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The nomenclatures used to describe HLA and killer-cell immunoglobulin-like receptor (KIR) alleles distinguish unique nucleotide and peptide sequences, and patterns of expression, but are insufficient for describing genotyping results, as description of ambiguities and relations across loci require terminology beyond allele names. The genotype list (GL) String grammar describes genotyping results for genetic systems with defined nomenclatures, like HLA and KIR, documenting what is known and unknown about a given genotyping result. However, the accuracy of a GL String is dependent on the reference database version under which it was generated. Here, we describe the GL string code (GLSC) system, which associates each GL String with meta-data describing the specific reference context in which the GL String was created, and in which it should be interpreted. GLSC is a defined syntax for exchanging GL Strings in the context of a specific gene-family namespace, allele-name code-system, and pertinent reference database version. GLSC allows HLA and KIR genotyping data to be transmitted, parsed and interpreted in the appropriate context, in an unambiguous manner, on modern data-systems, including Health Level 7 Fast Healthcare Interoperability Resource systems. Technical specification for GLSC can be found at https://glstring.org.

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.

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called "education" to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression ("Missing-self" hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1+C2+Bw4+) was not associated with MM occurrence. However, MM patients were more likely to be C1-/C2+/Bw4+ (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM. [ABSTRACT FROM AUTHOR]

Background. The using of killer-cell immunoglobulin-like receptor (KIR) composition data is of increasing interest in clinical practice to select an optimal donor for allogeneic hematopoietic stem cell transplantation for treatment of hematologic malignancies to reduce graft versus host disease and the risk of relapse. It is also of interest to study the frequencies of KIR genes and genotypes in different populations. For the Russian Federation, KIR gene and genotype frequencies have been described for only a few relatively small samples and have not been fully studied. The study of KIR gene and genotype frequencies has not been conducted for the Samara region population to date.Aim. To study the frequencies of KIR genes and genotypes in the population of Samara region and to compare the data with previously described Russian populations.Materials and methods. To study the frequencies of KIR genes and genotypes, molecular genetic typing of 142 CBUs from the public cord blood bank of the Samara Regional Medical Centre “Dynasty” was performed. Molecular genetic typing of KIR genes was performed by polymerase chain reaction with sequence-specific primers with subsequent visualization of products in agarose gel. 16 KIR genes and pseudogenes were analyzed: 2DL1, 2DL2, 2DL3, 3DL1, 3DL2, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2DP1, 3DL3, 2DL4, 2DL5, 3DP1. KIR gene frequencies were determined by direct counting. Genotypes were determined using Allele Frequencies database. A determination B-content group was performed using the Donor KIR B-content group calculator. Statistical analysis was performed using the χ2 test.Results. The highest frequency of KIR inhibitory genes was found for KIR2DL1 (98.6 %), KIR3DL1 (98.6 %), KIR2DL3 (96.5 %), KIR2DL5 (46.5 %), and KIR2DL2 (34.5 %). The most frequent among the activating receptor genes was KIR2DS4 (89.4 %), the frequencies of other KIR activating genes were KIR2DS2 – 45.1 %, KIR2DS1 – 35.9 %, KIR2DS3 33.8 %, and KIR2DS5 – 26.1 %. Comparative analysis of KIR gene frequencies in the population of Samara region and other Russian populations revealed certain differences. Significant differences in the frequencies of occurrence were found for KIR2DL3, KIR2DS4, KIR2DL2, KIR2DL5, KIR2DS3, KIR2DS5, as well as KIR2DP1 and KIR3DP1. Examination of 142 samples revealed 45 different genotypes: AA genotypes were detected in 30 % and Bx genotypes in 70 % of cases. AA genotype ID195 with a frequency of 5.6 % was detected, which has not been previously described in Russian populations. Among the Samara region population sample, only 3.5 % had the “best” status, 20.4 % had the “better” status, and 76.1 % had the “neutral” status of the B-content.Conclusion. The results obtained in this sample on the frequencies of KIR genes and genotypes differ from the previously published data for the Russian Federation. Of interest is the finding of a greater diversity of genotypes among a rather small study group, the detection of an atypical ID195 genotype, and the difference in the representation of B-content groups. The analysis of KIR genotypes in the population of Samara region can be used in the selection of optimal CBU and hematopoietic cell/bone marrow donors in addition to HLA typing. Studying the frequency distribution of KIR and HLA genes and genotypes can play a role in the study of fundamental aspects of human immunology and population genetics.

