Search Results (21)

Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Cetuximab improves survival by combining EGFR inhibition with immune activation. This study evaluated the influence of killer cell immunoglobulin-like receptor (KIR)-mediated immune responses on cetuximab efficacy in 124 metastatic CRC patients: 55 with wild-type (WT) KRAS and 69 with KRAS mutations. Peripheral blood was genotyped for 19 KIR genes and relevant HLA alleles, focusing on key KIR–HLA interactions (2DL1–C2, 3DL1–Bw4, 3DS1–Bw4). KRAS-WT patients showed better outcomes, receiving more treatment cycles (median: 17 vs. 4) and showing slower disease progression (60% vs. 92.8% at 12 months). WT patients had higher frequencies of inhibitory KIRs and the Bw4 allele, with KIR3DS1–Bw4 heterozygosity linked to longer survival (p = 0.013). In KRAS-mutant patients, heterozygous KIR genotypes (AB) and mixed A/B semi-haplotypes were associated with improved survival (p = 0.002). Multivariate analysis confirmed KIR3DS1–Bw4 as a favorable factor in WT patients and AB genotypes as beneficial in KRAS-mutants. In conclusion, KIR–HLA interactions significantly impact cetuximab efficacy in metastatic CRC, with distinct immunogenetic profiles in WT and KRAS-mutant patients. These results highlight the potential of KIR–HLA profiling to guide personalized treatment strategies. Full article

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. Full article

Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is the main limitation of transfusion, which can worsen anaemia and lead to delayed haemolytic transfusion reaction or transfusion deadlock. Although biological risk factors have been identified for immunisation, patient alloimmunisation remains difficult to predict. We aimed to characterise genetic alloimmunisation factors to optimise the management of blood products compatible with extended antigen matching to ensure the self-sufficiency of labile blood products. Considering alloimmunisation in other clinical settings, like pregnancy and transplantation, many studies have shown that HLA Ib molecules (HLA-G, -E, and -F) are involved in tolerance mechanism; these molecules are ligands of immune effector cell receptors (LILRB1, LILRB2, and KIR3DS1). Genetic polymorphisms of these ligands and receptors have been linked to their expression levels and their influence on inflammatory and immune response modulation. Our hypothesis was that polymorphisms of HLA Ib genes and of their receptors are associated with alloimmunisation susceptibility in SCD patients. The alloimmunisation profile of thirty-seven adult SCD patients was analysed according to these genetic polymorphisms and transfusion history. Our results suggest that the alloimmunisation of SCD patients is linked to both HLA-F and LILRB1 genetic polymorphisms located in their regulatory region and associated with their protein expression level. Full article

Decompensated cirrhosis is the most common cause of ascites due to hemodynamic and renal alteration by continuous fluid leakage from the hepatic sinusoids and splanchnic capillaries into the interstitial space. Then, fluid leakage exceeds lymphatic return, leading to progressive fluid accumulation directly into the peritoneal cavity. Alcohol consumption is one of the main risks of developing alcoholic cirrhosis (AC), but not all AC patients develop ascites. Avoiding the development of ascites is crucial, given that it deteriorates prognosis and increases the patient mortality patient. The innate immune system plays a crucial role in cirrhosis through natural killer cells, which are abundant in the liver. The aim of this study was to analyze the KIR/HLA-C genetic profile in AC patients with and without ascites to understand this pathology and find predictive clinical susceptibility biomarkers that can help to establish risks and prevent the development of ascites in AC patients. A total of 281 AC patients with and without ascites were analyzed and compared with 319 healthy controls. Genomic DNA was extracted from peripheral blood in all groups. A PCR-SSO assay was performed for KIR/HLA genotyping analysis. A total of 16 activating and inhibitor KIR genes and their corresponding known ligands, epitopes of HLA-C, and their genotypes were analyzed. According to our analysis, C1 epitopes were statistically significantly decreased in AC patients with and without ascites. When comparing AC patients with ascites and healthy controls, a significant decrease in C1 epitope frequency was also observed. A statistically significant decrease was also found when comparing the C1C2 genotype in AC patients without ascites with controls. In conclusion, the absence of KIR2DL2 and KIR3DL1 genes may be a predisposing factor for the development of ascites in AC patients. The KIR2DS2/KIR2DL2 may could be involved in grade I ascites development, and the presence of the C1+ epitope and the homozygous C2C2 genotype may be protective genetic factors against ascites development in AC patients. Full article

