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B cells and antibodies in multiple sclerosis pathogenesis and therapy

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Abstract

B cells and antibodies account for the most prominent immunodiagnostic feature in patients with multiple sclerosis (MS), namely oligoclonal bands. Furthermore, evidence is accumulating that B cells and antibodies contribute to MS pathogenesis in at least a subset of patients. The CNS provides a B-cell-fostering environment that includes B-cell trophic factors such as BAFF (B-cell-activating factor of the TNF family), APRIL (a proliferation-inducing ligand), and the plasma-cell survival factor CXCL12. Owing to this environment, the CNS of patients with MS is not only the target of the immunopathological process, but also becomes the site of local antibody production. B cells can increase or dampen CNS inflammation, but their proinflammatory effects seem to be more prominent in most patients, as B-cell depletion is a promising therapeutic strategy. Other therapies not primarily designed to target B cells have numerous effects on the B-cell compartment. This Review summarizes key features of B-cell biology, the role of B cells and antibodies in CNS inflammation, and current attempts to identify the targets of pathogenic antibodies in MS. We also review the effects of approved and investigational interventions—including CD20-depleting antibodies, BAFF/APRIL-depleting agents, alemtuzumab, natalizumab, FTY720, IFN-β, glatiramer acetate, steroids and plasma exchange—on B-cell immunology.

Key Points

  • B cells regulate CNS inflammation in various ways

  • The CNS in multiple sclerosis (MS) provides a B-cell-fostering environment

  • Cerebrospinal fluid levels of the B-cell-attracting chemokine CXCL13 are linked to CNS inflammation and local IgG production, and have prognostic value in MS

  • B-cell depletion is a promising MS therapy, largely unrelated to effects on IgG production

  • Many immunomodulatory therapies in MS affect the B-cell compartment

  • Identification and validation of novel autoantibodies in MS is a current research focus; candidate antigens include myelin oligodendrocyte protein, axoglial targets around the node of Ranvier, and the potassium channel KIR4.1

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Figure 1: Proinflammatory and regulatory effects of B cells.
Figure 2: Surface markers during physiological B-cell development.
Figure 3: Effects of BAFF-targeting compounds.

Change history

  • 22 October 2012

    In the version of this article initially published online, in Figure 2 the bar indicating expression of IgM, IgA, IgG or IgE was erroneously extended to include centroblasts, and bars indicating expression of cell-surface markers were incomplete. This has been corrected for the print, HTML and PDF versions of the article.

References

  1. Hiepe, F. et al. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7, 170–178 (2011).

    CAS  PubMed  Google Scholar 

  2. Anthony, R. M. & Nimmerjahn, F. The role of differential IgG glycosylation in the interaction of antibodies with FcγRs in vivo. Curr. Opin. Organ Transplant. http://dx.doi.org/10.1097/MOT.0b013e328342538f.

  3. Barr, T. A. et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J. Exp. Med. 209, 1001–1010 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3, 944–950 (2002).

    CAS  PubMed  Google Scholar 

  5. Iwata, Y. et al. Characterization of a rare IL-10 competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530–541 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Weber, M. S. et al. B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann. Neurol. 68, 369–383 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Meinl, E., Krumbholz, M. & Hohlfeld, R. B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann. Neurol. 59, 880–892 (2006).

    CAS  PubMed  Google Scholar 

  8. Pöllinger, B. et al. Spontaneous relapsing–remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J. Exp. Med. 206, 1303–1316 (2009).

    PubMed  PubMed Central  Google Scholar 

  9. Hauser, S. L. et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Kappos, L. et al. Ocrelizumab in relapsing–remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378, 1779–1787 (2011).

    CAS  PubMed  Google Scholar 

  11. Jarius, S. & Wildemann, B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat. Rev. Neurol. 6, 383–392 (2010).

    CAS  PubMed  Google Scholar 

  12. Keegan, M. et al. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366, 579–582 (2005).

    PubMed  Google Scholar 

  13. Elliott, C. et al. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 135, 1819–1833 (2012).

    PubMed  PubMed Central  Google Scholar 

  14. Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).