KIR3DP1*00604 differs from KIR3DP1*0060101 by one single nucleotide substitution G > C at position 252. [ABSTRACT FROM AUTHOR]

Problem: Natural killer (NK) cells undergo education for full functionality via interactions between killer immunoglobulin-like receptors (KIRs) or NKG2A and human leukocyte antigen (HLA) ligands. Presumably, education is important during early pregnancy as insufficient education has been associated with impaired vascular remodeling and restricted fetal growth in mice. NK cell education is influenced by receptor co-expression patterns, human cytomegalovirus (CMV), the HLA-E R 107 G dimorphism, and HLA-B leader peptide variants. We hypothesized altered NK cell education status and differences in frequencies of HLA-E genotypes and HLA-B leader peptide variants in women with recurrent pregnancy loss (RPL) compared to women with previously uncomplicated pregnancies, and between CMV seropositive and seronegative RPL women., Methods of Study: Peripheral blood mononuclear cells were analyzed by flow cytometry. HLA-ABC was typed by sequence-specific oligonucleotide PCR, and HLA-E by Sanger sequencing. CMV status was determined by anti-CMV IgG immunoassay. NK cells were considered "educated" if the HLA ligand to a KIR or NKG2A was present., Results: KIR/NKG2A co-expression patterns and percentages of educated NK cells were similar between RPL and controls, and between seropositive and seronegative RPL women. Frequencies of HLA-E genotypes and HLA-B leader peptide variants were comparable. RPL women with the HLA-B T/T variant had a lower percentage of NKG2A-educated NK cells (47.8%) compared to controls (66.4%) (p = 0.025)., Conclusions: HLA-B leader peptide variants might impact NKG2A-specific NK cell education in RPL, warranting validation in larger studies. Follow-up studies are needed to investigate the education status of uterine NK cells and their role in pregnancy., (© 2025 The Author(s). American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Abstract Background Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches. Methods High throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1344 participants, aged 6 months to 10 years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity. Results The prevalence of KIR3DS1, KIR2DL5, KIR2DS5, and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6 vs 13.2%: p = 0.006, 57.2 vs 66.4%: p = 0.005, 33.2 vs 46.6%: p

Psoriasis (Ps) is an autoimmune dermatosis. Previous studies have shown an association between KIR genes and susceptibility to some clinical variants of Ps. Therefore, we conducted an exhaustive systematic review with meta-analysis to evaluate the relationship between KIR genes and susceptibility to clinical variants of Ps in the overall population and according to ethnicity. According to PRISMA guidelines, we performed a systematic review through PubMed and Web of Science to identify relevant available scientific publications about KIR genes and Ps. The quality of the studies was evaluated using the Newcastle–Ottawa scale. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using random and fixed effect models for the analyzed genes. Heterogeneity was tested using Cochran's Q-Statistic and I2, and the risk of bias was tested using the Begg test and Egger linear regression. A total of 10 case-control studies were included, comprising a variable number of KIR typified genes and psoriasis vulgaris (PsV) as the main clinical variant studied. In the total pooled results, the KIR2DS1 gene (OR = 1.518, p =.010, 95%CI: 1.105 to 2.086) was related to higher susceptibility to PsV, while the KIR2DS4 (OR = 0.563, p =.005, 95%CI: 0.376 to 0.842) and KIR3DL1 (OR = 0.602, p =.040, 95%CI: 0.370 to 0.977) genes were related to protection against PsV. This meta-analysis demonstrates that subjects that carry the KIR2DS1 gene could have a potential risk factor for the development of PsV. Conversely, KIR2DS4 and 3DL1 genes appear to confer protection against PsV. [ABSTRACT FROM AUTHOR]

Objectives: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. Methods: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. Results: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). Conclusions: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.

