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Background and aimsSecond-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.MethodsParticipants underwent full HLA class I/KIR typing and long-term HCV follow-up.ResultsA 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.ConclusionCirrhosis 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.

Precise typing of human leukocyte antigens (HLA) is crucial for clinical hematopoietic stem cell and solid organ transplantations, transfusion medicine, HLA-related disease association, and drug hypersensitivity analysis. The UCLA Cell Exchange program has played a vital role in providing educational and proficiency testing surveys to HLA laboratories worldwide for the past 5 decades. This article highlights the significant contribution of the UCLA Cell and DNA Exchange Programs in advancing HLA antibody testing, genotyping, crossmatches, and, more recently, virtual crossmatches. Additionally, we discuss future directions of the UCLA Cell Exchange program to support histocompatibility testing to adapt to the fast-evolving field of immunotherapy, tolerance and xenotransplantation.

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. [ABSTRACT FROM AUTHOR]

Background: HIV-1-associated neurocognitive disorders (HAND) in stable patients undergoing antiretroviral therapy (ART) may result from ongoing immune dysregulation and chronic inflammation. A contributing factor may result from the unstable HLA class I allele, HLA-C*07. Objective: To assess the genetic profile of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigens (HLA), and immune activation or senescence markers and their association with HAND in stable HIV-1 patients receiving ART. Methods: An observational cross-sectional study was carried out with 96 patients with asymptomatic or symptomatic HAND. HLA and KIR as well as immune activation/senescence biomarkers in peripheral blood cells were assessed by SSO-Luminex typing and flow cytometry, respectively. Results: HLA-C*07 is associated with symptomatic HAND. The frequency of two copies of HLA-C*07 was higher in patients with symptomatic than with asymptomatic HAND (12.0 vs. 2.2%, ρ < 0.001). The percentage of senescent CD8+CD28- T-cells was higher in patients with two copies of HLA-C*07 (ρ < 0.05). In patients with symptomatic HAND, the percentages of non-senescent CD8+CD28+ T cells were inversely proportional to the number of copies of the HLA-C*07 (ρ < 0.05). Conclusion: Patients with symptomatic HAND showed a higher frequency of the homozygotic unstable HLA-C*07 allotype, which could be associated with neurocognitive complications. Two copies of HLA-C*07 were associated with immune senescent T lymphocyte profiles characterized by the loss of CD28 expression. [ABSTRACT FROM AUTHOR]

Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion. [ABSTRACT FROM AUTHOR]

Abstract Background HIV-exposed uninfected infants (HEU) appear more vulnerable to infections compared to their HIV-unexposed uninfected (HUU) peers, generally attributed to poor passive immunity acquired from the mother. This may be due to some genetic factors that could alter the immune system. We thus sought to determine the distribution of Killer Cell Immunoglobulin-Like Receptors (KIRs) genes in HEU versus HUU and study their associations with the occurrence of infection-related hospitalization. Methods A cohort study was conducted from May 2019 to April 2020 among HEU and HUU infants, including their follow-up at weeks 6, 12, 24, and 48, in reference pediatric centers in Yaoundé-Cameroon. The infant HIV status and infections were determined. A total of 15 KIR genes were investigated using the sequence-specific primer polymerase chain reaction (PCR-SSP) method. The KIR genes that were significantly associated with HIV-1 status (HEU and HUU) were analyzed for an association with infection-related hospitalizations. This was only possible if, and to the extent that, infection-related hospitalizations varied significantly according to status. Multivariate logistic regression analyses were conducted to determine the association between KIR gene content variants and HIV status, while considering a number of potential confounding factors. Furthermore, the risk was quantified using relative risk, odds ratio, and a 95% confidence interval. The Fisher exact test was employed to compare the frequency of occurrences. A p-value of less than 0.05 was considered statistically significant. Results In this cohort, a total of 66 infants participated, but only 19 acquired infections requiring hospitalizations (14.81%, 04/27 HUU and 38.46%, 15/39 HEU, p = 0.037). At week 48 (39 HEU and 27 HUU), the relative risk (RR) for infection-related hospitalizations was 2.42 (95% CI: 1.028–5.823) for HEU versus HUU with OR 3.59 (1.037–12.448). KIR2DL1 gene was significantly underrepresented in HEU versus HUU (OR = 0.183, 95%CI: 0.053–0.629; p = 0.003), and the absence of KIR2DL1 was significantly associated with infection-related hospitalization (p

