Killer Immunoglobulin-like Receptors Genes Research Articles

The role of Killer immunoglobulin-like receptors (KIRs) in the genetic susceptibility to non-celiac wheat sensitivity (NCWS).

Non-celiac wheat sensitivity (NCWS) is an emerging clinical condition characterized by gastrointestinal and extraintestinal symptoms following the ingestion of gluten-containing foods in patients without celiac disease (CD) or wheat allergy. Despite the great interest for NCWS, the genetic risk factors still need to be fully clarified. In this study, we first assessed the possible contribution of KIR genes and KIR haplotypes on the genetic predisposition to NCWS. Fifty patients with NCWS, 50 patients with CD, and 50 healthy controls (HC) were included in this study. KIR genes and KIR genotyping were investigated in all subjects by polymerase chain reaction with the sequence oligonucleotide probe (PCR-SSOP) method using Luminex technology. We found a statistically different distribution of some KIR genes among NCWS, CD, and HC. Specifically, NCWS showed a decreased frequency of KIR2DL1, -2DL3, -2DL5, -2DS2, -2DS3, -2DS4, -2DS5, and -3DS1 genes, and an increased frequency of -3DL1 gene respect to both CD and HC. No difference was detected in the KIR haplotype expression. At the multivariate analysis, KIR2DL5, -2DS4, and -2DS5 were independent predictors of NCWS. Our findings suggest a role of KIR genes in NCWS susceptibility, with KIR2DL5, -2DS4, and -2DS5 having a protective effect. Further large-scale multicentric studies are required to validate these preliminary findings.

Increased donor inhibitory KIR are associated with reduced GVHD and improved survival following HLA-matched unrelated donor HCT in paediatric acute leukaemia.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after haematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting. Paediatric acute leukaemia patients were retrospectively analysed, and KIR-KIRL combinations and maximal inhibitory KIR ligand (IM-KIR) scores were determined. Clinical outcomes were examined using a series of graphs depicting clinical events and endpoints. The graph methodology demonstrated that prognostic variables significant in the occurrence of specific clinical endpoints remained significant for relevant downstream events. KIR-KIRL combinations were significantly predictive for reduced grade 3-4 aGVHD likelihood, in patients transplanted with increased inhibitory KIR gene content and IM-KIR = 5 scores. Improvements were also observed in associated outcomes for both ALL and AML patients, including relapse-free survival, GRFS and overall survival. This study demonstrates that NK cell KIR HLA interactions may be relevant to the paediatric acute leukaemia transplant setting. Reduction in aGVHD suggests KIR effects may extend beyond NK cells. Moving forward clinical trials utilizing donors with a higher iKIR should be considered for URD HCT in paediatric recipients with acute leukaemia to optimize clinical outcomes.

Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure

Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case–control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal–fetal KIR-HLA-C mismatch in patients.

