Killer Immunoglobulin-like Receptor Repertoire Research Articles

Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency.

During human pregnancy, the uterine lining is highly populated with killer-immunoglobulin-like receptor (KIR)-expressing NK cells that recognize HLA-C molecules on trophoblast cells. The goal of this study was to analyze the KIR gene contents and frequencies in a N. American cohort of women with RPL of unknown etiology to evaluate whether there is a genetic susceptibility to RPL based on a woman's KIR repertoire and her HLA-C group, as well as the HLA-C group of the partner. The frequencies of KIR and HLA-C1 and HLA-C2 genes were evaluated in 139 Caucasian women with RPL; HLA-C1, and HLA-C2 group genes were analyzed in their partners (n=42). The gene frequencies were compared with data reported from corresponding populations. Overall, the frequencies of HLA-C groups and KIR genes and genotypes in RPL cohort resembled the frequencies for US Caucasians. The HLA-C1 and HLA-C2 group distribution was significantly different between women with or without KIR2DS1. Women positive for KIR2DS1 (45.3% of the study cohort) had an increased frequency of its ligand, HLA-C2 (0.5159 versus 0.3684 in KIR2DS1 negative women, P=0.014). Our results indicate that among KIR2DS1 pos women, the co-expression of HLA-C2 is associated with RPL.

The effect of pregnancy on the uterine NK cell KIR repertoire

The major leukocyte population in the decidua during the first trimester of pregnancy consists of NK cells that express receptors capable of recognizing MHC class I molecules expressed by placental trophoblast. These include members of the killer immunoglobulin-like receptor (KIR) family, the two-domain KIR (KIR2D), which recognize HLA-C. Interactions between decidual NK (dNK) cell KIR2D and placental HLA-C contribute to the success of pregnancy and dNK cells express KIR2D at higher frequency than peripheral NK (pNK) cells. Thus, they are biased toward recognizing HLA-C. In order to investigate when this unusual KIR repertoire appears, we compared the phenotype of NK cells isolated from non-pregnant (endometrium) and pregnant (decidua) human uterine mucosa. Endometrial NK (eNK) cells did not express KIR2D at a higher level than matched pNK cells, so the bias toward HLA-C recognition occurs as a response to pregnancy. Furthermore, HLA-C expression was upregulated on uterine stromal cells as the mucosa transformed from endometrium to decidua at the onset of pregnancy. As uterine NK (uNK) cells can mature from NK precursors and acquire KIR expression in utero, the pregnancy-specific bias of uNK cells toward HLA-C recognition could arise as developing uNK cells interact with uterine stromal cells, which express higher levels of HLA-C during pregnancy.

Interaction between KIR3DS1 and HLA-Bw4 predicts for progression-free survival after autologous stem cell transplantation in patients with multiple myeloma

AbstractNatural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1+ (P = .01). This was most evident for patients in complete or partial remission (good risk; GR) at ASCT. The relative risk (RR) of progression or death for patients with KIR3DS1+ compared with KIR3DS1− was 1.9 (95% CI, 1.3-3.1; P = .002). The most significant difference in PFS was observed in patients with GR KIR3DS1+ in whom HLA-Bw4, the ligand for the corresponding inhibitory receptor KIR3DL1, was missing. Patients with KIR3DS1+KIR3DL1+HLA-Bw4− had a significantly shorter PFS than patients who were KIR3DS1−, translating to a difference in median PFS of 12 months (12.2 vs 24 months; P = .002). Our data show that KIR–human leukocyte antigen immunogenetics represent a novel prognostic tool for patients with myeloma, shown here in the context of ASCT, and that KIR3DS1 positivity may identify patients at greater risk of progression.

Killer immunoglobulin-like receptor repertoire on uterine natural killer cell subsets in women with recurrent spontaneous abortions

Objective The objective of this study is to investigate the distribution of inhibitory and activating killer immunoglobulin-like receptors (KIRs) on uterine natural killer (uNK) cells and the compatibility of KIR/HLA-C at the maternal–fetal interface in women with unexplained recurrent spontaneous abortion (RSA) in the Chinese population. Study design Sixteen patients with unexplained recurrent spontaneous abortion were enrolled in this study. The PCR sequence-specific primers (SSP) method was used to detect the inhibitory/activating KIRs in uterine NK cells and the HLA-C gene polymorphism expressed on the trophoblast. Results The frequencies of inhibitory KIR2DL2 in the RSA group were increased significantly compared with those of the controls. The other inhibitory KIR2DL families did not show significantly different frequencies in the RSA group. No difference in numbers of inhibitory KIR genes with statistical significance was observed between the RSA group and the controls. When analyzing activating KIRs, none of the KIR2DS1–5 family showed statistically different frequencies in the RSA group compared with the controls. Similarly, there was no statistically significant difference between the numbers of activating KIR genes in the RSA group and the controls. Finally, the matching of the inhibitory or activating KIRs/HLA combination at the maternal–fetal interface did not play a dominant role in the pathogenesis of pregnancy loss. Conclusions This study suggests that the imbalance of inhibitory and activating KIRs in uterine NKs might confer susceptibility to the occurrence of pregnancy loss. The maternal inhibitory/activating KIRs-HLA-C polymorphism expressed on trophoblast cells from decidual tissues seems to play a limited role in abortion.

