Analysis of KIR and HLA Polymorphism in Chinese Individuals With COVID-19.

Killer-cell immunoglobulin-like receptor (KIR) interactions with HLA class I have crucial roles in modulating NK cell function in response to viral infections. To explore the correlation between KIR/HLA and susceptibility to SARS-CoV-2 infection, we analysed polymorphism of KIR genes, haplotypes, HLA allotypes, and the interplay between KIR and HLA in individuals diagnosed with COVID-19. Compared to a population control group, we observed a significantly increased frequency of KIR3DL3*00802 in the COVID-19 group. When encoded by the HLA-B gene, the frequency of HLA-Bw4, a ligand for KIR3DL1, was at lower frequency in the COVID-19 group. Additionally, significantly elevated frequencies of KIR-Bx3, KIR3DL3*00301, 3DL3*048, and C1+HLA-C were identified in the COVID-19 group before multiple test correction, suggesting associations with susceptibility to SARS-CoV-2 infection. Our findings indicate that the KIR3DL3*00802 allele may be a high-risk factor for SARS-CoV-2 infection, while Bw4 encoded by HLA-B gene may confer protective effects against the infection.

Association of the Genetic Diversity of Killer Cell Immunoglobulin-like Receptor Genes and HLA-C Ligand in Saudi Women With Thyroid Cancer.

INTRODUCTION: Genetic diversity in the killer immunoglobulin-like receptor (KIR) gene composition and human leukocyte antigen (HLA) class I ligands, such as HLA-C, can affect the activity of natural killer cells and determine anti-cancer immunity. Specific KIR-HLA combinations can enhance cancer predisposition by promoting immune evasion. Studying the relationship between KIR-HLA polymorphisms and thyroid cancer (TC) risk can offer insights into how natural immunity fails, leading to disease development. Therefore, we investigated the association between KIR and HLA-C genotypes and TC risk in Saudi women. METHODS: In this retrospective study, sixteen KIR genotypes and 2 HLA-C allotypes were determined using the polymerase chain reaction-sequence-specific primer (PCR-SSP) method, and the genotypes of 50 Saudi female patients with TC were compared with those of 50 Saudi female healthy controls (HC). RESULTS: We observed a highly significant decrease in the presence of the KIR2DS2 and KIR2DS4 genes (OR = 0.15, 95% CI = 0.05-0.41, P = 0.0001; OR = 0.06, 95% CI = 0.02-0.2, P = 0.000, respectively) and in the presence of the KIR2DL5A gene (OR = 0.05, 95% CI = 0.02-0.14, P = 0.0000) in the TC group compared to the HC group. The frequency of the HLA-C2C2 allotype was significantly higher in HC compared to patients with TC (P = 0.02). The KIR haplotype group A and AB genotypes revealed a protective effect against TC (P = 0.0003 and P = 0.000, respectively), while the BB genotype showed a risk effect on TC compared to HC. Our results showed significant differences in the KIR gene combinations and KIR-HLA combinations between Saudi female TC patients and HC. CONCLUSION: These results suggest that the expression of KIR genes and their HLA-C ligands may influence the risk of TC development in Saudi women.

Genetic diversity in killer immunoglobulin-like receptors (KIR) gene composition and human leukocyte antigen class I (HLA) ligands such as HLA-C can impact the activity of natural killer cells (NK cells) and determine the results of cancer immunity. Specific KIR-HLA combinations can enhance vulnerability by promoting immune evasion. Studying the relationship between KIR-HLA polymorphisms and thyroid cancer (TC) risk can offer insights into how natural immunity failing leading to disease development. Therefore, we investigated the association between KIR and HLA-C genotypes and TC risk in Saudi women.

Interfering with KIR and NKG2A immune checkpoint axes to unleash NK cell immunotherapy.