The Impact of KIR-HLA Interplay in T-LGL Leukemia

T-Cell large granulocyte lymphocyte leukemia (T-LGLL), characterized by clonal expansions of cytotoxic T cells (CTLs), arises from polyclonal lymphoproliferative responses. Various triggers have been stipulated, ranging from autoimmune, viral or tumor antigens. However, one could also posit that an inherent propensity to overshooting CTL responses contributing to the initial clonal expansions or affecting normal termination of immune response might be at play. For instance, specific HLA risk alleles may be overrepresented or even diagnostic for certain autoimmune conditions. In contrast to the risk allele theory, which enriches haplotypes within the patient population, the concept of HLA evolutionary diversity (HED) posits that the structural divergence between alleles widen the recognition spectrum. HLA alleles also serve as ligands for killer immunoglobulin-like receptors (KIRs). Indeed, the KIR gene family, consisting of 15 genes and 2 pseudogenes, is responsible for regulating the activity of NK and a subset of T cells and thus may play a role in T-LGLL. The main KIR genes are classified as either activating or inhibiting, based on their ability to up or downregulate NK and T cells. As the KIR genes and their HLA ligands genetically assort independently of each other, KIR-HLA “mismatches” are possible. We analyzed HLA alleles in 91 T-LGLL patients vs 130 controls and investigated whether specific presentations of T-LGLL, namely neutropenia and anemia enrich for certain HLA alleles. We found that HLA-A*02 was more frequent in cases with neutropenia (59 vs 47%, p=0.045) and HLA-A*68 in patients with anemia (17 vs 8%, p=0.02) as compared to controls. Interestingly, HLA-A*02/HLA-C*05 was observed typically in STAT3 MT vs WT cases (22 vs 11%). Using the HLA calls, we calculated the HED for HLA class 1/2, but no increased HED could be asserted (consistent with the presence of risk alleles as described above). We then explored whether specific KIR-HLA interactions enhanced an individual's risk for clonal CTL expansion and subsequent T-LGLL occurrence. As KIR gene frequencies can vary based on ethnicity, controls were chosen to match T-LGLL cohort (European ancestry). We applied T1K as a computational method for KIR genotyping and validated the calls by the 4 framework KIR genes (always present): 3DL2, 3DL3, 3DP1, and 2DL4. Along with the framework KIRs, there were no differences in the frequency of KIR genotype between T-LGLL and ethnicity matched controls. However, we found that the frequency of individuals with the 3DL2 gene and either HLA A*03 or HLA A*11 was significantly higher in the T-LGLL compared to controls (26 vs 8%, p = .006). Moreover, we found a higher frequency of 2DL3 combined with HLA C2/C2, (31 vs 14%, p=0.05) in T-LGLL patients with neutropenia. As this KIR-ligand (KIRL) configuration is a mismatch, the normally inhibiting receptor will have no effect on cell activity. Stratified by the presence of anemia, the LGLL cohort had instead a significantly higher proportion of 2DS2 co-expressed with the HLA C1 allele (75.68 vs 35.39%, p=.001), indicating activating genotype. We also found that the number of cases with the co-occurrence of the 3DL2 receptor and absent HLA A*03/A*11 ligands paired with 2DL3 and the HLA C1/C1 allotype was higher in STAT3 MT compared to WT (39.1 vs 16.7% p=0.06). Finally, we attempted to estimate and compare the net KIR activity of T-LGLL patients and controls by creating a formula in which, for each individual, we subtracted the sum of the number of KIR/KIRL inhibitory matches from that of activating KIR/KIRL matches. Mismatches were also included either as activating or inhibiting depending on the KIR/KIRL configuration. Using this formula, we found that the net KIR average value for the control cohort was 0.85 compared to 0.69 for the T-LGLL cohort, indicating that the control cohort had slightly more activating KIR-ligand configurations. Even when mismatches were treated as neutral, the preexcitation balance was not changed in T-LGLL. These findings suggest that other factors may contribute to the baseline preexcitation levels of clonal CTLs in this disease. In conclusion, our study of HLA and KIR-HLA interactions shows modest impact of KIR and KIR-ligand genotype on the propensity for overshooting clonal CTL proliferation and points towards other possible mechanisms such as hypersecretion of high affinity IL6R or other stimulatory factors.

HLA-B*44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia.

