Interferon‐β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS‐mediated apoptosis

Abstract

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.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…The MOA of IFN-b in MS is not clear but is thought to involve anti-inflammatory mechanisms. Nevertheless, IFN-b is known to inhibit the infectivity of EBV, cytomegalovirus (CMV), and other viruses, influence proliferative T cell responses to EBNA1 [68], and decrease the memory B cell compartment that is considered to be a pathogenic cell subset and key trigger in MS [69]. It is tempting to suggest that the MOA of IFN-b and other disease-modifying therapies (DMTs) [70] includes overlapping antiviral and anti-inflammatory mechanisms that support future simultaneous testing of MS drugs with divergent MOAs.…”

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis

“…As such, their actions have been ascribed to mechanisms such as: CD8 T suppressor cells activity, anergy, Th1 to Th2 switching, T regulatory cell induction (Compston and Coles, 2002, Marta and Giovannoni, 2012, Martin et al, 2016). Whilst many putative mechanisms have their origins in T cell biology (Deiß et al, 2013, Marta and Giovannoni, 2012, Martin et al, 2016), since the efficacy exhibited by CD20-specific monoclonal antibodies (mAb) (Hauser et al, 2008, Kappos et al, 2011, Sorensen et al, 2014), many mechanisms of action have been re-evaluated in the context of B lymphocyte function (Ireland et al, 2014, Rizzo et al, 2016, Schubert et al, 2015). Teriflunomide inhibits both proliferating T and B cells (Li et al, 2013) and the vast majority of cytostatic agents, such as mitoxantrone and cyclophosphamide, described to target activated T cells, actually preferentially inhibit B cells, including memory B cells (Fig.…”

“…DOI: 10.1002/acn3.155. (E) Beta interferon (Rizzo et al, 2016). The results show a reduction in the individual percentage of CD19 +, CD27 + B memory cells before (T0) and one month (T1) after weekly treatment.…”

Thymosins in multiple sclerosis and its experimental models: moving from basic to clinical application

“…Based on this background and having in mind the strong immunomodulatory and pleiotropic activity of Tα1 molecule as well as our previous data showing a TLR7-driven dysregulation of B cell response in MS patients (Giacomini et al, 2013;Rizzo et al, 2016), we set up an in vitro PBMC-based experimental procedure to study differentiation of B reg subsets and the impact of Tα1 in this context (Giacomini et al, 2017). In particular, differently from studies on purified B cells, the mixed cell population of PBMC resemble the in vivo scenario and, upon stimulation with a specific TLR7 agonist (the socalled Imiquimod), could account for cytokine production as well as triggering of CD40 signaling generating an in vitro B cell proliferating milieu unique for either healthy individuals or patients.…”