RESUMO
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.
Assuntos
Anemia Hemolítica Autoimune , Anemia Falciforme , Adulto , Feminino , Gravidez , Humanos , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Ligantes , Genes MHC Classe I , Anemia Falciforme/genética , Anemia Falciforme/terapia , Antígenos CDRESUMO
Several studies investigated KIR3DS1 and KIR3DL1 in the context of various infections. However, none of the studies were performed on KIR3DS1/L1 in association with IFN-É£/IL-10 in TB, HIV-1, and their confections. We aimed to evaluate KIR3DS1/KIR3DL1 expression in association with IFNÉ£/IL-10 in HIV-1 and TB mono-infections and HIV-1/TB confection and compared with uninfected controls using RTq PCR. We also performed correlation analysis between KIR3DS1, KIR3DL1, IFN-É£ and IL-10 in the respective cohorts. The overall expression of KIR3DS1 was found to be downregulated in all groups, whereas in HIV-1 and HIV-1/TB, the frequency of KIR3DS1(+) expression was significantly (p < 0.05) associated with undetected HIV-1 viral load. However, expression of KIR3DL1 was found to be significantly (p < 0.05) upregulated in HIV-1 only. In addition, IFNÉ£ expression was significantly (p < 0.05) decreased in TB, whereas in HIV-1/TB, IFNÉ£ expression was significantly (p < 0.05) increased. In contrast, IL-10 expression was significantly (p < 0.05) increased in HIV-1 and HIV-1/TB but not in TB. Also, we found significant positive correlation (p < 0.05, r = 0.61) between KIR3DL1 and IFNÉ£ expression in TB and negative correlation (p < 0.05, r = - 0.62) between KIR3DS1 and IL-10 in HIV-1/TB. In conclusion, we suggest that expression of KIR3DS1/L1 is associated with IFNÉ£/IL-10 responses and it is involved in modulating disease severity in HIV-1 and TB infections.
Assuntos
Infecções por HIV , HIV-1 , Tuberculose , Humanos , Infecções por HIV/genética , HIV-1/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Células Matadoras Naturais , Receptores KIR3DL1/genética , Receptores KIR3DL1/metabolismo , Receptores KIR3DS1/genética , Receptores KIR3DS1/metabolismo , Tuberculose/genéticaRESUMO
BK polyomavirus-associated nephropathy is a common complication after kidney transplantation leading to reduced graft function or loss. The molecular pathogenesis of BK polyomavirus-induced nephropathy is not well understood. A recent study had described a protective effect of the activating natural killer cell receptor KIR3DS1 in BK polyomavirus-associated nephropathy, suggesting a role of NK cells in modulating disease progression. Using an in vitro cell culture model of human BK polyomavirus infection and kidney biopsy samples from patients with BK polyomavirus-associated nephropathy, we observed significantly increased surface expression of the ligand for KIR3DS1, HLA-F, on BK polyomavirus-infected kidney tubular cells. Upregulation of HLA-F expression resulted in significantly increased binding of KIR3DS1 to BK polyomavirus-infected cells and activation of primary KIR3DS-positive natural killer cells. Thus, our data provide a mechanism by which KIR3DS-positive natural killer cells can control BK polyomavirus infection of the kidney, and rationale for exploring HLA-F/KIR3DS1 interactions for immunotherapeutic approaches in BK polyomavirus-associated nephropathy.
Assuntos
Vírus BK , Nefropatias , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Células Matadoras Naturais/metabolismo , Receptores KIR3DS1/genética , Receptores KIR3DS1/metabolismo , Regulação para CimaRESUMO
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.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Hemoglobinas/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Fragmentos de Peptídeos/metabolismo , Proteoma/análise , Receptores KIR3DS1/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ligação Proteica , Receptores KIR3DS1/metabolismoRESUMO
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-ABw4 (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-Bw4Ile80 (OR 0.522, p = 0.022) were negatively associated with susceptibility to this disease. These results suggest an implication of the KIR3DS1/HLA-ABw4 genotype in PsV pathology.
