Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Reassessing B cell contributions in multiple sclerosis

Abstract

There is growing recognition that B cell contributions to normal immune responses extend well beyond their potential to become antibody-producing cells, including roles at the innate–adaptive interface and their potential to modulate the responses of other immune cells such as T cells and myeloid cells. These B cell functions can have both pathogenic and protective effects in the context of central nervous system (CNS) inflammation. Here, we review recent advances in the field of multiple sclerosis (MS), which has traditionally been viewed as primarily a T cell–mediated disease, and we consider antibody-dependent and, particularly, emerging antibody-independent functions of B cells that may be relevant in both the peripheral and CNS disease compartments.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: An evolving view of cell-subset contributions to MS pathophysiology.
Fig. 2: Different therapies applied in MS preferentially target distinct cell stages along the B cell lineage.

Similar content being viewed by others

References

  1. Dutta, R. & Trapp, B. D. Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr. Opin. Neurol. 27, 271–278 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lassmann, H. Multiple sclerosis pathology. Cold Spring Harb. Perspect. Med. 8, a028936 (2018).

    Article  PubMed  Google Scholar 

  3. Klineova, S. & Lublin, F.D. Clinical course of multiple sclerosis. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a028928 (2018).

  4. Baranzini, S. E. & Oksenberg, J. R. The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends Genet. 33, 960–970 (2017).

    Article  PubMed  CAS  Google Scholar 

  5. Olsson, T., Barcellos, L. F. & Alfredsson, L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat. Rev. Neurol. 13, 25–36 (2017).

    Article  PubMed  CAS  Google Scholar 

  6. Glatigny, S. & Bettelli, E. Experimental autoimmune encephalomyelitis (EAE) as animal models of multiple sclerosis (MS). Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a028977 (2018).

  7. Dendrou, C. A., Fugger, L. & Friese, M. A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15, 545–558 (2015).

    Article  PubMed  CAS  Google Scholar 

  8. Kaskow, B. J. & Baecher-Allan, C. Effector T cells in multiple sclerosis. Cold Spring Harb. Perspect. Med. 8, a029025 (2018).

    Article  PubMed  Google Scholar 

  9. Kitz, A., Singer, E., Hafler, D. & Regulatory, T. Regulatory T cells: from discovery to autoimmunity. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a029041 (2018).

  10. Bar-Or, A. et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann. Neurol. 63, 395–400 (2008).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Sorensen, P. S. et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 82, 573–581 (2014).

    Article  PubMed  CAS  Google Scholar 

  14. Hauser, S. L. et al. Ocrelizumab versus Interferon beta-1a in relapsing multiple sclerosis. N. Engl. J. Med. 376, 221–234 (2017).

    Article  PubMed  CAS  Google Scholar 

  15. Bar-Or, A. et al. Subcutaneous ofatumumab in relapsing-remitting multiple sclerosis patients: the MIRROR study. Neurology doi:https://doi.org/10.1212/WNL.0000000000005516 (2018).

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Michel, L. et al. B cells in the multiple sclerosis central nervous system: trafficking and contribution to CNS-compartmentalized inflammation. Front. Immunol. 6, 636 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Magliozzi, R. et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann. Neurol. 68, 477–493 (2010). This paper provides the first description of links between meningeal inflammation and both neuronal loss and microglia activation.

    Article  PubMed  CAS  Google Scholar 

  19. Ransohoff, R. M. Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat. Neurosci. 15, 1074–1077 (2012).

    Article  PubMed  CAS  Google Scholar 

  20. Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).

    Article  PubMed  Google Scholar 

  21. Nikolakopoulou, A. M., Dutta, R., Chen, Z., Miller, R. H. & Trapp, B. D. Activated microglia enhance neurogenesis via trypsinogen secretion. Proc. Natl. Acad. Sci. USA 110, 8714–8719 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mahad, D. H., Trapp, B. D. & Lassmann, H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14, 183–193 (2015).

    Article  PubMed  CAS  Google Scholar 

  23. Zrzavy, T. et al. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 140, 1900–1913 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. McHeyzer-Williams, M. G. & Nossal, G. J. Clonal analysis of autoantibody-producing cell precursors in the preimmune B cell repertoire. J. Immunol. 141, 4118–4123 (1988).

