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

• Published in: European journal of immunology 2013-07, Vol.43 (7), p.1963-1972
• Main Authors: Giacomini, Elena, Severa, Martina, Rizzo, Fabiana, Mechelli, Rosella, Annibali, Viviana, Ristori, Giovanni, Riccieri, Valeria, Salvetti, Marco, Coccia, Eliana Marina
• Format: Article
• Language: English
• Subjects: Adult; B cell; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Cell Separation; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; IFN‐β; Immunologic Factors - therapeutic use; Interferon-beta - therapeutic use; Male; Monocyte; Monocytes - drug effects; Monocytes - metabolism; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - metabolism; Real-Time Polymerase Chain Reaction; Receptor Cross-Talk - drug effects; Receptor Cross-Talk - immunology; Reverse Transcriptase Polymerase Chain Reaction; TLR; Toll-Like Receptor 7 - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201243212

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‐cell‐activating 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.