Asunto(s)
Antígeno CD48/genética , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica/genética , Interleucina-6/metabolismo , Células Asesinas Naturales/inmunología , Linfohistiocitosis Hemofagocítica/genética , Mutación/genética , Biología Computacional , Células HEK293 , Heterocigoto , Humanos , Inflamación , Interleucina-6/genética , Linaje , Proteínas Qa-SNARE/genética , Recurrencia , Regulación hacia Arriba , Secuenciación del Exoma , Adulto JovenRESUMEN
Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/ß, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/ß, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
Asunto(s)
Candidiasis Mucocutánea Crónica/genética , Candidiasis Mucocutánea Crónica/inmunología , Interleucina-17/inmunología , Modelos Moleculares , Factor de Transcripción STAT1/genética , Linfocitos T/inmunología , Secuencia de Bases , Ensayo de Cambio de Movilidad Electroforética , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Mutación de Línea Germinal/genética , Humanos , Immunoblotting , Interferón gamma/sangre , Interferón gamma/metabolismo , Interferones , Interleucinas/metabolismo , Masculino , Datos de Secuencia Molecular , Linaje , Fosforilación , Receptor de Interferón alfa y beta/inmunología , Factor de Transcripción STAT1/química , Factor de Transcripción STAT1/metabolismo , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
OBJECTS: To study the long-term outcome of surgically treated low-grade cerebellar astrocytomas in children. MATERIALS AND METHODS: We followed 31 consecutive patients under 16 years of age who were diagnosed between 1980 and 2005 in a single institution. In 21 of 31 survivors (median follow-up time 7.9 years; range 5.6-27.4 years) who agreed to participate, tumor control, neurological and cognitive complications, and their impact on behavioral and emotional adjustment and health-related quality of life (HRQoL) were comprehensively assessed qualitatively and quantitatively. RESULTS: Neurological sequelae were found in 43%. However, age-appropriate ability to perform daily life activities was normal in all patients. Remarkably, cognitive deficits leading to significant school problems occurred in 19% and behavioral and emotional adjustment disturbances in 27%. In comparison with healthy controls, the survivors rated their HRQoL similarly or even higher. CONCLUSION: Childhood low-grade cerebellar astrocytomas have an excellent cure rate by tumor surgery alone. When compared with other pediatric brain tumors, the risk of neurological, cognitive, emotional, and behavioral complications is relatively small. HRQoL is similar to that of healthy controls.