HLA-B alleles are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. The encodedHLA-B proteins are pivotal in antigen presentation to cytotoxic T cells, and some variants containing a Bw4 motif also serve as ligands to the killer immunoglobulin-like receptors (KIR) 3DL1/S1 of NK cells. We investigated the potential impact of HLA-B genotypes on the efficacy of immunotherapy for relapse prevention in acute myeloid leukemia (AML). Seventy-eight non-transplanted AML patients receiving HDC/IL-2 in the post-consolidation phase were genotyped for HLA-B and KIR genes. HLA-B*44 heralded impaired LFS (leukemia-free survival) and overall survival (OS), but the negative association with outcome was not shared across alleles of the HLA-B44 supertype. Notably, HLA-B*44 is one of few HLA-B44 supertype alleles containing a Bw4 motif with a threonine at position 80, which typically results in weak binding to the inhibitory NK receptor, KIR3DL1. Accordingly, a strong interaction between KIR3DL1 and Bw4 was associated with superior LFS and OS (p = 0.014 and p = 0.027, respectively). KIR3DL1+ NK cells from 80T-Bw4 donors showed significantly lower degranulation responses and cytokine responses than NK cells from 80I-Bw4 donors, suggesting impaired KIR3DL1-mediated education in 80T-Bw4 subjects. We propose that presence of a strong KIR3DL1+-Bw4 interaction improves NK cell education and thus is advantageous in AML patients receiving HDC/IL-2 immunotherapy for relapse prevention.

Decision trees to evaluate the risk of developing multiple sclerosis.

Multiple sclerosis (MS) is a persistent neurological condition impacting the central nervous system (CNS). The precise cause of multiple sclerosis is still uncertain; however, it is thought to arise from a blend of genetic and environmental factors. MS diagnosis includes assessing medical history, conducting neurological exams, performing magnetic resonance imaging (MRI) scans, and analyzing cerebrospinal fluid. While there is currently no cure for MS, numerous treatments exist to address symptoms, decelerate disease progression, and enhance the quality of life for individuals with MS. This paper introduces a novel machine learning (ML) algorithm utilizing decision trees to address a key objective: creating a predictive tool for assessing the likelihood of MS development. It achieves this by combining prevalent demographic risk factors, specifically gender, with crucial immunogenetic risk markers, such as the alleles responsible for human leukocyte antigen (HLA) class I molecules and the killer immunoglobulin-like receptors (KIR) genes responsible for natural killer lymphocyte receptors. The study included 619 healthy controls and 299 patients affected by MS, all of whom originated from Sardinia. The gender feature has been disregarded due to its substantial bias in influencing the classification outcomes. By solely considering immunogenetic risk markers, the algorithm demonstrates an ability to accurately identify 73.24% of MS patients and 66.07% of individuals without the disease. Given its notable performance, this system has the potential to support clinicians in monitoring the relatives of MS patients and identifying individuals who are at an increased risk of developing the disease.

Polymorphism of KIR Genes in Women with Human Papillomavirus Infection

Molecular biology screening techniques for early detection of human papillomavirus (HPV) infection in the National CervicalUterine Cancer Program in Cuba provide the opportunity to treat premalignant lesions and prevent progression to cervicaluterine cancer. Objectives: To identify 14 high-risk HPV genotypes in women aged 30 to 50 with negative previous cytology and to identify the polymorphism of killer immunoglobulin-like receptor (KIR) genes in a subsample of HPV-positive women. Methods: HPV screening tests were performed on 3,115 women using the COBAS 4800 system with the HPV COBAS kit (Roche, Germany). For KIR gene typing, 60 randomly selected HPV-positive women were analyzed using a molecular method based on hybridization probes on a LUMINEX flow analyzer with the LIFECODES KIR-SSO typing kit (Immucor, USA). Results: 295 (9.5%) women tested positive for one of the 14 high-risk genotypes. The highest percentage of positive women was found among those aged 30 to 39 years (12.0%). Fourteen women had coinfection with HPV16 or HPV18 along with another highrisk genotype. There was a high frequency of genes encoding activating receptors such as KIR 2DL1 (98.3%), KIR 2DL3 (98.3%), and KIR 2DS4*all full length (93.3%). Conclusions: The prevalence of HPV in Cuban women with normal cytology is lower than the global average, with activating KIR genes predominating among positive cases.

Large case-control study indicates no association of KIR genotype and risk of developing acute myeloid leukemia.