Due to their intrinsic ability to eliminate malignant cells, natural killer (NK) cells emerge as a promising immunotherapy for cancer. While clinical studies have affirmed the safety of NK cell infusions and combination therapies have demonstrated encouraging outcomes in hematological malignancies, the efficacy of NK cell immunotherapeutic interventions remains heterogeneous across patient cohorts. Moreover, the implementation of NK cell immunotherapy in solid tumors presents notable challenges. Interfering with key NK cell inhibitory signaling pathways by targeting inhibitory killer cell immunoglobulin-like receptors (KIRs) and CD94/NK group 2 member A (NKG2A), holds promise for unleashing the full potential of NK cell-based immunotherapy. In this review, we provide an overview of the current approaches for interfering with inhibitory KIR and NKG2A signaling, exploring a selection of the multitude of combination strategies available. We discuss the significance of maintaining the delicate balance between achieving optimal suppression of NK cell inhibition and ensuring effective activation of anti-tumor effector function, while preserving the favorable safety profiles. The consideration of strategies to modulate inhibitory signaling pathways associated with KIR and NKG2A presents promising avenues for enhancing the efficacy of NK cell immunotherapy.

Genetic complexity of killer-cell immunoglobulin-like receptor genes in human pangenome assemblies.

The killer-cell immunoglobulin-like receptor (KIR) gene complex, a highly polymorphic region of the human genome that encodes proteins involved in immune responses, poses strong challenges in genotyping owing to its remarkable genetic diversity and structural intricacy. Accurate analysis of KIR alleles, including their structural variations, is crucial for understanding their roles in various immune responses. Leveraging the high-quality genome assemblies from the Human Pangenome Reference Consortium (HPRC), we present a novel bioinformatic tool, the structural KIR annoTator (SKIRT), to investigate gene diversity and facilitate precise KIR allele analysis. In 47 HPRC-phased assemblies, SKIRT identifies a recurrent novel KIR2DS4/3DL1 fusion gene in the paternal haplotype of HG02630 and maternal haplotype of NA19240. Additionally, SKIRT accurately identifies eight structural variants and 15 novel nonsynonymous alleles, all of which are independently validated using short-read data or quantitative polymerase chain reaction. Our study has discovered a total of 570 novel alleles, among which eight haplotypes harbor at least one KIR gene duplication, six haplotypes have lost at least one framework gene, and 75 out of 94 haplotypes (79.8%) carry at least five novel alleles, thus confirming KIR genetic diversity. These findings are pivotal in providing insights into KIR gene diversity and serve as a solid foundation for understanding the functional consequences of KIR structural variations. High-resolution genome assemblies offer unprecedented opportunities to explore polymorphic regions that are challenging to investigate using short-read sequencing methods. The SKIRT pipeline emerges as a highly efficient tool, enabling the comprehensive detection of the complete spectrum of KIR alleles within human genome assemblies.

Characterisation of novel KIR alleles: KIR3DL3*0070105, KIR3DL3*0130202, KIR3DL1*0080104 and KIR3DL1*0010121.

KIR3DL3*0070105, KIR3DL3*0130202, KIR3DL1*0080104 and KIR3DL1*0010121, identified by next generation sequencing in individuals from India.

A New Look at Immunogenetics of Pregnancy: Maternal Major Histocompatibility Complex Class I Educates Uterine Natural Killer Cells.

Our incomplete knowledge of maternal-fetal interface (MFI) physiology impedes a better understanding of the pathological mechanisms leading to pregnancy complications, such as pre-eclampsia and fetal growth restriction. At the MFI, uterine natural killer (uNK) cells do not attack fetal cells but engage in crosstalk with both fetal and maternal cells to support feto-placental development. However, mother and fetus are genetically half-mismatched and certain combinations of variable immune genes-human leukocyte antigens (HLAs) and killer-cell immunoglobulin-like receptor (KIR), indeed, the most variable gene sets in the genome-associate with pregnancy outcomes, suggesting that these interactions regulate uNK cell function. How do these interactions influence the physiology and pathology at the MFI? Uterine NK cell function is regulated by both maternal and fetal Major Histocompatibility Complex (MHC); however, evidence for fetal cells educating uNK cells is lacking, and new evidence shows that maternal rather than fetal MHC class I molecules educate uNK cells. Furthermore, uNK cell education works through self-recognition by the ancient and conserved NKG2A receptor. Pregnant mice lacking this receptor produce normal litter sizes, but a significant portion of the offspring have low birthweight and abnormal brain development. Evidence from a genome-wide association study of over 150,000 human pregnancies validates the finding because women whose NKG2A receptor is genetically determined to engage their own MHC class I molecules are exposed to lower risk of developing pre-eclampsia, suggesting that maternal uNK cell education is a pre-requisite for a healthy pregnancy and, likely, for healthy offspring too.

