RESUMO
We describe here the novel HLA-C*01:224N allele which has a premature stop codon in exon 3.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Alelos , Éxons/genética , Antígenos HLA-C/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The novel HLA-B*48:53 allele was characterized using two next generation sequencing technologies.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MutaçãoRESUMO
The novel HLA-C*07:977 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-C/genética , HumanosRESUMO
The novel HLA-C*05:01:68 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-C/genética , HumanosRESUMO
The novel HLA-A*03:425 allele was characterized using two next-generation sequencing technologies.
Assuntos
Antígenos HLA-A , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Antígenos HLA-A/genética , HumanosRESUMO
The novel HLA-C*02:207 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-C/genética , HumanosRESUMO
The novel HLA-A*23:118 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-A , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Antígenos HLA-A/genética , HumanosRESUMO
The novel HLA-A*01:406 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-A , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Antígenos HLA-A/genética , HumanosRESUMO
The novel HLA-C*06:346 allele was characterized using two next generation sequencing technologies.
Assuntos
Genes MHC Classe I , Antígenos HLA-C , Alelos , Antígenos HLA-C/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The novel HLA-DRB1*11:296 allele was characterized using two next generation sequencing technologies.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Cadeias HLA-DRB1/genética , HumanosRESUMO
The novel HLA-DRB1*04:334 allele was characterized using two next-generation sequencing technologies.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Cadeias HLA-DRB1/genética , HumanosRESUMO
The novel HLA-B*15:10:08 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-B , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-B/genética , HumanosRESUMO
The novel HLA-B*40:02:35 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-B , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-B/genética , HumanosRESUMO
The novel HLA-C*07:01:105 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-C , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Genes MHC Classe I , Antígenos HLA-C/genética , HumanosRESUMO
The novel HLA-A*01:405 allele was characterized using two next generation sequencing technologies.
Assuntos
Antígenos HLA-A , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Antígenos HLA-A/genética , HumanosRESUMO
MOTIVATION: The HLA system plays a pivotal role in both clinical applications and immunology research. Typing HLA genes in patient and donor is indeed required in hematopoietic stem cell and solid-organ transplantation, and the histocompatibility complex region exhibits countless genetic associations with immune-related pathologies. Since the discovery of HLA antigens, the HLA system nomenclature and typing methods have constantly evolved, which leads to difficulties in using data generated with older methodologies. RESULTS: Here, we present Easy-HLA, a web-based software suite designed to facilitate analysis and gain knowledge from HLA typing, regardless of nomenclature or typing method. Easy-HLA implements a computational and statistical method of HLA haplotypes inference based on published reference populations containing over 600 000 haplotypes to upgrade missing or partial HLA information: 'HLA-Upgrade' tool infers high-resolution HLA typing and 'HLA-2-Haplo' imputes haplotype pairs and provides additional functional annotations (e.g. amino acids and KIR ligands). We validated both tools using two independent cohorts (total n = 2500). For HLA-Upgrade, we reached a prediction accuracy of 92% from low- to high-resolution of European genotypes. We observed a 96% call rate and 76% accuracy with HLA-2-Haplo European haplotype pairs prediction. In conclusion, Easy-HLA tools facilitate large-scale immunogenetic analysis and promotes the multi-faceted HLA expertise beyond allelic associations by providing new functional immunogenomics parameters. AVAILABILITY AND IMPLEMENTATION: Easy-HLA is a web application freely available (free account) at: https://hla.univ-nantes.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Antígenos HLA , Alelos , Genótipo , Haplótipos , Teste de Histocompatibilidade , HumanosRESUMO
The clinical use of endogenous neuropeptides has historically been limited due to pharmacokinetic issues, including plasma stability and blood-brain barrier permeability. In this study, we show that the rapidly metabolized Leu-enkephalin (LENK) neuropeptide may become pharmacologically efficient owing to a simple conjugation with the lipid squalene (SQ). The corresponding LENK-SQ bioconjugates were synthesized using different chemical linkers in order to modulate the LENK release after their formulation into nanoparticles. This new SQ-based nanoformulation prevented rapid plasma degradation of LENK and conferred on the released neuropeptide a notable antihyperalgesic effect that lasted longer than after treatment with morphine in a rat model of inflammation (Hargreaves test). The biodistribution study as well as the use of brain-permeant and -impermeant opioid receptor antagonists indicated that LENK-SQ NPs act through peripherally located opioid receptors. This study represents a novel nanomedicine approach, allowing the specific delivery of LENK neuropeptide into inflamed tissues for pain control.
