ABSTRACT
BACKGROUND AND AIMS: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. METHODS: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. RESULTS: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. CONCLUSION: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.
Subject(s)
Antiviral Agents , Carcinoma, Hepatocellular , Hepacivirus , Killer Cells, Natural , Liver Neoplasms , Receptors, KIR , Humans , Carcinoma, Hepatocellular/immunology , Liver Neoplasms/immunology , Killer Cells, Natural/immunology , Male , Antiviral Agents/therapeutic use , Female , Middle Aged , Receptors, KIR/immunology , Aged , Hepacivirus/immunology , Hepatitis C/immunology , Hepatitis C/drug therapy , Hepatitis C/complications , HLA Antigens/immunology , Adult , Immunity, Cellular , Follow-Up Studies , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/complicationsABSTRACT
Pre-eclampsia (PE) is a hypertension condition that occurs exclusively during pregnancy and has the potential to impact nearly all organ systems. It is estimated to complicate approximately 2-8% of pregnancies worldwide. PE is a prominent medical disorder that poses a significant risk to pregnant mothers and their infants. This review commences by giving the most up-to- date concepts about the pathophysiology of PE. The condition involves atypical infiltration of trophoblast cells into the spiral arteries of the decidua and myometrium, resulting in an insufficient establishment of proper blood flow between the uterus and placenta. The aberrant activation of natural killer (NK) cells in both the peripheral blood and the decidua has been identified as one of the contributing factors to the development of PE. The strong evidence for the genetic etiology of PE is provided by the association between maternal killer cell immunoglobulin-like receptor (KIR) and Human Leukocyte Antigen (HLA-C) in trophoblast cells. Recent observations provide evidence that changes in the expression of anti-angiogenic factors in the placenta are the underlying cause of the clinical symptoms associated with the condition. This review also provides a comprehensive overview of the latest advancements in understanding the underlying causes of PE. It specifically highlights the emergence of new diagnostic biomarkers and their potential implications for therapeutic interventions in managing this medical condition.
Subject(s)
Biomarkers , Pre-Eclampsia , Animals , Female , Humans , Pregnancy , Biomarkers/analysis , Decidua/immunology , HLA-C Antigens/immunology , HLA-C Antigens/genetics , HLA-C Antigens/metabolism , Killer Cells, Natural/immunology , Placenta/immunology , Placenta/pathology , Pre-Eclampsia/immunology , Pre-Eclampsia/diagnosis , Pre-Eclampsia/therapy , Receptors, KIR/immunology , Receptors, KIR/metabolism , Receptors, KIR/genetics , Trophoblasts/immunologyABSTRACT
Natural killer cell alloreactivity is determined by killer cell immunoglobulin-like receptor (KIR) ligands in donor and recipient pairs. A small, single institution study suggested that the risk of primary graft failure after cord blood hematopoietic cell transplantation (CBT) can be predicted by host-versus-graft (HvG)-directed natural killer cell alloreactivity. In the haploidentical transplantation (Haplo HCT) cohort, graft failures were observed only in graft-versus-host (GvH) KIR ligand mismatched pairs. A subsequent study was designed to explore the association between HvG and GvH KIR ligand mismatching and engraftment in both CBT and Haplo HCT using the large, multicenter transplant population of the Center for International Blood and Transplant Research database. Nine hundred single CBT (sCBT), 954 double CBT (dCBT), and 671 Haplo HCT performed between 2008 and 2017 for acute leukemias and myelodysplastic syndrome were examined. Several models of KIR-L interactions were analyzed by multiple regression analyses for their association with engraftment, overall survival (OS), and transplant-related mortality (TRM). In sCBT, although HvG or bidirectional KIR ligand mismatch (KIR-L-MM) was initially associated with higher TRM in the first 6 months after transplantation, this effect was nullified after 6 months such that long-term survival was not different compared to GvH KIR-L-MM or KIR-L matched (KIR-L-M) pairs. There was no significant difference in neutrophil and platelet engraftment. In dCBT, no significant differences were seen in engraftment, OS and TRM. In the Haplo cohort there was faster platelet recovery in the GvH KIR-L-MM/KIR-L-M pairs versus HvG KIR-L-MM or bidirectional mismatch (HR 1.23, P= .0116). There was no significant association with OS, TRM, or neutrophil engraftment. In this large registry study, KIR-L mismatching did not significantly impact engraftment, TRM, or survival in CBT and Haplo HCT, although an association with platelet engraftment in Haplo HCT was demonstrated.
