RESUMEN
Epstein-Barr virus (EBV) is an aetiologic risk factor for the development of multiple sclerosis (MS). However, the role of EBV-infected B cells in the immunopathology of MS is not well understood. Here we characterized spontaneous lymphoblastoid cell lines (SLCLs) isolated from MS patients and healthy controls (HC) ex vivo to study EBV and host gene expression in the context of an individual's endogenous EBV. SLCLs derived from MS patient B cells during active disease had higher EBV lytic gene expression than SLCLs from MS patients with stable disease or HCs. Host gene expression analysis revealed activation of pathways associated with hypercytokinemia and interferon signalling in MS SLCLs and upregulation of forkhead box protein 1 (FOXP1), which contributes to EBV lytic gene expression. We demonstrate that antiviral approaches targeting EBV replication decreased cytokine production and autologous CD4+ T cell responses in this ex vivo model. These data suggest that dysregulation of intrinsic B cell control of EBV gene expression drives a pro-inflammatory, pathogenic B cell phenotype that can be attenuated by suppressing EBV lytic gene expression.
Asunto(s)
Linfocitos B , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Esclerosis Múltiple , Humanos , Herpesvirus Humano 4/genética , Esclerosis Múltiple/virología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/virología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Citocinas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD4-Positivos/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Transcriptoma , Replicación Viral , Regulación Viral de la Expresión Génica , Línea Celular , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Perfilación de la Expresión Génica , Adulto , Femenino , MasculinoRESUMEN
This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC50 > 100 µM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S-3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S-3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S-3a's safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S-3a antagonized M1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.