Background: HIV-exposed uninfected infants (HEU) appear more vulnerable to infections compared to their HIV-unexposed uninfected (HUU) peers, generally attributed to poor passive immunity acquired from the mother. This may be due to some genetic factors that could alter the immune system. We thus sought to determine the distribution of Killer Cell Immunoglobulin-Like Receptors (KIRs) genes in HEU versus HUU and study their associations with the occurrence of infection-related hospitalization. Methods: A cohort study was conducted from May 2019 to April 2020 among HEU and HUU infants, including their follow-up at weeks 6, 12, 24, and 48, in reference pediatric centers in Yaoundé-Cameroon. The infant HIV status and infections were determined. A total of 15 KIR genes were investigated using the sequence-specific primer polymerase chain reaction (PCR-SSP) method. The KIR genes that were significantly associated with HIV-1 status (HEU and HUU) were analyzed for an association with infection-related hospitalizations. This was only possible if, and to the extent that, infection-related hospitalizations varied significantly according to status. Multivariate logistic regression analyses were conducted to determine the association between KIR gene content variants and HIV status, while considering a number of potential confounding factors. Furthermore, the risk was quantified using relative risk, odds ratio, and a 95% confidence interval. The Fisher exact test was employed to compare the frequency of occurrences. A p-value of less than 0.05 was considered statistically significant. Results: In this cohort, a total of 66 infants participated, but only 19 acquired infections requiring hospitalizations (14.81%, 04/27 HUU and 38.46%, 15/39 HEU, p = 0.037). At week 48 (39 HEU and 27 HUU), the relative risk (RR) for infection-related hospitalizations was 2.42 (95% CI: 1.028–5.823) for HEU versus HUU with OR 3.59 (1.037–12.448). KIR2DL1 gene was significantly underrepresented in HEU versus HUU (OR = 0.183, 95%CI: 0.053–0.629; p = 0.003), and the absence of KIR2DL1 was significantly associated with infection-related hospitalization (p < 0.001; aOR = 0.063; 95%CI: 0.017–0.229). Conclusion: Compared to HUU, the vulnerability of HEU is driven by KIR2DL1, indicating the protective role of this KIR against infection and hospitalizations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). PCAcontrolled 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. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless depths of complexity. In recent years, a surge of high-powered genome-wide association studies (GWASs) utilizing single nucleotide polymorphism (SNP) arrays has occurred, significantly advancing our understanding of disease pathogenesis. Additionally, advances in HLA reference panels have enabled higher resolution and more reliable imputation, allowing for finer-grained evaluation of the association between sequence variations and disease risk. However, it is essential to note that the majority of these GWASs have focused primarily on populations of Caucasian and Asian origins, neglecting underrepresented populations in Latin America and Africa. This omission not only leads to disparities in health care access but also restricts our knowledge of novel genetic variants involved in disease pathogenesis within these overlooked populations. Since the KIR and HLA haplotypes prevalent in each population are clearly modelled by the specific environment, the aim of this review is to encourage studies investigating HLA/KIR involvement in infection and autoimmune diseases, reproduction, and transplantation in underrepresented populations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Genotype List (GL) String grammar for reporting HLA and Killer-cell Immunoglobulin-like Receptor (KIR) genotypes in a text string was described in 2013. Since this initial description, GL Strings have been used to describe HLA and KIR genotypes for more than 40 million subjects, allowing these data to be recorded, stored and transmitted in an easily parsed, text-based format. After a decade of working with HLA and KIR data in GL String format, with advances in HLA and KIR genotyping technologies that have fostered the generation of full-gene sequence data, the need for an extension of the GL String system has become clear. Here, we introduce the new GL String delimiter ?, which addresses the need to describe ambiguity in assigning a gene sequence to gene paralogs. GL Strings that do not include a ? delimiter continue to be interpreted as originally described. This extension represents version 1.1 of the GL String grammar.

Killer cell immunoglobulin like receptor (KIR) genes and human leukocyte antigen (HLA) genes play important roles in innate and adaptive immunity. They are highly polymorphic and cannot be genotyped with standard variant calling pipelines. Compared with HLA genes, many KIR genes are similar to each other in sequences and may be absent in the chromosomes. Therefore, although many tools have been developed to genotype HLA genes using common sequencing data, none of them work for KIR genes. Even specialized KIR genotypers could not resolve all the KIR genes. Here we describe T1K, a novel computational method for the efficient and accurate inference of KIR or HLA alleles from RNA-seq, whole-genome sequencing, or whole-exome sequencing data. T1K jointly considers alleles across all genotyped genes, so it can reliably identify present genes and distinguish homologous genes, including the challenging KIR2DL5A/KIR2DL5B genes. This model also benefits HLA genotyping, where T1K achieves high accuracy in benchmarks. Moreover, T1K can call novel single-nucleotide variants and process single-cell data. Applying T1K to tumor single-cell RNA-seq data, we found that KIR2DL4 expression was enriched in tumor-specific CD8+ T cells. T1K may open the opportunity for HLA and KIR genotyping across various sequencing applications.

Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.

Outcomes of haploidentical hematopoietic stem cell transplantation (haplo-SCT) have improved over time. Graft failure and graft-versus-host disease (GVHD), which were important complications in major human leukocyte antigen (HLA)-disparity stem cell transplantation, have significantly decreased. These improvements have led to an exponential increase in the use of haploidentical donors for transplantation, as well as in the number of publications evaluating haplo-SCT outcomes. Many studies focused on factors important in donor selection, novel conditioning regimens or GVHD prophylaxis, the impact of donor-specific anti-HLA antibodies (DSA), as well as strategies to prevent disease relapse post-transplant. DSA represents an important limitation and multimodality desensitization protocols, including plasma exchange, rituximab, intravenous immunoglobulin and donor buffy coat infusion, can contribute to the successful engraftment in patients with high DSA levels and is currently the standard therapy for highly allosensitized individuals. With regards to donor selection, younger donors are preferred due to lower risk of complications and better transplant outcomes. Moreover, recent studies also showed that younger haploidentical donors may be a better choice than older-matched unrelated donors. Improvement of disease relapse remains a top priority, and several studies have demonstrated that higher natural killer (NK) cell numbers early post-transplant are associated with improved outcomes. Prospective studies have started to assess the role of NK cell administration in decreasing post-transplant relapse. These studies suggest that the incorporation of other cell products post-transplant, including the administration of chimeric antigen receptor T-cells, should be explored in the future.

BackgroundIn the Children's Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated.MethodsPatients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated.ResultsOf the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant.ConclusionsThese findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing.Trial registration numberNCT01767194.

