Interferon-β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis.
Growing evidences put B lymphocytes on a central stage in multiple sclerosis (MS) immunopathology. While investigating the effects of interferon-β (IFN-β) therapy, one of the most used first-line disease-modifying drugs for the treatment of relapsing-remitting MS, in circulating B-cell sub-populations, we found a specific and marked decrease of CD27+memory B cells. Interestingly, memory B cells are considered a population with a great disease-driving relevance in MS and resulted to be also target of B-cell depleting therapies. In addition, Epstein-Barr virus (EBV), associated with MS etiopathogenesis, harbors in this cell type and an IFN-β-induced reduction of the memory B-cell compartment, in turn, resulted in a decreased expression of the EBV gene latent membrane protein 2A in treated patients. We found that in vivo IFN-β therapy specifically and highly induced apoptosis in memory B cells, in accordance with a strong increase of the apoptotic markers Annexin-V and active caspase-3, via a mechanism requiring the FAS-receptor/TACI (transmembrane activator and CAML interactor) signaling. Thus, efficacy of IFN-β therapy in MS may rely not only on its recognized anti-inflammatory activities but also on the specific depletion of memory B cells, considered to be a pathogenic cell subset, reducing their inflammatory impact in target organs.
Department of Infectious, Parasitic and Immune-mediated Disease, Istituto Superiore di Sanità, Rome, Italy.
Fabiana
F
Rizzo
Department of Infectious, Parasitic and Immune-mediated Disease, Istituto Superiore di Sanità, Rome, Italy.
Elena
E
Giacomini
Centre for Experimental Neurological Therapies (CENTERS), S Andrea Hospital Site, Sapienza University, Rome, Italy.
Rosella
R
Mechelli
Centre for Experimental Neurological Therapies (CENTERS), S Andrea Hospital Site, Sapienza University, Rome, Italy.
Maria Chiara
MC
Buscarinu
Centre for Experimental Neurological Therapies (CENTERS), S Andrea Hospital Site, Sapienza University, Rome, Italy.
Marco
M
Salvetti
Department of Infectious, Parasitic and Immune-mediated Disease, Istituto Superiore di Sanità, Rome, Italy.
Martina
M
Severa
Department of Infectious, Parasitic and Immune-mediated Disease, Istituto Superiore di Sanità, Rome, Italy.
Eliana Marina
EM
Coccia
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D019014:fas Receptor / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; C491901:FAS protein, human; D053222:Fas Ligand Protein; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014763:Viral Matrix Proteins; D019014:fas Receptor; D016899:Interferon-beta