Killer Immunoglobulin-like Receptors Polymorphisms Research Articles

HLA Polymorphisms Are Associated with Treatment-Free Remission Following Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Treatment-free remission (TFR) is one of the therapeutic goals for patients with chronic phase chronic myeloid leukemia (CML-CP). Although previous reports indicated that antitumor immunity contributes to TFR, its determinants are still unclear. We previously reported that allelic polymorphisms of killer immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA) are associated with achievement of deep molecular response (DMR) in patients with CML-CP. Here, we examined the association between TFR and polymorphisms of KIRs and HLAs in patients who discontinued tyrosine kinase inhibitors (TKI). Seventy-six patients were enrolled, and their KIR and HLA polymorphisms and natural killer (NK) cell activation status were investigated as previously described. Overall, 33 patients discontinued TKIs, and 21 of 33 achieved TFR [63.6%; 95% confidence interval (CI), 44.9%-77.5%] at 1 year. Multivariate analysis revealed that male sex (HR, 0.157; 95% CI, 0.031-0.804; P = 0.003) and HLA-A*02:01, *11:01, or *24:02 (HR, 6.386; 95% CI, 1.701-23.980; P = 0.006) were associated with TFR. Patients who achieved DMR and discontinued TKIs exhibited higher NK cell activation status than those who did not. By contrast, there were no significant differences in NK cell activation status between the patients who achieved TFR and those who experienced molecular relapse. These results suggest NK cell activation status contributes to achievement of DMR, whereas T-cell-mediated immunity contributes to TFR in patients with CML-CP.

Redox, immune and genetic biomarker system for personalized treatments in colorectal cancer.

BACKGROUNDIdentifying biomarkers for the risk of developing degenerative processes linked to aging and colorectal cancer (CRC) onset that could improve clinical strategies.AIMTo determine valid targets and a predictive biomarker’s system of chronicization of inflammation for cancer treatment.METHODSA group of 147 CRC patients was studied. Clinical diagnosis was confirmed histopathologically, and patients were sub-typed using the pathological tumor-node-metastasis classification. Thirteen colon adenoma patients and 219 healthy subjects were also studied. A system biology study on Thioredoxin1/CD30 redox-immune systems (Trx1/CD30), T helper cytokines and polymorphisms of killer immunoglobulin-like receptors, FcγRIIa-131H/R and FcγRIIIa-158V/F was carried out. Enzyme-linked immunosorbent assay was performed to analyze sera. Genetic study was executed by polymerase chain reaction sequence-specific primers and sequence-based typing method. Statistical analysis was performed by using the “Statgraphics software systems”.RESULTSWe found a positive increase between Trx1/RTrx1 levels and sCD30 level and increased age. With respect to the gender relationships, there were distinct differences. Females showed a primary relationship between transforming growth factor beta (TGFβ) with Trx1, whereas males had one with TGFβ and RTrx1. Trx1/CD30 controls the redox immune homeostasis, and an imbalance in the relationship between the Trx1/RTrx1 and sCD30 levels is linked to the onset and progression of tumor. This event happens through different gender-specific cytokine pathways. Our study demonstrated that the serum levels of Trx1/RTrx1, TGFβ/interleukin (IL)6 and TGFβ/IL4 combinations and the sCD30, IFNγ and IL2 combination constitute a predictive gender specific biomarker system. This is relevant for clinical screening to detect the risk of the potential development or progression of a tumor.CONCLUSIONOxidative stress on Trx1/CD30 is a trigger of cancer disease, and the selected oxidation and immune products are a biomarker system for aging and cancer.

Association study between killer immunoglobulin-like receptor polymorphisms and ankylosing spondylitis disease: An updated meta-analysis.