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. Full article

Purpose: The immune responses of natural killer (NK) cells against cancer cells vary by patient. Killer Ig-like receptors (KIRs), which are some of the major receptors involved in regulating NK cell activity for killing cancer cells, have significant genetic variation. Numerous studies have suggested a potential association between the genetic variation of KIR genes and the risk of development or prognosis of various cancer types. However, an association between genetic variations of KIR genes and glioblastoma (GB) remains uncertain. We sought to evaluate the association of genetic variations of KIRs and their ligand genes with the risk of GB development in Koreans. Methods: A case–control study was performed to identify the odds ratios (ORs) of KIR genes and Classes A, B, and, C of the human leukocyte antigen (HLA) for GB. The GB group was comprised of 77 patients with newly diagnosed IDH-wildtype GB at our institution, and the control group consisted of 200 healthy Korean volunteers. Results: There was no significant difference in the frequency of KIR genes and KIR haplotypes between the GB and control groups. Genetic variations of KIR-2DL1, 3DL1, and 3DS1 with their ligand genes (HLA-C2, HLA-Bw4/6, and Bw4, respectively) had effects on the risk of GB in Korean patients. The frequency of KIR-2DL1 with HLA-C2 (OR 2.05, CI 1.19–3.52, p = 0.009), the frequency of KIR-3DL1 without HLA-Bw4 (80I) (OR 8.36, CI 4.06–17.18, p < 0.001), and the frequency of KIR-3DL1 with Bw6 (OR 4.54, CI 2.55–8.09, p < 0.001) in the GB group were higher than in the control group. In addition, the frequency of KIR-2DL1 without HLA-C2 (OR 0.44, CI 0.26–0.75, p = 0.003), the frequency of KIR-3DL1 with HLA-Bw4 (80T) (OR 0.13, CI 0.06–0.27, p < 0.001), the frequency of KIR-3DL1 without Bw6 (OR 0.27, CI 0.15–0.49, p < 0.001), and the frequency of KIR-3DS1 with Bw4 (80I) (OR 0.03, CI 0.00–0.50, p < 0.001) in the GB group were lower than in the control group. Conclusions: This study suggests that genetic variations of KIRs and their ligand genes may affect GB development in the Korean population. Further investigations are needed to demonstrate the different immune responses for GB cells according to genetic variations of KIR genes and their ligand genes. Full article

Chronic lymphocytic leukaemia (CLL) is characterised by the expansion of a neoplastic mature B cell clone. CLL clinical outcome is very heterogeneous, with some subjects never requiring therapy and some showing an aggressive disease. Genetic and epigenetic alterations and pro-inflammatory microenvironment influence CLL progression and prognosis. The involvement of immune-mediated mechanisms in CLL control needs to be investigated. We analyse the activation profile of innate and adaptive cytotoxic immune effectors in a cohort of 26 CLL patients with stable disease, as key elements for immune-mediated control of cancer progression. We observed an increase in CD54 expression and interferon (IFN)-γ production by cytotoxic T cells (CTL). CTL ability to recognise tumour-targets depends on human leukocyte antigens (HLA)-class I expression. We observed a decreased expression of HLA-A and HLA-BC on B cells of CLL subjects, associated with a significant reduction in intracellular calnexin that is relevant for HLA surface expression. Natural killer (NK) cells and CTL from CLL subjects show an increased expression of the activating receptor KIR2DS2 and a reduction of 3DL1 and NKG2A inhibiting molecules. Therefore, an activation profile characterises CTL and NK cells of CLL subjects with stable disease. This profile is conceivable with the functional involvement of cytotoxic effectors in CLL control. Full article