Subject(s)
Fetal Blood , Hematopoietic Stem Cell Transplantation , Killer Cells, Natural , Histocompatibility Antigens/immunology , Humans , Killer Cells, Natural/immunology , Ligands , Receptors, KIR/immunologyABSTRACT
Interactions of killer cell immunoglobin-like receptors (KIR) with human leukocyte antigens (HLA) class I regulate effector functions of key cytotoxic cells of innate and adaptive immunity. The extreme diversity of this interaction is genetically determined, having evolved in the ever-changing environment of pathogen exposure. Diversity of KIR and HLA genes is further facilitated by their independent segregation on separate chromosomes. That fetal implantation relies on many of the same types of immune cells as infection control places certain constraints on the evolution of KIR interactions with HLA. Consequently, specific inherited combinations of receptors and ligands may predispose to specific immune-mediated diseases, including autoimmunity. Combinatorial diversity of KIR and HLA class I can also differentiate success rates of immunotherapy directed to these diseases. Progress toward both etiopathology and predicting response to therapy is being achieved through detailed characterization of the extent and consequences of the combinatorial diversity of KIR and HLA. Achieving these goals is more tractable with the development of integrated analyses of molecular evolution, function, and pathology that will establish guidelines for understanding and managing risks. Here, we present what is known about the coevolution of KIR with HLA class I and the impact of their complexity on immune function and homeostasis.
Subject(s)
Evolution, Molecular , Genes, MHC Class I , Histocompatibility Antigens Class I , Immunogenetic Phenomena , Killer Cells, Natural , Receptors, KIR , Genes, MHC Class I/genetics , Genes, MHC Class I/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Health , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunogenetic Phenomena/genetics , Killer Cells, Natural/immunology , Receptors, KIR/genetics , Receptors, KIR/immunologyABSTRACT
Tumor cells of classic Hodgkin lymphoma (cHL) are derived from antigen presenting B cells that are infected by Epstein Barr virus (EBV) in ~30% of patients. Polymorphic Killer cell immunoglobulin-like receptors (KIRs) expressed on NK cells interact with human leukocyte antigen (HLA) class I and play a key role in immune surveillance against virally infected cells and tumor cells. We investigated the effect of KIR types on cHL susceptibility overall (n=211) and in EBV-stratified subgroups using the Dutch GoNL cohort as controls (n=498). The frequency of the KIR haplotype B subgroup was significantly different between EBV+ and EBV- cHL patients (62% vs. 77%, p=0.04) and this difference was more pronounced in nodular sclerosis (NS) cHL (49% vs. 79%, p=0.0003). The frequency of KIR haplotype B subgroup was significantly lower in EBV+ NS cHL compared to controls (49% vs. 67%, p=0.01). Analyses of known KIR - HLA interaction pairs revealed lower carrier frequencies of KIR2DS2 - HLA-C1 (29% vs. 46%, p=0.03) and KIR2DL2 - HLA-C1 (29% vs. 45%, p=0.04) in EBV+ NS cHL patients compared to controls. Carriers of the KIR haplotype B subgroup are less likely to develop EBV+ NS cHL, probably because of a more efficient control over EBV-infected B cells.
