RESUMO
BACKGROUND: Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I-mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage in vitro, and has been associated with HLA-DSA-negative MVI. However, missing self's clinical importance as a nonhumoral trigger of allograft rejection remains unclear. METHODS: In a population-based study of 924 consecutive kidney transplantations between March 2004 and February 2013, we performed high-resolution donor and recipient HLA typing and recipient KIR genotyping. Missing self was defined as the absence of A3/A11, Bw4, C1, or C2 donor genotype, with the presence of the corresponding educated recipient inhibitory KIR gene. RESULTS: We identified missing self in 399 of 924 transplantations. Co-occurrence of missing self types had an additive effect in increasing MVI risk, with a threshold at two concurrent types (hazard ratio [HR], 1.78; 95% confidence interval [95% CI], 1.26 to 2.53), independent of HLA-DSA (HR, 5.65; 95% CI, 4.01 to 7.96). Missing self and lesions of cellular rejection were not associated. No HLA-DSAs were detectable in 146 of 222 recipients with MVI; 28 of the 146 had at least two missing self types. Missing self associated with transplant glomerulopathy after MVI (HR, 2.51; 95% CI, 1.12 to 5.62), although allograft survival was better than with HLA-DSA-associated MVI. CONCLUSION: Missing self specifically and cumulatively increases MVI risk after kidney transplantation, independent of HLA-DSA. Systematic evaluation of missing self improves understanding of HLA-DSA-negative MVI and might be relevant for improved diagnostic classification and patient risk stratification.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/genética , Vasculite/genética , Adulto , Idoso , Anticorpos/sangue , Feminino , Genótipo , Sobrevivência de Enxerto , Antígeno HLA-A11/genética , Antígeno HLA-A11/imunologia , Antígeno HLA-A3/genética , Antígeno HLA-A3/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Teste de Histocompatibilidade , Humanos , Transplante de Rim , Masculino , Microvasos , Pessoa de Meia-Idade , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Doadores de Tecidos , Transplantados , Vasculite/complicaçõesRESUMO
BACKGROUND: Heterozygosity at HLA class I loci is generally considered beneficial for host defense. We report here an element of HLA class I homozygosity that may or may not help preserve its existence in populations but which could indicate a new avenue for antiviral research. METHODS: Lymphocytes from serologically HLA-homozygous or -heterozygous donors were examined for synthesis of influenza virus proteins and RNA after exposure to virus as peripheral blood mononuclear cells. The virus-exposed lymphocytes were also examined for internalization of the virus after exposure, and for susceptibility to virus-specific cytotoxic T lymphocytes in comparison with virus-exposed monocytes/macrophages and unseparated peripheral blood mononuclear cells. Results were compared using two-tailed Fisher's exact test. RESULTS: Serologically-defined HLA-A2-homozygous lymphocytes, in contrast to heterozygous lymphocytes, did not synthesize detectable influenza virus RNA or protein after exposure to the virus. HLA-A2-homozygous lymphocytes, including both homozygous and heterozygous donors by genetic sequence subtyping, did internalize infectious virus but were not susceptible to lysis by autologous virus-specific cytotoxic T lymphocytes ("fratricide"). Similar intrinsic resistance to influenza virus infection was observed with HLA-A1- and HLA-A11-homozygous lymphocytes and with HLA-B-homozygous lymphocytes. CONCLUSIONS: A significant proportion of individuals within a population that is characterized by common expression of HLA class I alleles may possess lymphocytes that are not susceptible to influenza virus infection and thus to mutual virus-specific lysis. Further study may identify new approaches to limit influenza virus infection.
Assuntos
Genes MHC Classe I/imunologia , Influenza Humana/genética , Influenza Humana/imunologia , Macrófagos/virologia , Linfócitos T Citotóxicos/imunologia , Alelos , Feminino , Antígeno HLA-A1/imunologia , Antígeno HLA-A11/imunologia , Antígeno HLA-A2/imunologia , Homozigoto , Humanos , Leucócitos Mononucleares/virologia , Macrófagos/imunologia , MasculinoRESUMO
Osteosarcoma is the most common malignancy of bone that affects young people. Neoadjuvant chemotherapy and surgery have significantly improved the prognosis. However, the prognosis of non-responders to chemotherapy is still poor. To develop peptide-based immunotherapy for osteosarcoma, we previously identified CTL epitopes derived from papillomavirus binding factor (PBF) in the context of human leukocyte antigen (HLA)-A2, HLA-A24 and HLA-B55. In the present study, we identified two novel CTL epitopes, QVT (QVTVWLLEQK) and LSA (LSALPPPLHK), in the context of HLA-A11 using a sequence of screenings based on the predicted affinity of peptides, in vitro folding ability of peptide/HLA-A11 complex, reactivity of peptide/HLA-A11 tetramer and interferon (IFN)-γ production of T cells that was induced by mixed lymphocyte peptide culture under a limiting dilution condition. CTL clones directed to QVT and LSA peptides showed specific cytotoxicity against HLA-A11+ PBF+ osteosarcoma (HOS-A11) cells. In contrast, another epitope, ASV (ASVLSRRLGK), could highly induce cognate tetramer-positive CTL. This might be because the ASV peptide mimics the peptide ASV (R6Q) (ASVLSQRLGK) derived from bacterial polypeptides, ROK family proteins. However, ASV-induced CTL did not show cytokine production against the cognate peptide. In conclusion, the CTL epitopes QVT and LSA peptides might be useful for the development of immunotherapy targeting PBF for patients with osteosarcoma.
