Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome.
Immunity
; 55(11): 2074-2084.e5, 2022 11 08.
Article
em En
| MEDLINE
| ID: mdl-36243008
ABSTRACT
Down syndrome (DS) is typically caused by triplication of chromosome 21. Phenotypically, DS presents with developmental, neurocognitive, and immune features. Epidemiologically, individuals with DS have less frequent viral infection, but when present, these infections lead to more severe disease. The potent antiviral cytokine type I Interferon (IFN-I) receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21. While increased IFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessive negative feedback. This led to a hypo-response to subsequent IFN-I stimuli and an ensuing viral susceptibility in DS compared to control cells. Upregulation of IFNAR2 expression phenocopied the DS IFN-I dynamics independent of trisomy 21. CD14+ monocytes from individuals with DS exhibited markers of prior IFN-I exposure and had muted responsiveness to ex vivo IFN-I stimulation. Our findings unveil oscillations of hyper- and hypo-response to IFN-I in DS, predisposing individuals to both lower incidence of viral disease and increased infection-related morbidity and mortality.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interferon Tipo I
/
Síndrome de Down
Limite:
Humans
Idioma:
En
Revista:
Immunity
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article