IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

Abstract

The implication of B lymphocytes in the immunopathology of multiple sclerosis (MS) is increasingly recognized. Here we investigated the response of B cells to IFN-β, a first-line therapy for relapsing-remitting MS patients, upon stimulation with TLR. IFN-β restored the frequency of TLR7-induced IgM and IgG-secreting cells in MS patients to the levels found in healthy donors, showing a specific deficiency in the TLR7 pathway. However, no difference was observed in the TLR9 response. Furthermore, in MS-derived PBMCs, TLR7-mediated production of IL-6 and the ex vivo expression of B-cell-activating factor of the TNF family, two crucial cytokines for B-cell differentiation and survival, were induced by IFN-β. Depletion of monocytes, which are key producers of both IL-6 and B-cellactivating factor of the TNF family, showed that TLR7-mediated B-cell differentiation into Ig-secreting cells is strongly dependent on the cross-talk between B cells and monocytes. Accordingly, impaired expression of TLR7 mRNA was observed in PBMCs and monocytes isolated from MS-affected individuals as compared with those from healthy donors, which was rescued by IFN-β therapy. Collectively, our data unveil a novel TLR7-regulated mechanism in in vivo IFN-β-stimulated whole leukocytes that could be exploited to define new TLR7-based strategies for the treatment of MS.Keywords: B cell r IFN-β r Monocyte r Multiple sclerosis r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionGrowing evidence is accumulating on the central role that B lymphocytes play in the immunopathology of multiple sclerosis (MS) [1,2]. For example, oligoclonal IgG bands, found in the cerebrospinal fluid of more than 90% of patients with MS, indicate an intrathecal Ab production [3]. The presence of clonally Correspondence: Dr. Eliana Marina Coccia e-mail: eliana.coccia@iss.it expanded B cells, plasma cells, complement and myelin-specific Abs in chronic MS lesions also suggested an intrathecal, Agdriven humoral immune response in the central nervous system of MS sufferers [4][5][6]. In addition, B-cell follicle-like structures are detectable in the meninges of MS patients [7,8]. More recently, B-cell depleting therapies, such as Rituximab (that targets the B lymphocyte surface antigen CD20 [9][10][11]), together with * These authors contributed equally to this work. Eur. J. Immunol. 2013Immunol. . 43: 1963Immunol. -1972 Ocrelizumab and Ofatumumab (two other humanized anti-CD20 monoclonal Abs), are proving their efficacy at various stages of clinical development [12]. All together these findings contribute to the compelling evidence that B cells and the humoral immune response are implicated in the pathogenesis of MS and suggest the therapeutic implications that all this may have for the treatment of this disease. B lymphocytes play an essential role in bridging innate and adaptive immunity. To differentiate into specialized cells capable of communicating with helper T cells and undergo Ab divers...

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

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