    CAS  PubMed  Google Scholar 

  15. Barnett, M. H., Parratt, J. D., Cho, E. S. & Prineas, J. W. Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann. Neurol. 65, 32–46 (2009).

    PubMed  Google Scholar 

  16. Breij, E. C. et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann. Neurol. 63, 16–25 (2008).

    CAS  PubMed  Google Scholar 

  17. Barnett, M. H., Parratt, J. D., Pollard, J. D. & Prineas, J. W. MS: is it one disease? Int. MS J. 16, 57–65 (2009).

    CAS  PubMed  Google Scholar 

  18. Mathey, E. K. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 204, 2363–2372 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Derfuss, T. et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc. Natl Acad. Sci. USA 106, 8302–8307 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Genain, C. P. et al. Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J. Clin. Invest. 96, 2966–2974 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mayer, M. C. & Meinl, E. Glycoproteins as targets of autoantibodies in CNS inflammation: MOG and more. Ther. Adv. Neurol. Disord. 5, 147–159 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. O'Connor, K. C. et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 13, 211–217 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McLaughlin, K. A. et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J. Immunol. 183, 4067–4076 (2009).

    CAS  PubMed  Google Scholar 

  24. Pröbstel, A. K. et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 77, 580–588 (2011).

    PubMed  Google Scholar 

  25. Mader, S. et al. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J. Neuroinflammation 8, 184 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Owens, G. P. et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann. Neurol. 65, 639–649 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. von Büdingen, H.-C., Harrer, M. D., Kuenzle, S., Meier, M. & Goebels, N. Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies. Eur. J. Immunol. 38, 2014–2023 (2008).

    PubMed  Google Scholar 

  28. Lambracht-Washington, D. et al. Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS. J. Neuroimmunol. 186, 164–176 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dhaunchak, A. S. et al. Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann. Neurol. 71, 601–613 (2012).

    PubMed  Google Scholar 

  30. Kanter, J. L. et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat. Med. 12, 138–143 (2006).

    CAS  PubMed  Google Scholar 

  31. Brennan, K. M. et al. Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis. J. Neuroimmunol. 238, 87–95 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ho, P. P. et al. Identification of naturally occurring fatty acids of the myelin sheath that resolve neuroinflammation. Sci. Transl. Med. 4, 137ra73 (2012).

    PubMed  PubMed Central  Google Scholar 

  33. Quintana, F. J. et al. Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Proc. Natl Acad. Sci. USA 105, 18889–18894 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Srivastava, R. et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N. Engl. J. Med. 367, 115–123 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Obermeier, B. et al. Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat. Med. 14, 688–693 (2008).

    CAS  PubMed  Google Scholar 

  36. Tintore, M. et al. Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS. Mult. Scler. 7, 359–363 (2001).

    CAS  PubMed  Google Scholar 

  37. Sharief, M. K. & Thompson, E. J. The predictive value of intrathecal immunoglobulin synthesis and magnetic resonance imaging in acute isolated syndromes for subsequent development of multiple sclerosis. Ann. Neurol. 29, 147–151 (1991).

    CAS  PubMed  Google Scholar 

  38. Villar, L. M. et al. Intrathecal synthesis of oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS. J. Clin. Invest. 115, 187–194 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Stauch, C. et al. Intrathecal IgM synthesis in pediatric MS is not a negative prognostic marker of disease progression: quantitative versus qualitative IgM analysis. Mult. Scler. 17, 327–334 (2011).

    CAS  PubMed  Google Scholar 

  40. Jarius, S. et al. The intrathecal, polyspecific antiviral immune response: specific for MS or a general marker of CNS autoimmunity? J. Neurol. Sci. 280, 98–100 (2009).

