KIR receptors and HLA‐C in the maintenance of pregnancy

BackgroundNatural Killer (NK) cells are the most abundant lymphocytes in the decidua during early gestation. The interactions of NK cells with the extravillous cytotrophoblast have been associated with a normal spiral artery remodeling process, an essential event for a successful pregnancy. Recent data indicate that alterations in the amount of decidual NK (dNK) cells contribute to the development of preeclampsia (PE). Moreover, genetic studies suggest that Killer Immunoglobulin-like Receptors (KIR) expressed in dNK cells influence the susceptibility to PE. Although dNK cells have been well characterized during early pregnancy, they have been scarcely studied in the third trimester of gestation. The aim of this work was to characterize dNK cells at the last trimester of gestation and to analyze the KIR genotype of healthy and PE women.MethodsDecidual samples were obtained during Caesarean section from control (n = 10) and PE (n = 9) women. Flow cytometric analysis of CD3, CD56, CD16 and CD9 was used to characterize and quantify dNK cells in both groups. Cell surface markers from decidual leukocytes were compared with PBMC from healthy donors.KIR genotyping was performed in genomic DNA (control, n = 86; PE, n = 90) using PCR-SSP.ResultsThe results indicate that dNK cells persist throughout pregnancy. They represented 20% of total leukocytes in control and PE groups, and they expressed the same cell surface markers (CD3-, CD56+, CD16- and CD9+) as dNK in the first trimester of gestation. There were no significant differences in the percentage of dNK cells between control and PE groups. The analysis of KIR gene frequencies and genotypes was not statistically different between control and PE groups. The ratio of activating to inhibitory genes indicated that the overall inhibitory balance (0.2-0.5) was more frequent in the PE group (control, 31.3% vs PE, 45.5%), and the activating balance (0.6-1.1) was more frequent in the control group (control, 68.6% vs PE, 54.4%). However this difference was not significant.ConclusionWe demonstrated the persistence of dNK cells in PE and control women at the third trimester of pregnancy; these dNK cells had a similar phenotype to those found during early pregnancy. The predominance of a KIR inhibitory balance in the PE group could be associated to the physiopathology of PE.

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“…However, this difference was not statistically significant. Interestingly, similar results have been reported in recurrent miscarriage [42]. …”

Section: Discussionsupporting

confidence: 88%

Persistence of decidual NK cells and KIR genotypes in healthy pregnant and preeclamptic women: a case-control study in the third trimester of gestation

Sánchez-Rodríguez

Nava-Salazar

Mendoza-Rodríguez

et al. 2011

Reprod Biol Endocrinol

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“…Concerning KIR receptors, the study went further than the previous one, as the analysis was not limited to women's KIR repertoire but included maternal KIR2DL—fetal HLA‐C combinations. For the KIR repertoire, the results did not show statistically significant differences between groups in the percentage of women with a limited inhKIR repertoire (lack of one or two inhKIRs), thus confirming the results of the previous Workshop's study and are in accordance with the study by Witt et al (11), but not to the initial study by Varla‐Leftherioti et al (12) or the more r%, 14 ecent study by Flores et al (13).…”

Section: Discussionsupporting

confidence: 87%

HLA-DQA1*0505 sharing and Killer Immunoglobulin-like Receptors in sub fertile couples: report from the 15th International Histocompatibility Workshop

et al. 2010

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This aim of the study was to investigate whether human leukocyte antigen (HLA)-DQA1*0505 sharing or the maternal killer immunoglobulin-like receptor (KIR) repertoire is associated with recurrent spontaneous abortion (RSA) or repeated implantation failure (RIF). The study included 224 couples with RSA, 61 couples with RIF, 182 fertile couples, and 10 couples with successful in vitro fertilization and embryo transfer (IVF)/ET at first cycle. HLA-DQA1*0505 typing using polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) was performed in 185 RSA (117 with alloimmune abnormalities and 68 of autoimmune etiology), 61 RIF and 182 control couples, and KIR genotyping using polymerase chain reaction-sequence-specific primer (PCR-SSP) in 167 RSA and 55 RIF cases as well as 46 RSA and 10 IVF controls. No differences in DQA1*0505 sharing were found between patients and controls. In RSA and RIF women, the ratio of inhibitory to activating KIRs was slightly lower (1.53 and 1.85 vs 2.03 in controls). The analysis of maternal inhKIR and fetal HLA-C molecule pairs showed that the 'less inhibiting' combination KIR2DL3-C1 was found in higher percentage in subfertile (mainly RIF) than in fertile couples. In contrast, the percentage of cases possessing the 'strong inhibiting' combination KIR2DL1-C2 was lower in the RSA and RIF groups in comparison with that in the control groups (17.36% vs 23.91 and 16.36% vs 40%, respectively). In women with >or= 6 implantation failures, the KIR2DL1-C2 combination was not found in any of them (P = 0.0014), and the KIR2DL3-C1 combination was not found in the control IVF group. The results oppose the suggestion that increased HLA-DQA1*0505 sharing predispose to RSA or RIF. The KIR2DL3-C1 combination (or lack of the KIR2DL1-C2 one) is associated with implantation failure.

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“…This is in-line with earlier studies on KIR frequencies in RIF patients (13,18). Moreover, in literature conflicting results on frequencies of both the KIR A- (15,38,39) and KIR B-haplotype (40) exists in patients with RSA. Hiby et al also reported increased C2 carrier frequencies in women with complicated pregnancies and showed an increased risk when women were confronted with an additional, paternal C2 (15)(16)(17).…”

Section: Discussionsupporting

confidence: 90%

Maternal HLA‐C2 and 14 bp insertion in HLA‐G is associated with recurrent implantation failure after in vitro fertilization treatment

et al. 2014

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The major rate-limiting step in in vitro fertilization (IVF) success appears to be the implantation of the semi-allogeneic embryo into the maternal endometrium. To determine possible risk factors of recurrent failure of embryos to implant, we investigated immunogenetic determinants as level of human leukocyte antigen (HLA) histocompatibility, frequency of killer-cell immunoglobulin-like receptors (KIR) and HLA-C alleles and HLA-G polymorphism. We DNA typed women with recurrent implantation failure (RIF) and their partners for classical HLA Class I, HLA Class II, HLA-G and KIR alleles and compared these results with couples with successful embryo implantation after their first IVF and normal fertile couples. No association was found between RIF and the degree of histocompatibility between partners or sharing of a specific antigen. Also, no significant difference in KIR haplotype or combination of HLA-C group and KIR was observed. We did find a higher frequency of HLA-C2 and a higher frequency of 14 base pair (bp) insertion in HLA-G in women with RIF. Therefore we conclude that the degree of histocompatibility between partners is not a determining factor for the occurrence of RIF. However, presence of the HLA-C2 allotype and the HLA-G allele with a 14 bp insertion is a significant risk factor.

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KIR receptors and HLA‐C in the maintenance of pregnancy

Cited by 40 publications

References 4 publications

Persistence of decidual NK cells and KIR genotypes in healthy pregnant and preeclamptic women: a case-control study in the third trimester of gestation

Persistence of decidual NK cells and KIR genotypes in healthy pregnant and preeclamptic women: a case-control study in the third trimester of gestation

HLA-DQA1*0505 sharing and Killer Immunoglobulin-like Receptors in sub fertile couples: report from the 15th International Histocompatibility Workshop

Maternal HLA‐C2 and 14 bp insertion in HLA‐G is associated with recurrent implantation failure after in vitro fertilization treatment

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