The killer cell immunoglobulin-like receptor (KIR) gene cluster on chromosome 19 encodes cell surface glycoproteins that bind class I human leukocyte antigen (HLA) molecules as well as some other ligands. Through regulation of natural killer (NK) cell activity KIRs participate in tumour surveillance and clearing viral infections. KIR gene gene copy number variation associates with the outcome of transplantations and susceptibility to immune-mediated diseases. Inferring KIR gene content from genetic variant data is therefore desirable for immunogenetic analysis, particularly in the context of growing biobank genome data collections that rely on genotyping by microarray. Here we describe a stand-alone and freely available gene content imputation for 12 KIR genes. The models were trained using 807 Finnish biobank samples genotyped for 5900 KIR-region SNPs and analysed for KIR gene content with targeted sequencing. Cross-validation results demonstrate a high mean overall accuracy of 98.5% (95% CI [97.0–99.2]%) which compares favourably with previous methods including short-read sequencing based approaches.

The killer cell immunoglobulin-like receptor (KIR) gene cluster on chromosome 19 encodes cell surface glycoproteins that bind class I human leukocyte antigen (HLA) molecules as well as some other ligands. Through regulation of natural killer (NK) cell activity KIRs participate in tumour surveillance and clearing viral infections. KIR gene gene copy number variation associates with the outcome of transplantations and susceptibility to immune-mediated diseases. Inferring KIR gene content from genetic variant data is therefore desirable for immunogenetic analysis, particularly in the context of growing biobank genome data collections that rely on genotyping by microarray. Here we describe a stand-alone and freely available gene content imputation for 12 KIR genes. The models were trained using 807 Finnish biobank samples genotyped for 5900 KIR-region SNPs and analysed for KIR gene content with targeted sequencing. Cross-validation results demonstrate a high mean overall accuracy of 98.5% (95% CI [97.0-99.2]%) which compares favourably with previous methods including short-read sequencing based approaches. [ABSTRACT FROM AUTHOR]

The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR–HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR–HLA interactions among all described worldwide populations, and that 83–97% of their KIR–HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR–HLA coevolution and its impact on human health and survival. [ABSTRACT FROM AUTHOR]

© 2015. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen (HLA) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA-DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS.

Knowledge of an individual's human leukocyte antigen (HLA) genotype is essential for modern medical genetics, and is crucial for hematopoietic stem cell and solid-organ transplantation. However, the high levels of polymorphism known for the HLA genes make it difficult to generate an HLA genotype that unambiguously identifies the alleles that are present at a given HLA locus in an individual. For the last 20 years, the histocompatibility and immunogenetics community has recorded this HLA genotyping ambiguity using allele codes developed by the National Marrow Donor Program (NMDP). While these allele codes may have been effective for recording an HLA genotyping result when initially developed, their use today results in increased ambiguity in an HLA genotype, and they are no longer suitable in the era of rapid allele discovery and ultra-high allele polymorphism. Here, we present a text string format capable of fully representing HLA genotyping results. This Genotype List (GL) String format is an extension of a proposed standard for reporting killer-cell immunoglobulin-like receptor (KIR) genotype data that can be applied to any genetic data that use a standard nomenclature for identifying variants. The GL String format uses a hierarchical set of operators to describe the relationships between alleles, lists of possible alleles, phased alleles, genotypes, lists of possible genotypes, and multilocus unphased genotypes, without losing typing information or increasing typing ambiguity. When used in concert with appropriate tools to create, exchange, and parse these strings, we anticipate that GL Strings will replace NMDP allele codes for reporting HLA genotypes.