Immunogenetic association studies may give rise to new hypotheses on the immune surveillance of cancer. We hypothesized that certain combinations of killer immunoglobulin-like receptor (KIR) and HLA genotypes may enhance natural killer (NK) cell immunity against nascent acute myeloid leukemia (AML) and, thereby, lead to a skewed genotype distribution among patients. For this purpose, we analyzed KIR and HLA genotypes of 1767 German patients with AML and compared the results with that of the data of 51 890 German volunteers who had registered with German bone marrow donor file (DKMS). Patient samples were retrieved from the Collaborative Biobank and the biorepository of the Study Alliance Leukemia. All samples were genotyped with high-resolution amplicon-based next-generation sequencing. Because of the large number of controls, this study was very sensitive to detect the impact of KIR genotype. Knowledge on KIRs and their cognate HLA ligands allowed for testing of several hypotheses of NK cell-mediated endogenous leukemia surveillance. We did not find significant differences between the 2 cohorts in regard to the presence or absence of single KIR genes. When grouped based on telomeric or centromeric gene content, the major haplotypes A/A, A/B, and B/B were equally distributed among patients and control subjects. Using information on KIRs and their HLA ligands, we further tested receptor-ligand models and summation models without revealing markedly significant differences between patients and controls, albeit we observed a trend pointing at a minor protective effect of a low number of inhibitory KIR/KIR-ligand pairs. The results suggest that the KIR/KIR-ligand genotype has no effect on the susceptibility for the development of de novo AML.

P-498 Towards precision medicine: maternal genetic profiles as determinant of adequate decidualization and reproductive success; a prospective study in oocyte donation cycles.

Abstract Study question To determine the impact of genes related to decidualization and immune cell activation as predictors for reproductive success. Summary answer Women with unfavorable genetic profiles for Human Leukocyte Antigen (HLA)-F and Killer Immunoglobulin-like Receptor (KIR) genes showed decreased pregnancy rates. What is known already KIR genes encode receptors present on uterine Natural Killer (uNK) cells that are essential during placentation and early gestation. It has been established that women of KIR AA genotype show lower reproductive success than KIR BX, due to the lack of activation of these immune cells. Additionally, another gene, HLA-F, expressed in endometrial cells, also seems to be involved in the recruitment and supplementary activation of uNKs. Certain alleles of this gene appear to decrease its expression in the uterus and hinder the processes in which it is involved during the decidualization process, decreasing implantation rates and increasing time-to-pregnancy. Study design, size, duration We conducted a prospective cohort study with 75 patients, with no history of recurrent miscarriage or implantation failure, who attended our institution to undergo assisted reproduction treatments (ART) with donated oocytes, between January 2021 and December 2022. By using the egg donation model, we were able to investigate the endometrial cell population avoiding the oocyte factor bias Participants/materials, setting, methods All patients included were under 45 years of age (40.5 ± 2.9 years), had a normal BMI (21.6 ± 1.9 kg/m2) and had not been diagnosed with uterine pathologies or immunological conditions. All recipients were genotyped for the KIR and HLA-F genes and pregnancy, miscarriage (MR) and live birth rates (LBR) obtained in their egg donation cycles were recorded. Fisher's test was used to determine statistically significant differences (p &amp;lt; 0.05) between groups Main results and the role of chance Patients were divided into two groups according to their KIR genotype: 29 KIR AA (inhibitor) and 46 KIR BX (activator). In each group, allelic load was determined for the three HLA-F regions studied (RS1362126, RS2523405 and RS2523393). For all these regions, patients with favorable HLA-F alleles and KIR BX genotype had higher pregnancy rates than KIR AA patients with unfavorable HLA-F alleles (85.42 % vs 54.17% for RS1362126 region, OR = 4.956, p = 0.008; 83.33% vs 58.62% for RS2523405 region, OR = 3.529, p = 0.0295; 82.5% vs 57.69% for RS2523393 region, OR = 3.457, p = 0.0462). No significant differences were obtained for MR or LBR. This demonstrates the involvement of KIR and HLA-F in embryo implantation and that the coincidence of unfavorable alleles for both decreases reproductive success considerably, probably due to impaired decidualization and lack of uNK recruitment and activation. No significant differences were obtained for the rest of the genetic profiles, except when comparing pregnancy rate of KIR AA women with favorable HLA-F alleles to KIR AA women with unfavorable HLA-F alleles for the RS1362126 region (79.41% vs 54.17%, OR = 3.264, p = 0.04). The latter finding suggests that the lack of uNK cell activation, so evident in KIR AA patients, could be compensated by expressing favorable HLA-F alleles. Limitations, reasons for caution The low sample size of this study does not allow us to compare groups taking into account other genes, such as embryonic HLA-C, which also, and in combination with KIR genotypes, has been shown to play a role in proper implantation and placentation. Wider implications of the findings uNKs activation is required to promote embryo implantation. Combination of unfavorable genetic profiles involved in these immune mechanism leads to lower pregnancy rate. The study of these genetic profiles can help to predict reproductive success, thus identifying patients susceptible to receive immunological treatment before embryo transfer, possibly decreasing their time-to-pregnancy. Trial registration number Not applicable

