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1.
Cell ; 183(7): 1826-1847.e31, 2020 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-33296702

RESUMEN

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.


Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Interferón gamma/inmunología , Mycobacterium/inmunología , Proteínas de Dominio T Box/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Linaje de la Célula , Preescolar , Cromatina/metabolismo , Islas de CpG/genética , Metilación de ADN/genética , Células Dendríticas/metabolismo , Epigénesis Genética , Femenino , Homocigoto , Humanos , Mutación INDEL/genética , Lactante , Interferón gamma/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Mutación con Pérdida de Función/genética , Masculino , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/microbiología , Linaje , Proteínas de Dominio T Box/química , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Linfocitos T Colaboradores-Inductores/inmunología , Transcriptoma/genética
2.
Psychoneuroendocrinology ; 97: 131-134, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30016711

RESUMEN

Low socioeconomic status (SES) in early-life and adulthood independently contribute to increased risk for aging-related chronic diseases. One mechanistic hypothesis for these associations involves faster cellular aging of immune cells, which could plausibly contribute to chronic disease pathogenesis by compromising host resistance and/or up-regulating inflammation. However, little is known about the association between life-course SES and cellular aging. The present study examines the association of early-life and current SES with a novel biomarker of cellular aging termed the "epigenetic clock," in monocytes. Additionally, we examine health behaviors and depressive symptoms as potential explanatory pathways. The study involved 335 participants between the ages of 15 and 55 from Vancouver, Canada and surrounding areas. Enrolled participants had to fit into four life-course SES trajectories, corresponding to low-low, low-high, high-low and high-high combinations of early-life (ages 0 to 5) and current SES respectively. Cellular aging of monocytes was measured using Horvath's DNA methylation derived measure of epigenetic age acceleration. Results indicated that socioeconomic disadvantage during early-life, but not later in life, was associated with accelerated epigenetic aging of monocytes. No early-life SES by current SES interaction was detected, suggesting that socioeconomic mobility is unrelated to epigenetic age acceleration. In path analyses, neither current health behaviors nor current depressive symptoms emerged as mediators of the early-life SES effect. These findings suggest socioeconomic disadvantage in early-life is independently predictive of cellular aging of immune cells, with potential implications for aging-related diseases later in life.


Asunto(s)
Experiencias Adversas de la Infancia/ética , Metilación de ADN/genética , Predicción/métodos , Adolescente , Adulto , Envejecimiento , Biomarcadores , Canadá , Senescencia Celular/fisiología , ADN/genética , Depresión , Epigénesis Genética/fisiología , Femenino , Conductas Relacionadas con la Salud , Humanos , Masculino , Persona de Mediana Edad , Monocitos/fisiología , Clase Social , Factores Socioeconómicos
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