The killer-cell immunoglobulin-like receptor (KIR) proteins evolve to fight viruses and mediate the body’s reaction to pregnancy. These roles provide selection pressure for variation at both the structural/haplotype and base/allele levels. At the same time, the genes have evolved relatively recently by tandem duplication and therefore exhibit very high sequence similarity over thousands of bases. These variation-homology patterns make it impossible to interpret KIR haplotypes from abundant short-read genome sequencing data at population scale using existing methods. Here, we developed an efficient computational approach for in silico KIR probe interpretation (KPI) to accurately interpret individual’s KIR genes and haplotype-pairs from KIR sequencing reads. We designed synthetic 25-base sequence probes by analyzing previously reported haplotype sequences, and we developed a bioinformatics pipeline to interpret the probes in the context of 16 KIR genes and 16 haplotype structures. We demonstrated its accuracy on a synthetic data set as well as a real whole genome sequences from 748 individuals from The Genome of the Netherlands (GoNL). The GoNL predictions were compared with predictions from SNP-based predictions. Our results show 100% accuracy rate for the synthetic tests and a 99.6% family-consistency rate in the GoNL tests. Agreement with the SNP-based calls on KIR genes ranges from 72%–100% with a mean of 92%; most differences occur in genes KIR2DS2, KIR2DL2, KIR2DS3, and KIR2DL5 where KPI predicts presence and the SNP-based interpretation predicts absence. Overall, the evidence suggests that KPI’s accuracy is 97% or greater for both KIR gene and haplotype-pair predictions, and the presence/absence genotyping leads to ambiguous haplotype-pair predictions with 16 reference KIR haplotype structures. KPI is free, open, and easily executable as a Nextflow workflow supported by a Docker environment at https://github.com/droeatumn/kpi.

The homology, recombination, variation, and repetitive elements in the natural killer-cell immunoglobulin-like receptor (KIR) region has made full haplotype DNA interpretation impossible in a high-throughput workflow. Here, we present a new approach using long-read sequencing to efficiently capture, sequence, and assemble diploid human KIR haplotypes. Probes were designed to capture KIR fragments efficiently by leveraging the repeating homology of the region. IDT xGen® Lockdown probes were used to capture 2–8 kb of sheared DNA fragments followed by sequencing on a PacBio Sequel. The sequences were error corrected, binned, and then assembled using the Canu assembler. The location of genes and their exon/intron boundaries are included in the workflow. The assembly and annotation was evaluated on 16 individuals (8 African American and 8 Europeans) from whom ground truth was known via long-range sequencing with fosmid library preparation. Using only 18 capture probes, the results show that the assemblies cover 97% of the GenBank reference, are 99.97% concordant, and it takes only 1.8 haplotigs to cover 75% of the reference. We also report the first assembly of diploid KIR haplotypes from long-read WGS. Our targeted hybridization probe capture and sequencing approach is the first of its kind to fully sequence and phase all diploid human KIR haplotypes, and it is efficient enough for population-scale studies and clinical use. The open and free software is available at https://github.com/droeatumn/kass and supported by a environment at https://hub.docker.com/repository/docker/droeatumn/kass.

Background: Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches. Methods: High throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1344 participants, aged 6 months to 10 years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity. Results: The prevalence of KIR3DS1, KIR2DL5, KIR2DS5, and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6 vs 13.2%: p = 0.006, 57.2 vs 66.4%: p = 0.005, 33.2 vs 46.6%: p < 0.001, and 19.7 vs 26.7%: p = 0.014, respectively) or Jinja (7.6 vs 18.1%: p < 0.001, 57.2 vs 63.8%: p = 0.048, 33.2 vs 43.5%: p = 0.002, and 19.7 vs 30.4%: p < 0.001, respectively). The prevalence of homozygous HLA-C2 was significantly higher in populations from Kanungu (31.6%) compared to Jinja (21.4%), p = 0.043, with no significant difference between Kanungu and Tororo (26.7%), p = 0.296. Conclusions: The KIR3DS1, KIR2DL5, KIR2DS5 and KIR2DS1 genes may partly explain differences in transmission intensity of malaria since these genes have been positively selected for in places with historically high malaria transmission intensity. The high-throughput, multiplex, real-time HLA-C genotyping PCR method developed will be useful in disease-association studies involving large cohorts. [ABSTRACT FROM AUTHOR]