Exploration of KIR genes and hematological-related diseases in Chinese Han population

The function of natural killer (NK) cells has previously been implicated in hematopoietic-related diseases. Killer immunoglobulin-like receptors (KIR) play an important role in NK cells after hematopoietic stem cell transplantation. To explore the immunogenetic predisposition of hematological-related diseases, herein, a multi-center retrospective study in China was conducted, analyzing and comparing 2519 patients with hematopathy (mainly, acute lymphoblastic leukemia, acute myeloid leukemia, aplastic anemia, and myelodysplastic syndrome) to 18,108 individuals without known pathology. Genotyping was performed by polymerase chain reaction with specific sequence primers (PCR-SSP). As a result, we discovered four genes including KIR2DL5 (OR: 0.74, 95% CI 0.59–0.93; Pc = 0.0405), 2DS1 (OR: 0.74, 95% CI 0.59–0.93; Pc = 0.0405), 2DS3 (OR: 0.58, 95% CI 0.41–0.81; Pc = 0.0180), and 3DS1 (OR: 0.74, 95% CI 0.58–0.94; Pc = 0.0405) to be protective factors that significantly reduce the risk of aplastic anemia. Our findings offer new approaches to immunotherapy for hematological-related diseases. As these therapies mature, they are promising to be used alone or in combination with current treatments to help to make blood disorders a manageable disease.

Influence of killer immunoglobulin-like receptors genes on the recurrence rate of ocular toxoplasmosis in Brazil.

Recurrence is a hallmark of ocular toxoplasmosis (OT), and conditions that influence its occurrence remain a challenge. Natural killer cells (NK) are effectors cells whose primary is cytotoxic function against many parasites, including Toxoplasma gondii. Among the NK cell receptors, immunoglobulin-like receptors (KIR) deserve attention due to their high polymorphism. This study aimed to analyse the influence of KIR gene polymorphism in the course of OT infection and its association with recurrences after an active episode. Ninety-six patients from the Ophthalmologic Clinic of the National Institute of Infectology Evandro Chagas were followed for up to five years. After DNA extraction, genotyping of the patients was performed by polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) utilising Luminex equipment for reading. During follow-up, 60.4% had a recurrence. We identified 25 KIR genotypes and found a higher frequency of genotype 1 (31.7%) with worldwide distribution. We note that the KIR2DL2 inhibitor gene and the gene activator KIR2DS2 were more frequent in patients without recurrence. Additionally, we observed that individuals who carry these genes progressed recurrence episodes slowly compared to individuals who do not carry these genes. The KIR2DL2 and KIR2DS2 are associated as possible protection markers against ocular toxoplasmosis recurrence (OTR).

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population.

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR-HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR-HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies.

ERAP/HLA-C and KIR Genetic Profile in Couples with Recurrent Implantation Failure.

