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The aim of the study was to investigate whether human leukocyte antigen (HLA) allele sharing between partners or the maternal killer immunoglobulin-like receptor (KIR) repertoire is associated with recurrent spontaneous abortion (RSA) and repeated implantation failure after in vitro fertilization (IVF)/embryo transfer. From a total population of 158 RSA couples, 40 couples with repeated implantation failures (IVF) and 81 control couples, reported by five different laboratories, analysis was performed for (a) HLA sharing in 50 RSA, 31 IVF and 31 control couples, (b) DQA1*0505 sharing/homozygosity among partners in 108 RSA, 40 IVF and 36 control couples, and (c) the women's KIR repertoire in 46 RSA, 26 IVF and 36 control wives. RSA couples were divided into alloimmune aborter (RSAallo) and autoimmune aborter (RSAauto). The results oppose to the suggestion that increased HLA sharing per se or a limited maternal KIR repertoire predisposes to RSA or IVF failure. However, the observation of a slightly higher percentage of DQA1*0505 sharing in the RSAauto and the IVF group needs further investigation. The ratio of inhibitory to activating KIR (actKIR) was slightly lower in RSAallo and IVF women (1.9 vs 2.6 in controls), while in a high percentage of these women, the standard receptors of the KIR A haplotype were combined with actKIR/s of the haplotype B (66.6% and 45.4% vs 20% and 15.3% in RSAauto and control groups). This may suggest a possible involvement of actKIRs in embryo implantation and the maintenance of pregnancy and also requires further investigation.

Previous studies have revealed that women with unexplained recurrent spontaneous abortions have a limited repertoire of inhibitory KI receptors (inhKIRs) and that the inhKIRs they possess do not have specificity for the human leukocyte antigen (HLA)-Cw molecules that would be expressed on trophoblast. We sought to confirm these findings by direct definition of maternal inhKIR and trophoblastic HLA-Cw allotypes on the placental material of spontaneously missed pregnancies. The study included 30 women undergoing vacuum uterine curettage for first-trimester missed pregnancy (group A; n = 15) or for elective termination of normal pregnancy (group C, n = 15). DNA extracted from isolated decidual and trophoblastic cells was used for molecular detection of maternal inhKIRs (2DL1, 2DL2, 2DL3) and fetal HLA-Cw alleles, respectively. The results revealed that in the group of women who experienced abortion, 60% did not have the full repertoire of three inhKIRs (group A vs group C; p = 0.006); that in five of 15 patients (none in the controls), no epitope matching existed between maternal inhKIRs and trophoblastic HLA-Cw alleles (group A vs group C; p = 0.01); and that more cases were found with limited epitope matching (less than three inhKIRs with specificity for fetal HLA-Cw alleles). The results provide additional evidence that in some cases of spontaneous abortions, the women lack the appropriate inhKIRs to interact with the HLA-Cw molecules on trophoblasts and to deliver signals to inhibit natural killer cell activation and protect the embryo.

The interaction between killer cell immunoglobulin-like receptors (KIR) expressed on natural killer (NK) cells, and human leukocyt antigen (HLA) molecules expressed on target cells is known to regulate the cytolytic activity. A wide range of KIR genotypes is observed in the population, as the number of KIR loci can vary. In the present study we have determined the frequencies and combinations of 13 KIR genes and two CD94:NKG2 receptor genes and their distribution in the two haplotype groups in a panel of 233 unrelated healthy Greek Caucasians. We have typed genomic DNA for the presence of the putative KIR loci KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1 using modified polymerase chain reaction sequence-specific primers. The frequency of KIR loci combined with the linkage disequilibrium values suggest that the Greek population shares several general features with other Caucasoid populations studied before, but still distinguishes itself by the increased or decreased frequency of several alleles. The majority of the 45 different KIR genotypes seen in Greeks have been observed in Caucasoid populations studied before. Nevertheless, two of these genotypes, although met in other populations, have not been found in Caucasians before. One individual possesses a novel profile with no KIR inhibitory gene. The A haplotypes remain the most prevalent, with AA1 being the most common genotype, and the number of inhibitory KIRs being more variable than the number of noninhibitory KIRs in most haplotypes.

Problem: Natural killer (NK) cell receptors (NKRs) have been suggested to protect trophoblast, but their function at the fetomaternal interface remains unknown. To investigate if the outcome of pregnancy depends on women's NKRs, we studied the NKR repertoire in couples with recurrent spontaneous abortions (RSA)., Methods: Twenty-six childless couples with > or = 2 abortions, characterized by alloimmune abnormalities, and 26 control couples were genotyped for five killer immunoglobulin-like receptors (KIR) and two CD94/NKG receptors, known to have as ligands human leukocyte antigen (HLA) class I molecules with trophoblastic expression: inhibitory 2DL1,2,3 and activating 2DS1,4 KIRs, inhibitory NKG2A and activating NKG2C. Detected repertoires of women and partners were compared between the two groups., Results: Less aborters than controls were found to have all three inhibitory KIRs (30.77% versus 69.23%, P = 0.01), some of them had only one inhibitory KIR (19.23% versus 3.85%, P = 0.08) and most of them were lacking inhibitory KIRs possessed by their husbands (57.69% versus 15.38%, P = 0.001)., Conclusions: Women with alloimmune abortions have a limited inhibiting KIR repertoire and such miscarriages may occur because trophoblastic HLA class I molecules are recognized by decidual NK cells lacking the appropriate inhibitory KIRs.