14th International HLA and Immunogenetics Workshop: Report from the reproductive immunology component

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.

Distribution of the killer cell immunoglobulin‐like receptors in Mexican Mestizos

Understanding the complex interaction between human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) requires study of both HLA and KIR diversity in the same population. The presence of KIR genes 2DL1, 2, 3, 4, 5, KIR3DL1, 3DL2, 3DL3, KIR2DS1, 2DS2, 2DS3, 2DS4, 2DS5, KIR3DS1, KIR3DP1, KIR2DP1 was determined in 54 unrelated Mexican Mestizo donors. The PCR sequence-specific oligonucleotide probe One Lambda kit (Luminex) kindly given by J. Lee was used for typing. The software analyses the combination obtained for each of the five exons. Five controls (UCLA DNA exchange) were run as quality control. The gene frequency (GF) was calculated for the 16 KIR loci; the GF of individual genes was 100% for 2DL4, 3DL1, 3DL2, 3DL3, 3DP1. KIR2DL1 (76.43%), KIR2DL2 (37.64%), KIR2DL3 (76.43%), KIR2DL5 (29.29%), KIR3DS1 (23.02%), KIR2DS1 (21.83%), KIR2DS2 (37.64%), KIR2DS3 (50.93%), KIR2DS4 (86.93%), KIR2DS5 (29.29%), KIR2DP1 (86.39%). We observed similar frequencies with Caucasians and Mediterraneans, with exceptions: KIR3DL1 which was present in 100% Mexicans, ranged from 62% to 75% in Caucasians; 2DS3 (50.9%) vs 14-20% 2DS4 (86.39%) vs 65-79% and 2DS5 (29.29%) vs 11-18% in Caucasians. The finding of 23 phenotypes in 54 individuals accounting for both chromosomes, demonstrates the enormous diversity. We found 14 different combinations of stimulatory KIRs in the phenotypes; every subject had at least one stimulatory KIR; in all of them, 2DS4 existed except for one person who may have some new combination: 2DS2 2DS3. Extended family data will offer accurate and precise haplotypes to provide an insight on the significance of ethnic distribution and KIR repertoire.

Presence of Restricted Killer Immunoglobulin-Like Receptor Repertoire and Monoclonal T-Cell Receptor γ Rearrangement as Evidence of Mixed NK/T-Cell Differentiation in a Subset of Sinonasal Lymphomas

Most sinonasal lymphomas have a restricted killer immunoglobulin-like receptor (KIR) repertoire without a monoclonal T-cell receptor-γ (TCR-γ) rearrangement, implying an NK lineage. However, the lineage assignment of sinonasal lymphoma with a monoclonal TCR-γ rearrangement is unclear because of its mixed NK/T phenotype. The possibility of a mixed NK/T lineage arises with the discovery of T cells with NK features, such as KIR+ T cells or Vα24+ NKT cells. The former might transform into a T-cell lymphoma with both a monoclonal TCR-γ rearrangement and a restricted KIR repertoire; the latter might give rise to a T-cell lymphoma with a monoclonal Vα24 rearrangement and possibly a restricted KIR repertoire. To identify such mixed-lineage lymphomas, we undertook a survey of 15 consecutive sinonasal lymphomas and found six with both a restricted KIR repertoire and a monoclonal TCR-γ rearrangement, consistent with KIR+ T-cell lymphomas. Among these six cases, four female CD56−/CD44−/CD8−/CD45RO+/CD45RA− cases constituted a distinct group with a better prognosis than the rest of the male cases of sinonasal lymphomas. None of the six cases had a monoclonal Vα24 repertoire, thus excluding a derivation from NKT cells. The predominance of KIR+ T cells that normally function in chronic viral infections over Vα24+ NKT cells that typically recognize glycolipid antigens is consistent with the known association of Epstein-Barr virus infection with sinonasal lymphoma. The demonstration of mixed lineage in a mature lymphoid neoplasm is unusual and echoes the World Health Organization classification that placed NK-cell and T-cell lymphomas in a mixed group.