    PubMed  CAS  Google Scholar 

  25. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  PubMed  CAS  Google Scholar 

  26. Shlomchik, M. J. Sites and stages of autoreactive B cell activation and regulation. Immunity 28, 18–28 (2008).

    Article  PubMed  CAS  Google Scholar 

  27. Meffre, E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann. NY Acad. Sci. 1246, 1–10 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hervé, M. et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J. Exp. Med. 204, 1583–1593 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kinnunen, T. et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood 121, 1595–1603 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Samuels, J., Ng, Y. S., Coupillaud, C., Paget, D. & Meffre, E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J. Exp. Med. 201, 1659–1667 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Yurasov, S. et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J. Exp. Med. 201, 703–711 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Kinnunen, T. et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J. Clin. Invest. 123, 2737–2741 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Dhaeze, T. et al. Circulating follicular regulatory T cells are defective in multiple sclerosis. J. Immunol. 195, 832–840 (2015).

    Article  PubMed  CAS  Google Scholar 

  34. Viglietta, V., Baecher-Allan, C., Weiner, H. L. & Hafler, D. A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Coles, A. J. et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380, 1829–1839 (2012).

    Article  PubMed  CAS  Google Scholar 

  36. Prineas, J. W. & Graham, J. S. Multiple sclerosis: capping of surface immunoglobulin G on macrophages engaged in myelin breakdown. Ann. Neurol. 10, 149–158 (1981).

    Article  PubMed  CAS  Google Scholar 

  37. Genain, C. P., Cannella, B., Hauser, S. L. & Raine, C. S. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat. Med. 5, 170–175 (1999).

    Article  PubMed  CAS  Google Scholar 

  38. Villar, L. M. et al. Early differential diagnosis of multiple sclerosis using a new oligoclonal band test. Arch. Neurol. 62, 574–577 (2005).

    Article  PubMed  Google Scholar 

  39. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Villar, L. M. et al. Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis. Ann. Neurol. 76, 231–240 (2014). This paper indicates that IgM OCB is an important biomarker for anti-CD20 treatment in patients with PPMS.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Colombo, M. et al. Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J. Immunol. 164, 2782–2789 (2000).

    Article  PubMed  CAS  Google Scholar 

  44. Qin, Y. 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. 83, 1081–1088 (2003).

    Article  PubMed  Google Scholar 

  45. Von Büdingen, H. C. et al. Clonally expanded plasma cells in the cerebrospinal fluid of patients with central nervous system autoimmune demyelination produce “oligoclonal bands”. J. Neuroimmunol. 218, 134–139 (2010).

    Article  CAS  Google Scholar 

  46. Colombo, M. et al. Maintenance of B lymphocyte-related clones in the cerebrospinal fluid of multiple sclerosis patients. Eur. J. Immunol. 33, 3433–3438 (2003).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  48. Von Büdingen, H. C. et al. B cell exchange across the blood-brain barrier in multiple sclerosis. J. Clin. Invest. 122, 4533–4543 (2012).

    Article  CAS  Google Scholar 

  49. Palanichamy, A. et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci. Transl. Med. 6, 248ra106 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Stern, J. N. H. et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci. Transl. Med. 6, 248ra107 (2014). Refs. 48–50 together demonstrate the dynamic changes in B cells across the blood–brain barrier.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Eggers, E. L. et al. Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients. JCI Insight 2, 92724 (2017).

    Article  PubMed  Google Scholar 

  52. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6, e29738 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Bar-Or, A. et al. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 126, 2738–2749 (2003).

    Article  PubMed  Google Scholar 

  56. Alter, A. et al. Determinants of human B cell migration across brain endothelial cells. J. Immunol. 170, 4497–4505 (2003).

    Article  PubMed  CAS  Google Scholar 

  57. Blauth, K., Owens, G. P. & Bennett, J. L. The ins and outs of B cells in multiple sclerosis. Front. Immunol. 6, 565 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Alvarez, E. et al. Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using CXCL13 index, magnetic resonance imaging and clinical measures. Mult. Scler. J. Exp. Transl. Clin. 1, 2055217315623800 (2015).

    PubMed  PubMed Central  Google Scholar 

  59. Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol. 15, 317–331 (2016).