Allogeneic hematopoietic cell transplantation (HCT) has transformed over the past several decades through enhanced supportive care, reduced intensity conditioning (RIC), improved human leukocyte antigen (HLA) typing, and novel graft-versus-host disease (GVHD)-prevention and treatment strategies. Most notably, the implementation of post-transplantation cyclophosphamide (PTCy) has dramatically increased the safety and availability of this life-saving therapy. Given reductions in nonrelapse mortality (NRM) with these advances, the HCT community has placed even greater emphasis on developing ways to reduce relapse - the leading cause of death after HCT. When using RIC HCT, protection from relapse relies predominantly on graft-versus-leukemia (GVL) reactions. Donor lymphocyte infusion (DLI), adoptive cellular therapy, checkpoint inhibition, and post-HCT maintenance strategies represent approaches under study that aim to augment or synergize with the GVL effects of HCT. Optimizing donor selection algorithms to leverage GVL represents another active area of research. Many of these strategies seek to harness the effects of T cells, which for decades were felt to be the primary mediators of GVL and the focus of investigation in relapse reduction. However, there is growing interest in capitalizing on the ability of natural killer (NK) cells to yield potent anti-tumor effects. A potential advantage of NK cell-based approaches over T cell-mediated is the potential to reduce NRM in addition to relapse. By decreasing infection, without increasing the risk of GVHD, NK cells may mitigate NRM, while still yielding relapse reduction through identification and clearance of cancer cells. Most T cell-focused relapse-prevention strategies must weigh the benefits of relapse reduction against the increased risk of NRM from GVHD. In contrast, NK cells have the potential to reduce both, potentially tipping the scales significantly in favor of survival. Here, we will review the role of NK cells in GVL, optimization of NK cell match or mismatch, and burgeoning areas of research in NK cell therapy such as adoptive transfer and chimeric antigen receptor (CAR) NK cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nowadays, recurrent pregnancy loss (RPL) is an undesirable condition suffered by many patients of reproductive age. In this scenario, certain immune cell populations and molecules, involved in maternal–fetal compatibility, have emerged as factors related with the pathogenesis of RPL. Among them, uterine Natural Killer cells (uNKs) appear to be of great relevance. These cells are involved in numerous processes during pregnancy, such as the remodeling of uterine spiral arteries or the control of trophoblast invasion. These functions are regulated by the interactions that these cells establish with the extravillous trophoblast, mainly through their Killer Immunoglobulin-like Receptors (KIRs) and the Human Leukocyte Antigen-C (HLA-C) molecules expressed by the embryo. A high level of polymorphism has been reported for both molecules involved in this interaction, with some of the possible KIR–HLA-C combinations being associated with an increased risk of RPL. However, the complexity of the maternal–fetal interface goes beyond this, as other HLA molecules also appear to be related to this reproductive pathology. In this review, we will discuss the role of uNKs in pregnancy, as well as the polymorphisms and clinical implications of KIR–HLA-C binding. We will also address the involvement of other, different HLA molecules in RPL, and the current advice on the appropriate management of patients with 'immunological mismatch', thus covering the main aspects regarding the involvement of maternal–fetal compatibility in RPL. [ABSTRACT FROM AUTHOR]

The role of human leukocyte antigen (HLA) class I and killer immunoglobulin-like receptor molecules in mediating acute retroviral syndrome (ARS) during human immunodeficiency virus type 1 (HIV-1) infection is unclear. Among 72 sub-Saharan African adults, HLA-A*23 was associated with lower odds of ARS (adjusted odds ratio, 0.10 [95% confidence interval,.01–.48]; P =.009), which warrants further studies to explore its role on HIV-1–specific immunopathogenesis. [ABSTRACT FROM AUTHOR]

Polymorphism of killer‐cell immunoglobulin‐like receptors (KIRs) and their HLA class I ligands impacts the effector activity of cytotoxic NK cell and T cell subsets. Therefore, understanding the extent and implications of KIR and HLA class I genetic polymorphism across various populations is important for immunological and medical research. In this study, we conducted a high‐resolution investigation of KIR and HLA class I diversity in three distinct Chinese ethnic minority populations. We studied the She, Yugur, and Tajik, and compared them with the Zhejiang Han population (Zhe), which represents the majority Southern Han ethnicity. Our findings revealed that the Tajik population exhibited the most diverse KIR copy number, allele, and haplotype diversity among the four populations. This diversity aligns with their proposed ancestral origin, closely resembling that of Iranian populations, with a relatively higher presence of KIR‐B genes, alleles, and haplotypes compared with the other Chinese populations. The Yugur population displayed KIR distributions similar to those of the Tibetans and Southeast Asians, whereas the She population resembled the Zhe and other East Asians, as confirmed by genetic distance analysis of KIR. Additionally, we identified 12.9% of individuals across the three minority populations as having KIR haplotypes characterized by specific gene block insertions or deletions. Genetic analysis based on HLA alleles yielded consistent results, even though there were extensive variations in HLA alleles. The observed variations in KIR interactions, such as higher numbers of 2DL1‐C2 interactions in Tajik and Yugur populations and of 2DL3‐C1 interactions in the She population, are likely shaped by demographic and evolutionary mechanisms specific to their local environments. Overall, our findings offer valuable insights into the distribution of KIR and HLA diversity among three distinct Chinese ethnic minority populations, which can inform future clinical and population studies. [ABSTRACT FROM AUTHOR]

Killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) play crucial roles in regulating NK cell activity. Here, we report a real-time quantitative PCR (qPCR) to genotype all KIR genes and their copy numbers simultaneously. With 18 pairs of locus-specific primers, we identified KIR genes by Ct values and determined KIR copy number using the 2−∆Ct method. Haplotypes were assigned based on KIR gene copy numbers. The real-time qPCR results were consistent with the NGS method, except for one sample with KIR2DL5 discrepancy. qPCR is a multiplex method that can identify KIR copy number, which helps obtain a relatively accurate haplotype structure, facilitating increased KIR research in laboratories where NGS or other high-resolution methods are not available. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells, with a unique NK cell receptor phenotype, are abundantly present in the non-pregnant (endometrium) and pregnant (decidua) humanuterine mucosa. It is hypothesized that NK cells in the endometrium are precursors for decidual NK cells present during pregnancy. Microenvironmental changes can alter the phenotype of NK cells, but it is unclear whether decidual NK cell precursors in the endometrium alter their NK cell receptor repertoire under the influence of pregnancy. To examine whether decidual NK cell precursors reveal phenotypic modifications upon pregnancy, we immunophenotyped the NK cell receptor repertoire of both endometrial and early-pregnancy decidual NK cells using flow cytometry. We showed that NK cells in pre-pregnancy endometrium have a different phenotypic composition compared to NK cells in early-pregnancy decidua. The frequency of killer-immunoglobulin-like receptor (KIR expressing NK cells, especially KIR2DS1, KIR2DL2L3S2, and KIR2DL2S2 was significantly lower in decidua, while the frequency of NK cells expressing activating receptors NKG2D, NKp30, NKp46, and CD244 was significantly higher compared to endometrium. Furthermore, co-expression patterns showed a lower frequency of NK cells coexpressing KIR3DL1S1 and KIR2DL2L3S2 in decidua. Our results provide new insights into the adaptations in NK cell receptor repertoire composition that NK cells in the uterine mucosa undergo upon pregnancy. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a known virus that leads to a respiratory disease called coronavirus disease 19 (COVID-19). Natural killer (NK) cells, as members of innate immunity, possess crucial roles in restricting viral infections, including COVID-19. Their functions and development depend on receiving signals through various receptors, of which killer cell immunoglobulin-like receptors (KIRs) belong to the most effective ones. Different studies investigated the association between KIR gene content and susceptibility to COVID-19. Since previous studies have yielded contradictory results, we designed this meta-analysis study to draw comprehensive conclusions about COVID-19 risk and KIR gene association. According to PRISMA guidelines, a systematic search was performed in the electronic databases to find all studies investigating KIR gene contents in COVID-19 patients before March 2023. Any association between KIR genes and COVID-19 risk was determined by calculating pooled odds ratio (OR) and 95% confidence interval (CI). After applying the inclusion and exclusion criteria, 1673 COVID-19 patients and 1526 healthy controls from eight studies were included in this meta-analysis. As the main results, we observed a positive association between the 2DL3 (OR = 1.48, 95% CI = 1.17–1.88, P < 0.001) and susceptibility to COVID-19 and a negative association between the 2DP1 and the risk for COVID-19 (OR = 0.48, 95% CI = 0.23–0.99, P = 0.049). This meta-analysis demonstrated that KIR2DL3, as a member of iKIRs, might be associated with an increased risk of COVID-19 disease. [ABSTRACT FROM AUTHOR]

