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1.
Cell ; 186(23): 5114-5134.e27, 2023 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-37875108

RESUMEN

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.


Asunto(s)
Interferón gamma , Janus Quinasa 2 , Infecciones por Mycobacterium , Humanos , Masculino , Proteínas de Ciclo Celular/metabolismo , Interferón gamma/inmunología , Interleucina-12 , Interleucina-23 , Janus Quinasa 2/metabolismo , Mycobacterium/fisiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Proteínas Oncogénicas/metabolismo
2.
J Exp Med ; 218(4)2021 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-33544838

RESUMEN

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Autoanticuerpos/inmunología , Enfermedades Autoinmunes , COVID-19 , Enfermedades Genéticas Congénitas , Interferón-alfa , Receptor de Interferón alfa y beta , SARS-CoV-2 , Vacuna contra la Fiebre Amarilla , Virus de la Fiebre Amarilla , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , COVID-19/genética , COVID-19/inmunología , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Células HEK293 , Humanos , Interferón-alfa/genética , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/inmunología , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Vacuna contra la Fiebre Amarilla/efectos adversos , Vacuna contra la Fiebre Amarilla/genética , Vacuna contra la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/genética , Virus de la Fiebre Amarilla/inmunología
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