Subject(s)
Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/immunology , Hodgkin Disease/immunology , Receptors, KIR2DL2/immunology , Receptors, KIR/immunology , Adolescent , Adult , Aged , Aged, 80 and over , B-Lymphocytes/immunology , Female , Haplotypes/immunology , Humans , Male , Middle Aged , Young AdultABSTRACT
The interaction of inhibitory receptors with self-MHC class I (MHC-I) molecules is responsible for NK cell education. The intensity of DNAM-1 expression correlates with NK cell education. However, whether DNAM-1 expression directly influences the functional competence of NK cells via the KIR/MHC-I interaction remains unclear. Based on allogeneic haploidentical hematopoietic stem cell transplantation, we investigated the intensity of DNAM-1 expression on reconstituted NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after hematopoietic stem cell transplantation. The reconstituted NK cells educated by donor and recipient HLA molecules showed the highest DNAM-1 expression, whereas DNAM-1 expression on educated NK cells with only recipient HLA molecules was higher than that on educated NK cells with only donor HLA molecules, indicating that NK cells with donor or recipient HLA molecules regulate DNAM-1 expression and thereby affect NK cell education. Additionally, the effects of recipient cells on NK cell education were greater than those of donor cells. However, only when the DNAM-1, NKP30, and NKG2D receptors were blocked simultaneously was the function of educated and uneducated NK cells similar. Therefore, activating receptors may collaborate with DNAM-1 to induce educated NK cell hyperresponsiveness. Our data, based on in vitro and in vivo studies, demonstrate that the functional competence of NK cells via the KIR/MHC-I interaction correlates with DNAM-1 expression in human NK cells.
Subject(s)
Antigens, Differentiation, T-Lymphocyte/metabolism , Histocompatibility Antigens Class I/immunology , Killer Cells, Natural/immunology , Receptors, KIR/immunology , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Case-Control Studies , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Lymphoid/therapy , Leukemia, Myeloid/therapy , Myelodysplastic Syndromes/therapy , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Natural Cytotoxicity Triggering Receptor 3/metabolism , Prospective StudiesABSTRACT
Proper communication between natural killer cells and the human leukocyte antigens of the embryonic trophoblast at the maternal-fetal interface during pregnancy is essential for successful reproduction. However, specific combinations of embryonic human leukocyte antigen-C with killer immunoglobulin-like receptors on decidual natural killer cells (the immunological code of pregnancy) can be associated with obstetric morbidity and pregnancy loss. This article presents an updated review of the mechanisms underlying the interaction between embryonic human leukocyte antigen-C and maternal killer immunoglobulin-like receptors and their relevance to the physiology and pathophysiology of human reproduction.
Una adecuada comunicación entre las células asesinas naturales en la interfase materno-fetal con las moléculas de los antígenos de histocompatibilidad del trofoblasto embrionario es clave en el éxito de la reproducción. Sin embargo, combinaciones de determinados antígenos leucocitarios humanos tipo C embrionarios con los receptores tipo inmunoglobulina presentes en las células asesinas naturales deciduales (el código inmunológico del embarazo), pueden asociarse con morbilidad obstétrica y pérdidas gestacionales. En este artículo se presenta una revisión actualizada de los mecanismos subyacentes a la interacción entre el antígeno de histocompatibilidad tipo C embrionario y los receptores tipo inmunoglobulina maternos, y su relevancia tanto en la fisiología como en la fisiopatología de la reproducción humana.
Subject(s)
Abortion, Habitual/immunology , HLA-C Antigens/immunology , Killer Cells, Natural/immunology , Placentation/physiology , Receptors, KIR/immunology , Reproductive Medicine , Uterus/immunology , Abortion, Spontaneous/immunology , Embryo Implantation/immunology , Female , HLA Antigens , HLA-C Antigens/physiology , Humans , Killer Cells, Natural/physiology , Pregnancy , Receptors, KIR/physiologyABSTRACT
Alveolar echinococcosis (AE) is a malignant and fatal parasitic disease caused by the larvae of Echinococcus multilocularis (E. multilocularis), which inhibits the activity and proliferation of natural killer (NK) cells. In this study, the functional alteration of hepatic NK cells and their related molecules were studied. The AE-infected patients tissue was fixed with formalin, embedded in paraffin, and stained with Massons trichrome or hematoxylin and eosin (H&E). Single cells from AE-infected patient or E. multilocularis-infected mice were blocked with Fc-receptor (FcR), and stained with monoclonal antibodies, including CD16, CD56, CD3, KIR2DL1, granzyme B, perforin, Interferon gamma (IFN-γ), and tumor necrosis factor-α (TNFα) or isotype control, to measure molecules and cytokines of NK cells and analyzed by flow cytometry. The Sirius red staining was used to quantitate hepatic fibrosis by calculating quantitative collagen deposition. AE can adjust both the number of hepatic CD56+ NK cells and its KIR2DL1 expression processes. Moreover, the overexpression of KIR2DL1 in NK cells could downregulate the functioning of immune cells in the liver area close to parasitic lesions. The number and dysfunction of NK cells in E. multilocularis infection could be related to the molecule dynamics of cell surface inhibitory receptor Ly49A, leading to hepatic damage and progression of fibrosis. This study illustrated significant increase in hepatic fibrogenesis and apparent upregulation of hepatic CD56+ NK cell population and its KIR2DL1 expression in AE-infected patients. This opposite variation might be related to the impaired NK cells functioning, such as granzyme B, IFN-γ, and TNF-α secretion. In addition, the cell surface inhibitory receptor Ly49A was related to the intracellular cytokine secretion functions of NK cells (AU)
Subject(s)
Humans , Animals , Male , Female , Adult , Middle Aged , Mice , Echinococcosis, Hepatic/immunology , Echinococcus multilocularis , Killer Cells, Natural/immunology , Receptors, KIR/immunology , Tumor Necrosis Factor-alpha/immunology , Interferon-gamma/immunology , Granzymes/immunologyABSTRACT
BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.
Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , Receptors, KIR/immunology , Adult , Aged , COVID-19/metabolism , Case-Control Studies , Female , Gene Frequency/genetics , Genes, MHC Class I/immunology , Genetic Predisposition to Disease , HLA-C Antigens/genetics , Haplotypes/genetics , Humans , Immunity/immunology , Immunogenetics/methods , Killer Cells, Natural/metabolism , Ligands , Male , Middle Aged , Receptors, KIR/genetics , Receptors, KIR/metabolism , SARS-CoV-2/pathogenicity , Severity of Illness IndexABSTRACT
Atopic dermatitis (AD) is a chronic illness that is associated with immune dysregulation. NK cell function has previously been associated with AD. NK cells directly interact with polymorphic HLA class I ligand variants using killer cell Ig-like receptors (KIRs). The purpose of this study was to identify potential associations between NK cell function and AD by evaluating variation in the presence of KIR genes as well as KIR gene interactions with the appropriate HLA class I KIR-specific ligands. Human DNA from the genetics of AD case-control study was used to genotype HLA class I KIR-specific ligands and the presence of KIR genes. In the full cohort, an increased risk of AD was noted for KIR2DL5 (1.51 [1.13, 2.01]), KIR2DS5 (1.72 [1.26, 2.34]), and KIR2DS1 (1.41 [1.04, 1.91]). Individuals with KIR2DS5 or KIR2DS1 and the HLA-C*C2 epitope were at an increased risk of AD (1.74 [1.21, 2.51] and 1.48 [1.04, 2.12], respectively). The HLA-B*-21T (TT) leader sequence increased the risk of AD across ethnicity. African Americans with KIR2DL2, KIR2DS1, KIR2DL5, and KIR2DS5 are more likely to have AD, and the risk increased for KIR2DS1 and KIR2DS5 in the presence of appropriate HLA-C C2 epitope. The risk of AD also increased for individuals with the HLA-B*-21T leader sequence. Future studies should focus on KIR gene allelic variation as well as consider cell-based measurements of KIR and the associated HLA class I epitopes.
Subject(s)
Alleles , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology , Histocompatibility Antigens Class I/genetics , Receptors, KIR/genetics , Receptors, KIR/immunology , Adolescent , Adult , Black or African American/genetics , Base Sequence , Case-Control Studies , Child , Child, Preschool , Dermatitis, Atopic/ethnology , Epitopes/immunology , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genetic Testing/methods , Genotype , Histocompatibility Antigens Class I/immunology , Humans , Killer Cells, Natural/immunology , Ligands , Male , Young AdultABSTRACT
The B7 family ligand HERV-H LTR-associating protein 2 (HHLA2) is an attractive target for cancer immunotherapy because of its coinhibitory function, overexpression in human cancers, and association with poor prognoses. However, the knowledge of the HHLA2 pathway is incomplete. HHLA2 has an established positive receptor transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) but a poorly characterized negative receptor human killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3). Here, KIR3DL3 and TMIGD2 simultaneously bound to different sites of HHLA2. KIR3DL3 was mainly expressed on CD56dim NK and terminally differentiated effector memory CD8+ T (CD8+ TEMRA) cells. KIR3DL3+ CD8+ TEMRA acquired an NK-like phenotype and function. HHLA2 engagement recruited KIR3DL3 to the immunological synapse and coinhibited CD8+ T and NK cell function and killing, inducing immune-evasive HHLA2+ tumors. KIR3DL3 recruited SHP-1 and SHP-2 to attenuate Vav1, ERK1/2, AKT, and NF-κB signaling. HHLA2+ tumors from human kidney, lung, gallbladder, and stomach were infiltrated by KIR3DL3+ immune cells. KIR3DL3 blockade inhibited tumor growth in multiple humanized mouse models. Thus, our findings elucidated the molecular and cellular basis for the inhibitory function of KIR3DL3, demonstrating that the KIR3DL3-HHLA2 pathway is a potential immunotherapeutic target for cancer.