Background: Several studies have associated members of the KIR genes as susceptibility factors to inflammatory bowel diseases (IBD): ulcerative colitis (UC) and Crohn's disease (CD). Objectives: To assess the association between the presence and absence KIR genes and IBD susceptibility through a meta-analysis. Method: A systematic search was performed through the PubMed, Scopus, and Web of Science databases to obtain relevant articles published before March 2024. Associations between genes and susceptibility to IBDs were estimated by OR with 95 % CI. Results: We found positive associations of the KIR2DS1 and KIR2DS3 genes with susceptibility to UC, while the KIR2DL3 and KIR2DS4full genes showed a negative association. In addition, the KIR2DS1, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1 genes showed a positive association with susceptibility to CD, whereas the KIR2DL1 gene showed a negative association. Conclusions: Our meta-analysis indicates that individuals carrying the KIR2DS1 and KIR2DS3 genes exhibit increased susceptibility to UC, whereas carriers of the KIR2DS1, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1 genes are more prone to CD. However, further studies are required to clarify the role of the KIR genes and their corresponding ligands in the pathology of IBD.

IntroductionGenetic 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.MethodsWe 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.ResultsAnti-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.DiscussionOur 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.

Killer-cell immunoglobulin-like receptors (KIR) are essential for acquiring natural killer (NK) cell effector function, which is modulated by a balance between the net input of signals derived from inhibitory and activating receptors through engagement by human leukocyte antigen (HLA) class I ligands. KIR and HLA loci are polygenic and polymorphic and exhibit substantial variation between individuals and populations. We attempted to investigate the contribution of KIR complex and HLA class I ligands to the genetic predisposition to lung cancer in the native population of southern Iran. We genotyped 16 KIR genes for a total of 232 patients with lung cancer and 448 healthy controls (HC), among which 85 patients and 178 HCs were taken into account for evaluating combined KIR-HLA associations. KIR2DL2 and 2DS2 were increased significantly in patients than in controls, individually (OR 1.63, and OR 1.42, respectively) and in combination with HLA-C1 ligands (OR 1.99, and OR 1.93, respectively). KIR3DS1 (OR 0.67) and 2DS1 (OR 0.69) were more likely presented in controls in the absence of their relative ligands. The incidence of CxTx subset was increased in lung cancer patients (OR 1.83), and disease risk strikingly increased by more than fivefold among genotype ID19 carriers (a CxTx genotype that carries 2DL2 in the absence of 2DS2, OR 5.92). We found that genotypes with iKIRs > aKIRs (OR 1.67) were more frequently presented in lung cancer patients. Additionally, patients with lung cancer were more likely to carry the combination of CxTx/2DS2 compared to controls (OR 2.04), and iKIRs > aKIRs genotypes in the presence of 2DL2 (OR 2.05) increased the likelihood of lung cancer development. Here we report new susceptibility factors and the contribution of KIR and HLA-I encoding genes to lung cancer risk, highlighting an array of genetic effects and disease setting which regulates NK cell responsiveness. Our results suggest that inherited KIR genes and HLA-I ligands specifying the educational state of NK cells can modify lung cancer risk.

Four novel KIR alleles KIR3DL1*0010120, KIR3DS1*01315, KIR3DL3*0020703 and KIR2DL4*0010310 identified using next‐generation sequencing. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = -0.27; 95% CI, -0.49 to -0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.

Precise typing of human leukocyte antigens (HLA) is crucial for clinical hematopoietic stem cell and solid organ transplantations, transfusion medicine, HLA-related disease association, and drug hypersensitivity analysis. The UCLA Cell Exchange program has played a vital role in providing educational and proficiency testing surveys to HLA laboratories worldwide for the past 5 decades. This article highlights the significant contribution of the UCLA Cell and DNA Exchange Programs in advancing HLA antibody testing, genotyping, crossmatches, and, more recently, virtual crossmatches. Additionally, we discuss future directions of the UCLA Cell Exchange program to support histocompatibility testing to adapt to the fast-evolving field of immunotherapy, tolerance and xenotransplantation. [ABSTRACT FROM AUTHOR]