The killer-cell immunoglobulin-like receptor (KIR) proteins evolve to fight viruses and mediate the body's reaction to pregnancy. These roles provide selection pressure for variation at both the structural/haplotype and base/allele levels. At the same time, the genes have evolved relatively recently by tandem duplication and therefore exhibit very high sequence similarity over thousands of bases. These variation-homology patterns make it impossible to interpret KIR haplotypes from abundant short-read genome sequencing data at population scale using existing methods. Here, we developed an efficient computational approach for in silico KIR probe interpretation (KPI) to accurately interpret individual's KIR genes and haplotype-pairs from KIR sequencing reads. We designed synthetic 25-base sequence probes by analyzing previously reported haplotype sequences, and we developed a bioinformatics pipeline to interpret the probes in the context of 16 KIR genes and 16 haplotype structures. We demonstrated its accuracy on a synthetic data set as well as a real whole genome sequences from 748 individuals from The Genome of the Netherlands (GoNL). The GoNL predictions were compared with predictions from SNP-based predictions. Our results show 100% accuracy rate for the synthetic tests and a 99.6% family-consistency rate in the GoNL tests. Agreement with the SNP-based calls on KIR genes ranges from 72%–100% with a mean of 92%; most differences occur in genes KIR2DS2 , KIR2DL2 , KIR2DS3 , and KIR2DL5 where KPI predicts presence and the SNP-based interpretation predicts absence. Overall, the evidence suggests that KPI's accuracy is 97% or greater for both KIR gene and haplotype-pair predictions, and the presence/absence genotyping leads to ambiguous haplotype-pair predictions with 16 reference KIR haplotype structures. KPI is free, open, and easily executable as a Nextflow workflow supported by a Docker environment at https://github.com/droeatumn/kpi. [ABSTRACT FROM AUTHOR]

Background: The prognosis of high‐risk neuroblastoma stage 4 with bone marrow metastasis, MYCN amplified, or refractory neuroblastoma is poor. To date, no standard treatment has been established. In four selected cases, we challenged the killer‐cell immunoglobulin‐like receptor ligand mismatch cord blood transplantation in graft‐versus‐host disease (GVHD) with reduced‐intensity conditioning. Methods: Prior to this study, conventional chemotherapy, autologous peripheral blood stem cell transplantation with high‐dose chemotherapy (busulfan and melphalan), surgery and radiation therapy were completed in every case. The status before cord blood transplantation in two cases was not complete remission (CR) and in the others it was CR. The primary site was the mediastinum, two adrenal glands and a retroperitoneum, respectively. Three patients had bone and bone marrow metastasis and one had MYCN amplification. In all cases, international neuroblastoma pathology classification was unfavorable histology. All patients were >2 years of age. Results: Relapse occurred only in one patient 17 months after the last transplantation, and the other three patients maintained disease‐free survival for 74, 36, and 24 months, respectively. In one case of relapse the disease could be controlled by conventional chemotherapy. Except one, all patients had no severe complications, such as acute or chronic GVHD. One patient had gastric antral vascular ectasia and hemorrhagic cystitis. Conclusion: This strategy might be feasible and should be investigated for efficacy in the future. No definite conclusion can be made, however, due to the very small number of patients. Further prospective studies are required to determine its efficacy. [ABSTRACT FROM AUTHOR]