Background: The second-most frequent diagnosis among patients receiving liver transplants (LTs) is alcoholic liver disease. The multifactorial pathophysiology of alcoholic liver disease depends on the innate immune system and the inflammatory cascade. According to recent studies on these receptors, killer-cell immunoglobulin-like receptors (KIRs) may be involved in sepsis, liver rejection, and virus relapse. We aimed to investigate the impact of preclinical issues like ascites and encephalopathy and KIR genetic traits on death from sepsis, multiorgan failure (MF), and graft failure (GF) in AC patients undergoing LTs. Methods: We retrospectively reviewed 164 consecutive and deceased Caucasian AC patients who underwent LTs. Pre-transplant complications, cause of death, and patient survival were analyzed. Genomic DNA was taken from peripheral blood, and PCR-SSO was used for genotyping KIR. Results: Compared to GF patients, there was a statistically significant increase in the frequency of KIR2DL2+ (75.8% vs. 51.2%; p = 0.047). Another increase in frequency was also observed in KIR2DS2+ in sepsis compared to the GF group (51.2% vs. 43.7%; p = 0.018). In patients who passed away from MF, a decrease in KIR2DL5+ was observed in AC patients with and without encephalopathy (p = 0.018). The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.045), which was confirmed by multivariate logistic regression. The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.012) and was confirmed by multivariate logistic regression. KIR2DS1+ and KIR2DS4+ showed increased mortality due to GF compared to patients without these genes (p = 0.011 and 0.012, respectively). However, this fact was confirmed only for KIR2DS1+ by multivariate logistic Cox regression. Conclusions: The presence of the KIR2DL2/S2+, KIR2DL5+, and KIR3DL1+ genes increases the frequency of death from multiple organ failure or graft failure. Our findings highlight the AC patient’s vulnerability to a LT during hospitalization. Following the transplant and outside of it, we adopt essential preventive measures to create a routine healthcare screening to enhance and modify treatments to increase survival. Full article

Asthma heterogeneity complicates the search for targeted treatment against airway inflammation and remodeling. We sought to investigate relations between eosinophilic inflammation, a phenotypic feature frequent in severe asthma, bronchial epithelial transcriptome, and functional and structural measures of airway remodeling. We compared epithelial gene expression, spirometry, airway cross-sectional geometry (computed tomography), reticular basement membrane thickness (histology), and blood and bronchoalveolar lavage (BAL) cytokines of n = 40 moderate to severe eosinophilic (EA) and non-eosinophilic asthma (NEA) patients distinguished by BAL eosinophilia. EA patients showed a similar extent of airway remodeling as NEA but had an increased expression of genes involved in the immune response and inflammation (e.g., KIR3DS1), reactive oxygen species generation (GYS2, ATPIF1), cell activation and proliferation (ANK3), cargo transporting (RAB4B, CPLX2), and tissue remodeling (FBLN1, SOX14, GSN), and a lower expression of genes involved in epithelial integrity (e.g., GJB1) and histone acetylation (SIN3A). Genes co-expressed in EA were involved in antiviral responses (e.g., ATP1B1), cell migration (EPS8L1, STOML3), cell adhesion (RAPH1), epithelial–mesenchymal transition (ASB3), and airway hyperreactivity and remodeling (FBN3, RECK), and several were linked to asthma in genome- (e.g., MRPL14, ASB3) or epigenome-wide association studies (CLC, GPI, SSCRB4, STRN4). Signaling pathways inferred from the co-expression pattern were associated with airway remodeling (e.g., TGF-β/Smad2/3, E2F/Rb, and Wnt/β-catenin). Full article

Postoperative cognitive dysfunction (POCD) is cognitive decline after surgery. The authors hypothesized that gene-level changes could be involved in the pathogenesis of POCD. The present study evaluated the incidence of POCD and its associated differentially expressed genes. This was a prospective cohort study conducted on high-risk coronary artery bypass graft patients aged 40 to 75 years. POCD classification was based on a one standard deviation decline in the postoperative scores compared to the preoperative scores. The differentially expressed genes were identified using microarray analysis and validated using quantitative RT-PCR. Forty-six patients were recruited and completed the study. The incidence of POCD was identified using a set of neurocognitive assessments and found to be at 17% in these high-risk CABG patients. Six samples were selected for the gene expression analyses (3 non-POCD and 3 POCD samples). The findings showed five differentially expressed genes in the POCD group compared to the non-POCD group. The upregulated gene was ERFE, whereas the downregulated genes were KIR2DS2, KIR2DS3, KIR3DL2, and LIM2. According to the results, the gene expression profiles of POCD can be used to find potential proteins for POCD diagnostic and predictive biomarkers. Understanding the molecular mechanism of POCD development will further lead to early detection and intervention to reduce the severity of POCD, and hence, reduce the mortality and morbidity rate due to the condition. Full article