Subject(s)
Immunoglobulins/immunology , Neoplasms/immunology , Receptors, KIR/immunology , Animals , Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/immunology , Cell Survival , Cells, Cultured , Humans , Immune Tolerance , Immunoglobulins/genetics , Killer Cells, Natural/immunology , Mice, Inbred BALB C , Neoplasms/drug therapy , Receptors, KIR/antagonists & inhibitorsABSTRACT
BACKGROUND: Natural killer (NK) cells are increasingly being recognized as agents for cancer immunotherapy. The killer cell immunoglobulin-like receptors (KIRs) are expressed by NK cells and are immunogenetic determinants of the outcome of cancer. In particular, KIR2DS2 is associated with protective responses to several cancers and also direct recognition of cancer targets in vitro. Due to the high homology between activating and inhibitory KIR genes to date, it has been challenging to target individual KIR for therapeutic benefit. METHODS: A novel KIR2DS2-targeting therapeutic peptide:MHC DNA vaccine was designed and used to immunize mice transgenic for KIR genes (KIR-Tg). NK cells were isolated from the livers and spleens of vaccinated mice and then analyzed for activation by flow cytometry, RNA profiling and cytotoxicity assays. In vivo assays of NK cell function using a syngeneic cancer model (B16 melanoma) and an adoptive transfer model for human hepatocellular carcinoma (Huh7) were performed. RESULTS: Injecting KIR-Tg mice with the vaccine construct activated NK cells in both liver and spleens of mice, with preferential activation of KIR2DS2-positive NK cells. KIR-specific activation was most marked on the CD11b+CD27+ mature subset of NK cells. RNA profiling indicated that the DNA vaccine upregulated genes associated with cellular metabolism and downregulated genes related to histone H3 methylation, which are associated with immune cell maturation and NK cell function. Vaccination led to canonical and cross-reactive peptide:MHC-specific NK cell responses. In vivo, DNA vaccination led to enhanced antitumor responses against B16F10 melanoma cells and also enhanced responses against a tumor model expressing the KIR2DS2 ligand HLA-C*0102. CONCLUSION: We show the feasibility of a peptide-based KIR-targeting vaccine strategy to activate NK cells and hence generate functional antitumor responses. This approach does not require detailed knowledge of the tumor peptidomes nor HLA matching with the patient. It therefore offers a novel opportunity for targeting NK cells for cancer immunotherapy.
Subject(s)
Cancer Vaccines/administration & dosage , Cytotoxicity, Immunologic/drug effects , Killer Cells, Natural/drug effects , Liver Neoplasms/drug therapy , Lymphocyte Activation/drug effects , Lymphocytes, Tumor-Infiltrating/drug effects , Melanoma, Experimental/drug therapy , Receptors, KIR/metabolism , Skin Neoplasms/drug therapy , Vaccines, DNA/administration & dosage , Animals , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Cell Line, Tumor , HLA-C Antigens/administration & dosage , HLA-C Antigens/genetics , HLA-C Antigens/immunology , Haplotypes , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/immunology , Liver Neoplasms/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Peptides/administration & dosage , Peptides/genetics , Peptides/immunology , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , Receptors, KIR/genetics , Receptors, KIR/immunology , Skin Neoplasms/genetics , Skin Neoplasms/immunology , Skin Neoplasms/metabolism , Vaccination , Vaccines, DNA/genetics , Vaccines, DNA/immunologyABSTRACT
Introduction: In pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance. Methods: Genotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309). Results: In uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies. Conclusion: The data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy.