Several genetic studies have assessed the association between polymorphisms in killer immunoglobulin-like receptors (KIR) genes and susceptibility of individuals to ankylosing spondylitis (AS), but the findings have been inconclusive and incongruous. Therefore, we conducted this meta-analysis of all case-control studies meeting the inclusion criteria for obtaining an exact conclusion of the effect of KIR polymorphisms on the risk of AS. A systematic literature search was conducted in electronic databases, including Scopus web of science, ScienceDirect, and PubMed to find all eligible studies exploring the association between KIR polymorphisms and the risk of AS, prior to June 2017. Pooled odds ratios (OR) and their corresponding 95% CIs were used to evaluate the strength of the association between KIR polymorphisms and the risk of AS. A total of 16 case-control studies, encompassed in 12 papers, with 1770 cases and 2907 healthy subjects were included in the meta-analysis. This meta-analysis revealed three significant positive associations of 2DS1, 2DS5, and 3DS1 with susceptibility to AS, while two significant negative associations of 2DL2 and 2DS2 with susceptibility to AS were identified. In the subgroup analysis based on human leukocyte antigen (HLA)-B*27 positive patients and healthy subjects, results indicated that there were four significant positive associations between 2DL5, 2DS4, 2DS5, 3DS1 polymorphisms and susceptibility to AS in HLA-B*27-positive patients; a significant negative association of 3DL1 in HLA-B*27-positive patients was found. While 2DS1, 2DS5, and 3DS1 polymorphisms increased AS risk, 2DL2 and 2DS2 polymorphisms were associated with reduced AS susceptibility.

Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML.

Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR-HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109-3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745-54. ©2018 AACR.

Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility.

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

Natural killer cell killer immunoglobulin-like gene receptor polymorphisms in non-Hodgkin lymphoma: possible association with clinical course

Natural killer (NK) cell killer immunoglobulin-like receptors (KIRs) contribute to the pathogenesis of many diseases. We determined the association between polymorphisms of KIR and their ligands and susceptibility to non-Hodgkin lymphoma (NHL), clinical features and prognosis. We included 90 patients with NHL and 94 controls. In the NHL group, KIR2DS1, HLA-Bw4 (Thr80) and HLA-Bw4 (Thr80)+/Bw4 (Iso80)− ligands were significantly more frequent. Patients with early-stage NHL had more frequent KIR2DL5 and KIR2DL5B than patients with advanced-stage NHL. During a median follow-up of 27 months, 26 patients with NHL died. Poor prognostic factors in univariate analysis were KIR2DL5A, KIR2DS1 and KIR3DS1 genotypes. In multivariate Cox regression analysis, advanced age and early relapse were poor prognostic factors. KIR genes and ligands had no significant effect on survival. The activating KIR2DS1 gene might activate NK cells, contributing to the production of more lymphoma cells. In addition, KIR2DS1, KIR2DL5A and KIR3DS1 might also be associated with a poor prognosis in NHL.

Specific KIR and HLA Genotypes Affect Outcomes Of Single-Agent Anti-CD20 Immunotherapy Of Follicular Lymphoma