    Article  PubMed  CAS  Google Scholar 

  60. Brändle, S. M. et al. Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc. Natl. Acad. Sci. USA 113, 7864–7869 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Winger, R. C. & Zamvil, S. S. Antibodies in multiple sclerosis oligoclonal bands target debris. Proc. Natl. Acad. Sci. USA 113, 7696–7698 (2016). This study identifies antibodies, found in the CSF in patients with MS, that recognize intracellular antigens.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Kuhle, J. et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N. Engl. J. Med. 356, 371–378 (2007).

    Article  PubMed  CAS  Google Scholar 

  63. Zhou, D. et al. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc. Natl. Acad. Sci. USA 103, 19057–19062 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Ketelslegers, I. A. et al. Anti-MOG antibodies plead against MS diagnosis in an acquired demyelinating syndromes cohort. Mult. Scler. 21, 1513–1520 (2015).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Kraus, V. et al. Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease. Neurology 82, 470–473 (2014).

    Article  PubMed  CAS  Google Scholar 

  67. Brickshawana, A. et al. Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study. Lancet Neurol. 13, 795–806 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Nerrant, E. et al. Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis. Mult. Scler. 20, 1699–1703 (2014).

    Article  PubMed  CAS  Google Scholar 

  69. Waters, P. J. et al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 78, 665–671 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

    Article  PubMed  CAS  Google Scholar 

  71. Lisak, R. P. et al. Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J. Neuroimmunol. 246, 85–95 (2012).

    Article  PubMed  CAS  Google Scholar 

  72. Lisak, R. P. et al. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J. Neuroimmunol. 309, 88–99 (2017).

    Article  PubMed  CAS  Google Scholar 

  73. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Krumbholz, M., Derfuss, T., Hohlfeld, R. & Meinl, E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 8, 613–623 (2012).

    Article  PubMed  CAS  Google Scholar 

  75. Touil, H. et al. Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis. J. Neuroinflammation 15, 114 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Montalban, X. et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N. Engl. J. Med. 376, 209–220 (2017).

    Article  PubMed  CAS  Google Scholar 

  77. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Monson, N. L., Cravens, P. D., Frohman, E. M., Hawker, K. & Racke, M. K. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch. Neurol. 62, 258–264 (2005).

    Article  PubMed  Google Scholar 

  79. Rodríguez-Pinto, D. B cells as antigen presenting cells. Cell. Immunol. 238, 67–75 (2005).

    Article  PubMed  CAS  Google Scholar 

  80. Pierce, S. K. et al. Antigen-presenting function of B lymphocytes. Immunol. Rev. 106, 149–180 (1988).

    Article  PubMed  CAS  Google Scholar 

  81. Rivera, A., Chen, C. C., Ron, N., Dougherty, J. P. & Ron, Y. Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. Int. Immunol. 13, 1583–1593 (2001).

    Article  PubMed  CAS  Google Scholar 

  82. Molnarfi, N. et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med. 210, 2921–2937 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Barnett, L. G. et al. B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation. J. Immunol. 192, 3607–3617 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Walters, S. N., Webster, K. E., Daley, S. & Grey, S. T. A role for intrathymic B cells in the generation of natural regulatory T cells. J. Immunol. 193, 170–176 (2014).

    Article  PubMed  CAS  Google Scholar 

  85. Milich, D. R. et al. Role of B cells in antigen presentation of the hepatitis B core. Proc. Natl. Acad. Sci. USA 94, 14648–14653 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Zeng, Q. et al. B cells mediate chronic allograft rejection independently of antibody production. J. Clin. Invest. 124, 1052–1056 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Serreze, D. V. et al. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Immunol. 161, 3912–3918 (1998).

    PubMed  CAS  Google Scholar 

  88. Li, R. et al. Antibody-independent function of human B cells contributes to antifungal T cell responses. J. Immunol. 198, 3245–3254 (2017).

    Article  PubMed  CAS  Google Scholar 

  89. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Bar-Or, A. et al. Immunological memory: contribution of memory B cells expressing costimulatory molecules in the resting state. J. Immunol. 167, 5669–5677 (2001).

    Article  PubMed  CAS  Google Scholar 

  92. Henn, A. D. et al. Functionally distinct subpopulations of CpG-activated memory B cells. Sci. Rep. 2, 345 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. O’Neill, S. K. et al. Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis. J. Immunol. 179, 5109–5116 (2007).

