• 1
    Franciotta, D., Salvetti, M., Lolli, F., Serafini, B. and Aloisi, F., B cells and multiple sclerosis. Lancet Neurol. 2008. 7: 852858.
  • 2
    Krumbholz, M., Derfuss, T., Hohlfeld, R. and Meinl, E., B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 2012. 8: 613623.
  • 3
    Walsh, M. J., Tourtellotte, W. W., Roman, J. and Dreyer, W., Immunoglobulin G, A, and M–clonal restriction in multiple sclerosis cerebrospinal fluid and serum–analysis by two-dimensional electrophoresis. Clin. Immunol. Immunopathol. 1985. 35: 313327.
  • 4
    Genain, C. P., Cannella, B., Hauser, S. L. and Raine, C. S., Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat. Med. 1999. 5: 170175.
  • 5
    O'Connor, K. C., Appel, H., Bregoli, L., Call, M. E., Catz, I., Chan, J. A., Moore, N. H. et al., Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein. J. Immunol. 2005. 175: 19741982.
  • 6
    Qin, Y., Duquette, P., Zhang, Y., Olek, M., Da, R. R., Richardson, J., Antel, J. P. et al., Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis. Lab. Invest. 2003. 83: 10811088.
  • 7
    Magliozzi, R., Howell, O., Vora, A., Serafini, B., Nicholas, R., Puopolo, M., Reynolds, R. et al., Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007. 130: 10891104.
  • 8
    Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. and Aloisi, F., Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004. 14: 164174.
  • 9
    Hauser, S. L., Waubant, E., Arnold, D. L., Vollmer, T., Antel, J., Fox, R. J., Bar-Or, A. et al., B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 2008. 358: 676688.
  • 10
    Bar-Or, A., Calabresi, P. A., Arnold, D., Markowitz, C., Shafer, S., Kasper, L. H., Waubant, E. et al., Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann. Neurol. 2008. 63: 395400.
  • 11
    Stuve, O., Leussink, V. I., Frohlich, R., Hemmer, B., Hartung, H. P., Menge, T. and Kieseier, B. C., Long-term B-lymphocyte depletion with rituximab in patients with relapsing-remitting multiple sclerosis. Arch. Neurol. 2009. 66: 259261.
  • 12
    Dreyfus, D. H., Autoimmune disease: a role for new anti-viral therapies? Autoimmun. Rev. 2011. 11: 8897.
  • 13
    Lanzavecchia, A. and Sallusto, F., Toll-like receptors and innate immunity in B-cell activation and antibody responses. Curr. Opin. Immunol. 2007. 19: 268274.
  • 14
    Browne, E. P., Regulation of B-cell responses by Toll-like receptors. Immunology 2012. 136: 370379.
  • 15
    Gambuzza, M., Licata, N., Palella, E., Celi, D., Foti Cuzzola, V., Italiano, D., Marino, S. et al., Targeting Toll-like receptors: emerging therapeutics for multiple sclerosis management. J. Neuroimmunol. 2011. 239: 112.
  • 16
    Tomai, M. A., Imbertson, L. M., Stanczak, T. L., Tygrett, L. T. and Waldschmidt, T. J., The immune response modifiers imiquimod and R-848 are potent activators of B lymphocytes. Cell Immunol. 2000. 203: 5565.
  • 17
    Krieg, A. M., Yi, A. K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A. et al., CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995. 374: 546549.
  • 18
    Gonzalez-Navajas, J. M., Lee, J., David, M. and Raz, E., Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 2012. 12: 125135.
  • 19
    Kavanaugh, A., Tomar, R., Reveille, J., Solomon, D. H. and Homburger, H. A., Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch. Pathol. Lab. Med. 2000. 124: 7181.
  • 20
    Remoli, M. E., Gafa, V., Giacomini, E., Severa, M., Lande, R. and Coccia, E. M., IFN-beta modulates the response to TLR stimulation in human DC: involvement of IFN regulatory factor-1 (IRF-1) in IL-27 gene expression. Eur. J. Immunol. 2007. 37: 34993508.