Lymphoma immunotherapy with anti-CD20 antibody (rituximab) acts primarily through Antibody Dependent Cellular Cytotoxicity (ADCC), implying a role for NK cells. The activation and inhibition of NK cells are influenced by Killer Immunoglobulin-like Receptors (KIRs) and their HLA ligands. To evaluate the involvement of NK cells in response to immunotherapy, we investigated the role of both KIR and HLA polymorphisms in response to single agent rituximab. We have analyzed the relationship between patient genotype and clinical parameters to determine if there are beneficial KIR/HLA interactions that can lead to improved clinical outcome. Methods204 follicular lymphoma (FL) patients participating in the Eastern Cooperative Oncology Group (ECOG) RESORT trial (E4402) were treated with rituximab. The patients who showed an initial response were randomized into two different rituximab treatment regimens. Approximately 70% of FL patients showed initial response to 4 weekly doses of rituximab, and were randomized between arm A: therapy “as needed” (4 weekly doses, only upon progression) or arm B: scheduled maintenance (1 dose every 13 weeks). Clinical outcomes analyzed included duration of response, time to rituximab failure (TTRF), time to cytotoxic therapy (TCT) and decrease in tumor size. The data presented here represent both treatment arms combined, i.e. arms A+B, for all clinical data parameters mentioned. Genomic DNA samples were used for genotyping patients for the presence of 15 KIR loci using a Real Time PCR-based method as previously published (Alves, Tissue Antigens, 2008). HLA specificities corresponding to KIR ligands (HLA-C1, C2, Bw4 and ABw4) were typed using a combination of PCR-SSP methods (Olerup and Invitrogen). ResultsThose patients homozygous for HLA-C1 (C1C1) showed a trend towards a longer duration of response (p=0.06) as compared to those that were heterozygous (C1C2) or homozygous for HLA-C2 (C2C2). A similar difference was observed where patients that were HLA-C1 positive [C1+ (C1C1 or C1C2)] showed a trend towards longer TTRF (p=0.071), as well as a significantly longer TCT (p=0.003), compared to C2C2 patients. Further analyses revealed that the influence of these HLA C specificities on clinical outcome could be related to the presence or absence of inhibitory and/or activating KIR genes. Specifically, HLA-C1 is a ligand for the inhibitory KIR genes 2DL2 and 2DL3. Among the patients who had the KIR2DL2 inhibitory gene (KIR2DL2+), those that were C1+ showed a prolonged duration of response (p=0.049), TCT [Figure 1A, (p=0.003)] and TTRF (p<0.001)] compared to KIR2DL2+ patients who were C2C2 and thus lacked the C1 cognate ligand. Similarly, KIR2DL3+ patients that were C1+ had a significantly longer TCT (p=0.007) than patients that were C2C2, but significant effects were not observed for these KIR2DL3+/C1+ patients with respect to the three other analyzed clinical parameters. Therefore, further studies are required to confirm that KIR2DL3 has an effect independent of other KIRs. [Display omitted] [Display omitted] HLA-C2 alleles are ligands for an activating KIR gene, KIR2DS1. The observed HLA-C genotype effect on clinical outcome could potentially be conveyed by the interaction of HLA-C2 with KIR2DS1. Among the C2C2 patients, KIR2DS1+ patients had a significantly shorter TTRF than those without KIR2DS1 (p=0.023), as well as a significantly smaller decrease in tumor size (p=0.039), implying that the interaction of the activating KIR receptor (KIR2DS1) with its cognate ligand (HLA-C2) conveys a disadvantage to patient outcome. ConclusionSingle-agent rituximab immunotherapy of FL reveals differences in outcomes based on KIR and HLA polymorphisms. The HLA-C2 homozygous individuals seem to be at a disadvantage. This may relate to 2 significant observations highlighting diverse effects of inhibitory and activating KIR-HLA interactions leading to NK cell “licensing” and “hyporesponsiveness”, respectively. Specifically, the data from this study are consistent with: A) a beneficial effect from inhibitory KIR2DL2 and KIR2DL3 interaction with HLA-C1, and B) a detrimental effect due to the contribution of activating KIR2DS1 interacting with its ligand HLA-C2.BG, AKE and WW are co-first authors. Disclosures:Horning:Genentech: Employment, Equity Ownership. Kahl:Genentech: Consultancy, Research Funding.

Polymorphisms of killer immunoglobulin-like receptors (KIRs) and HLA ligands in northeastern Thais