Our understanding of the genetic basis of host resistance to viral infection and disease has progressed significantly over the last century. Numerous genes coding for modifiers of immune functions have been identified, which impact a variety of critical cellular processes, including signaling via lymphocyte receptors and their ligands, signal transduction, cytokine signaling, production and release of cytotoxic effectors, transcriptional regulation, and proliferation. Genome‐wide association studies implicate an important role for both highly polymorphic NK cell receptors and their MHC class I ligands in modifying host resistance. These findings indicate NK cells are critical mediators of viral control with considerable potential to affect morbidity and mortality outcomes. They further suggest that both stimulatory and inhibitory NK receptor polymorphisms alter NK cell sensing of MHC I ligands on viral targets, which influences how NK cells respond to infection. In many cases, however, the underlying causes associated with host outcomes remain elusive. Herein, we discuss several modes of NK cell sensing of MHC I and MHC I‐like molecules on viral targets, and the role of genetic diversity in this evolutionarily dynamic process. We further suggest that natural selection for paired NK receptors with opposing function, but shared MHC I ligands may give rise to rare, but highly effective MHC I‐dependent modes of NK cell sensing of viral targets. NK inhibitory and activating receptors undergo natural selection together with their MHC l ligands which can affect optimal sensing of virus infected cells and host response. [ABSTRACT FROM AUTHOR]

BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.

Summary: Formation of supramolecular assemblies appears to be a general mechanism in immune signalling pathways. These supramolecular assemblies appear to form through a nucleated polymerization mechanism. This review examines selected immune signalling pathways that involve supramolecular assemblies, describes the concepts of protein polymerization, and discusses how those concepts of protein polymerization implicate new elegant ways for signal amplification, setting threshold and noise reduction in these pathways. Formation of supramolecular assemblies appears to be a general mechanism in immune signalling pathways. This review examines selected immune signalling pathways that involve supramolecular assemblies, describes the concepts of protein polymerization, and discusses how those concepts may implicate new molecular mechanisms in signal transduction. [ABSTRACT FROM AUTHOR]

Adaptive-like expansions of natural killer (NK) cell subsets are known to occur in response to human cytomegalovirus (CMV) infection. These expansions are typically made up of NKG2C+ NK cells with particular killer-cell immunoglobulin-like receptor (KIR) expression patterns. Such NK cell expansion patterns are also seen in patients with viral hepatitis infection. Yet, it is not known if the viral hepatitis infection promotes the appearance of such expansions or if effects are solely attributed to underlying CMV infection. In sizeable cohorts of CMV seropositive hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) infected patients, we analyzed NK cells for expression of NKG2A, NKG2C, CD57, and inhibitory KIRs to assess the appearance of NK cell expansions characteristic of what has been seen in CMV seropositive healthy individuals. Adaptive-like NK cell expansions observed in viral hepatitis patients were strongly associated with CMV seropositivity. The number of subjects with these expansions did not differ between CMV seropositive viral hepatitis patients and corresponding healthy controls. Hence, we conclude that adaptive-like NK cell expansions observed in HBV, HCV, and/or HDV infected individuals are not caused by the chronic hepatitis infections per se, but rather are a consequence of underlying CMV infection.

Adaptive-like expansions of natural killer (NK) cell subsets are known to occur in response to human cytomegalovirus (CMV) infection. These expansions are typically made up of NKG2C+ NK cells with particular killer-cell immunoglobulin-like receptor (KIR) expression patterns. Such NK cell expansion patterns are also seen in patients with viral hepatitis infection. Yet, it is not known if the viral hepatitis infection promotes the appearance of such expansions or if effects are solely attributed to underlying CMV infection. In sizeable cohorts of CMV seropositive hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) infected patients, we analyzed NK cells for expression of NKG2A, NKG2C, CD57, and inhibitory KIRs to assess the appearance of NK cell expansions characteristic of what has been seen in CMV seropositive healthy individuals. Adaptive-like NK cell expansions observed in viral hepatitis patients were strongly associated with CMV seropositivity. The number of subjects with these expansions did not differ between CMV seropositive viral hepatitis patients and corresponding healthy controls. Hence, we conclude that adaptive-like NK cell expansions observed in HBV, HCV, and/or HDV infected individuals are not caused by the chronic hepatitis infections per se, but rather are a consequence of underlying CMV infection. [ABSTRACT FROM AUTHOR]

