RESUMEN
OBJECTIVE: We examined the effect of glatiramer acetate (GA) on B-cell maturation, differentiation, and antigen presentation in MS and experimental autoimmune encephalomyelitis (EAE). METHODS: A cross-sectional study of blood samples from 20 GA-treated and 18 untreated patients with MS was performed by flow cytometry; 6 GA-treated patients with MS were analyzed longitudinally. GA-mediated effects on B-cell antigen-presenting function were investigated in EAE, or, alternatively, B cells were treated with GA in vitro using vehicle as a control. RESULTS: In MS, GA diminished transitional B-cell and plasmablast frequency, downregulated CD69, CD25, and CD95 expression, and decreased TNF-α production, whereas IL-10 secretion and MHC Class II expression were increased. In EAE, we observed an equivalent dampening of proinflammatory B-cell properties and an enhanced expression of MHC Class II. When used as antigen-presenting cells for activation of naive T cells, GA-treated B cells promoted development of regulatory T cells, whereas proinflammatory T-cell differentiation was diminished. CONCLUSIONS: GA immune modulates B-cell function in EAE and MS and efficiently interferes with pathogenic B cell-T cell interaction.
Asunto(s)
Células Presentadoras de Antígenos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Acetato de Glatiramer/farmacología , Factores Inmunológicos/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Animales , Estudios Transversales , Encefalomielitis Autoinmune Experimental/sangre , Femenino , Citometría de Flujo , Humanos , Estudios Longitudinales , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangreRESUMEN
BACKGROUND: In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. METHODS: Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. RESULTS: While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. CONCLUSION: Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. TRIAL REGISTRATION: Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).