Killer cell immunoglobulin-like receptors (KIRs) are cell surface receptors on natural killer (NK) cells and subsets of T cells. The functions of NK cells are partly regulated by interactions between KIRs and HLA ligands on target cells. In this study, the presence or absence of 17 KIR genes and their known HLA ligands have been investigated in 235 unrelated individuals living in northeastern Thailand (NET). Subtypes of KIR2DS4 including full length (KIR2DS4F) and deleted forms (KIR2DS4D) have also been determined. Framework genes (KIR2DL4, 3DL2, 3DL3, and 3DP1) were found in all individuals and KIR genes belonging to the A haplotype (KIR2DL1, 2DL3, 3DL1, and 2DS4) were present in more than 90% of NET. KIR2DS4D (61.7%) was more common than KIR2DS4F (52.8%). A total of 33 different KIR genotypes were observed. Of these, three new genotypes were identified. The most common genotype (AA) was observed in 35.7% of NET, and HLA-C alleles bearing the C1 epitope (HLA-C1) had the highest frequency (97%). All individuals had at least one inhibitory KIR and its corresponding HLA ligand; 40.9% of NET had three pairs of receptor-ligand combinations, and 18.3% had all three receptor-ligand combinations of KIR2DL3+C1, 3DL1+Bw4, and 3DL2+A11. Surprisingly, the patterns of KIR gene frequencies in NET are more similar to those of Caucasians than Japanese, Korean, and Chinese. This is the first report on complete analysis of KIR and known HLA ligands in Thais. These data provide basic knowledge on KIR for further studies on disease associations and transplantation in northeastern Thais.

KIR polymorphisms modulate peptide-dependent binding to an MHC class I ligand with a Bw6 motif.

Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05+ macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets.

The Impact of NOD2/CARD15 and KIR Polymorphisms on the Incidence of Infectious Complications in allo-HSCT Recipients.

BACKGROUND: Infections remain the major obstacle for successful allogeneic stem cell transplantation (alloHSCT). As specific immune response is profoundly suppressed during the first months after transplantation, the components of innate immunity are expected to play important role in anti-infectious responses. The goal of this prospective study was to evaluate the impact of NOD2/CARD15 gene single nucleotide polymorphisms (SNPs) as well as killer immunoglobulin-like receptors (KIRs), on the frequency of infectious complications after alloHSCT. NOD2/CARD15 protein is broadly expressed on epithelial cells, APCs and both B and T lymphocytes. KIRs regulate function of NK cells and a subset of T cells. Both were documented to take part in innate immunity.PATIENTS: One-hundred-two consecutive patients with hematological malignancies, aged 32 (18-58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG.METHODS: Donors and recipients were tested for SNP8,12,13 of the NOD2/CARD15 gene as well as 11 KIR genes. Study end-points included the incidence of G(+) and G(–) bacterial, fungal and clinically relevant viral infections. Infections were recognized based on clinical symptoms, microbial cultures and in case of CMV and EBV- PCR screening. Pneumonia was confirmed by radiograms. We analyzed separately infections occurring in the early, cytopenic phase and those occurring after engraftment.RESULTS: Presence of KIR2DS3 gene in the donor protected against bacterial pharyngitis (46% vs. 66%, p=0.05), whereas KIR2DS1 in the donor was associated with decreased incidence of pneumonia (12% vs. 32%, p=0.02). Presence of KIR2DS1 in the donor correlated with lower rate of EBV infection (0% vs. 10,2%, p=0.04). SNP8 of the NOD2/CARD15 gene in the recipient tended to increase the risk of severe bacterial pharyngitis (100% vs. 57%, p=0.08) and neutropenic pneumonia (40% vs 7%; p=0.06). As in our previous report there was a lower incidence of urinary tracts infection in NOD2/CARD15 SNPs carriers (32% vs. 59%; p=0.04). As well, NOD2/CARD15 SNPs carriers tended to be protected against HSV infections (0% vs. 9,6%, p=0.08).CONCLUSIONS: NOD2/CARD15 and KIR gene polymorphisms both influence the incidence of infections after alloHSCT. In particular, the effect of donor activating KIRs is generally protective while recipients with NOD2/CARD15 SNPs seems to more susceptible to respiratory tract infections. The genomic analysis may be useful for prediction of infectious complications. Pathogen-specific antibiotic and antiviral prophylaxis based on individual risk assessment may contribute to reduction of infection-related alloHSCT failures.