  • 21
    Zula, J. A., Green, H. C., Ransohoff, R. M., Rudick, R. A., Stark, G. R. and van Boxel-Dezaire, A. H., The role of cell type-specific responses in IFN-beta therapy of multiple sclerosis. Proc. Natl. Acad. Sci. USA 2011. 108: 1968919694.
  • 22
    Severa, M., Remoli, M. E., Giacomini, E., Annibali, V., Gafa, V., Lande, R., Tomai, M. et al., Sensitization to TLR7 agonist in IFN-beta-preactivated dendritic cells. J. Immunol. 2007. 178: 62086216.
  • 23
    Jego, G., Bataille, R. and Pellat-Deceunynck, C., Interleukin-6 is a growth factor for nonmalignant human plasmablasts. Blood 2001. 97: 18171822.
  • 24
    Krumbholz, M., Faber, H., Steinmeyer, F., Hoffmann, L. A., Kumpfel, T., Pellkofer, H., Derfuss, T. et al., Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain 2008. 131: 14551463.
  • 25
    Tosato, G., Seamon, K. B., Goldman, N. D., Sehgal, P. B., May, L. T., Washington, G. C., Jones, K. D. et al., Monocyte-derived human B-cell growth factor identified as interferon-beta 2 (BSF-2, IL-6). Science 1988. 239: 502504.
  • 26
    Bauer, J., Ganter, U., Geiger, T., Jacobshagen, U., Hirano, T., Matsuda, T., Kishimoto, T. et al., Regulation of interleukin-6 expression in cultured human blood monocytes and monocyte-derived macrophages. Blood 1988. 72: 11341140.
  • 27
    Tribouley, C., Wallroth, M., Chan, V., Paliard, X., Fang, E., Lamson, G., Pot, D. et al., Characterization of a new member of the TNF family expressed on antigen presenting cells. Biol. Chem. 1999. 380: 14431447.
  • 28
    Jiang, H., Milo, R., Swoveland, P., Johnson, K. P., Panitch, H. and Dhib-Jalbut, S., Interferon beta-1b reduces interferon gamma-induced antigen-presenting capacity of human glial and B cells. J. Neuroimmunol. 1995. 61: 1725.
  • 29
    Ramgolam, V. S., Sha, Y., Marcus, K. L., Choudhary, N., Troiani, L., Chopra, M. and Markovic-Plese, S., B cells as a therapeutic target for IFN-beta in relapsing-remitting multiple sclerosis. J. Immunol. 2011. 186: 45184526.
  • 30
    Ruprecht, C. R. and Lanzavecchia, A., Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol. 2006. 36: 810816.
  • 31
    Bernasconi, N. L., Traggiai, E. and Lanzavecchia, A., Maintenance of serological memory by polyclonal activation of human memory B cells. Science 2002. 298: 21992202.
  • 32
    Tangye, S. G., Avery, D. T., Deenick, E. K. and Hodgkin, P. D., Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses. J. Immunol. 2003. 170: 686694.
  • 33
    Green, N. M., Laws, A., Kiefer, K., Busconi, L., Kim, Y. M., Brinkmann, M. M., Trail, E. H. et al., Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop. J. Immunol. 2009. 183: 15691576.
  • 34
    Bekeredjian-Ding, I. B., Wagner, M., Hornung, V., Giese, T., Schnurr, M., Endres, S. and Hartmann, G., Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J. Immunol. 2005. 174: 40434050.
  • 35
    Douagi, I., Gujer, C., Sundling, C., Adams, W. C., Smed-Sorensen, A., Seder, R. A., Karlsson Hedestam, G. B. et al., Human B cell responses to TLR ligands are differentially modulated by myeloid and plasmacytoid dendritic cells. J. Immunol. 2009. 182: 19912001.
  • 36
    Jego, G., Palucka, A. K., Blanck, J. P., Chalouni, C., Pascual, V. and Banchereau, J., Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 2003. 19: 225234.
  • 37
    Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y., Matsuda, T., Kashiwamura, S. et al., Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986. 324: 7376.
  • 38
    Roldan, E., Garcia-Pardo, A. and Brieva, J. A., VLA-4-fibronectin interaction is required for the terminal differentiation of human bone marrow cells capable of spontaneous and high rate immunoglobulin secretion. J. Exp. Med. 1992. 175: 17391747.