    Article  PubMed  Google Scholar 

  94. Gimmi, C. D. et al. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc. Natl. Acad. Sci. USA 88, 6575–6579 (1991).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Genç, K., Dona, D. L. & Reder, A. T. Increased CD80+ B cells in active multiple sclerosis and reversal by interferon beta-1b therapy. J. Clin. Invest. 99, 2664–2671 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Bodhankar, S., Galipeau, D., Vandenbark, A. A. & Offner, H. PD-1 interaction with PD-L1 but not PD-L2 on B-cells mediates protective effects of estrogen against EAE. J. Clin. Cell. Immunol. 4, 143 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ray, A., Basu, S., Williams, C. B., Salzman, N. H. & Dittel, B. N. A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J. Immunol. 188, 3188–3198 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Zuccarino-Catania, G. V. et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637 (2014). This study proposes that costimulatory/inhibitory molecules can be used as markers to define functionally distinct B cell subpopulations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Shen, P. & Fillatreau, S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 15, 441–451 (2015).

    Article  PubMed  CAS  Google Scholar 

  100. Li, R. et al. Cytokine-defined B cell responses as therapeutic targets in multiple sclerosis. Front. Immunol. 6, 626 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Duddy, M. E., Alter, A. & Bar-Or, A. Distinct profiles of human B cell effector cytokines: a role in immune regulation? J. Immunol. 172, 3422–3427 (2004).

    Article  PubMed  CAS  Google Scholar 

  102. Duddy, M. et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J. Immunol. 178, 6092–6099 (2007). This is the first study indicating abnormal B cell cytokine responses in MS.

    Article  PubMed  CAS  Google Scholar 

  103. Bar-Or, A. et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann. Neurol. 67, 452–461 (2010).

    Article  PubMed  CAS  Google Scholar 

  104. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Miyazaki, Y. et al. A novel microRNA-132-sirtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis. PLoS One 9, e105421 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Li, R. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 7, 310ra166 (2015). This paper describes novel B cell subpopulations and how abnormal B cell–myeloid cell interactions might play an important role in MS pathogenesis.

    Article  PubMed  CAS  Google Scholar 

  107. Correale, J., Farez, M. & Razzitte, G. Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann. Neurol. 64, 187–199 (2008).

    Article  PubMed  Google Scholar 

  108. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Hilgendorf, I. et al. Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation 129, 1677–1687 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Weber, G. F. et al. Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis. J. Exp. Med. 211, 1243–1256 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. 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).

    Article  PubMed  CAS  Google Scholar 

  112. Lampropoulou, V. et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 180, 4763–4773 (2008).

    Article  PubMed  CAS  Google Scholar 

  113. Matsushita, T., Yanaba, K., Bouaziz, J. D., Fujimoto, M. & Tedder, T. F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Invest. 118, 3420–3430 (2008). This paper raises the possibility that different B cell subsets may play opposing roles in the pathogenesis of neuroinflammatory diseases.

    PubMed  PubMed Central  CAS  Google Scholar 

  114. Yoshizaki, A. et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Matsumoto, M. et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 41, 1040–1051 (2014).

    Article  PubMed  CAS  Google Scholar 

  116. Ochoa-Repáraz, J., Mielcarz, D. W., Haque-Begum, S. & Kasper, L. H. Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes 1, 103–108 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1β and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014).

    Article  PubMed  CAS  Google Scholar 

  118. Blair, P. A. et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32, 129–140 (2010).

    Article  PubMed  CAS  Google Scholar 

  119. 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). Refs. 118,119 show the existence of regulatory B cell subpopulations in humans.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Rieger, A. & Bar-Or, A. B-cell-derived interleukin-10 in autoimmune disease: regulating the regulators. Nat. Rev. Immunol. 8, 486–487 (2008).

    Article  PubMed  CAS  Google Scholar 

  121. Correale, J. & Farez, M. Association between parasite infection and immune responses in multiple sclerosis. Ann. Neurol. 61, 97–108 (2007).

