Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency.
Blood
; 126(14): 1658-69, 2015 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-26289640
ABSTRACT
Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopenia with homeostatic proliferation, and lack of regulatory T cells are considered key factors in OS pathogenesis. We report 2 siblings presenting with cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150*), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ativação Linfocitária
/
Imunodeficiência Combinada Severa
/
Linfócitos T Reguladores
/
Proteínas Adaptadoras de Sinalização CARD
/
Guanilato Ciclase
/
Mutação
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Female
/
Humans
/
Infant
/
Male
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article