Subject(s)
HLA Antigens/immunology , Histocompatibility, Maternal-Fetal/immunology , Pre-Eclampsia/immunology , Receptors, KIR/immunology , Adult , Female , Humans , Immune Privilege/immunology , PregnancyABSTRACT
Killer cell immunoglobulin-like receptor (KIR) receptor-ligand mismatch has been shown to be protective for acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia. Mesenchymal stem cells (MSC) have been considered as one of the most promising prophylaxis for severe GVHD. However, there are no prospective or retrospective studies determining whether they can work synergistically on GVHD. To investigate the potential influence of KIR matching and MSCs, and their synergism on aGVHD and cGVHD after allo-HSCT in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Data from 104 patients with AML and 50 patients with ALL treated with allo-HSCT in the transplantation unit were retrospectively analyzed. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software to generate KIR data. Cox proportional hazards models were used in multivariate analyses. KIR receptor-ligand matching was associated with an increased risk of grade II-IV aGVHD compared to KIR receptor-ligand mismatching (p < 0.001) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD or cGVHD in ALL patients. In contrast, MSCs reduced the incidence of grade II-IV aGVHD in both AML and ALL patients (AML: p = 0.006; ALL: p = 0.008) regardless of KIR mismatching. The combination of KIR receptor-ligand mismatch and MSC transplantation significantly suppressed grade II-IV aGVHD occurrence in AML patients (p = 0.039). In the KIR mismatch group, the incidence of aGVHD was 2.8% in patients receiving MSC compared to 14.6% in those who did not (p = 0.047). KIR receptor-ligand mismatch, MSC transplantation and their combined use significantly reduced the risk of aGVHD after allo-HSCT. These data provide a clinically applicable strategy to reduce aGVHD, thus improving allo-HSCT outcome.
Subject(s)
Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Mesenchymal Stem Cells/immunology , Neoplasm Proteins/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, KIR/immunology , Acute Disease , Adolescent , Adult , Aged , Allografts , Child , Child, Preschool , Female , Graft vs Host Disease/pathology , Humans , Infant , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/pathology , Male , Mesenchymal Stem Cells/pathology , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Retrospective StudiesABSTRACT
Natural killer (NK) cells are essential for the elimination of the transformed and cancerous cells. Killer cell immunoglobulin-like receptors (KIRs) which expressed by T and NK cells, are key regulator of NK cell function. The KIR and their ligands, MHC class I (HLA-A, B and C) molecules, are highly polymorphic and their related genes are located on 19 q13.4 and 6 q21.3 chromosomes, respectively. It is clear that particular interaction between the KIRs and their related ligands can influence on the prevalence, progression and outcome of several diseases, like complications of pregnancy, viral infection, autoimmune diseases, and hematological malignancies. The mechanisms of immune signaling in particular NK cells involvement in causing pathological conditions are not completely understood yet. Therefore, better understanding of the molecular mechanism of KIR-MHC class I interaction could facilitate the treatment strategy of diseases. The present review focused on the main characteristics and functional details of various KIR and their combination with related ligands in diseases and also highlights ongoing efforts to manipulate the key checkpoints in NK cell-based immunotherapy.
Subject(s)
Autoimmune Diseases/therapy , Histocompatibility Antigens Class I/immunology , Immunotherapy/methods , Killer Cells, Natural/immunology , Receptors, KIR/immunology , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Histocompatibility Antigens Class I/metabolism , Humans , Killer Cells, Natural/metabolism , Receptors, KIR/metabolismABSTRACT
The development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) markedly improved the prognosis of patients with chronic myeloid leukemia (CML). Approximately 50% of patients who achieve deep molecular response (DMR) remain in treatment-free remission (TFR) even after discontinuation of TKIs. Although TKIs may achieve clinical "cure" after TKI treatment for specific periods, there are no reliable biomarkers for predicting the response to TKIs and the probability of TFR in CML. An increase in natural killer (NK) cells in the peripheral blood of TKI-treated CML patients is correlated with better outcomes, suggesting that TKIs induce antitumor NK cell immunity against CML cells. Killer immunoglobulin-like receptors (KIRs) are highly polymorphic NK cell receptors that play important roles in the regulation of immune responses. The identification of allelic polymorphisms of KIRs by next-generation sequencing uncovered novel aspects of KIRs. Here we summarize the current knowledge of the genetic and immunological aspects of KIRs and discuss the association between allelic polymorphisms of KIRs and TKI-treated CML.