    CAS  PubMed  Google Scholar 

  41. Bednarova, J., Stourac, P. & Adam, P. Relevance of immunological variables in neuroborreliosis and multiple sclerosis. Acta Neurol. Scand. 112, 97–102 (2005).

    CAS  PubMed  Google Scholar 

  42. Cepok, S. et al. Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 124, 2169–2176 (2001).

    CAS  PubMed  Google Scholar 

  43. Cepok, S. et al. Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128, 1667–1676 (2005).

    PubMed  Google Scholar 

  44. Corcione, A. et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc. Natl Acad. Sci. USA 101, 11064–11069 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kuenz, B. et al. Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis. PLoS ONE 3, e2559 (2008).

    PubMed  PubMed Central  Google Scholar 

  46. Cameron, E. M. et al. Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis. J. Neuroimmunol. 213, 123–130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ligocki, A. J. et al. A unique antibody gene signature is prevalent in the central nervous system of patients with multiple sclerosis. J. Neuroimmunol. 226, 192–193 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lovato, L. et al. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 134, 534–541 (2011).

    PubMed  PubMed Central  Google Scholar 

  49. Obermeier, B. et al. Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin. J. Neuroimmunol. 233, 245–248 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).

    PubMed  Google Scholar 

  51. Lucchinetti, C. F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188–2197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Howell, O. W. et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134, 2755–2771 (2011).

    PubMed  Google Scholar 

  53. Kutzelnigg, A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705–2712 (2005).

    PubMed  Google Scholar 

  54. Kooi, E.-J., Geurts, J. J., van Horssen, J., Bø, L. & van der Valk, P. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J. Neuropathol. Exp. Neurol. 68, 1021–1028 (2009).

    CAS  PubMed  Google Scholar 

  55. Ascherio, A., Munger, K. L. & Lunemann, J. D. The initiation and prevention of multiple sclerosis. Nat. Rev. Neurol. http://dx.doi.org/10.1038/nrneurol.2012.198.

  56. Charo, I. F. & Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).

    CAS  PubMed  Google Scholar 

  57. Krumbholz, M. et al. CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J. Neuroimmunol. 190, 72–79 (2007).

    CAS  PubMed  Google Scholar 

  58. Krumbholz, M. et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 129, 200–211 (2006).

    PubMed  Google Scholar 

  59. Pashenkov, M., Soderstrom, M. & Link, H. Secondary lymphoid organ chemokines are elevated in the cerebrospinal fluid during central nervous system inflammation. J. Neuroimmunol. 135, 154–160 (2003).

    CAS  PubMed  Google Scholar 

  60. Rupprecht, T. A. et al. The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis. Neurology 65, 448–450 (2005).

    CAS  PubMed  Google Scholar 

  61. Kowarik, M. et al. CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J. Neuroinflammation 9, 93 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Khademi, M. et al. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult. Scler. 17, 335–343 (2011).

    CAS  PubMed  Google Scholar 

  63. Brettschneider, J. et al. The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS ONE 5, e11986 (2010).

    PubMed  PubMed Central  Google Scholar 

  64. MacKay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).

    CAS  PubMed  Google Scholar 

  65. Krumbholz, M. et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J. Exp. Med. 201, 195–200 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Martin, F. & Chan, A. C. B cell immunobiology in disease: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).

    CAS  PubMed  Google Scholar 

  67. Martin Mdel, P. et al. Depletion of B lymphocytes from cerebral perivascular spaces by rituximab. Arch. Neurol. 66, 1016–1020 (2009).

    PubMed  Google Scholar 

  68. Pers, J. O. et al. BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren's syndrome. Arthritis Rheum. 56, 1464–1477 (2007).

    PubMed  Google Scholar 

  69. Cambridge, G. et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum. 54, 3612–3622 (2006).

    CAS  PubMed  Google Scholar 

  70. Cornec, D., Avouac, J., Youinou, P. & Saraux, A. Critical analysis of rituximab-induced serological changes in connective tissue diseases. Autoimmun. Rev. 8, 515–519 (2009).