    Article  PubMed  CAS  Google Scholar 

  122. Bjarnadóttir, K. et al. B cell-derived transforming growth factor-β1 expression limits the induction phase of autoimmune neuroinflammation. Sci. Rep. 6, 34594 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014). This is the first study demonstrating antibody-independent roles of plasma cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Wang, R. X. et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat. Med. 20, 633–641 (2014). Refs. 123,124 identify a novel population of regulatory B cells characterized by IL-35 expression.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Fritz, J. H. et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481, 199–203 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Patel, D. J. & Wang, Z. Readout of epigenetic modifications. Annu. Rev. Biochem. 82, 81–118 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Zan, H. & Casali, P. Epigenetics of peripheral B-cell differentiation and the antibody response. Front. Immunol. 6, 631 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Wu, H. et al. Epigenetic regulation in B-cell maturation and its dysregulation in autoimmunity. Cell. Mol. Immunol. https://doi.org/10.1038/cmi.2017.133 (2018).

  129. Sievers, C. et al. Altered microRNA expression in B lymphocytes in multiple sclerosis: towards a better understanding of treatment effects. Clin. Immunol. 144, 70–79 (2012).

    Article  PubMed  CAS  Google Scholar 

  130. Palanichamy, A. et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J. Immunol. 193, 580–586 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Kappos, L. et al. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 13, 353–363 (2014).

    Article  PubMed  CAS  Google Scholar 

  132. Sergott, R. C. et al. ATON: results from a phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis. J. Neurol. Sci. 351, 174–178 (2015).

    Article  PubMed  CAS  Google Scholar 

  133. Bossen, C. & Schneider, P. BAFF, APRIL and their receptors: structure, function and signaling. Semin. Immunol. 18, 263–275 (2006).

    Article  PubMed  CAS  Google Scholar 

  134. Steri, M. et al. Overexpression of the cytokine BAFF and autoimmunity risk. N. Engl. J. Med. 376, 1615–1626 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Baker, D., Marta, M., Pryce, G., Giovannoni, G. & Schmierer, K. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine 16, 41–50 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Miyazaki, Y. et al. Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations. Clin. Immunol. 151, 127–135 (2014).

    Article  PubMed  CAS  Google Scholar 

  137. Nakamura, M. et al. Differential effects of fingolimod on B-cell populations in multiple sclerosis. Mult. Scler. 20, 1371–1380 (2014).

    Article  PubMed  CAS  Google Scholar 

  138. Grützke, B. et al. Fingolimod treatment promotes regulatory phenotype and function of B cells. Ann. Clin. Transl. Neurol. 2, 119–130 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Lundy, S. K. et al. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets. Neurol. Neuroimmunol. Neuroinflamm. 3, e211 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Li, R. et al. Dimethyl fumarate treatment mediates an anti-inflammatory shift in B cell subsets of patients with multiple sclerosis. J. Immunol. 198, 691–698 (2017).

    Article  PubMed  CAS  Google Scholar 

  141. Longbrake, E.E. et al. Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count. Mult. Scler. https://doi.org/10.1177/1352458517707069 (2017).

  142. Smith, M. D., Martin, K. A., Calabresi, P. A. & Bhargava, P. Dimethyl fumarate alters B-cell memory and cytokine production in MS patients. Ann. Clin. Transl. Neurol. 4, 351–355 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Agius, M.A. et al. Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Mult. Scler. https://doi.org/10.1177/1352458517740641 (2017).

  144. Satterthwaite, A. B. Bruton’s tyrosine kinase, a component of B cell signaling pathways, has multiple roles in the pathogenesis of lupus. Front. Immunol. 8, 1986 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Rizzo, F. et al. Interferon-β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis. Immunol. Cell Biol. 94, 886–894 (2016).

    Article  PubMed  CAS  Google Scholar 

  146. Rudick, R. A. et al. Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. J. Neuroimmunol. 93, 8–14 (1999).

    Article  PubMed  CAS  Google Scholar 

  147. Noronha, A., Toscas, A. & Jensen, M. A. Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis. J. Neuroimmunol. 46, 145–153 (1993).

    Article  PubMed  CAS  Google Scholar 

  148. Rep, M. H. et al. Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients. J. Neuroimmunol. 96, 92–100 (1999).

    Article  PubMed  CAS  Google Scholar 

  149. Lucas, M. et al. Regulation by interferon beta-1a of reactive oxygen metabolites production by lymphocytes and monocytes and serum sulfhydryls in relapsing multiple sclerosis patients. Neurochem. Int. 42, 67–71 (2003).

