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1.
Kidney Int ; 104(2): 367-377, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37230224

RESUMO

X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing. Bulk RNAseq and/or targeted RNAseq using a capture panel of kidney genes was performed. Alternative splicing events were compared to those of 15 controls by a developed bioinformatic score. When using targeted RNAseq, COL4A5 coverage was found to be 23-fold higher than with bulk RNASeq and revealed 30 significant alternative splicing events in 17 of the 19 patients. After computational scoring, a pathogenic transcript was found in all patients. A causative variant affecting COL4A5 splicing and absent in the general population was identified in all cases. Altogether, we developed a simple and robust method for identification of aberrant transcripts due to pathogenic deep-intronic COL4A5 variants. Thus, these variants, potentially targetable by specific antisense oligonucleotide therapies, were found in a high percentage of patients with XLAS in whom pathogenic variants were missed by conventional DNA sequencing.


Assuntos
Nefrite Hereditária , Humanos , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Mutação , Éxons , Splicing de RNA
2.
Immunity ; 38(3): 425-36, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23521884

RESUMO

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígeno HLA-B27/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Clonais/virologia , Cristalografia por Raios X , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Proteína do Núcleo p24 do HIV/genética , Proteína do Núcleo p24 do HIV/imunologia , Proteína do Núcleo p24 do HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Antígeno HLA-B27/química , Antígeno HLA-B27/metabolismo , Humanos , Epitopos Imunodominantes/química , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ligação Proteica/imunologia , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
3.
J Exp Med ; 204(10): 2473-85, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17893201

RESUMO

The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)-B27 patients. To understand further the nature of CD8+ T cell-mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27-restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10-specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.


Assuntos
Linfócitos T CD8-Positivos/imunologia , HIV-1/fisiologia , Replicação Viral , Sequência de Aminoácidos , Antígenos CD57/metabolismo , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Senescência Celular , Produtos do Gene gag/imunologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Antígeno HLA-B27/química , Antígeno HLA-B27/imunologia , Humanos , Contagem de Linfócitos , Dados de Sequência Molecular
4.
Birth Defects Res ; 115(5): 563-571, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36538874

RESUMO

BACKGROUND: Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. CASES: In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. CONCLUSION: Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.


Assuntos
Hidropisia Fetal , Linfedema , Humanos , Gravidez , Feminino , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Hibridização Genômica Comparativa , Linfedema/congênito , Linfedema/diagnóstico , Linfedema/genética , Ultrassonografia Pré-Natal , Mutação , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética
5.
Liver Transpl ; 10(2): 295-300, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14762870

RESUMO

Human herpesvirus 8 (HHV-8) is associated with the development of Kaposi's sarcoma (KS) and rare lymphoproliferative disorders in immunosuppressed patients. The risk of HHV-8 transmission by liver transplantation and the clinical manifestations of primary infection in this setting have yet to be determined. In order to evaluate this risk, we measured the seroprevalence of HHV-8 among 122 liver donors and their respective recipients before and after transplantation. Molecular methods and immunohistochemical analyses were performed to study the features of HHV-8 infection. Antibodies to HHV-8 were detected in sera of 4 donors before transplantation (3.3%) and of 3 recipients (2.4%). None of the 3 recipients, who were HHV-8 seropositive before transplantation, developed a KS during the follow-up. Four primary HHV-8 infections were detected among the 4 HHV-8 seronegative recipients who received a liver from an HHV-8 positive donor. Among these 4 recipients, 2 particularly immunosuppressed patients developed symptomatic diseases and died a few months after transplantation, harboring disseminated KS and HHV-8 positive lymphoproliferation. In these 2 patients, HHV-8 DNA genome sequences were detectable in peripheral blood mononuclear cells and other tissues with high viremia levels before and at the beginning of HHV-8-related diseases. In conclusion, in liver transplantation recipients, HHV-8 primary infection can be associated with fatal outcome. This study raises the question of screening liver donors for HHV-8--even in low HHV-8 infection prevalence countries--not systematically to exclude the graft but to monitor, clinically and biologically, patients who received a graft from an HHV-8-infected donor.


Assuntos
Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/transmissão , Herpesvirus Humano 8 , Transplante de Fígado/efeitos adversos , Sarcoma de Kaposi/virologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/análise , Criança , Evolução Fatal , Feminino , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/isolamento & purificação , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos , Resultado do Tratamento
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