    CAS  PubMed  Google Scholar 

  71. Pellkofer, H. L. et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 76, 1310–1315 (2011).

    CAS  PubMed  Google Scholar 

  72. Huang, H., Benoist, C. & Mathis, D. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc. Natl Acad. Sci. USA 107, 4658–4663 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lehmann-Horn, K. et al. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders. J. Neuroinflammation 8, 146 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. European Medicines Agency. Human Medicines Database: EMEA-000310-PIP03-10. European Medicines Agency [online], (2012).

  75. Tak, P. P. et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Arthritis Rheum. 64, 360–370 (2012).

    CAS  PubMed  Google Scholar 

  76. Sorensen, P. S. et al. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing–remitting multiple sclerosis (RRMS)—24-week results of a phase II study. Presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (2010).

  77. CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. New Engl. J. Med. 359, 1786–1801 (2008).

  78. Coles, A. J. et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial. Neurology 78, 1069–1078 (2012).

    CAS  PubMed  Google Scholar 

  79. Kirk, A. D. et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation 76, 120–129 (2003).

    CAS  PubMed  Google Scholar 

  80. Sanofi. Alemtuzumab (Lemtrada™*) significantly reduces relapses in multiple sclerosis vs interferon beta-1a in a phase III study. Sanofi [online], (2011).

  81. Jones, J. L. & Coles, A. J. Spotlight on alemtuzumab. Int. MS J. 16, 77–81 (2009).

    CAS  PubMed  Google Scholar 

  82. Cossburn, M. et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77, 573–579 (2011).

    CAS  PubMed  Google Scholar 

  83. Thompson, S., Jones, J., Cox, A., Compston, D. & Coles, A. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J. Clin. Immunol. 30, 99–105 (2010).

    CAS  PubMed  Google Scholar 

  84. Darce, J. R., Arendt, B. K., Wu, X. & Jelinek, D. F. Regulated expression of BAFF-binding receptors during human B cell differentiation. J. Immunol. 179, 7276–7286 (2007).

    CAS  PubMed  Google Scholar 

  85. Stohl, W. & Hilbert, D. M. The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat. Biotech. 30, 69–77 (2012).

    CAS  Google Scholar 

  86. Hartung, H. P. & Kieseier, B. C. Atacicept: targeting B cells in multiple sclerosis. Ther. Adv. Neurol. Disord. 3, 205–216 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Tak, P. P. et al. Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study. Arthritis Rheum. 58, 61–72 (2007).

    Google Scholar 

  88. Genovese, M. C., Kinnman, N., de La Bourdonnaye, G., Pena Rossi, C. & Tak, P. P. Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum. 63, 1793–1803 (2011).

    CAS  PubMed  Google Scholar 

  89. Yang, M. et al. Novel function of B cell-activating factor in the induction of IL-10 producing regulatory B cells. J. Immunol. 184, 3321–3325 (2010).

    CAS  PubMed  Google Scholar 

  90. Stohl, W. et al. Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 63, 1096–1103 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, L. et al. Identification of BLyS (B lymphocyte stimulator), a non-myelin-associated protein, as a functional ligand for Nogo-66 receptor. J. Neurosci. 29, 6348–6352 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Huntington, N. D. et al. A BAFF antagonist suppresses experimental autoimmune encephalomyelitis by targeting cell-mediated and humoral immune responses. Int. Immunol. 18, 1473–1485 (2006).

    CAS  PubMed  Google Scholar 

  93. Kim, S. S., Richman, D. P., Zamvil, S. S. & Agius, M. A. Accelerated central nervous system autoimmunity in BAFF-receptor-deficient mice. J. Neurol. Sci. 306, 9–15 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

    CAS  PubMed  Google Scholar 

  95. Krumbholz, M., Meinl, I., Kümpfel, T., Hohlfeld, R. & Meinl, E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology. 71, 1350–1354 (2008).