Proper embryo implantation depends on the tolerance of the maternal immune system to the fetus and its foreign paternal antigens. During implantation and early pregnancy, the dominant leukocytes in the uterus are uterine NK cells, expressing killer immunoglobulin-like receptors (KIR). KIRs recognize human leukocyte antigens (HLA-C) on the human trophoblast inherited from the father and mother. The antigenic peptides presented by the HLA are formed via their cleavage by endoplasmic reticulum aminopeptidases ERAP1 and ERAP2. The aim of this study was to assess the association of combined KIR genes and their HLA-C ligands, as well as ERAP1 and ERAP2 polymorphisms with recurrent implantation failure after in vitro fertilization (RIF). We tested 491 couples who underwent in vitro fertilization (IVF) and 322 fertile couples. Genotype CC rs27044 ERAP1 in female with a male’s HLA-C1C1 or HLA-C1C2 protected from RIF (p/pcorr. = 0.005/0.044, OR = 0.343; p/pcorr. = 0.003/0.027, OR = 0.442, respectively). Genotype TT rs30187 ERAP1 in female with a male’s HLA-C1C2 genotype increased the risk of RIF. Summarizing, in the combination of female ERAP1 and an HLA-C partner, the rs30187 C>T and rs27044 C>G polymorphisms play an important role in implantation failure.

Killer-Cell Immunoglobulin-like Receptor Diversity in an Admixed South American Population.

Natural Killer (NK) cells are innate immune cells that mediate antiviral and antitumor responses. NK cell activation and induction of effector functions are tightly regulated by the integration of activating and inhibitory receptors such as killer immunoglobulin-like receptors (KIR). KIR genes are characterized by a high degree of diversity due to presence or absence, gene copy number and allelic polymorphism. The aim of this study was to establish the distribution of KIR genes and genotypes, to infer the most common haplotypes in an admixed Colombian population and to compare these KIR gene frequencies with some Central and South American populations and worldwide. A total of 161 individuals from Medellin, Colombia were included in the study. Genomic DNA was used for KIR and HLA genotyping. We analyzed only KIR gene-content (presence or absence) based on PCR-SSO. The KIR genotype, most common haplotypes and combinations of KIR and HLA ligands frequencies were estimated according to the presence or absence of KIR and HLA genes. Dendrograms, principal component (PC) analysis and Heatmap analysis based on genetic distance were constructed to compare KIR gene frequencies among Central and South American, worldwide and Amerindian populations. The 16 KIR genes analyzed were distributed in 37 different genotypes and the 7 most frequent KIR inferred haplotypes. Importantly, we found three new genotypes not previously reported in any other ethnic group. Our genetic distance, PC and Heatmap analysis revealed marked differences in the distribution of KIR gene frequencies in the Medellin population compared to worldwide populations. These differences occurred mainly in the activating KIR isoforms, which are more frequent in our population, particularly KIR3DS1. Finally, we observed unique structural patterns of genotypes, which evidences the potential diversity and variability of this gene family in our population, and the need for exhaustive genetic studies to expand our understanding of the KIR gene complex in Colombian populations.

Allelic Polymorphisms of Killer Immunoglobulin-Like Receptor Genes in Malay and Orang Asli Populations of Peninsular Malaysia

Next-generation DNA sequencing (NGS) technology advancements provide new insight into the level of variation in killer immunoglobulin-like receptor (KIR) genes. High resolution allele genotyping of seven KIR genes was conducted among 94 unrelated Malay and Orang Asli (OA) individuals of Peninsular Malaysia. A manual bioinformatics analysis is performed and optimised by Sanger sequencing method. The Malays expressed a total of 22 alleles, as compared to only 15 alleles in the OA population. In total, 12 centromeric and 9 telomeric allelic haplotypes were identified in the Malays, whereas 8 centromeric and 5 telomeric allelic haplotypes were identified in the OA. The KIR2DL1, KIR2DL3, and KIR2DS4 genes exhibited a high degree of variation and balanced distribution in the Malay and OA populations. On the other hand, KIR2DL4, KIR3DL1, KIR3DL2 and KIR3DL3 genes exhibited a high degree of conservation, with less number of alleles identified and the dominance of a single allele at high frequency. High-resolution KIR allele genotyping has revealed unique sequence variations and allelic haplotypes between individuals and populations. The distributions of KIR alleles and haplotypes are useful for genetic population studies and serve as a baseline for future transplantation matching and disease association research.