Assuntos
Epitopos de Linfócito T/imunologia , Antígeno HLA-A11/genética , Proteínas de Membrana/imunologia , Osteossarcoma/genética , Osteossarcoma/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Sequência de Aminoácidos , Reações Cruzadas/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica , Epitopos de Linfócito T/química , Antígeno HLA-A11/química , Antígeno HLA-A11/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/química , Osteossarcoma/metabolismo , Peptídeos/química , Peptídeos/imunologia , Ligação Proteica , Dobramento de Proteína , Multimerização ProteicaRESUMO
BACKGROUND: Haploidentical hematopoietic stem cell transplant (haplo-HSCT) recipients are at high risk for Epstein Barr virus (EBV)-related diseases. EBV-specific CD8+ cytotoxic T cells can control EBV-infected B cell expansion; however, no studies have investigated EBV-specific immune reconstitution after HSCT, particularly haplo-HSCT. Therefore, in this study, we aimed to characterize EBV-specific immune cell reconstitution after haplo-HSCT. METHODS: HLA-A*1101 and HLA-A*0201 pentamers folded with immunodominant EBV peptides were used to detect EBV-specific CD8+ T cells by flow cytometry in peripheral blood mononuclear cells from 19 haplo-HSCT recipients and the results were compared with those in controls. We also compared the EBV-specific pentamer-binding cell frequencies in patients with or without EBV-related diseases by flow cytometry. RESULTS: Pentamer-binding EBV-specific CD8+ T cells were detected at + 30, + 60 and + 90 days after haplo-HSCT in EBV-seropositive patients subjected to haplo-HSCT from an EBV-seropositive donor. The frequencies of the HLA-A*0201/BMLF1-GLC pentamer in haplo-HSCT patients at + 30 days were significantly lower than those in HLA-A*0201-positive healthy controls (p = 0.019) and patients at + 60 days (p = 0.003). The frequencies of the HLA-A*1101/LMP2-SSC pentamer at + 30, + 60, and + 90 days were significantly decreased compared with those in healthy controls (p = 0.009, 0.019, and 0.039, respectively); however, the frequencies of the HLA-A*1101/LMP2-SSC pentamer did not differ significantly among patients at + 30, + 60, and + 90 days (p = 0.886). There was a significant difference in the frequency of the HLA-A*0201/BMLF1-GLC pentamer at + 60 days between patients with and without EBV-related diseases (p = 0.024). Patients with EBV-related diseases showed lower percentages of HLA-A*0201/BMLF1-GLC specific CD8+ T cells. CONCLUSIONS: Haplo-HSCT recipients could generate EBV-specific CD8+ T cells within + 30 days after transplantation. The HLA-A*0201/BMLF1-GLC pentamer cell frequency at + 60 days may be a useful indicator for monitoring EBV-related diseases in patients after haplo-HSCT. Transfusion with EBV-CTLs within 60 days after haplo-HSCT may have prophylactic effects against EBV-related diseases.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Antígeno HLA-A11/imunologia , Antígeno HLA-A2/imunologia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/imunologia , Reconstituição Imune , Linfócitos T Citotóxicos/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplantados , Adulto JovemRESUMO
The Ebola virus (EBOV) is a very contagious virus that is highly fatal in humans and animals. The largest epidemic was in West Africa in 2014, in which over 11,000 people died. However, to date, there are no licensed vaccines against it. Studies show that CD4+ and CD8+ T-cell responses, especially cytotoxic T-lymphocyte (CTL) responses, play key roles in protecting individuals from EBOV infection. Since HLA-restricted epitope vaccines are likely to be effective and safe immunization strategies for infectious diseases, the present study screened for CTL epitopes in the EBOV-nucleoprotein that are restricted by HLA-A11 (a common allele in Chinese people). Predictive computer analysis of the amino-acid sequence of EBOV-nucleoprotein identified ten putative HLA-A11-restricted epitopes. ELISPOT assay of immunized HLA-A11/DR1 transgenic mice showed that five (GR-9, VR-9, EK-9, PK-9, and RK-9) induced effective CTL responses. Additional epitope analyses will aid the design of epitope vaccines against EBOV.