  • 39
    Mackay, F., Silveira, P. A. and Brink, R., B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr. Opin. Immunol. 2007. 19: 327336.
  • 40
    Serafini, B., Severa, M., Columba-Cabezas, S., Rosicarelli, B., Veroni, C., Chiappetta, G., Magliozzi, R. et al., Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J. Neuropathol. Exp. Neurol. 2010. 69: 677693.
  • 41
    Coccia, E. M., Severa, M., Giacomini, E., Monneron, D., Remoli, M. E., Julkunen, I., Cella, M. et al., Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur. J. Immunol. 2004. 34: 796805.
  • 42
    Molnarfi, N., Benkhoucha, M., Bjarnadottir, K., Juillard, C. and Lalive, P. H., Interferon-beta induces hepatocyte growth factor in monocytes of multiple sclerosis patients. PLoS One 2013. 7: e49882.
  • 43
    Comabella, M., Lunemann, J. D., Rio, J., Sanchez, A., Lopez, C., Julia, E., Fernandez, M. et al., A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain 2009. 132: 33533365.
  • 44
    Prinz, M., Schmidt, H., Mildner, A., Knobeloch, K. P., Hanisch, U. K., Raasch, J., Merkler, D. et al., Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 2008. 28: 675686.
  • 45
    Poovassery, J. S. and Bishop, G. A., Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms. J. Immunol. 2012. 189: 17571764.
  • 46
    Ciccarelli, O., Bagnato, F., Mainero, C., Salvetti, M., Paolillo, A., Gasperini, C., Bastianello, S. et al., Antinuclear antibodies and response to IFNbeta-1a therapy in relapsing-remitting multiple sclerosis. Mult. Scler. 2000. 6: 137139.
  • 47
    Warrington, A. E., Van Keulen, V., Pease, L. R. and Rodriguez, M., Naturally occurring antibodies as therapeutics for neurologic disease: can human monoclonal IgMs replace the limited resource IVIG? Adv. Exp. Med. Biol. 2012. 750: 4455.
  • 48
    Buljevac, D., Flach, H. Z., Hop, W. C., Hijdra, D., Laman, J. D., Savelkoul, H. F., van Der Meche, F. G. et al., Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002. 125: 952960.
  • 49
    Correale, J., Fiol, M. and Gilmore, W., The risk of relapses in multiple sclerosis during systemic infections. Neurology 2006. 67: 652659.
  • 50
    De Keyser, J., Zwanikken, C. and Boon, M., Effects of influenza vaccination and influenza illness on exacerbations in multiple sclerosis. J. Neurol. Sci. 1998. 159: 5153.
  • 51
    Merelli, E. and Casoni, F., Prognostic factors in multiple sclerosis: role of intercurrent infections and vaccinations against influenza and hepatitis B. Neurol. Sci. 2000. 21: S853S856.
  • 52
    Loebermann, M., Winkelmann, A., Hartung, H. P., Hengel, H., Reisinger, E. C. and Zettl, U. K., Vaccination against infection in patients with multiple sclerosis. Nat. Rev. Neurol. 2012. 8: 143151.
  • 53
    Clanchy, F. I. and Sacre, S. M., Modulation of toll-like receptor function has therapeutic potential in autoimmune disease. Expert. Opin. Biol. Ther. 2010. 10: 17031716.
  • 54
    Enevold, C., Oturai, A. B., Sorensen, P. S., Ryder, L. P., Koch-Henriksen, N. and Bendtzen, K., Polymorphisms of innate pattern recognition receptors, response to interferon-beta and development of neutralizing antibodies in multiple sclerosis patients. Mult. Scler. 2010. 16: 942949.
  • 55
    Kawasaki, A., Furukawa, H., Kondo, Y., Ito, S., Hayashi, T., Kusaoi, M., Matsumoto, I. et al., TLR7 single-nucleotide polymorphisms in the 3’ untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study. Arthritis Res. Ther. 2011. 13: R41. doi:10.1186/ar3277.
  • 56
    Polman, C. H., Reingold, S. C., Edan, G., Filippi, M., Hartung, H. P., Kappos, L., Lublin, F. D. et al., Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 2005. 58: 840846.