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1.
Am J Hum Genet ; 110(4): 551-564, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36933558

RESUMO

DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred for genetic testing for almost 1,900 disease-related genes. We observed 5,939 mosaic sequence or intragenic copy number variants distributed across 509 genes in nearly 5,700 individuals, constituting approximately 2% of molecular diagnoses in the cohort. Cancer-related genes had the most mosaic variants and showed age-specific enrichment, in part reflecting clonal hematopoiesis in older individuals. We also observed many mosaic variants in genes related to early-onset conditions. Additional mosaic variants were observed in genes analyzed for reproductive carrier screening or associated with dominant disorders with low penetrance, posing challenges for interpreting their clinical significance. When we controlled for the potential involvement of clonal hematopoiesis, most mosaic variants were enriched in younger individuals and were present at higher levels than in older individuals. Furthermore, individuals with mosaicism showed later disease onset or milder phenotypes than individuals with non-mosaic variants in the same genes. Collectively, the large compendium of variants, disease correlations, and age-specific results identified in this study expand our understanding of the implications of mosaic DNA variation for diagnosis and genetic counseling.


Assuntos
Variações do Número de Cópias de DNA , Mosaicismo , Variações do Número de Cópias de DNA/genética , Testes Genéticos , Fenótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação
2.
J Immunol ; 184(11): 6343-9, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20435925

RESUMO

Pulmonary surfactant protein D (SP-D), a member of the collectin family, is an innate immune molecule critical for defense that can also modulate adaptive immune responses. We previously showed that SP-D-deficient mice exhibit enhanced allergic responses and that SP-D induction requires lymphocytes. Thus, we postulated that SP-D may decrease adaptive allergic responses through interaction with T cells. In this study, we used two forms of SP-D, a dodecamer and a shorter fragment containing the trimeric neck and carbohydrate recognition domains (SP-D NCRD). Both forms decreased immune responses in vitro and in a murine model of pulmonary inflammation. SP-D NCRD increased transcription of CTLA4, a negative regulator of T cell activation, in T cells. SP-D NCRD no longer decreased lymphoproliferation and IL-2 cytokine production when CTLA4 signals were abrogated. Administration of SP-D NCRD in vivo no longer decreased allergen induced responses when CTLA4 was inhibited. Our results indicate that SP-D decreases allergen responses, an effect that may be mediated by increase of CTLA4 in T cells.


Assuntos
Antígenos CD/imunologia , Inflamação/imunologia , Proteína D Associada a Surfactante Pulmonar/imunologia , Hipersensibilidade Respiratória/imunologia , Linfócitos T/imunologia , Alérgenos/imunologia , Animais , Antígeno CTLA-4 , Ensaio de Imunoadsorção Enzimática , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
3.
J Immunol ; 184(10): 5835-41, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20385880

RESUMO

Acute lung injury (ALI) is a frequent pulmonary complication in critically ill patients. We characterized a murine model of LPS-induced ALI, focusing on Th cells. Following LPS administration, bronchoalveolar lavage lymphocytes, neutrophils, IL-6, TNF-alpha, and albumin were increased. Analysis of LPS-induced T cells revealed increased Th cell-associated cytokines (IL-17A, -17F, and -22), as well as increased expression of CD69 (a cell activation marker), Foxp3, and CTLA4 in CD4(+) T cells. Administration of anti-CTLA4 Ab decreased LPS-induced bronchoalveolar lavage albumin and IL-17A, while increasing CD4(+)Foxp3(+) cell number and Foxp3 expression in CD4(+)Foxp3(+) cells. These data suggest that pulmonary LPS administration promotes CD4(+) T cells and that T cell pathways involving CTLA4 contribute to ALI.


Assuntos
Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Antígenos CD/fisiologia , Modelos Animais de Doenças , Mediadores da Inflamação/fisiologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos CD/biossíntese , Antígenos CD/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno CTLA-4 , Feminino , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/toxicidade , Lipopolissacarídeos/fisiologia , Lipopolissacarídeos/toxicidade , Contagem de Linfócitos , Linfopenia/imunologia , Linfopenia/metabolismo , Linfopenia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/patologia
5.
Antimicrob Agents Chemother ; 50(1): 226-9, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16377690

RESUMO

Carbapenem resistance rates in Pseudomonas aeruginosa isolates in Colombia, as in many South American countries, are high for reasons that remain unclear. From our nationwide network, we describe the first detection of the metallo-beta-lactamase VIM-2 in clinical isolates of P. aeruginosa from multiple cities within Colombia. Metallo-beta-lactamases were not detected in the two centers with the highest imipenem resistance rates. Clonality was noted in five of the eight centers with strains meeting the criteria for molecular typing. The high carbapenem resistance in P. aeruginosa in Colombia may be attributable to a combination of factors, including the presence of metallo-beta-lactamases and nosocomial transmission.


Assuntos
Imipenem/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Resistência beta-Lactâmica , beta-Lactamases/análise , Colômbia , Hospitais , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/isolamento & purificação , beta-Lactamases/genética
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