RESUMO
HLA-B*39:06, HLA-B*39:01, and HLA-B*38:01 are closely related HLA allotypes differentially associated with type 1 diabetes (T1D) risk and progression. B*39:06 is highly predisposing, while B*39:01 and B*38:01 are weakly predisposing and protective allotypes, respectively. Here, we aimed to decipher molecular mechanisms underlying the differential association of these allotypes with T1D pathogenesis. We addressed peptide binding and conformational stability of HLA-B allotypes using computational and experimental approaches. Computationally, we found that B*39:06 and B*39:01 allotypes had more rigid peptide-binding grooves and were more promiscuous in binding peptides than B*38:01. Peptidomes of B*39:06 and B*39:01 contained fewer strong binders and were of lower affinity than that of B*38:01. Experimentally, we demonstrated that B*39:06 and B*39:01 had a higher capacity to bind peptides and exit to the cell surface but lower surface levels and were degraded faster than B*38:01. In summary, we propose that promiscuous B*39:06 and B*39:01 may bind suboptimal peptides and transport them the cell surface, where such unstable complexes may contribute to the pathogenesis of T1D.
Assuntos
Diabetes Mellitus Tipo 1 , Antígenos HLA-B , Peptídeos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Humanos , Peptídeos/química , Peptídeos/genética , Peptídeos/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Polimorfismo Genético , Ligação Proteica , Alelos , Estabilidade Proteica , Predisposição Genética para DoençaRESUMO
In type 1 diabetes (T1D), autoreactive cytotoxic CD8+ T cells are implicated in the destruction of insulin-producing ß cells. The HLA-B*3906 and HLA-A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8+ T cells that recognize peptides presented by these class I molecules on pancreatic ß cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)-specific and insulin B (InsB)-specific CD8+ T cells in HLA-B*3906+ children newly diagnosed with T1D and in high-risk HLA-A*2402+ children before the appearance of disease-specific autoantibodies and before diagnosis of T1D. Antigen-specific CD8+ T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA-B*3906+ children with T1D, we observed an increase in PPI5-12 -specific transitional memory CD8+ T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI5-12 -specific CD8+ T cells in HLA-B*3906+ children with T1D showed a significantly more antigen-experienced phenotype compared to polyclonal CD8+ T cells. In longitudinal samples from high-risk HLA-A*2402+ children, the percentage of terminal effector cells within the InsB15-24 -specific CD8+ T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA-B*3906-restricted autoreactive CD8+ T cells in T1D. Collectively, our results provide evidence that ß cell-reactive CD8+ T cells restricted by disease-associated HLA class I molecules display an antigen-experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Secretoras de Insulina/imunologia , Autoimunidade/imunologia , Linfócitos T CD8-Positivos/metabolismo , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Antígeno HLA-A24/imunologia , Antígeno HLA-A24/metabolismo , Antígenos HLA-B/imunologia , Antígenos HLA-B/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Lactente , Insulina/imunologia , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Precursores de Proteínas/imunologia , Precursores de Proteínas/metabolismo , Fatores de RiscoRESUMO
A novel HLA-B*39:01:01-related variant, HLA-B*39:130, has been identified in a normal individual of Han ethnicity in Hunan province, southern China. Following Sanger polymerase chain reaction-sequence-based typing (PCR-SBT), this new allele was further confirmed by cloning, phasing and sequencing. Aligned with HLA-B*39:01:01, HLA-B*39:130 has a nonsynonymous thymine substitution at nucleotide position 94 in exon 4, resulting in amino acid change from threonine to isoleucine at codon 214 (ACAâATA) of the mature HLA-BmRNA molecule.
Assuntos
Alelos , Antígenos HLA-B/genética , Adulto , Sequência de Bases , Clonagem Molecular , Humanos , MasculinoRESUMO
A 19-year-old woman with a history of recurrent aphthous stomatitis and genital ulceration was diagnosed with Behçet disease. She was treated with steroids and immunosuppressive agents for more than 30 years, but multiple complications manifested including ileocecal ulcer, aortic valve regurgitation, renal failure, ischemic enterocolitis, and arteriosclerotic obliterans until her death at the age of 56 from pneumonia. An autopsy examination demonstrated an entirely calcified aorta and major aortic branches. The ascending aorta was dilatated 55 mm in diameter and branches were all stenosed. Microscopically, the aortic arch and its branches showed collagenous fibrosis of the outer media and adventitia, whereas coronary and abdominal aortic branches showed conventional atherosclerosis. Although the ante-mortem diagnosis was angio-Behçet disease, its pathophysiology along with her clinical history, morphology of the lead pipe-like aorta, predominant destruction of the outer arteries, and a human leukocyte antigen (HLA) haplotype of B39 were all suggestive of Takayasu arteritis. Thus, this case implies that HLA-B39 may be associated with the pathogenesis of arteritis like Takayasu arteritis, even if the primary disease is Behçet disease.