Chronic liver rejection (CR) represents a complex clinical situation because many patients do not respond to increased immunosuppression. Killer cell immunoglobulin-like receptors/Class I Human Leukocyte Antigens (KIR/HLA-I) interactions allow for predicting Natural Killer (NK) cell alloreactivity and influence the acute rejection of liver allograft. However, its meaning in CR liver graft remains controversial. KIR and HLA genotypes were studied in 513 liver transplants using sequence-specific oligonucleotides (PCR-SSO) methods. KIRs, human leucocyte antigen C (HLA-C) genotypes, KIR gene mismatches, and the KIR/HLA-ligand were analyzed and compared in overall transplants with CR (n = 35) and no-chronic rejection (NCR = 478). Activating KIR (aKIR) genes in recipients (rKIR2DS2⁺ and rKIR2DS3⁺) increased CR compared with NCR groups (p = 0.013 and p = 0.038). The inhibitory KIR (iKIR) genes in recipients rKIR2DL2⁺ significantly increased the CR rate compared with their absence (9.1% vs. 3.7%, p = 0.020). KIR2DL3 significantly increases CR (13.1% vs. 5.2%; p = 0.008). There was no influence on NCR. CR was observed in HLA-I mismatches (MM). The absence of donor (d) HLA-C2 ligand (dC2⁻) ligand increases CR concerning their presence (13.1% vs. 5.6%; p = 0.018). A significant increase of CR was observed in rKIR2DL3⁺/dC1⁻ (p = 0.015), rKIR2DS4/dC1⁻ (p = 0.014) and rKIR2DL3⁺/rKIR2DS4⁺/dC1⁻ (p = 0.006). Long-term patient survival was significantly lower in rKIR2DS1⁺rKIR2DS4⁺/dC1⁻ at 5–10 years post-transplant. This study shows the influence of rKIR/dHLA-C combinations and aKIR gene-gene mismatches in increasing CR and KIR2DS1⁺/C1-ligands and the influence of KIR2DS4⁺/C1-ligands in long-term graft survival. Full article

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

Background: coronavirus disease 2019 (COVID-19) causes severe illness including cytokine storms, but mortality among countries differs largely. In the present study, we investigated the association between human leukocyte antigen (HLA) class I, which plays a major role in susceptibility to viral infections, and the mortality of COVID-19. Methods: data of allele frequencies of HLA-A, -B and -C and COVID-19 mortality were obtained for 74 countries from the Allele Frequency Net Database and worldometer.info. Association between allele frequency of each HLA and mortality was assessed by linear regression followed by multivariable regression. Subsequently, association of HLA-C*05 to its receptor KIR2DS4fl, expressed on natural killer (NK) cells, and differential mortality to historic pandemics were analyzed. Results: HLA-A*01, -B*07, -B*08, -B*44 and -C*05 were significantly associated with the risk of deaths (adjusted p = 0.040, 0.00081, 0.047, 0.0022, 0.00032, respectively), but only HLA-C*05 remained statistically significant (p = 0.000027) after multivariable regression. A 1% increase in the allele frequency of HLA-C*05 was associated with an increase of 44 deaths/million. Countries with different mortality could be categorized by the distribution of HLA-C*05 and its receptor KIR2DS4fl, which in combination cause NK cell-induced hyperactive immune response. Countries with similar ethnic and/or geographic background responded in a similar pattern to each pandemic. Conclusions: we demonstrated that allele frequency of HLA-C*05 and the distribution pattern with its receptor KIR2DS4fl strongly correlated with COVID-19 mortality. Host genetic variance of innate immunity may contribute to the difference in mortality among various countries and further investigation using patient samples is warranted. Full article

The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4⁺ T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4⁺/HIV⁻ and CD4⁺/HIV⁺ cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4⁺ T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape. Full article

NK and some T cell functions are regulated by the interaction between KIR and HLA molecules. Several studies have shown an association between activating KIR genes and the development of autoimmune diseases, including psoriasis vulgaris (PsV). Our objective was to determine the association between KIR/HLA genes and genotypes with PsV in the Western mestizo Mexican population. One hundred subjects diagnosed with PsV (SP) and 108 healthy subjects (HS) were genotyped for 14 KIR genes, HLA-Bw4, HLA-C1, and HLA-C2 by PCR-single specific primer (SSP). Positive associations of the KIR3DS1 gene (odds ratio (OR) 1.959, p = 0.021), G11 genotype (OR 19.940, p = 0.008), and KIR3DS1/HLA-A^Bw4 (OR 2.265, p = 0.009) were found with susceptibility to PsV. In contrast, the G1 genotype (OR 0.448, p = 0.031) and KIR3DL1/HLA-Bw4^Ile80 (OR 0.522, p = 0.022) were negatively associated with susceptibility to this disease. These results suggest an implication of the KIR3DS1/HLA-A^Bw4 genotype in PsV pathology. Full article