Subcutaneous G-CSF administration improves IVF outcomes in patients with recurrent implantation failure presenting a KIR/HLA-C mismatch.

RESEARCH QUESTION: Despite advances in assisted reproductive technologies, many blastocysts are lost unexpectedly during implantation. Alterations in maternal immune tolerance towards fetal antigens may contribute to adverse IVF outcomes. The purpose of this study is to evaluate whether administering Granulocyte Colony-Stimulating Factor (G-CSF) to couples with a Human Leukocyte Antigen/Killer-Cell Immunoglobulin-Like Receptor (HLA/KIR) mismatch could positively modulate the implantation process in patients with recurrent implantation failure (RIF). A KIR/HLA-C mismatch occurs when the interaction between KIRs and HLA-C causes an inhibition of NK cells, which may result in reduced G-CSF secretion leading to impaired placentation and increased risk of miscarriage, pre-eclampsia and fetal growth restriction. DESIGN: A retrospective monocentric cohort study conducted at the IVI Clinic in Rome, including women with a history of at least two failed blastocyst transfers. Couples underwent KIR and HLA-C testing. Couples with a KIR/HLA-C mismatch received G-CSF subcutaneously up to week nine of gestation. The mismatch included cases with inhibitory KIR genotypes and HLA-C2C2 females with HLA-C1C1, or C1C2 males or HLA-C1C2 females with male HLA-C2C2. The reproductive outcomes were assessed, and the logistic regression models controlled for potential confounders affecting IVF outcomes. RESULTS: 79 patients with RIF and a KIR/HLA-C mismatch were included in the study. 30 patients were administered G-CSF, and 49 received no treatment. In the univariate analysis, no statistically significant differences were reported in the reproductive outcomes after IVF between the women treated with G-CSF and the control group. However, the logistic regression analysis that controlled for confounding factors showed that patients treated with subcutaneous G-CSF had statistically significant higher ongoing-pregnancy (aOR=3.808) and live-birth (aOR=4.998) rates, and a lower miscarriage rate (aOR=0.057). No statistically significant differences were found in other reproductive outcomes. CONCLUSION: The use of subcutaneous G-CSF in patients with a KIR/HLA-C mismatch undergoing IVF may reduce miscarriage and improve live-birth rates. G-CSF may modulate NK-mediated immune mechanisms and improve trophoblast invasion and development. Randomized trials are warranted to validate these findings and enhance the chances of successful pregnancies in couples with an immunological mismatch.

Killer-cell immunoglobulin-like receptor polymorphism is associated with COVID-19 outcome: Results of a pilot observational study.

The pathogenesis of COVID-19 warrants unravelling. Genetic polymorphism analysis may help answer the variability in disease outcome. To determine the role of KIR and HLA polymorphisms in susceptibility, progression, and severity of SARS-CoV-2 infection, 458 patients and 667 controls enrolled in this retrospective observational study from April to December 2020. Mild/moderate and severe/death study groups were established. HLA-A, -B, -C, and KIR genotyping were performed using the Lifecodes® HLA-SSO and KIR-SSO kits on the Luminex® 200™ xMAP fluoroanalyser. A probability score using multivariate binary logistic regression analysis was calculated to estimate the likelihood of severe COVID-19. ROC analysis was used to calculate the best cut-off point for predicting a worse clinical outcome with high sensitivity and specificity. A p ≤ 0.05 was considered statistically significant. KIR AA genotype protected positively against severity/death from COVID-19. Furthermore, KIR3DL1, KIR2DL3 and KIR2DS4 genes protected patients from severe forms of COVID-19. KIR Bx genotype, as well as KIR2DL2, KIR2DS2, KIR2DS3 and KIR3DS1 were identified as biomarkers of severe COVID-19. Our logistic regression model, which included clinical and KIR/HLA variables, categorised our cohort of patients as high/low risk for severe COVID-19 disease with high sensitivity and specificity (Se = 94.29%, 95% CI [80.84-99.30]; Sp = 84.55%, 95% CI [79.26-88.94]; OR = 47.58, 95%CI [11.73-193.12], p < 0.0001). These results illustrate an association between KIR/HLA ligand polymorphism and different COVID-19 outcomes and remarks the possibility of use them as a surrogate biomarkers to detect severe patients in possible future infectious outbreaks.