    CAS  PubMed  Google Scholar 

  96. Kowarik, M. C. et al. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS. Neurology 76, 1214–1221 (2011).

    CAS  PubMed  Google Scholar 

  97. Putzki, N., Baranwal, M. K., Tettenborn, B., Limmroth, V. & Kreuzfelder, E. Effects of natalizumab on circulating B cells, T regulatory cells and natural killer cells. Eur. Neurol. 63, 311–317 (2010).

    CAS  PubMed  Google Scholar 

  98. Lesesve, J. F., Debouverie, M., Decarvalho Bittencourt, M. & Bene, M. C. CD49d blockade by natalizumab therapy in patients with multiple sclerosis increases immature B-lymphocytes. Bone Marrow Transplant. 46, 1489–1491 (2011).

    CAS  PubMed  Google Scholar 

  99. Planas, R., Jelcic, I., Schippling, S., Martin, R. & Sospedra, M. Natalizumab treatment perturbs memory- and marginal zone-like B-cell homing in secondary lymphoid organs in multiple sclerosis. Eur. J. Immunol. 42, 790–798 (2012).

    CAS  PubMed  Google Scholar 

  100. Stuve, O. et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann. Neurol. 59, 743–747 (2006).

    CAS  PubMed  Google Scholar 

  101. Villar, L. M. et al. Immunological markers of optimal response to natalizumab in multiple sclerosis. Arch. Neurol. 69, 191–197 (2012).

    PubMed  Google Scholar 

  102. Schwab, S. R. & Cyster, J. G. Finding a way out: lymphocyte egress from lymphoid organs. Nat. Immunol. 8, 1295–1301 (2007).

    CAS  PubMed  Google Scholar 

  103. Hohlfeld, R., Barkhof, F. & Polman, C. Future clinical challenges in multiple sclerosis: relevance to sphingosine 1-phosphate receptor modulator therapy. Neurology 76, S28–S37 (2011).

    CAS  PubMed  Google Scholar 

  104. Aktas, O., Kury, P., Kieseier, B. & Hartung, H.-P. Fingolimod is a potential novel therapy for multiple sclerosis. Nat. Rev. Neurol. 6, 373–382 (2010).

    CAS  PubMed  Google Scholar 

  105. Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat. Immunol. 5, 713–720 (2004).

    CAS  PubMed  Google Scholar 

  106. Ando, S. et al. FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice. Biochem. Biophys. Res. Commun. 394, 804–810 (2010).

    CAS  PubMed  Google Scholar 

  107. Han, S. et al. FTY720 suppresses humoral immunity by inhibiting germinal center reaction. Blood 104, 4129–4133 (2004).

    CAS  PubMed  Google Scholar 

  108. Boulton, C., Meiser, K., David, O. J. & Schmouder, R. Pharmacodynamic effects of steady-state fingolimod on antibody response in healthy volunteers: a 4-week, randomized, placebo-controlled, parallel-group, multiple-dose study. J. Clin. Pharmacol. http://dx.doi.org/10.1177/0091270011427908.

  109. Mehling, M. et al. Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients. Ann. Neurol. 69, 408–413 (2011).

    CAS  PubMed  Google Scholar 

  110. Sinha, R. K., Park, C., Hwang, I. Y., Davis, M. D. & Kehrl, J. H. B lymphocytes exit lymph nodes through cortical lymphatic sinusoids by a mechanism independent of sphingosine-1-phosphate-mediated chemotaxis. Immunity 30, 434–446 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    CAS  PubMed  Google Scholar 

  112. Kabashima, K. et al. Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J. Exp. Med. 203, 2683–2690 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Cinamon, G., Zachariah, M. A., Lam, O. M., Foss, F. W. Jr & Cyster, J. G. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat. Immunol. 9, 54–62 (2008).