Assuntos
Genótipo , Antígenos HLA-B/genética , Psoríase/genética , Receptores KIR3DS1/genética , Adolescente , Adulto , Idoso , Alelos , Feminino , Humanos , Masculino , México , Pessoa de Meia-IdadeRESUMO
HIV-exposed seronegative KIR3DS1 homozygotes have a reduced risk of HIV infection. HLA-F is the ligand for the activating NK cell receptor (NKR) KIR3DS1. HLA-F is expressed on HIV-infected CD4 T cells. Coculture of sorted, HIV-infected CD4- (siCD4-) T cells with NK cells activated a higher frequency of KIR3DS1+ than KIR3DS1- NK cells from KIR3DS1 homozygotes to elicit anti-HIV functions such as CCL4, gamma interferon (IFN-γ), and CD107a expression. This was the case whether KIR3DS1+/- NK cells were analyzed inclusively or exclusively by gating out NK cells coexpressing the NKRs, KIR2DL1/L2/L3, 3DL2, KIR2DS1/S2/S3/S5, NKG2A, and ILT2. Blocking the interaction of HLA-F on siCD4- cells with KIR3DS1 on exclusively gated KIR3DS1+ NK cells with KIR3DS1-Fc chimeric protein or an HLA-F-specific monoclonal antibody reduced the frequency of activated KIR3DS1+ cells compared to that under control conditions. KIR3DS1+ NK cell activation by HIV-infected CD4+ cells may underlie the reduced risk of KIR3DS1 homozygotes to HIV infection.IMPORTANCE This study investigated a mechanism that may underly epidemiological studies showing that carriage of the KIR3DS1 homozygous genotype is more frequent among HIV-exposed seronegative subjects than among HIV-susceptible individuals. Carriage of this genotype is associated with a reduced risk of HIV infection. The protective mechanism involves the interaction of HLA-F on CD4+ cells infected with replication-competent HIV with the activating NK receptor, KIR3DS1. This interaction leads to the activation of KIR3DS1+ NK cells for secretion of cytokines and chemokines with anti-HIV activity. Among these is CCL4, which binds and blocks CCR5, the coreceptor for HIV entry of HIV into new target cells. In the setting of an exposure to HIV, incoming HIV-infected cells expressing HLA-F rapidly activate KIR3DS1+ NK cells to elicit anti-HIV activity. Exclusive gating strategies and blocking experiments support the notion that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cell functions.
Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Receptores KIR3DS1/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Quimiocina CCL4/metabolismo , Feminino , Genótipo , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Masculino , Receptores CCR5/metabolismo , Receptores KIR , Receptores KIR3DS1/genéticaRESUMO
Objective: To investigate whether killer cell immunoglobulin-like receptor 3DS1(KIR3DS1)and Bw4(80Ile) could play a protective role during HIV-1 infection. Methods: KIR3DL1/3DS1 and Bw4, Bw6 were genotyped by SSP-PCR and Bw4 allotypes (Bw4(80Ile) and Bw4(80Thr))were classified via sequencing among 109 individuals acutely infected with HIV-1 in Beijing You'an Hospital between 2006 and 2012. Results: (1)Of the 109 patients, 65, 7, and 37 subjects respectively harbored KIR3DL1/KIR3DL1, KIR3DS1/KIR3DS1, and KIR3DL1/KIR3DS1 genotypes. Their viral set points were determined as 4.35±0.79, 4.24±0.49 and 3.99±0.85 respectively. The viral set point of patients carrying KIR3DL1/KIR3DS1 was significantly lower than the KIR3DL1/KIR3DL1 genotype patients (P=0.032). (2)26, 41, 42 subjects harbored Bw4(80Ile,) Bw4(80Thr,) Bw6/6, respectively. Viral set points of these subjects were respectively 3.89±0.49, 4.20±1.03 and 4.44±0.59.One-way ANOVA indicated that Bw4(80Ile)influenced the levels of viral set point(P=0.027). Moreover, the level of viral set point of the Bw4(80Ile) genotype was significantly lower than the Bw6/6 genotype (P=0.020). These outcomes indicated Bw4(80Ile) was associated with lower levels of viral set point.(3)Viral set point of patients harboring KIR3DS1 and Bw4(80Ile)was 3.26±0.81 and significantly lower than individuals possessing other genotypes (all P<0.05). KIR3DS1 and Bw4(80Ile) conferred an advantage over other genotypes, especially over KIR3DS1 and Bw6/6 (P=0.006), KIR3DL1 and Bw6/6 (P=0.015) and even KIR3DL1 and Bw4(80Ile) (P=0.019 6) in delaying CD4 count decline within 3 years after HIV-1 infection. Conclusions: KIR3DS1 and Bw4(80Ile) are synergistically related to lower viral set point and slowing down the CD4 count decline as Bw4(80Ile) in the presence of KIR3DS1.