Subject(s)
Alleles , Killer Cells, Natural/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Polymorphism, Genetic , Receptors, KIR/genetics , Receptors, KIR/immunology , Fusion Proteins, bcr-abl/antagonists & inhibitors , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Treatment OutcomeABSTRACT
Natural killer (NK) cell assessment has been attempted since the 1990s and, apart from antibody testing, is probably the commonest immune test available to clinicians. It is clear that simple enumeration of uterine NK cells by immunohistochemistry is inadequate, although better methodology such as flow cytometry may prove to be more beneficial in the future. Blood testing is an appealing noninvasive test that may be a marker for immune dysfunction, rather than a guide to uterine numbers per se. It is currently performed in women with repeated reproductive failure and should be done using tests of activation. Patients value investigation and clinicians should prefer it to blind empirical immune therapy in repeated reproductive failure cases. But, in addition to blood NK testing, a fundamental new NK genetic test (the KIR/HLA-C interaction) is likely to provide an even more effective diagnostic tool. Insights from KIR/HLA-C analysis imply that new immune therapy trials will need to take KIR/HLA-C results into account.
Subject(s)
Killer Cells, Natural/immunology , Reproduction/immunology , Abortion, Habitual/immunology , Abortion, Habitual/therapy , Animals , Female , HLA-C Antigens/immunology , Humans , Immunotherapy , Pregnancy , Receptors, KIR/immunology , Uterus/cytology , Uterus/immunologyABSTRACT
A vast proportion of coronavirus disease 2019 (COVID-19) individuals remain asymptomatic and can shed severe acute respiratory syndrome (SARS-CoV) type 2 virus to transmit the infection, which also explains the exponential increase in the number of COVID-19 cases globally. Furthermore, the rate of recovery from clinical COVID-19 in certain pockets of the globe is surprisingly high. Based on published reports and available literature, here, we speculated a few immunovirological mechanisms as to why a vast majority of individuals remain asymptomatic similar to exotic animal (bats and pangolins) reservoirs that remain refractile to disease development despite carrying a huge load of diverse insidious viral species, and whether such evolutionary advantage would unveil therapeutic strategies against COVID-19 infection in humans. Understanding the unique mechanisms that exotic animal species employ to achieve viral control, as well as inflammatory regulation, appears to hold key clues to the development of therapeutic versatility against COVID-19.
Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Receptors, KIR/immunology , Receptors, NK Cell Lectin-Like/immunology , Zoonoses/immunology , Animals , Animals, Exotic/virology , Asymptomatic Diseases , COVID-19/genetics , COVID-19/transmission , COVID-19/virology , Chiroptera/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Disease Reservoirs , Eutheria/virology , Gene Expression , Host Specificity , Humans , Immune Tolerance , Immunity, Innate , Interferon-beta/deficiency , Interferon-beta/genetics , Interferon-beta/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , Monocytes/immunology , Monocytes/virology , NLR Family, Pyrin Domain-Containing 3 Protein/deficiency , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Receptors, KIR/deficiency , Receptors, KIR/genetics , Receptors, NK Cell Lectin-Like/deficiency , Receptors, NK Cell Lectin-Like/genetics , SARS-CoV-2/pathogenicity , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Zoonoses/genetics , Zoonoses/transmission , Zoonoses/virologyABSTRACT
Blockade of the PD1 pathway is a broadly effective cancer therapy, but additional immune-inhibitory pathways contribute to tumor immune evasion. HERV-H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7) is a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2). However, HHLA2 has also been known to have inhibitory effects on T cells. Here, we report that we have identified killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells and have generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. It is known that HHLA2 is frequently expressed in several tumor types, including clear cell renal cell carcinoma (ccRCC). We found that HHLA2 expression was nonoverlapping with PDL1 expression in ccRCC, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PDL1. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion.See related Spotlight on p. 128.