Besides donor T cells, natural killer (NK) cells are considered to have a major role in preventing relapse after allogeneic hematopoietic stem cell transplantation (HSCT). After T-cell-depleted haploidentical HSCT, a strong NK alloreactivity has been described. These effects have been attributed to killer-cell immunoglobulin-like receptors (KIR). Abundant reports suggest a major role of KIR not only on outcome after haploidentical HSCT but also in the unrelated donor setting. In this review, we give a brief overview of the mechanism of NK cell activation, nomenclature of KIR haplotypes, human leukocyte antigen (HLA) groups, and distinct models for prediction of NK cell alloreactivity. It can be concluded that KIR-ligand mismatch seems to provoke adverse effects in unrelated donor HSCT with reduced overall survival and increased risk for high-grade acute graftversus- host disease. The presence of activating KIR, as seen in KIR haplotype B, as well as the patient's HLA C1/x haplotype might reduce relapse in myeloid malignancies. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth. Natural killer (NK) cells play a pivotal role in immunological surveillance. Activation of NK cells partially depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. We herein investigated the association of KIRs and HLA ligands with survival in metastatic NSCLC (mNSCLC) patients treated with chemotherapy in a Chinese Han population. Polymerase chain reaction with sequence-specific primers was used to type 15 KIRs at the DNA and mRNA level and 6 HLA ligands in 70 mNSCLC patients. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression model was applied for multivariate survival analysis, with the stepwise selection, to determine independent predictors of survival. It was observed that patients with KIR2DS4del gene expression at the mRNA level or HLA-Bw4T80 exhibited poor overall survival (OS). The multivariate analysis revealed that HLA-Bw4T80 and KIR2DS4del expression were independent predictors of OS. This observation indicated that the KIR/HLA ligand is a promising predictor of survival in mNSCLC and may also provide a strategy for treatment stratification and patient management. [ABSTRACT FROM AUTHOR]

BK virus is a common opportunistic post-transplantation viral infection. Although some risk factors have been studied in this context, the contribution of NK cells has not been assessed in detail. In a group of kidney transplant recipients, we studied the association between (i) the likelihood of BK virus replication during the two-year period after kidney transplantation and (ii) the genotypes of the killer cell immunoglobulin-like receptor (KIR) repertoire and their human leukocyte antigen (HLA) ligands. Other clinical factors (such as defective organ recovery and immunosuppressive treatment) were also assessed. BK virus replication was observed in 43 of the 103 recipients (41%). Patients with BK virus replication in the plasma were more likely to display defective organ recovery in the first seven days post-transplantation. BK virus replication was not associated with Missing KIR ligands. However, BK virus replication was more frequent in patients with responsive NK cells (i.e. when a ligand for activating KIRs was not homozygous in the recipient and present in the donor). Our results suggest that defective organ recovery and the recipient's activating KIR repertoire may be related (depending on HLA ligands present in the couple recipient / donor) to the reactivation of BK virus replication after kidney transplantation. [ABSTRACT FROM AUTHOR]

Background: We aimed herein to investigate the killer-cell immunoglobulin-like receptor (KIR) genes and human leukocyte antigen (HLA)-C alleles in patients with common variable immunodeficiency (CVID), and to reveal their differences from those in healthy population. Methods: In all, 18 patients who have been diagnosed with CVID and 15 living donors of kidney transplant recipients were enrolled in the study. Polymerase chain reaction-sequence-specific primer (PCR-SSP) typing method was used in molecular genetic analysis. The frequencies of the genes in the study groups were statistically compared with each other using chi-square or Fisher exact tests, whichever were appropriate. Results: Although there was no significant difference between both study groups with respect to distribution of KIR and HLA-C2 group genes, HLA-Cw7 allele frequency in patients with CVID was significantly lower than that in healthy population ( P = 0.008). Conclusion: This present study results support that HLA-Cw7 allele, an inhibitor of KIR ligand, may play a role in the pathogenesis of CVID. [ABSTRACT FROM AUTHOR]