Assuntos
Ebolavirus/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-A11/imunologia , Doença pelo Vírus Ebola/imunologia , Proteínas do Nucleocapsídeo/imunologia , Adenoviridae/genética , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Feminino , Antígeno HLA-A11/genética , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Imunização , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Nucleocapsídeo/química , Linfócitos T Citotóxicos/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologiaRESUMO
Adaptation of hepatitis C virus (HCV) to CD8+ T cell selection pressure is well described; however, it is unclear if HCV differentially adapts in different populations. Here, we studied HLA class I-associated viral sequence polymorphisms in HCV 1b isolates in a Chinese population and compared viral substitution patterns between Chinese and German populations. We identified three HLA class I-restricted epitopes in HCV NS3 with statistical support for selection pressure and found evidence for differential escape pathways between isolates from China and Germany depending on the HLA class I molecule. The substitution patterns particularly differed in the epitope VTLTHPITK1635-1643 , which was presented by HLA-A*03 as well as HLA-A*11, two alleles with highly different frequencies in the two populations. In Germany, a substitution in position seven of the epitope was the most frequent substitution in the presence of HLA-A*03, functionally associated with immune escape and nearly absent in Chinese isolates. In contrast, the most frequent substitution in China was located at position two of the epitope and became the predominant consensus residue. Moreover, substitutions in position one of the epitope were significantly enriched in HLA-A*11-positive individuals in China and associated with different patterns of CD8+ T cell reactivity. Our study confirms the differential escape pathways selected by HCV that depended on different HLA class I alleles in Chinese and German populations, indicating that HCV differentially adapts to distinct HLA class I alleles in these populations. This result has important implications for vaccine design against highly variable and globally distributed pathogens, which may require matching antigen sequences to geographic regions for T cell-based vaccine strategies.
Assuntos
Apresentação de Antígeno , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Antígenos HLA-A/imunologia , Hepacivirus/genética , Proteínas não Estruturais Virais/genética , Alelos , China , Epitopos de Linfócito T/imunologia , Alemanha , Antígenos HLA-A/genética , Antígeno HLA-A11/genética , Antígeno HLA-A11/imunologia , Antígeno HLA-A3/genética , Antígeno HLA-A3/imunologia , Hepacivirus/imunologia , Hepatite C/etnologia , Hepatite C/imunologia , Humanos , Evasão da Resposta Imune , Mutação , Seleção Genética , Proteínas não Estruturais Virais/imunologiaRESUMO
The signal peptide region of preproinsulin (PPI) contains epitopes targeted by HLA-A-restricted (HLA-A0201, A2402) cytotoxic T cells as part of the pathogenesis of ß-cell destruction in type 1 diabetes. We extended the discovery of the PPI epitope to disease-associated HLA-B*1801 and HLA-B*3906 (risk) and HLA-A*1101 and HLA-B*3801 (protective) alleles, revealing that four of six alleles present epitopes derived from the signal peptide region. During cotranslational translocation of PPI, its signal peptide is cleaved and retained within the endoplasmic reticulum (ER) membrane, implying it is processed for immune recognition outside of the canonical proteasome-directed pathway. Using in vitro translocation assays with specific inhibitors and gene knockout in PPI-expressing target cells, we show that PPI signal peptide antigen processing requires signal peptide peptidase (SPP). The intramembrane protease SPP generates cytoplasm-proximal epitopes, which are transporter associated with antigen processing (TAP), ER-luminal epitopes, which are TAP independent, each presented by different HLA class I molecules and N-terminal trimmed by ER aminopeptidase 1 for optimal presentation. In vivo, TAP expression is significantly upregulated and correlated with HLA class I hyperexpression in insulin-containing islets of patients with type 1 diabetes. Thus, PPI signal peptide epitopes are processed by SPP and loaded for HLA-guided immune recognition via pathways that are enhanced during disease pathogenesis.
Assuntos
Ácido Aspártico Endopeptidases/imunologia , Diabetes Mellitus Tipo 1/imunologia , Epitopos/imunologia , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Insulina/imunologia , Precursores de Proteínas/imunologia , Linfócitos T Citotóxicos/imunologia , Aminopeptidases , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular , Retículo Endoplasmático , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Antígeno HLA-A11/imunologia , Antígeno HLA-A2/imunologia , Antígeno HLA-A24/imunologia , Humanos , Técnicas In Vitro , Insulina/metabolismo , Antígenos de Histocompatibilidade Menor , Fatores de Proteção , Precursores de Proteínas/metabolismo , Sinais Direcionadores de Proteínas , Transporte Proteico , Fatores de RiscoRESUMO
B*58:01:21 has a single nucleotide change, c.264A>G (ACAâACG at codon 88) compared with B*58:01:01:01.