    CAS  PubMed  Google Scholar 

  114. Sedlakova, K., Muckersie, E., Robertson, M., Filipec, M. & Forrester, J. V. FTY720 in corneal concordant xenotransplantation. Transplantation 79, 297–303 (2005).

    CAS  PubMed  Google Scholar 

  115. Okazaki, H. et al. Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus. J. Rheumatol. 29, 707–716 (2002).

    CAS  PubMed  Google Scholar 

  116. Krumbholz, M. et al. Interferon-β increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain 131, 1415–1463 (2008).

    Google Scholar 

  117. Palace, J., Leite, M. I., Nairne, A. & Vincent, A. Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch. Neurol. 67, 1016–1017 (2010).

    PubMed  Google Scholar 

  118. Warabi, Y., Matsumoto, Y. & Hayashi, H. Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J. Neurol. Sci. 252, 57–61 (2007).

    CAS  PubMed  Google Scholar 

  119. Kantor, A. B. et al. Identification of short-term pharmacodynamic effects of interferon-beta-1a in multiple sclerosis subjects with broad-based phenotypic profiling. J. Neuroimmunol. 188, 103–116 (2007).

    CAS  PubMed  Google Scholar 

  120. Zanotti, C. et al. Opposite effects of interferon-beta on new B and T cell release from production sites in multiple sclerosis patients. J. Neuroimmunol. 240, 147–150 (2011).

    PubMed  Google Scholar 

  121. Farina, C., Weber, M. S., Meinl, E., Wekerle, H. & Hohlfeld, R. Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Lancet Neurol. 4, 567–575 (2005).

    CAS  PubMed  Google Scholar 

  122. Begum-Haque, S. et al. Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. J. Neuroimmunol. 232, 136–144 (2011).

    CAS  PubMed  Google Scholar 

  123. Kala, M. et al. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp. Neurol. 221, 136–145 (2010).

    CAS  PubMed  Google Scholar 

  124. Ireland, S. J. et al. Antibody-independent B cell effector functions in relapsing remitting multiple sclerosis: clues to increased inflammatory and reduced regulatory B cell capacity. Autoimmunity 45, 400–414 (2012).

    CAS  PubMed  Google Scholar 

  125. Andreau, K., Lemaire, C., Souvannavong, V. & Adam, A. Induction of apoptosis by dexamethasone in the B cell lineage. Immunopharmacology 40, 67–76 (1998).

    CAS  PubMed  Google Scholar 

  126. Lill-Elghanian, D., Schwartz, K., King, L. & Fraker, P. Glucocorticoid-induced apoptosis in early B cells from human bone marrow. Exp. Biol. Med. 227, 763–770 (2002).

    CAS  Google Scholar 

  127. Motyka, B., Bhogal, H. S. & Reynolds, J. D. Apoptosis of ileal Peyer's patch B cells is increased by glucocorticoids or anti-immunoglobulin antibodies. Eur. J. Immunol. 25, 1865–1871 (1995).

    CAS  PubMed  Google Scholar 

  128. Dau, P. C. Increased antibody production in peripheral blood mononuclear cells after plasma exchange therapy in multiple sclerosis. J. Neuroimmunol. 62, 197–200 (1995).

    CAS  PubMed  Google Scholar 

  129. Dau, P. C. Increased proliferation of blood mononuclear cells after plasmapheresis treatment of patients with demyelinating disease. J. Neuroimmunol. 30, 15–21 (1990).

    CAS  PubMed  Google Scholar 

  130. Paglieroni, T., Caggiano, V. & MacKenzie, M. R. Effects of plasmapheresis on peripheral blood mononuclear cell populations from patients with macroglobulinemia. J. Clin. Apher. 3, 202–208 (1987).

    CAS  PubMed  Google Scholar 

  131. Gold, R., Stangel, M. & Dalakas, M. C. The use of intravenous immunoglobulin in neurology—therapeutic considerations and practical issues. Nat. Clin. Pract. Neurol. 3, 36–44 (2007).

