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Blood ; 106(2): 626-34, 2005 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15817684

RESUMO

Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T-cell function (T-CVID). We have previously identified a subset of patients with T-CVID characterized by defective T-cell receptor (TCR)-dependent protein tyrosine phosphorylation. In these patients, ZAP-70 fails to be recruited to the TCR as the result of impaired CD3zeta phosphorylation, which is, however, not dependent on defective Lck expression or activity. Here we show that neither Fyn nor CD45 is affected in these patients. On the other hand, T-CVID T cells show dramatic defects in the Vav/Rac pathway controlling F-actin dynamics. A significant deficiency in Vav protein was indeed observed; in 3 of 4 patients with T-CVID, it was associated with reduced VAV1 mRNA levels. The impairment in Vav expression correlated with defective F-actin reorganization in response to TCR/CD28 co-engagement. Furthermore, TCR/CD28-dependent up-regulation of lipid rafts at the cell surface, which requires F-actin dynamics, was impaired in these patients. The actin cytoskeleton defect could be reversed by reconstitution of Vav1 expression in the patients' T cells. Results demonstrate an essential role of Vav in human T cells and strongly suggest Vav insufficiency in T-CVID.


Assuntos
Actinas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Complexo CD3/metabolismo , Sinalização do Cálcio , Imunodeficiência de Variável Comum/imunologia , DNA Complementar/genética , Gangliosídeo G(M1)/metabolismo , Expressão Gênica , Humanos , Técnicas In Vitro , Antígenos Comuns de Leucócito/genética , Microdomínios da Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fyn , Proteínas Proto-Oncogênicas c-vav , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína-Tirosina Quinase ZAP-70 , Quinases da Família src/genética
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