Association of recurrent spontaneous abortion with polycystic ovarian syndrome under the influence of killer immunoglobulin like receptors

AimsThe primary aim of the current study is to decide if genetic polymorphisms of the killer immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA-C) genes are related to recurrent spontaneous abortion (RSA) in the Saudi women who are affected with polycystic ovarian syndrome (PCO) and in PCO patients without RSA. Materials and methodsThe study was conducted in Riyadh and included 199 cases divided as follows: 69 PCO Saudi women with an RSA history, i.e. three or more spontaneous abortion cases, 65 patients were exclusively with PCO and 65 healthy controls, typed for 17 KIR genes and the HLA-C1 and HLA-C2 allotypes using polymerase chain reaction-sequence-specific primer methodology. ResultsThe study reported that the recurrences of KIR3DL1, 2DS4ins, 2DL2, and KIR2DS2 significantly reduced among RSA-PCO women in comparison with healthy controls (OR = 337.45, 39.08, 2.4, 4.59 with p < 0.01) and a connection with maternal HLA-C genotypes was also examined. Furthermore, the analysis of KIR-HLA-C combinations demonstrated a preventive impact of KIR2DS2, 2DL2, 2DL2/2DL3, 2DL3 with its counterpart HLA-C1 ligand in both homozygote or heterozygote combinations. Such findings were also reported in PCO women. With regard to recurrences, KIR2DL1 marked the highest significant frequenting in both PCO women and RSA-PCO women in comparison with control in the presence of HLA-C2 and homozygote form (HLA-C2C2). However, this frequency decreases in the absence of HLA-C2 ligand. In addition, KIR2DS2, KIR2DL3 significantly increased in the absence of HLA-C1 ligand in both PCO group and RSA-PCO group when compared with healthy cases. ConclusionIt can be concluded from the results of the study that the KIR genes (2DS2, 3DL1, 2DL2, 2DL3) may play a vital role in the protection opposing PCO and RSA in the presence of HLA-C1 ligand which ensures successful pregnancy, and KIR2DL1 is a risk factor for PCO and RSA with HLA-C2 ligand.

Clinical Impact of KIR2DS3 and KIR2DL3 Genes in Neuroblastoma Patients

Objective: Neuroblastoma is a common fatal tumor of childhood. Natural killer (NK) cells can exert direct cytotoxicity on tumor cells. The killer immunoglobulin-like receptor (KIR) family of NK cell receptors is involved in activation/inhibition of NK cells. In the KIR gene cluster, six of them (3DS1, 2DS1–5) encode receptors triggering activation, while seven of them (3DL1–3, 2DL1–3, 2DL5) encode receptors triggering inhibition. We aimed to assess the distribution of genetic polymorphisms of KIRs on the clinical course of neuroblastoma and provide guidance on potential therapeutic options. Methods: Our study group included 50 neuroblastoma patients and 100 healthy children as controls. Twenty-eight patients were boys, and twenty-two were girls; median age was 36 months. Fourteen patients had stage 1, 2, 3, or 4S disease, and 36 patients had stage 4 disease. Isolated DNA from the peripheral blood was amplified for sequence-specific oligonucleotide probe analysis of 16 KIR genes. The Fisher’s exact test was used to evaluate the variation of KIR gene distribution. Results: All patients had a lower frequency of KIR2DS3 compared to the control group (p = 0.005). Evaluation of individual KIR genes/genotypes in patients with early stages (stage 1, 2, 3, and 4S) versus stage 4 disease revealed that the frequency of KIR2DS3 was increased in early stages (p = 0.023). Inhibitory KIR2DL3 was increased in the patient group compared to controls (p = 0.038). Furthermore, the frequency of KIR2DL3 was higher in stage 4 neuroblastoma patients compared to the patients with early stages (p = 0.023). Conclusion: Our data suggest a role for KIR2DS3 and KIR2DL3 in development of neuroblastoma. Thus, modulation of KIR2SD3 and/or KIR2DL3 expression or function might present a novel therapeutic strategy for neuroblastoma.