    CAS  PubMed  Google Scholar 

  132. Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory actions of intravenous immunoglobulin. Annu. Rev. Immunol. 26, 513–533 (2008).

    CAS  PubMed  Google Scholar 

  133. Chen, S. et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179, 1634–1647 (2007).

    CAS  PubMed  Google Scholar 

  134. Kivity, S. et al. Vitamin D and autoimmune thyroid diseases. Cell. Mol. Immunol. 8, 243–247 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Simon, K. C., Munger, K. L. & Ascherio, A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Curr. Opin. Neurol. 25, 246–251 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Knippenberg, S. et al. Effect of vitamin D3 supplementation on peripheral B cell differentiation and isotype switching in patients with multiple sclerosis. Mult. Scler. 17, 1418–1423 (2011).

    CAS  PubMed  Google Scholar 

  137. Hedstrom, A. K., Baarnhielm, M., Olsson, T. & Alfredsson, L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 73, 696–701 (2009).

    PubMed  Google Scholar 

  138. Zivadinov, R. et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology 73, 504–510 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Healy, B. C. et al. Smoking and disease progression in multiple sclerosis. Arch. Neurol. 66, 858–864 (2009).

    PubMed  PubMed Central  Google Scholar 

  140. Handel, A. E., Giovannoni, G., Ebers, G. C. & Ramagopalan, S. V. Environmental factors and their timing in adult-onset multiple sclerosis. Nat. Rev. Neurol. 6, 156–166 (2010).

    PubMed  Google Scholar 

  141. Handel, A. E. et al. Smoking and multiple sclerosis: an updated meta-analysis. PLoS ONE 6, e16149 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Fusby, J. S. et al. Cigarette smoke-induced effects on bone marrow B-cell subsets and CD4+:CD8+ T-cell ratios are reversed by smoking cessation: influence of bone mass on immune cell response to and recovery from smoke exposure. Inhal. Toxicol. 22, 785–796 (2010).

    CAS  PubMed  Google Scholar 

  143. Palmer, V. L. et al. N-acetylcysteine increases the frequency of bone marrow pro-B/pre-B cells, but does not reverse cigarette smoking-induced loss of this subset. PLoS ONE 6, e24804 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Pan, F. et al. Impact of female cigarette smoking on circulating B cells in vivo: the suppressed ICOSLG, TCF3, and VCAM1 gene functional network may inhibit normal cell function. Immunogenetics 62, 237–251 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Baranzini, S. E. et al. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J. Immunol. 163, 5133–5144 (1999).

    CAS  PubMed  Google Scholar 

  146. Qin, Y. et al. Clonal expansion and somatic hypermutation of VH genes of B cells from cerebrospinal fluid in multiple sclerosis. J. Clin. Invest. 102, 1045–1050 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Reijmers, R. M. et al. Disruption of heparan sulfate proteoglycan conformation perturbs B cell maturation and APRIL-mediated plasma cell survival. Blood 117, 6162–6171 (2011).

    CAS  PubMed  Google Scholar 

  148. Hauser, S. et al. A phase II randomized, placebo-controlled, multicenter trial of rituximab in adults with relapsing remitting multiple sclerosis (RRMS). Neurology 68 (Suppl. 1), A99–A100 (2007).

    Google Scholar 

  149. Hawker, K. et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 66, 460–471 (2009).

    CAS  PubMed  Google Scholar 

  150. Kim, S. H., Kim, W., Li, X. F., Jung, I. J. & Kim, H. J. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch. Neurol. 68, 1412–1420 (2011).

    PubMed  Google Scholar 

  151. Cross, A. H., Stark, J. L., Lauber, J., Ramsbottom, M. J. & Lyons, J. A. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J. Neuroimmunol. 180, 63–70 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Piccio, L. et al. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch. Neurol. 67, 707–714 (2010).