Background: Middle East respiratory syndrome (MERS) is a lower respiratory tract disease caused by a beta coronavirus (CoV) called MERS-CoV, characterized by a high mortality rate. We aimed to evaluate the association between genetic variation in killer cell immunoglobulin-like receptors (KIRs) and the risk of MERS in South Koreans. Methods: KIR genes were genotyped by multiplex polymerase chain reaction with sequence-specific primers (PCR-SSP). A case-control study was performed to identify the odds ratios (OR) of KIR genes for MERS and the association of KIR genes and their ligands, human leukocyte antigens (HLA) genes. Results: KIR2DS4D and KIR3DP1F showed higher frequencies in the group of all patients infected with MERS-CoV than in the control group (p = 0.023, OR = 2.4; p = 0.039, OR = 2.7). KIR2DL1, KIR2DP1, and KIR3DP1D were significantly associated with moderate/mild (Mo/Mi) cases. KIR2DL2, KIR2DS1, and KIR3DP1F were affected in severe cases. When we investigated the association between KIR genes and their ligands in MERS patient and control groups, KIR3DL1+/Bw4(80I)+, KIR3DL1+/Bw6+, KIR3DL1+/Bw6−, KIR2DS1+/C2+, and KIR3DS+/Bw4(80I)+ were associated with MERS. KIR3DL1+/Bw6− was found in Mo/Mi cases. KIR2DS1+/C2+ and KIR2DS2+/C1+ were found in severe cases. Conclusion: Further investigations are needed to prove the various immune responses of MERS-CoV-infected cells according to variations in the KIR gene and ligand gene. A treatment strategy based on current research on the KIR gene and MERS-CoV will suggest potential treatment targets. [ABSTRACT FROM AUTHOR]

Although killer‐cell immunoglobulin‐like receptor (KIR) gene content has been widely studied in health and disease, with the advancement of next‐generation sequencing (NGS) technology the high‐resolution characterization of this complex gene region has become achievable. KIR allele‐level diversity has lately been described across human populations. The present study aimed to analyze for the first time the allele‐level polymorphism of nine KIR genes in 155 healthy, unrelated individuals from the Bulgarian population by applying NGS. The highest degree of polymorphism was detected for the KIR3DL3 gene with 40 observed alleles at five‐digit resolution in total, 22 of which were common. On the other hand, the KIR3DS1 gene was found to have the lowest degree of polymorphism among the studied KIR genes with one common allele: KIR3DS1*01301 (31.6%). To better understand KIR allelic associations and patterns in Bulgarians, we have estimated the pairwise linkage disequilibrium (LD) for the 10 KIR loci, where KIR2DL3*00501 allele was found in strong LD with KIR2DL1*00101 (D′ = 1.00, R2 = 0.742). This is the first study investigating KIR polymorphism at the allele level in a population from the South‐East European region. Considering the effect of the populationally shaped KIR allelic polymorphism on NK cell function, this data could lead to a better understanding of the genetic heterogeneity of this region and can be carried into clinical practice by improvement of the strategies taken for NK‐mediated diseases. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) offers the highest curative potential for patients with hematological malignancies. Complications including infection, graft‐versus‐host disease (GVHD), and relapse reflect delayed or dysregulated immune reconstitution. After transplantation, NK cells rapidly reconstitute and are crucial for immune surveillance and immune tolerance. NK cell function is tightly regulated by killer immunoglobin‐like receptors (KIRs). Previous studies have revealed that donor KIRs, especially some activated KIRs (aKIRs) are closely related to transplant outcomes. Here, we performed a retrospective study, including 323 patients who received haploidentical (haplo) HSCT in our center. In univariate analysis, donor KIR2DS1, KIR2DS3 and KIR3DS1 gene protected patients with lymphoid disease from Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivation, while donor KIR2DS1, KIR2DS5 and KIR3DS1 gene conferred a higher risk of CMV reactivation for patients with myeloid disease. Multivariate analysis confirmed that donor telomeric (Tel) B/x and KIR2DS3 gene best protected patients with lymphoid disease from EBV (p = 0.017) and CMV reactivation (p = 0.004). In myeloid disease, grafts lacking Tel B/x and KIR2DS5 gene correlated with the lowest risk of CMV reactivation (p = 0.018). Besides, donor aKIR genes did not influence the rates of GVHD, relapse, non‐relapse mortality (NRM) and overall survival (OS) in this study. The reactivation of EBV and CMV was associated with poor prognosis of haplo‐HSCT. In conclusion, we found that donor aKIR genes might have a synergistic effect on CMV and EBV reactivation after haplo‐HSCT. Whether the influence of donor aKIR genes varies with disease types remained to be studied. [ABSTRACT FROM AUTHOR]

HLA genotyping was performed on 99 type 1 diabetes (T1D) patients and 200 controls from Mali. Next‐generation sequencing of the classical HLA‐A, ‐B, ‐C, ‐DRB1, ‐DRB3, ‐DRB4, ‐DRB5, ‐DQA1, ‐DQB1, ‐DPA1, and ‐DPB1 loci revealed strong T1D association for all loci except HLA‐C and ‐DPA1. Class II association is stronger than class I association, with most observed associations predisposing or protective as expected based on previous studies. For example, HLA‐DRB1*03:01, HLA‐DRB1*09:01, and HLA‐DRB1*04:05 predispose for T1D, whereas HLA‐DRB1*15:03 is protective. HLA‐DPB1*04:02 (OR = 12.73, p = 2.92 × 10−05) and HLA‐B*27:05 (OR = 21.36, p = 3.72 × 10−05) appear highly predisposing, although previous studies involving multiple populations have reported HLA‐DPB1*04:02 as T1D‐protective and HLA‐B*27:05 as neutral. This result may reflect the linkage disequilibrium between alleles on the extended HLA‐A*24:02~HLA‐B*27:05~HLA‐C*02:02~HLA‐DRB1*04:05~HLA‐DRB4*01:03~HLA‐DQB1*02:02~HLA‐DQA1*02:01~HLA‐DPB1*04:02~HLA‐DPA1*01:03 haplotype in this population rather than an effect of either allele itself. Individual amino acid (AA) analyses are consistent with most T1D association attributable to HLA class II rather than class I in this data set. AA‐level analyses reveal previously undescribed differences of the HLA‐C locus from the HLA‐A and HLA‐B loci, with more polymorphic positions, spanning a larger portion of the gene. This may reflect additional mechanisms for HLA‐C to influence T1D risk, for example, through expression differences or through its role as the dominant ligand for killer cell immunoglobulin‐like receptors (KIR). Comparison of these data to those from larger studies and on other populations may facilitate T1D prediction and help elucidate elusive mechanisms of how HLA contributes to T1D risk and autoimmunity. [ABSTRACT FROM AUTHOR]