Assuntos
Analgésicos Opioides/farmacocinética , Barreira Hematoencefálica/metabolismo , Morfina/farmacocinética , Nanomedicina Teranóstica , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encefalina Leucina/química , Encefalina Leucina/farmacocinética , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Morfina/administração & dosagem , Morfina/química , Nanopartículas/química , Nanopartículas/ultraestrutura , Ratos , Esqualeno/química , Distribuição TecidualRESUMO
Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus control. HLA-E-restricted CD8 T cells targeting HCMV UL40 signal peptides (HLA-EUL40) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-EUL40 CD8 T-cell responses remain mostly unknown. Here, we detected and quantified these responses in blood samples from healthy blood donors (n = 25) and kidney transplant recipients (n = 121) and we investigated the biological determinants involved in their occurrence. Longitudinal and phenotype ex vivo analyses were performed in comparison to HLA-A*02/pp65-specific CD8 T cells. Using a set of 11 HLA-E/UL40 peptide tetramers we demonstrated the presence of HLA-EUL40 CD8 αßT cells in up to 32% of seropositive HCMV+ hosts that may represent up to 38% of total circulating CD8 T-cells at a time point suggesting a strong expansion post-infection. Host's HLA-A*02 allele, HLA-E *01:01/*01:03 genotype and sequence of the UL40 peptide from the infecting strain are major factors affecting the incidence of HLA-EUL40 CD8 T cells. These cells are effector memory CD8 (CD45RAhighROlow, CCR7-, CD27-, CD28-) characterized by a low level of PD-1 expression. HLA-EUL40 responses appear early post-infection and display a broad, unbiased, Vß repertoire. Although induced in HCMV strain-dependent, UL4015-23-specific manner, HLA-EUL40 CD8 T cells are reactive toward a broader set of nonapeptides varying in 1-3 residues including most HLA-I signal peptides. Thus, HCMV induces strong and life-long lasting HLA-EUL40 CD8 T cells with potential allogeneic or/and autologous reactivity that take place selectively in at least a third of infections according to virus strain and host HLA concordance.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Transplante de Rim , Fragmentos de Peptídeos/farmacologia , Proteínas Virais/metabolismo , Adulto , Idoso , Apresentação de Antígeno , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Estudos de Casos e Controles , Células Cultivadas , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/virologia , Transplante Autólogo , Antígenos HLA-ERESUMO
BACKGROUND: Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A). METHODS: We performed a retrospective study to assess the impact of PD-1.3 on graft outcome in donor CMV seropositive (D+) and donor CMV seronegative (D-) KTx and LTx. We also performed a case-control study to evaluate the anti-CMVpp65 response according to genotype. RESULTS: PD-1.3 was determined in 1,119 KTx and 181 LTx. In 481 D+ KTx, A allele carriers (24%) experienced significantly less graft failure compared with GG carriers (p = 0.001). Multivariate analysis showed that this association was independent of donor and recipient age, acute rejection episodes, and number of human leukocyte antigen mismatches (hazard ratio, 0.381; 95% confidence interval, 0.209-0.696; p = 0.002). Analysis in 85 D+ LTx showed similar results: A allele carriers had better survival (hazard ratio, 0.302; 95% confidence interval, 0.128-0.716; p = 0.006) and greater 6-month forced expiratory volume (71% ± 17% vs 54% ± 16%, p = 0.001). In D- recipients, PD-1.3 did not affect KTx or LTx outcome. Finally, AA recipients had a stronger anti-CMVpp65 T-cell response than matched GG recipients (p = 0.003). CONCLUSIONS: The A variant allele in PD-1.3 single nucleotide polymorphism improved graft survival in kidney and lung transplant recipients receiving grafts from CMV-positive donors.
Assuntos
Antígeno B7-H1/genética , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , Rejeição de Enxerto/genética , Polimorfismo Genético , Adulto , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Estudos Soroepidemiológicos , Doadores de Tecidos , TransplantadosRESUMO
Although it is well established that bulbo-spinal serotonergic projections contribute to pain control mechanisms, whether they exert anti- or pro-nociceptive modulations is still a matter of debate. In order to reappraise the role of 5-HT in descending controls, we used RNA interference to selectively inhibit 5-HT synthesis in B3 neurons and assess resulting changes in nociception. Rats were injected into the bulbar B3 group with a recombinant lentiviral vector, LV-shTPH2, encoding RNA interfering with tryptophan hydroxylase 2 expression. Together with the long term disappearance of this enzyme in the whole rostro-caudal extent of B3 group, 5-HT was markedly depleted selectively in the dorsal horn at all levels of the spinal cord. In contrast, immunolabeling of the 5-HT transporter was unaffected by LV-shTPH2 injection, indicating the preservation of serotonergic fibers integrity. Whereas mechanical and thermal nociceptive thresholds were unchanged by 5-HT depletion, marked reductions in intraplantar formalin (but not carrageenin)-evoked nocifensive responses, and, in contrast, significant increases in mechanical and thermal hyperalgesia evoked by sciatic nerve ligation were noted in LV-shTPH2-injected rats versus controls. Parallel changes in c-Fos immunolabeling within the dorsal horn confirmed that bulbo-spinal serotonergic projections modulate pain signaling under these various conditions. These results suggest that serotonergic neurons of the B3 group are only moderately concerned, if any, by acute nociception but exert modulatory influences under pain sensitizing conditions. The opposite changes in formalin injected- versus sciatic nerve ligated rats might be related to the implication of different receptors in 5-HT-mediated modulation of inflammatory versus neuropathic pain.