KIR-HLA Interactions Lack Clinical Utility in Matched Unrelated Donor Transplantation for AML: An Analysis of the CIBMTR and DRST Registries

KIR-HLA Interactions Lack Clinical Utility in Matched Unrelated Donor Transplantation for AML: An Analysis of the CIBMTR and DRST Registries

Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and 'great obstetrical syndromes' (Review).

Recurrent pregnancy loss (RPL), pre-eclampsia (PE), fetal growth restriction (FGR), and preterm delivery are examples of ‘great obstetrical syndromes’ (GOS). Placental dysfunction is the most common pathogenesis of GOS. In human pregnancies, the effects of uterine natural killer cells involve angiogenesis, promoting the remodeling of uterine spiral artery, and improving the invasion of trophoblast cells. The uNK cells supply killer immunoglobulin-like receptors (KIRs), which come into contact with human leukocyte antigen-C (HLA-C) ligands expressed by extravillous trophoblast cells (EVTs). Numerous studies have investigated the association between GOS and KIR/HLA-C combination. However, the outcomes have not been conclusive. The present review aimed to reveal the association between GOS and KIR/HLA-C combination to screen out high-risk pregnancies, strengthen the treatment of pregnancy complications, and reduce the frequency of adverse maternal and fetal outcomes. It has been reported that a female with a KIR AA genotype and a neonate with a paternal HLA-C2 molecule is more prone to develop GOS and have a small fetus since less cytokines were secreted by uNK cells. Conversely, the combination of KIR BB haplotype (including the activating KIR2DS1) and HLA-C2 can induce the production of cytokines and increase trophoblast invasion, leading to the birth of a large fetus. KIR/HLA-C combinations may be applicable in selecting third-party gametes or surrogates. Detection of maternal KIR genes and HLA-C molecules from the couple could serve as useful markers for predicting and diagnosing GOS.

New Evidence in the Pathogenesis of Celiac Disease and Type 1 Diabetes Mellitus: A Systematic Review.

Celiac disease (CD) and type 1 diabetes mellitus (T1DM) are autoimmune diseases that coexist frequently. These illnesses share a common genetic background. This study aims to review the different pathophysiologic mechanisms that have been studied about the coexistence of CD and T1DM, to contrast them, and to summarize their specific role in these autoimmune diseases. We conducted a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist and used the Medical Subject Headings (MeSH) search strategy to obtain relevant articles. We found 585 papers which were reduced to 355 after removing duplicates. Later, the filters and inclusion/exclusion criteria were applied which ended the search with 78 articles. Finally, we reviewed the articles that contained information about the pathogenesis of CD and T1DM, their coexistence, and how the pathogenesis impacts clinical outcomes. The reviewed studies strongly conclude that the presence of human leukocyte antigen (HLA) genes DQ2 and DQ8 are high-risk for developing the coexistence of CD and T1DM. We found that killer immunoglobulin-like receptor (KIR) genes, enterovirus infection in gut cells, and gut microbiota dysbiosis with the predominance of Bacteroides spp. also play a role in the pathogenesis and development of symptoms of CD in patients with the previous diagnosis of T1DM. CD4+ and CD8+ cell levels vary among patients and studies, consequently, more study on this topic is needed.