    PubMed  PubMed Central  Google Scholar 

  153. Vallerskog, T. et al. Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res. Ther. 8, R167 (2006).

    PubMed  PubMed Central  Google Scholar 

  154. Kreuzaler, M. et al. Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J. Immunol. 188, 497–503 (2012).

    CAS  PubMed  Google Scholar 

  155. Heidt, S., Hester, J., Shankar, S., Friend, P. J. & Wood, K. J. B-cell repopulation after alemtuzumab induction: transient increase in transitional B cells and long-term dominance of naive B cells. Am. J. Transplant. 12, 1784–1792 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Anderson, A. E. et al. Immunity 12 years after alemtuzumab in RA: CD5+ B-cell depletion, thymus-dependent T-cell reconstitution and normal vaccine responses. Rheumatology 51, 1397–1406 (2012).

    CAS  PubMed  Google Scholar 

  157. Bloom, D. et al. BAFF is increased in renal transplant patients following treatment with alemtuzumab. Am. J. Transplant. 9, 1835–1845 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. LaMattina, J. C. et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl. Int. 25, 518–526 (2012).

    CAS  PubMed  Google Scholar 

  159. Kikly, K., Manetta, J., Smith, H., Wierda, D. & Witcher, D. Characterization of LY2127399, a neutralizing antibody for BAFF [abstract]. Arthritis Rheum. 60 (Suppl. 10), 693 (2009).

    Google Scholar 

  160. Gandhi, K. S. et al. BAFF is a biological response marker to IFN-β treatment in multiple sclerosis. J. Interferon Cytokine Res. 28, 529–539 (2008).

    CAS  PubMed  Google Scholar 

  161. Vaknin-Dembinsky, A., Brill, L., Orpaz, N., Abramsky, O. & Karussis, D. Preferential increase of B-cell activating factor in the cerebrospinal fluid of neuromyelitis optica in a white population. Mult. Scler. 16, 1453–1457 (2010).

    CAS  PubMed  Google Scholar 

  162. Hedegaard, C. J. et al. Interferon-beta increases systemic BAFF levels in multiple sclerosis without increasing autoantibody production. Mult. Scler. 17, 567–577 (2011).

    CAS  PubMed  Google Scholar 

  163. Sellebjerg, F. et al. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis. Mult. Scler. 18, 305–313 (2012).

    CAS  PubMed  Google Scholar 

  164. Farina, C. et al. Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients. J. Neuroimmunol. 123, 188–192 (2002).

    CAS  PubMed  Google Scholar 

  165. Krumbholz, M. et al. BAFF is elevated in serum of patients with Wegener's granulomatosis. J. Autoimmun. 25, 298–302 (2005).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors' work is supported by the Deutsche Forschungsgemeinschaft (CRC TR 128), the Bundesministerium für Bildung und Forschung (“Krankheitsbezogenes Kompetenznetz Multiple Sklerose”), the Gemeinnützige-Hertie Stiftung, and the Verein zur Therapieforschung für MS Kranke.

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All authors contributed to researching data for the article, discussion of the content, writing, and review and/or editing of the manuscript before submission.

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Correspondence to Edgar Meinl.

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M. Krumbholz has received grant support and speaker's honoraria from Novartis.

T. Derfuss serves on scientific advisory boards for Novartis, Merck Serono, Mitsubishi Pharma, Biogen Idec, Teva, and Bayer Schering Pharma. He has received funding for travel and/or speaker's honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma. He receives research support from Biogen Idec, Novartis, and Merck Serono.

R. Hohlfeld has received personal compensations and grant support from Teva, Bayer, Merck-Serono, Sanofi-Aventis, Biogen-Idec, and Novartis.

E. Meinl has received honoraria from TEVA and Novartis, and grant support from Novartis.

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Krumbholz, M., Derfuss, T., Hohlfeld, R. et al. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 8, 613–623 (2012). https://doi.org/10.1038/nrneurol.2012.203

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