Genetically determined variation of killer cell immunoglobulin like receptors (KIR) and their HLA class I ligands affects multiple aspects of human health. Their extreme diversity is generated through complex interplay of natural selection for pathogen resistance and reproductive health, combined with demographic structure and dispersal. Despite significant importance to multiple health conditions of differential effect across populations, the nature and extent of immunogenetic diversity is under‐studied for many geographic regions. Here, we describe the first high‐resolution analysis of KIR and HLA class I combinatorial diversity in Northern Africa. Analysis of 125 healthy unrelated individuals from Cairo in Egypt yielded 186 KIR alleles arranged in 146 distinct centromeric and 79 distinct telomeric haplotypes. The most frequent haplotypes observed were KIR‐A, encoding two inhibitory receptors specific for HLA‐C, two that are specific for HLA‐A and ‐B, and no activating receptors. Together with 141 alleles of HLA class I, 75 of which encode a KIR ligand, we identified a mean of six distinct interacting pairs of inhibitory KIR and HLA allotypes per individual. We additionally characterize 16 KIR alleles newly identified in the study population. Our findings place Egyptians as one of the most highly diverse populations worldwide, with important implications for transplant matching and studies of immune‐mediated diseases. [ABSTRACT FROM AUTHOR]

The mechanisms of immune tolerance of a mother against an antigenically foreign fetus without a concomitant loss of defense capabilities against pathogens are the factors underlying the success of a pregnancy. A significant role in human defense is played by killer immunoglobulin-like receptor (KIR) receptors, which regulate the function of the natural killer (NK) cells capable of destroying antigenically foreign cells, virus-infected cells, or tumor-lesioned cells. A special subpopulation of NK cells called uterine NK cells (uNK) is found in the uterus. Disruption of the tolerance process or overactivity of immune-competent cells can lead to immune infertility, a situation in which a woman's immune system attacks her own reproductive cells, making it impossible to conceive or maintain a pregnancy. Since the prominent role of the inflammatory response in infertility, including KIR receptors and NK cells, has been postulated, the process of antigen presentation involving major histocompatibility complex (MHC) molecules (HLA) appears to be crucial for a successful pregnancy. Proper interactions between KIR receptors on female uNK cells and HLA class I molecules, with a predominant role for HLA-C, found on the surface of germ cells, are strategically important during embryo implantation. In addition, maintaining a functional balance between activating and inhibitory KIR receptors is essential for proper placenta formation and embryo implantation in the uterus. A disruption of this balance can lead to complications during pregnancy. The discovery of links between KIR and HLA-C has provided valuable information about the complexity of maternal–fetal immune interactions that determine the success of a pregnancy. The great diversity of maternal KIR and fetal HLA-C ligands is associated with the occurrence of KIR/HLA-C combinations that are more or less favorable for reproductive success. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) has transformed over the past several decades through enhanced supportive care, reduced intensity conditioning (RIC), improved human leukocyte antigen (HLA) typing, and novel graft-versus-host disease (GVHD)-prevention and treatment strategies. Most notably, the implementation of post-transplantation cyclophosphamide (PTCy) has dramatically increased the safety and availability of this life-saving therapy. Given reductions in nonrelapse mortality (NRM) with these advances, the HCT community has placed even greater emphasis on developing ways to reduce relapse - the leading cause of death after HCT. When using RIC HCT, protection from relapse relies predominantly on graft-versus-leukemia (GVL) reactions. Donor lymphocyte infusion (DLI), adoptive cellular therapy, checkpoint inhibition, and post-HCT maintenance strategies represent approaches under study that aim to augment or synergize with the GVL effects of HCT. Optimizing donor selection algorithms to leverage GVL represents another active area of research. Many of these strategies seek to harness the effects of T cells, which for decades were felt to be the primary mediators of GVL and the focus of investigation in relapse reduction. However, there is growing interest in capitalizing on the ability of natural killer (NK) cells to yield potent anti-tumor effects. A potential advantage of NK cell-based approaches over T cell-mediated is the potential to reduce NRM in addition to relapse. By decreasing infection, without increasing the risk of GVHD, NK cells may mitigate NRM, while still yielding relapse reduction through identification and clearance of cancer cells. Most T cell-focused relapse-prevention strategies must weigh the benefits of relapse reduction against the increased risk of NRM from GVHD. In contrast, NK cells have the potential to reduce both, potentially tipping the scales significantly in favor of survival. Here, we will review the role of NK cells in GVL, optimization of NK cell match or mismatch, and burgeoning areas of research in NK cell therapy such as adoptive transfer and chimeric antigen receptor (CAR) NK cells.

IntroductionPolymorphisms 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.MethodsIn 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. ResultsIn 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. DiscussionOverall, 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.

Natural killer (NK) cells, with a unique NK cell receptor phenotype, are abundantly present in the non-pregnant (endometrium) and pregnant (decidua) humanuterine mucosa. It is hypothesized that NK cells in the endometrium are precursors for decidual NK cells present during pregnancy. Microenvironmental changes can alter the phenotype of NK cells, but it is unclear whether decidual NK cell precursors in the endometrium alter their NK cell receptor repertoire under the influence of pregnancy. To examine whether decidual NK cell precursors reveal phenotypic modifications upon pregnancy, we immunophenotyped the NK cell receptor repertoire of both endometrial and early-pregnancy decidual NK cells using flow cytometry. We showed that NK cells in pre-pregnancy endometrium have a different phenotypic composition compared to NK cells in early-pregnancy decidua. The frequency of killer-immunoglobulin-like receptor (KIR expressing NK cells, especially KIR2DS1, KIR2DL2L3S2, and KIR2DL2S2 was significantly lower in decidua, while the frequency of NK cells expressing activating receptors NKG2D, NKp30, NKp46, and CD244 was significantly higher compared to endometrium. Furthermore, co-expression patterns showed a lower frequency of NK cells co-expressing KIR3DL1S1 and KIR2DL2L3S2 in decidua. Our results provide new insights into the adaptations in NK cell receptor repertoire composition that NK cells in the uterine mucosa undergo upon pregnancy.