Assuntos
Síndrome de Behçet/diagnóstico , Antígeno HLA-B39/metabolismo , Arterite de Takayasu/etiologia , Aorta/patologia , Aorta Torácica/patologia , Insuficiência da Valva Aórtica , Autopsia , Síndrome de Behçet/complicações , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/patologia , Evolução Fatal , Feminino , Fibrose/etiologia , Fibrose/patologia , Humanos , Pneumonia/complicações , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/patologia , Calcificação Vascular , Adulto JovemRESUMO
A novel HLA-B allele, B*39:93, was identified in a French family.
Assuntos
Alelos , Antígenos HLA-B/genética , Tipagem Molecular , Sequência de Bases , Éxons , Família , Feminino , França , Humanos , Masculino , Dados de Sequência Molecular , Alinhamento de SequênciaRESUMO
HLA-B*39:01:01:03 allele differs from HLA-B*39:01:01:01 allele by a single nucleotide substitution.
Assuntos
Alelos , Éxons , Antígenos HLA-B/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático , Sequência de Bases , Transplante de Medula Óssea , Antígenos HLA-B/imunologia , Teste de Histocompatibilidade , Homozigoto , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNA , Doadores de TecidosRESUMO
HLA-B*39:06:09 differs from HLA-B*39:06:02:01 by one nucleotide substitution in codon 135 in exon 3.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Teste de Histocompatibilidade , Códon , Antígenos HLA-B/genética , Análise de Sequência de DNARESUMO
One nucleotide substitution in codon 336 of HLA-B*39:01:01:01 results in the novel allele, HLA- B*39:198.
Assuntos
Antígenos HLA-B , Humanos , Sequência de Bases , Alelos , Éxons/genética , Teste de Histocompatibilidade , Antígenos HLA-B/genética , Federação Russa , Análise de Sequência de DNARESUMO
HLA-B*39:199 differs from HLA-B*39:10:01 by a G â A substitution in exon 5 in codon 282.
Assuntos
Transplante de Medula Óssea , Medula Óssea , Humanos , Alelos , Antígenos HLA-B/genética , Genes MHC Classe I , Sequenciamento de Nucleotídeos em Larga Escala , Doadores de TecidosRESUMO
HLA-B*39:01:16 differs from B*39:01:03 by one nucleotide 348 (codon 116) T to C.
Assuntos
Alelos , Antígenos HLA-B/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Povo Asiático , Sequência de Bases , Feminino , Teste de Histocompatibilidade , Humanos , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
The novel HLA-B*39:189 allele was characterized using next generation sequencing technology.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Four nucleotide substitutions in exon 3 of HLA-B*39:01:01:01 result in a novel allele, HLA-B*39:36.
Assuntos
Medula Óssea , Antígenos HLA-B , Alelos , Sequência de Bases , Antígenos HLA-B/genética , Teste de Histocompatibilidade , Humanos , Análise de Sequência de DNA , TaiwanRESUMO
HLA-B*39:01:32 differs from HLA-B*39:01:01:01 by one nucleotide substitution at 1050 C>T in exon 7.
Assuntos
Antígenos HLA-B , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Antígenos HLA-B/genética , Humanos , NucleotídeosRESUMO
HLA-B*39:119 allele differs from HLA-B*39:01:01:01 by a single nucleotide substitution at position 488.