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático , Sequência de Bases , Códon/química , Expressão Gênica , Genótipo , Antígeno HLA-A11/imunologia , Antígenos HLA-B , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores de TecidosRESUMO
HLA-A*11:141 has 1 nucleotide change from HLA-A*11:01:01 at position 470G>C.
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos , Substituição de Aminoácidos , Povo Asiático , Sequência de Bases , Transplante de Medula Óssea , Códon/química , Expressão Gênica , Genótipo , Antígeno HLA-A11/imunologia , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
Nucleotide deletions from residues 409 to 417 of HLA-A*11:02:01 results in a novel allele, HLA-A*11:256Q.
Assuntos
Alelos , Sequência de Bases , Éxons , Antígeno HLA-A11/genética , Deleção de Sequência , Doadores de Tecidos , Códon/química , Expressão Gênica , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , TaiwanRESUMO
One nucleotide substitution at residue 532 of HLA-A*11:02:01 results in a novel allele, HLA-A*11:255.
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos , Substituição de Aminoácidos , Sequência de Bases , Códon/química , Expressão Gênica , Genótipo , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , TaiwanRESUMO
Two new HLA class I alleles, HLA-A*11:01:01:04 and HLA-B*35:330, were characterized in a Spanish patient.
Assuntos
Alelos , Antígeno HLA-A11/genética , Antígeno HLA-B35/genética , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos , Substituição de Aminoácidos , Sequência de Bases , Clonagem Molecular , Códon/química , Éxons , Expressão Gênica , Genótipo , Antígeno HLA-A11/imunologia , Antígeno HLA-B35/imunologia , Transplante de Células-Tronco Hematopoéticas , Heterozigoto , Teste de Histocompatibilidade , Humanos , Íntrons , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , Irmãos , EspanhaRESUMO
HLA-A*11:241 differs from A*11:01:01:01 (215G > A, exon 2, R48Q); HLA-C*08:132 from C*08:02:01:01 (587 T > A exon 3, L172Q).
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Antígenos HLA-C/genética , Mutação Puntual , Doadores de Tecidos , Substituição de Aminoácidos , Anticorpos Monoclonais/química , Códon/química , Genótipo , Antígeno HLA-A11/imunologia , Antígenos HLA-C/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Imunoensaio , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , População BrancaRESUMO
A one nucleotide replacement in codon 31 of HLA-A*11:01:01 results in a novel allele, HLA-A*11:134.
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Mutação Puntual , Transplantados , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Códon/química , Feminino , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , TaiwanRESUMO
One nucleotide substitution at residue 484 of HLA-A*11:01:01:01 results in a novel allele, HLA-A*11:196.
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Mutação Puntual , Doadores não Relacionados , Substituição de Aminoácidos , Sequência de Bases , Clonagem Molecular , Expressão Gênica , Genótipo , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Alinhamento de Sequência , Análise de Sequência de DNA , TaiwanRESUMO
Nucleotide deletions from residue 120 to 125 of HLA-A*11:01:01:01 result in a novel allele, HLA-A*11:235Q.
Assuntos
Alelos , Sequência de Bases , Éxons , Antígeno HLA-A11/genética , Deleção de Sequência , Doadores não Relacionados , Códon/química , Genótipo , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Alinhamento de Sequência , Análise de Sequência de DNA , TaiwanRESUMO
Here, we report genomic full-length sequence of a novel HLA-A*11:01:01:02 allele identified in a Chinese individual. HLA-A*11:01:01:02 has three nucleotide differences from HLA-A*11:01:01:01, including 99 C>G of intron 1, 655 C>T and G deletion in position 656 of intron 2.
Assuntos
Alelos , Antígeno HLA-A11/genética , Povo Asiático , Medula Óssea/imunologia , China , Éxons/genética , Antígeno HLA-A11/imunologia , Humanos , Íntrons/genéticaRESUMO
One nucleotide substitution at residue 517 of HLA-A*11:01:01:01 results in a novel allele, HLA-A*11:231.
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Mutação Puntual , Substituição de Aminoácidos , Sequência de Bases , Códon , Genótipo , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Alinhamento de Sequência , Análise de Sequência de DNA , Taiwan , Doadores de TecidosRESUMO
HLA-A*11:120 has one nucleotide change from HLA-A*11:01:01:01 where 295 T(ACC) is changed to S(AGC).
Assuntos
Alelos , Éxons , Antígeno HLA-A11/genética , Mutação Puntual , Substituição de Aminoácidos , Povo Asiático , Sequência de Bases , Códon , Genótipo , Antígeno HLA-A11/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores de TecidosRESUMO
One nucleotide replacement at residue 210 of HLA-A*11:01:01:01 results in a novel allele, HLA-A*11:01:69.