In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR score (CF-iKIR) was associated with improved progression-free survival (adjusted hazard ratio [HR], 0.71; P = .029) and overall survival (OS) (HR, 0.66; P = .016), while none of the other models predicted for survival in these patients. Moreover, using exploratory classification and regression tree analysis, we found that donor age 58 years was associated with the worst OS. In the rest of our cohort (80%), cytomegalovirus-reactive recipients with a donor

Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless depths of complexity. In recent years, a surge of high-powered genome-wide association studies (GWASs) utilizing single nucleotide polymorphism (SNP) arrays has occurred, significantly advancing our understanding of disease pathogenesis. Additionally, advances in HLA reference panels have enabled higher resolution and more reliable imputation, allowing for finer-grained evaluation of the association between sequence variations and disease risk. However, it is essential to note that the majority of these GWASs have focused primarily on populations of Caucasian and Asian origins, neglecting underrepresented populations in Latin America and Africa. This omission not only leads to disparities in health care access but also restricts our knowledge of novel genetic variants involved in disease pathogenesis within these overlooked populations. Since the KIR and HLA haplotypes prevalent in each population are clearly modelled by the specific environment, the aim of this review is to encourage studies investigating HLA/KIR involvement in infection and autoimmune diseases, reproduction, and transplantation in underrepresented populations.

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.

Objective To study the correlation between platelet transfusion efficacy and KIR receptor-HLA ligand. Methods Thirty-three leukemia patients with positive HLA antibody were tested for cross-matching with donor platelets. Platelets from suitable donors were selected for transfusion, and the 24-hour platelet corrected count increment (CCI) was used to determine the transfusion effect. KIR and ligand genotyping were performed on blood samples from patients and donors by PCR-SSP method, and the relationship between platelet transfusion effects and KIR receptor-HLA ligand was analyzed. Results In 74 occasions of platelet transfusion, 42 were ineffective and 32 were effective. When the donor had C2 gene and HLA-B Bw4-80T gene, the frequency of ineffective platelet transfusion in the recipient was 69.0% (29/42) and 52.4% (22/35), respectively, which was significantly higher than that in the effective group [25.0% (8/32) and 25.0% (8/32)]. When the donor had C1 gene, and the frequency of effective platelet transfusion in the recipient was 100.0%(32/32), which was higher than that in the ineffective group [83.3%(35/42)]. When the recipient-donor matching mode was KIR2DL1-C2 and KIR3DL1-(HLA-B Bw4-80T), the frequency of ineffective platelet transfusion was 69.0%(29/42) and 40.5%(22/42),higher than that of the effective group [25% (8/32) and 18.8% (6/32)]. When the recipient-donor matching model was KIR2DL3-C1, the rate of effective platelet transfusion in 32 patients (100.0%), which was higher than that (35 patients 83. 3%) in the ineffective group. When the mismatch mode of recipient iKIR+donor HLA ligand receptor was KIR2DL1-C2, the frequency of effective platelet transfusion in the recipient was 78.1% (25/32), which was much higher than that in the ineffective group [31.0% (13/42)]. When the mismatch mode was KIR3DL1-(HLA-B Bw4-80T), the rate of effective platelet transfusion in the recipient was 68.8% (22/32), which was higher than that in the ineffective group (42.9%, 18/42). The difference between the above groups was statistically significant(P

In Egypt, hepatocellular carcinoma (HCC) is the most prevalent cancer in men and the second most prevalent cancer in women. In addition, Egypt has one of the highest prevalences of hepatitis C infection in the world. The aim of the present work was to study the potential role of the 16 KIR genes in the outcome of individuals with chronic hepatitis C virus (HCV) infection in Egypt. The study was carried out under an IRB-approved protocol. Sequence-Specific-Primer-PCR (SSP-PCR) was used for KIR genotyping of germline DNA extracted from peripheral blood leukocytes or from the non-tumor liver of 83 HCC patients, 100 patients with chronic HCV infection without HCC, and 120 matched healthy controls. Out of the 83 HCC patients, only 7 (8.4%) were treated by interferon and/or interferon Ribavirin combination, while for the remaining patients 50 (60.2%) received no prior HCV therapy and 26 (31.3%) were treated with direct-acting antiviral (DAA). Our results showed that KIR haplotype AA that contains more inhibitory KIR genes and fewer activating genes was observed with a significantly lower frequency in HCC patients (6/83, 7.2%) compared to chronic HCV (27/100, 27.0%) (p = 0.0005, OR = 0.21 [0.08–0.53]) and healthy controls (29/119, 24.4%) (p = 0.001, OR = 0.24 [0.09–0.61]). In addition, the frequency of genotype 6 (G6) which contains all the KIR genes was significantly high in the HCC patients (16/83, 19.3%) compared to chronic HCV (8/100, 8.0%) (p = 0.02, OR = 2.7 [1.11–6.79]) and healthy controls (8/119, 6.7%) (p = 0.006, OR = 3.31 [1.35–8.16]). Activating KIR genes 2DS1 and 3DS1 were significantly higher in HCC patients (48/83, 57.83% and 45/83, 54.22%) compared to the chronic HCV patients (36/100, 36% and 34/100, 34%), p = 0.028, 0.027, respectively. Our results are contrary to a prior work on HCC from patients with HCV who were mostly treated by interferon-based therapies. In conclusion, KIR haplotype AA has an important role in host defense against HCC progression especially in patients treated by DAA, suggesting an important role of the KIR genotype status on the outcome of chronic HCV infection.