Assuntos
Infecções por HIV , Contagem de Linfócito CD4 , Genótipo , HIV-1 , Antígenos HLA-B , Humanos , Células Matadoras Naturais , Receptores KIR3DS1RESUMO
Several studies described an association between killer-cell immunoglobulin-like receptor (KIR)/HLA gene combinations and clinical outcomes in various diseases. In particular, an important combined role for KIR3DS1 and HLA-B Bw4-I80 in controlling viral infections and a higher protection against leukemic relapses in donor equipped with activating KIRs in haplo-HSCT has been described. Here, we show that KIR3DS1 mediates positive signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells and that this activation occurs only in Bw4-I80neg individuals, including those carrying particular KIR/HLA combination settings. In addition, killing of HLA-B*51 transfected target cells mediated by KIR3DS1+/NKG2A+ natural killer (NK) cell clones from Bw4-I80neg donors could be partially inhibited by antibody-mediated masking of KIR3DS1. Interestingly, KIR3DS1-mediated recognition of HLA-B*51 could be better appreciated under experimental conditions in which the function of NKG2D was reduced by mAb-mediated blocking. This experimental approach may mimic the compromised function of NKG2D occurring in certain viral infections. We also show that, in KIR3DS1+/NKG2A+ NK cell clones derived from an HLA-B Bw4-T80 donor carrying 2 KIR3DS1 gene copy numbers, the positive signal generated by the engagement of KIR3DS1 by HLA-B*51 resulted in a more efficient killing of HLA-B*51-transfected target cells. Moreover, in these clones, a direct correlation between KIR3DS1 and NKG2D surface density was detected, while the expression of NKp46 was inversely correlated with that of KIR3DS1. Finally, we analyzed KIR3DS1+/NKG2A+ NK cell clones from a HLA-B Bw4neg donor carrying cytoplasmic KIR3DL1. Although these clones expressed lower levels of surface KIR3DS1, they displayed responses comparable to those of NK cell clones derived from HLA-B Bw4neg donors that expressed surface KIR3DL1. Altogether these data suggest that, in particular KIR/HLA combinations, KIR3DS1 may play a role in the process of human NK cell education.
RESUMO
KIR3DS1*083 allele differs from the closest allele KIR3DS1*01301 by 3 mutations in exon 4.
Assuntos
Alelos , Éxons , Mutação , Receptores KIR3DS1/genética , Povo Asiático , HumanosRESUMO
KIR3DS1*084 allele differs from the closest allele KIR3DS1*01301 at nucleotide 308 C>T in exon 3.
Assuntos
Alelos , Receptores KIR3DS1/genética , Povo Asiático , HumanosRESUMO
KIR3DS1*085 allele differs from the closest allele KIR3DS1*01301 at nucleotide 934 C>T in exon 5.
Assuntos
Alelos , Éxons , Receptores KIR3DS1/genética , Povo Asiático , HumanosRESUMO
KIR3DS1*082 allele differs from the closest allele KIR3DS1*01301 at nucleotide 1114T>C in exon 8.
Assuntos
Alelos , Éxons , Polimorfismo de Nucleotídeo Único , Receptores KIR3DS1/genética , Doadores de Tecidos , Substituição de Aminoácidos , Povo Asiático , Sequência de Bases , Transplante de Medula Óssea , Códon/química , Expressão Gênica , Genótipo , Humanos , Tipagem Molecular , Reação em Cadeia da Polimerase , Receptores KIR3DS1/imunologia , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
KIR3DS1*078 allele differs from the closest allele KIR3DS1*01301 at nucleotide 775 G>C in exon 5.
Assuntos
Alelos , Éxons , Polimorfismo de Nucleotídeo Único , Receptores KIR3DS1/genética , Doadores de Tecidos , Substituição de Aminoácidos , Povo Asiático , Sequência de Bases , Transplante de Medula Óssea , Códon/química , Expressão Gênica , Genótipo , Humanos , Tipagem Molecular , Reação em Cadeia da Polimerase , Receptores KIR3DS1/imunologia , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
KIR3DS1*0130109 is similar to KIR3DS1*0130101 except for a A > G change in intron 4.
Assuntos
Teste de Histocompatibilidade , Receptores KIR3DS1/química , Receptores KIR3DS1/genética , Análise de Sequência de DNA , Alelos , Sequência de Bases , Humanos , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Alinhamento de SequênciaRESUMO
KIR3DS1*0130111 differs from KIR3DS1*0130101 with two previously undescribed single nucleotide polymorphisms.
Assuntos
Alelos , Éxons , Polimorfismo de Nucleotídeo Único , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Substituição de Aminoácidos , Sequência de Bases , Genótipo , Humanos , Dados de Sequência Molecular , Tipagem Molecular , Reação em Cadeia da Polimerase , Receptores KIR3DL1/imunologia , Receptores KIR3DS1/imunologia , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
Killer cell immunoglobulin like receptor (KIR) 3DS1 is one of the most important activating receptors and some studies revealed that KIR3DS1 combined with HLA ligand was not related to acute myeloid leukemia (AML), but rare data was reported in Chinese population. In this study, KIR3DS1 gene polymorphisms and HLA-Bw4 were investigated in 189 Chinese AML patients compared with 166 healthy individuals. The results showed that the distributions of KIR3DS1, Bw4, 3DS1/Bw4 and 3DS1/Bw4-80I were insignificantly different between AML and healthy individuals. This study suggests that the presence of 3DS1 and HLA-Bw4 ligands have no effect on AML disease.
Assuntos
Antígenos HLA-B/genética , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Receptores KIR3DS1/genética , Idoso , China , Análise Mutacional de DNA , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Antígenos HLA-B/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Polimorfismo Genético , Ligação Proteica/genética , Receptores KIR3DS1/metabolismoRESUMO
KIR3DS1*0130110 differs from KIR3DS1*0130101 with two nucleotide substitutions at positions 7322 (G > T) and 12617 (C > A), respectively.