Orchestrating the Impact of KIR/HLA Interactions on Kidney Transplant.

This study examines the interplay between human leukocyte antigen (HLA) compatibility and killer-cell immunoglobulin-like receptor (KIR) genotypes in influencing kidney transplantation outcomes. Understanding these interactions is crucial for improving graft survival and minimizing rejection risks. We evaluated 84 kidney transplant recipients, dividing them into two groups based on post-transplant outcomes: there were 68 with stable graft function (SGF) and 16 who experienced chronic rejection (CR). Patients were selected based on specific inclusion criteria. HLA mismatches (Class I: HLA-A, -B; Class II: HLA-DR) and KIR genotypes were determined using standard genotyping techniques. Statistical analyses, including logistic regression, were performed to correlate these factors with transplant outcomes. Significant age differences were observed, with younger patients more likely to experience graft rejection, while no significant gender-based differences were noted. A significant correlation was found between Class II mismatches and increased rejection rates, highlighting the importance of HLA-DR compatibility. Further analysis revealed that certain inhibitory KIRs, such as KIR3DL1, were associated with favorable outcomes, suggesting a protective role against graft rejection. These findings were corroborated by evaluating serum creatinine levels over multiple years, serving as a biomarker for renal function post transplant. This study underscores the critical need for meticulous HLA matching and the consideration of KIR genotypes in pre-transplant evaluations to enhance graft survival and minimize rejection risks. Integrating these genetic factors into routine clinical assessments could significantly improve personalized transplant medicine strategies, ultimately enhancing patient outcomes. Further research is needed to explore the underlying mechanisms and validate these findings in larger, diverse populations.

Identification of four novel KIR alleles in haematopoietic stem cell donors of Indian origin.

Four novel KIR alleles KIR3DL1*0010120, KIR3DS1*01315, KIR3DL3*0020703 and KIR2DL4*0010310 identified using next-generation sequencing.

Unsupervised Clustering Analysis of Regimen and HLA Characteristics in Pediatric Umbilical Cord Blood Transplantation.

HLA matching is a critical factor in allogeneic unrelated hematopoietic cell transplantation (HCT) because of its impact on post-transplantation survival and quality of life. Umbilical cord blood transplantation (UCBT) offers unique advantages, but determining the optimal approach to graft selection and immunosuppression remains challenging. Unsupervised clustering, a machine learning technique, has potential for analyzing transplantation outcomes, but its application in investigating leukemia outcomes has been limited. This study aimed to identify optimal combinations of HLA/ killer immunoglobulin receptor (KIR) donor-patient pairing, conditioning, and immunosuppressive regimens in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) undergoing UCBT. Outcome data for single, unmanipulated UCBT in pediatric AML (n = 708) and ALL (n = 1034) patients from the Eurocord/EBMT registry were analyzed using unsupervised clustering. Resulting clusters were used to inform post hoc competing risks and Kaplan-Meier analyses. In AML, single HLA-C mismatches with other loci fully matched (7/8) were associated with poorer relapse-free survival (RFS) (P = .039), but a second mismatch at any other locus counteracted this effect. In ALL, total body irradiation (TBI) effectively prevented relapse mortality (P = .007). KIR/HLA-C match status affected RFS in AML (P = .039) but not in ALL (P = .8). Administration of antithymocyte globulin (ATG) substantially increased relapse, with no relapses occurring in the 85 patients who did not receive ATG. Our unsupervised clustering analyses generate several key statistical and mechanistic hypotheses regarding the relationships between HLA matching, conditioning regimens, immunosuppressive therapies, and transplantation outcomes in pediatric AML and ALL patients. HLA-C and KIR combinations significantly impact RFS in pediatric AML but not in ALL. ATG use in fully matched pediatric patients is associated with late-stage relapse. TBI regimens appear to be beneficial in ALL, with efficacy largely independent of histocompatibility variables. These findings reflect the distinct genetic and biological profiles of AML and ALL.

HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis.

Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

Investigating the role of killer cell immunoglobulin-like receptors and human leukocyte antigen genetic variants in hepatitis C virus infection.

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

Immunomodulatory Treatment Impact on IVF Outcomes in KIR AA Genotype: Personalized Fertility Insights.

Background and Objectives: Recurrent implantation failure (RIF) affects 10% of couples undergoing in vitro fertilization (IVF), spurring exploration into tailored treatments to enhance implantation rates. Maternal immune tolerance towards embryos, particularly killer-cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells, is a focal point in RIF research. Materials and Methods: This retrospective cohort study, conducted at fertility clinic in Oradea, Romania, involved 65 infertile couples undergoing IVF treatment between January 2022 and December 2023. Couples were divided into two groups: KIR AA (Group A) and KIR Bx (Group B). Results: Factors such as age, type of infertility, oocytes retrieved, embryos produced, pregnancy rates in Group A without and with immunomodulatory treatment were documented. Group A, receiving immunomodulatory treatment, achieved a pregnancy rate of 47.8%, significantly higher than the 23.73% rate without treatment (p = 0.008). Group B had a higher mean patient age than Group A. However, miscarriage rates did not significantly differ between Group A with treatment and Group B (p = 0.2457), suggesting comparable outcomes with immunomodulation. Conclusions: The impact of immunological factors on recurrent implantation failure is being more and more emphasized and warrants the attention of specialists in human reproduction. Uterine natural killers and their function though KIR receptors deserve particular attention as immunomodulatory treatment may improve pregnancy rates in patients with KIR AA haplotype.

The effects of killer cell immunoglobulin-like receptor (KIR) genes on susceptibility to severe COVID-19 in the Iranian population.

BACKGROUND: Variations in the innate and adaptive immune response systems are linked to variations in the severity of COVID-19. Natural killer cell (NK) function is regulated by sophisticated receptor system including Killer-cell immunoglobulin-like receptor (KIR) family. We aimed to investigate the impact of possessing certain KIR genes and genotypes on COVID19 severity in Iranians. KIR genotyping was performed on 394 age/sex matched Iranians with no underlying conditions who developed mild and severe COVID- 19. The presence and/or absence of 11 KIR genes were determined using the PCR with sequence specific primers (PCR-SSP). RESULTS: Patients with mild symptoms had higher frequency ofKIR2DS1 (p = 0.004) and KIR2DS2 (p = 0.017) genes compared to those with severe disease. While KIR3DL3 and deleted variant of KIR2DS4 occurred more frequently in patients who developed a severe form of the disease. In this study, a significant increase of and B haplotype was observed in the Mild group compared to the Severe group (respectively, p = 0.002 and p = 0.02). Also, the prevalence of haplotype A was significantly higher in the Severe group than in the Mild group (p = 0.02). CONCLUSIONS: These results suggest that the KIR2DS1, KIR2DS, and B haplotype maybe have a protective effect against COVID-19 severity. The results also suggest the inhibitory gene KIR2DL3 and haplotype A are risk factors for the severity of COVID-19.

Submitting Novel Full-Length HLA, MIC, and KIR Alleles with TypeLoader2.

The Immuno Polymorphism Database (IPD) plays a pivotal role for immunogenetics. Due to technical limitations, genotyping often focuses on specific key regions like the antigen recognition domain (ARD) for HLA genotyping, and the databases are populated accordingly. More recently, though, modern next generation sequencing (NGS) assays allow using larger gene segments or even complete genes for genotyping. It is therefore essential that the databases are updated with complete genetic reference sequences to fully serve current and future applications. However, the process of manually annotating and submitting full-length allele sequences to IPD is time-consuming and error-prone, which may discourage HLA-genotyping laboratories or researchers from submitting full-length sequences of novel alleles.Here, we detail the process of preparing and submitting novel HLA, MIC, and KIR alleles to ENA and IPD using TypeLoader2, a convenient software tool developed to streamline this process by automating the sequence annotation, the creation of all necessary files, as well as parts of the submission process itself. The software is freely available from GitHub ( https://github.com/DKMS-LSL/typeloader ).

Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity.

BACKGROUND AND AIMS: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. METHODS: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. RESULTS: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. CONCLUSION: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

Multifactorial determinants of NK cell repertoire organization: insights into age, sex, KIR genotype, HLA typing, and CMV influence.

Introduction: Polymorphisms in the KIR and HLA genes contribute to the diversity of the NK cell repertoire. Extrinsic factors also play a role in modifying this repertoire. The best example is cytomegalovirus, which promotes the expansion of memory-like NK cells. However, the mechanisms governing this phenotypic structure are poorly understood. Furthermore, the influence of age and sex has been understudied. Methods: In this study, we examined these parameters in a cohort of 200 healthy volunteer blood donors, focusing on the major inhibitory KIR receptors and CD94/NKG2A, as well as the differentiation marker CD57 and the memory-like population marker NKG2C. Flow cytometry and two joint analyses, unsupervised and semi-supervised, helped define the impact of various intrinsic and extrinsic markers on the phenotypic structure of the NK cell repertoire. Results: In the KIR NK cell compartment, the KIR3DL1 gene is crucial, as unexpressed alleles lead to a repertoire dominated by KIR2D interacting only with HLA-C ligands, whereas an expressed KIR3DL1 gene allows for a greater diversity of NK cell subpopulations interacting with all HLA class I ligands. KIR2DL2 subsequently favors the KIR2D NK cell repertoire specific to C1/C2 ligands, whereas its absence promotes the expression of KIR2DL1 specific to the C2 ligand. The C2C2Bw4+ environment, marked by strong -21T motifs, favors the expansion of the NK cell population expressing only CD57, whereas the absence of HLA-A3/A11 ligands favors the population expressing only NKG2A, a population highly represented within the repertoire. The AA KIR genotype favors NK cell populations without KIR and NKG2A receptors, whereas the KIR B+ genotypes favor populations expressing KIR and NKG2A. Interestingly, we showed that women have a repertoire enriched in CD57- NK cell populations, while men have more CD57+ NK cell subpopulations. Discussion: Overall, our data demonstrate that the phenotypic structure of the NK cell repertoire follows well-defined genetic rules and that immunological history, sex, and age contribute to shaping this NK cell diversity. These elements can contribute to the better selection of hematopoietic stem cell donors and the definition of allogeneic NK cells for cell engineering in NK cell-based immunotherapy approaches.cters are displayed correctly.

A higher CD34 + cell dose correlates with better event-free survival after KIR-ligand mismatched cord blood transplantation for childhood acute myeloid leukemia.

Although killer Ig-like receptor ligands (KIR-L) mismatch has been associated with alloreactive natural killer cell activity and potent graft-versus-leukemia (GVL) effect among adults with acute myeloid leukemia (AML), its role among children with AML receiving cord blood transplantation (CBT) has not been determined. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients who were diagnosed with de novo non-M3 AML and who underwent their first CBT in remission between 2000 and 2021 at under 16 years old were included. A total of 299 patients were included; 238 patients were in the KIR-L match group, and 61 patients were in the KIR-L mismatch group. The cumulative incidence rates of neutrophil recovery, platelet engraftment, and acute/chronic graft-versus-host disease did not differ significantly between the groups. The 5-year event-free survival (EFS) rate was 69.8% in the KIR-L match group and 74.0% in the KIR-L mismatch group (p = 0.490). Stratification by CD34 + cell dose into four groups revealed a significant correlation between CD34 + cell dose and EFS in the KIR-L mismatch group (p = 0.006) but not in the KIR-L match group (p = 0.325). According to our multivariate analysis, KIR-L mismatch with a high CD34 + cell dose (≥ median dose) was identified as an independent favorable prognostic factor for EFS (hazard ratio = 0.19, p = 0.029) and for the cumulative incidence of relapse (hazard ratio = 0.09, p = 0.021). Our results suggested that higher CD34 + cell doses are crucial for achieving a potent GVL effect in the context of KIR-L-mismatched CBT.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.