Abstract Declines in managed honey bee populations are multifactorial but closely associated with reduced virus immunocompetence and thus, mechanisms to enhance immune function are likely to reduce viral infection rates and increase colony viability. However, gaps in knowledge regarding physiological mechanisms or ‘druggable’ target sites to enhance bee immunocompetence has prevented therapeutics development to reduce virus infection. Our data bridge this knowledge gap by identifying ATP-sensitive inward rectifier potassium (KATP) channels as a pharmacologically tractable target for reducing virus-mediated mortality and viral replication in bees, as well as increasing an aspect of colony-level immunity. Bees infected with Israeli acute paralysis virus and provided KATP channel activators had similar mortality rates as uninfected bees. Furthermore, we show that generation of reactive oxygen species (ROS) and regulation of ROS concentrations through pharmacological activation of KATP channels can stimulate antiviral responses, highlighting a functional framework for physiological regulation of the bee immune system. Next, we tested the influence of pharmacological activation of KATP channels on infection of 6 viruses at the colony level in the field. Data strongly support that KATP channels are a field-relevant target site as colonies treated with pinacidil, a KATP channel activator, had reduced titers of seven bee-relevant viruses by up to 75-fold and reduced them to levels comparable to non-inoculated colonies. Together, these data indicate a functional linkage between KATP channels, ROS, and antiviral defense mechanisms in bees and define a toxicologically relevant pathway that can be used for novel therapeutics development to enhance bee health and colony sustainability in the field.

IntroductionThe killer cell immunoglobulin-like receptors (KIR) play a pivotal role in modulating the NK cell responses, for instance, through interaction with major histocompatibility complex (MHC) class I molecules. Both gene systems map to different chromosomes but co-evolved during evolution. The human KIR gene family is characterized by abundant allelic polymorphism and copy number variation. In contrast, our knowledge of the KIR repertoire in chimpanzees is limited to 39 reported alleles, with no available population data. Only three genomic KIR region configurations have been mapped, and seventeen additional ones were deduced by genotyping.MethodsPreviously, we documented that the chimpanzee MHC class I repertoire has been skewed due to an ancient selective sweep. To understand the depth of the sweep, we set out to determine the full-length KIR transcriptome – in our MHC characterized pedigreed West African chimpanzee cohort – using SMRT sequencing (PacBio). In addition, the genomic organization of 14 KIR haplotypes was characterized by applying a Cas9-mediated enrichment approach in concert with long-read sequencing by Oxford Nanopore Technologies.ResultsIn the cohort, we discovered 35 undescribed and 15 already recorded Patr-KIR alleles, and a novel hybrid KIR gene. Some KIR transcripts are subject to evolutionary conserved alternative splicing events. A detailed insight on the KIR region dynamics (location and order of genes) was obtained, however, only five new KIR region configurations were detected. The population data allowed to investigate the distribution of the MHC-C1 and C2-epitope specificity of the inhibitory lineage III KIR repertoire, and appears to be skewed towards C2.DiscussionAlthough the KIR region is known to evolve fast, as observed in other primate species, our overall conclusion is that the genomic architecture and repertoire in West African chimpanzees exhibit only limited to moderate levels of variation. Hence, the ancient selective sweep that affected the chimpanzee MHC class I region may also have impacted the KIR system.

Immigrants represented 21.8% of cases in a Spanish cohort of hospitalised patients with COVID-19, a proportion exceeding the percentage of immigrants in that area's total population. Among the ethnic-related genetic risk factors for COVID-19, human leukocyte antigen (HLA) genotypes in diverse populations might bias the response to SARS-CoV-2 infection and/or progression. Similarly, genetic differences in natural killer-activating and inhibitory receptors could play a role in the immune system's response to the viral infection. We characterised HLA alleles and KIR genes in 52 Ecuadorian patients hospitalised for moderate and severe COVID-19 and 87 Ecuadorian controls from the general population living in the same area. There was a significantly increased frequency of the HLA-B*39 antigen and the activating KIR2DS4 receptor in the presence of its HLA-C*04 ligand in the COVID-19 group when compared with the control group. In contrast, there was a significant reduction in the frequency of carriers of KIR2DL1 and of the KIR3DL1/Bw4 receptor/ligand combination among COVID-19 group. On the other hand, HLA-A*24:02 and HLA-DRB1*09:01 alleles showed significantly lower frequencies specifically in the severe COVID-19 group. HLA-B*39 alleles might be genetic risk factors for developing COVID-19 in Ecuadorian individuals. In the presence of its ligand C*04, the natural killer-activating receptor KIR2DS4 might also increase the risk of developing COVID-19, while, in the presence of HLA-Bw4 alleles, the inhibitory receptor KIR3DL1 might play a protective role. Patients with COVID-19 who carry HLA-A*24:02 and HLA-DRB1*09:01 alleles might be protected against more severe forms of COVID-19. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the leading malignant intracranial tumor, where prognosis for which has remained extremely poor for two decades. Immunotherapy has recently drawn attention as a cancer treatment, including for GBM. Natural killer (NK) cells are immune cells that attack cancer cells directly and produce antitumor immunity-related cytokines. The adoptive transfer of expanded and activated NK cells is expected to be a promising GBM immunotherapy. We previously established an efficient expansion method that produced highly purified, activated primary human NK cells, which we designated genuine induced NK cells (GiNKs). The GiNKs demonstrated antitumor effects in vitro and in vivo, which were less affected by blockade of the inhibitory checkpoint receptor programmed death 1 (PD-1). In the present study, we assessed the antitumor effects of GiNKs, both alone and combined with an antibody targeting killer Ig-like receptor 2DLs (KIR2DL1 and DL2/3, both inhibitory checkpoint receptors of NK cells) in vitro and in vivo with U87MG GBM-like cells and the T98G GBM cell line. Impedance-based real-time cell growth assays and apoptosis detection assays revealed that the GiNKs exhibited growth inhibitory effects on U87MG and T98G cells by inducing apoptosis. KIR2DL1 blockade attenuated the growth inhibition of the cell lines in vitro. The intracranial administration of GiNKs prolonged the overall survival of the U87MG-derived orthotopic xenograft brain tumor model. The KIR2DL1 blockade did not enhance the antitumor effects; rather, it attenuated it in the same manner as in the in vitro experiment. GiNK immunotherapy directly administered to the brain could be a promising immunotherapeutic alternative for patients with GBM. Furthermore, KIR2DL1 blockade appeared to require caution when used concomitantly with GiNKs. [ABSTRACT FROM AUTHOR]