR2DS5, and KIR2DS2 were associated with reduction of HIV-1 transmission from mother to child. Furthermore, maternal immune status is an important factor in the association of KIR with perinatal HIV transmission.

Interaction of parental KIR and fetal HLA-C genotypes with the risk of preeclampsia

Objective: The aim of this study is to investigate whether certain combination of maternal killer cell immunoglobulin-like receptors (KIR) and fetal human leukocyte antigen-C (HLA-C) is risk for preeclampsia in the Chinese Han population. Methods: A case–control study was conducted in 47 pregnant women with preeclampsia and 54 normal pregnant women. Twelve KIR genes were genotyped by PCR-sequence-specific primer in mothers. High-resolution HLA-C genotyping was performed in couples and fetuses by a routine sequencing-based typing method. Results: The frequency of KIR2DS1 was decreased (p = 0.028) and AA genotype was increased (p = 0.017) in preeclampsia compared with controls. More women with KIR AA genotype have fewer C2 genes than their fetuses in preeclampsia than controls. Conclusion: Women with KIR AA genotype and fewer C2 genes than their fetuses were at risk for preeclampsia in the Chinese Han population, supporting that maternal–fetal KIR-HLA-C interaction plays an important role in preeclampsia development.

Association of maternal KIR and fetal HLA-C genes with the risk of preeclampsia in the Chinese Han population

IntroductionThis study is to investigate the distribution of inhibitory and activating killer-cell immunoglobulin-like receptors (KIRs) and the combination of KIR/human leukocyte antigen (HLA)-C in women with preeclampsia in the Chinese Han population. MethodsA total of 271 patients and 295 controls were enrolled in our study. The inhibitory/activating KIR and HLA-C genes were detected using the PCR-SSP (polymerase chain reaction with sequence-specific primers) method. ResultsOur result showed that decreased numbers of individual activating KIR genes (2DS2, 2DS3, and 2DS5) were observed in women with preeclampsia. Furthermore, the gene frequency of total activating KIRs was significantly lower in patients compared with that of the controls (P = 0.03). The frequency of the KIR2DL1 gene was increased in women with preeclampsia when a homozygous HLA-C2 allele appeared in the fetus. ConclusionThe results suggest that a KIR genetic variation might influence the risk of preeclampsia. The lack of activating KIRs could possibly lower uterine natural killer (uNK) cell activation, thereby contributing to the pathogenesis of preeclampsia. Moreover, the imbalance of the inhibitory or activating signals at the maternal–fetal interface seems to play a regulatory role in the occurrence of preeclampsia.

Ligand specificity of Killer cell Immunoglobulin-like Receptors: a brief history of KIR

Ligand specificity of Killer cell Immunoglobulin-like Receptors: a brief history of KIR

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

The natural killer (NK) cells at the site of placentation express killer-cell immunoglobulin-like receptors (KIR) that can bind to human leukocyte antigen (HLA)-C molecules on trophoblast cells. Both these gene systems are polymorphic and an association of particular maternal KIR/fetal HLA-C genotypes has been shown in pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM) share the pathogenesis of defective placentation and therefore we have now genotyped couples with RM. DNA was obtained from the male (n = 67) and female (n = 95) partners of couples with three or more spontaneous miscarriages and genotyped for HLA-C groups and 11 KIR genes using the PCR-sequence-specific primer method (SSP). The frequency of the HLA-C2 group was increased in both parents (reaching significance only in the male partners, P = 0.018) compared with a parous control population. The KIR gene frequencies of the male partners were similar to controls, but the women had a high frequency of KIR AA haplotypes that lack activating KIR. In particular, the activating KIR for HLA-C2 groups (KIR2DS1) was significantly lower in these women (P = 0.00035, odds ratio 2.63, confidence interval 1.54-4.49). 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.

Maternal KIR repertoire is not associated with recurrent spontaneous abortion.

In view of evidence suggesting an immunological cause of recurrent spontaneous abortions (RSA) and the large number of maternal natural killer (NK) cells present in the pregnant uterus, we investigated the genetic polymorphism of the killer cell immunoglobulin-like receptors (KIR) in women with RSA. KIR gene repertoire and KIR2DL4 (a receptor for HLA-G) genotyping were determined by SSP and SSCP respectively, in women experiencing RSA and controls. The KIR repertoire did not differ between RSA patients and controls in terms of: (i) the number of inhibitory receptors; (ii) the number of activating receptors; (iii) the ratio of inhibitory to activating receptors. KIR2DL4, a receptor for HLA-G, has different transmembrane alleles, which produce functionally different phenotypes. The frequency of KIR2DL4 transmembrane genotypes differed significantly between RSA patients and controls (P=0.03). However, although homozygosity for a membrane-bound receptor was more frequent in patients (25%) than controls (10%), other genotypes that would produce the same phenotype were not more frequent in patients than controls. The data provide little evidence that KIR polymorphism plays a role in predisposition to RSA.