Assuntos
Alelos , Antígeno HLA-B39/genética , Povo Asiático , China , HumanosRESUMO
BACKGROUND: We analysed the previously reported association of the HLA-A*24:02, B*18 and B*39 alleles with type 1 diabetes and diabetes associated autoimmunity in the Finnish population applying HLA-DR/DQ stratification. MATERIALS & METHODS: Haplotype transmission was analysed in 2424 nuclear families from the Finnish Paediatric Diabetes Register. Survival analysis was applied to study the development of islet autoantibodies and further progression to clinical diabetes in the prospective follow-up cohort from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study. The subjects were genotyped for specific HLA class I alleles by sequence-specific hybridization using lanthanide labelled nucleotide probes. RESULTS: The HLA-B*39:06 allele was found almost exclusively on the (DR8)-DQB1*04 haplotype in which its presence changed the disease risk status of the whole haplotype from neutral to predisposing. The HLA-A*24:02 and the B*39:01 alleles increased the diabetes-associated risk of the DRB1*04:04-DQA1*03-DQB1*03:02 haplotype but the alleles were in linkage disequilibrium and no independent effect could be detected. Within the DIPP cohort, neither the A*24:02 nor the B*39:01 allele were associated with seroconversion but were in contrast associated with increased progression from seroconversion to clinical disease. DISCUSSION & CONCLUSIONS: The independent predisposing effect of the HLA-B*39:06 allele with type 1 diabetes was confirmed in the Finnish population but the association of the A*24:02 and B*39:01 alleles remained inconclusive whilst both A*24:02 and B*39:01 affected the progression rate from seroconversion to autoantibody positivity to overt type 1 diabetes.
Assuntos
Autoanticorpos/biossíntese , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Antígeno HLA-A24/genética , Antígeno HLA-B39/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Adulto , Alelos , Criança , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Família , Feminino , Finlândia , Expressão Gênica , Antígeno HLA-A24/imunologia , Antígeno HLA-B39/imunologia , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/imunologia , Haplótipos , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Masculino , Prognóstico , Estudos ProspectivosRESUMO
The new HLA-B*39:01:01:04 allele differs from HLA-B*39:01:01 by a C â T substitution in intron 1.
Assuntos
Alelos , Antígeno HLA-B39/genética , Íntrons , Polimorfismo de Nucleotídeo Único , Transplantados , Povo Asiático , Sequência de Bases , Códon/química , Éxons , Expressão Gênica , Genótipo , Antígeno HLA-B39/imunologia , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapiaRESUMO
HLA-B*39:97N differs from HLA-B*39:01:01 by a two nucleotide insertion at position 604-605.
Assuntos
Alelos , Códon sem Sentido , Éxons , Mutação da Fase de Leitura , Antígeno HLA-B39/genética , Doadores de Tecidos , Sequência de Bases , Transplante de Medula Óssea , Expressão Gênica , Genoma Humano , Antígeno HLA-B39/imunologia , Teste de Histocompatibilidade , Humanos , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
HLA-B*39:01:23 differs from HLA-B*39:01:01 by a single nucleotide substitution at position 153 C > T.
Assuntos
Alelos , Éxons , Antígeno HLA-B39/genética , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos , Sequência de Bases , Transplante de Medula Óssea , Códon/química , Expressão Gênica , Genoma Humano , Antígeno HLA-B39/imunologia , Teste de Histocompatibilidade , Humanos , Íntrons , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNARESUMO
Objective:To investigate influences of two different HLA-B antigens expressed on K562 cells on receptors expression of NK cells from peripheral blood lymphocytes.Methods:Studied the alteration of the percentage of CD16+CD56+ cells and the percentage of KIR3DL1+ cells before and after PBMC interaction with K562 cells for 24 hours,and also compared the percentage of CD16+CD56+ cells and the percentage of KIR3DL1+ cells after PBMC interaction with two different kind of K562 cells transfected with HLA-B39 and HLA-B51 respectively.Results:After PBMCs were incubated with K562 cells for 24 hours,the percentage of CD16+CD56+ cells and the percentage of KIR3DL1+ cells were both increased.However,after PBMCs were incubated with K562-HLA-B51 cells for 24 hours,the percentage of KIR3DL1+ cells and the percentage of CD16+CD56+ cells were both decreased in comparison with that interaction with K562-HLA-B39 cells.Conclusion:CD16 up-regulation was associated with an up-regulation of inhibitory receptors(KIR3DL1).The interaction between HLA-Bw4 and KIR3DL1 would down-regulate the expression of KIR3DL1.In addition,KIR3DL1 down-regulation was associated with down-regulation of activating receptors(CD16).