    Article  PubMed  CAS  Google Scholar 

  150. Hussien, Y., Sanna, A., Söderström, M., Link, H. & Huang, Y. M. Multiple sclerosis: expression of CD1a and production of IL-12p70 and IFN-gamma by blood mononuclear cells in patients on combination therapy with IFN-beta and glatiramer acetate compared to monotherapy with IFN-beta. Mult. Scler. 10, 16–25 (2004).

    Article  PubMed  CAS  Google Scholar 

  151. Zafranskaya, M. et al. Interferon-beta therapy reduces CD4+ and CD8+ T-cell reactivity in multiple sclerosis. Immunology 121, 29–39 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Hamamcioglu, K. & Reder, A. T. Interferon-beta regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis. Mult. Scler. 13, 459–470 (2007).

    Article  PubMed  CAS  Google Scholar 

  153. Korporal, M. et al. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch. Neurol. 65, 1434–1439 (2008).

    Article  PubMed  Google Scholar 

  154. Comabella, M. et al. Changes in matrix metalloproteinases and their inhibitors during interferon-beta treatment in multiple sclerosis. Clin. Immunol. 130, 145–150 (2009).

    Article  PubMed  CAS  Google Scholar 

  155. Rasouli, J. et al. Expression of GM-CSF in T cells is increased in multiple sclerosis and suppressed by IFN-β therapy. J. Immunol. 194, 5085–5093 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Trinschek, B., Luessi, F., Gross, C. C., Wiendl, H. & Jonuleit, H. Interferon-beta therapy of multiple sclerosis patients improves the responsiveness of T cells for immune suppression by regulatory T cells. Int. J. Mol. Sci. 16, 16330–16346 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Duda, P. W., Schmied, M. C., Cook, S. L., Krieger, J. I. & Hafler, D. A. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J. Clin. Invest. 105, 967–976 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Karandikar, N. J. et al. Glatiramer acetate (Copaxone) therapy induces CD8+ T cell responses in patients with multiple sclerosis. J. Clin. Invest. 109, 641–649 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Salama, H. H., Hong, J., Zang, Y. C., El-Mongui, A. & Zhang, J. Blocking effects of serum reactive antibodies induced by glatiramer acetate treatment in multiple sclerosis. Brain 126, 2638–2647 (2003).

    Article  PubMed  Google Scholar 

  160. Rieks, M. et al. Induction of apoptosis of CD4+ T cells by immunomodulatory therapy of multiple sclerosis with glatiramer acetate. Eur. Neurol. 50, 200–206 (2003).

    Article  PubMed  CAS  Google Scholar 

  161. Putheti, P., Soderstrom, M., Link, H. & Huang, Y. M. Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J. Neuroimmunol. 144, 125–131 (2003).

    Article  PubMed  CAS  Google Scholar 

  162. Dhib-Jalbut, S. et al. Glatiramer acetate-reactive peripheral blood mononuclear cells respond to multiple myelin antigens with a Th2-biased phenotype. J. Neuroimmunol. 140, 163–171 (2003).

    Article  PubMed  CAS  Google Scholar 

  163. Aharoni, R., Kayhan, B., Eilam, R., Sela, M. & Arnon, R. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc. Natl Acad. Sci. USA 100, 14157–14162 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Weber, M. S. et al. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127, 1370–1378 (2004).

    Article  PubMed  Google Scholar 

  165. Kim, H. J. et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J. Immunol. 172, 7144–7153 (2004).

    Article  PubMed  CAS  Google Scholar 

  166. Tennakoon, D. K. et al. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J. Immunol. 176, 7119–7129 (2006).

    Article  PubMed  CAS  Google Scholar 

  167. Blanco, Y. et al. Effect of glatiramer acetate (Copaxone) on the immunophenotypic and cytokine profile and BDNF production in multiple sclerosis: a longitudinal study. Neurosci. Lett. 406, 270–275 (2006).

    Article  PubMed  CAS  Google Scholar 

  168. Biegler, B. W. et al. Glatiramer acetate (GA) therapy induces a focused, oligoclonal CD8+ T-cell repertoire in multiple sclerosis. J. Neuroimmunol. 180, 159–171 (2006).

    Article  PubMed  CAS  Google Scholar 

  169. Burger, D. et al. Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1beta in human monocytes and multiple sclerosis. Proc. Natl Acad. Sci. USA 106, 4355–4359 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Pul, R. et al. Glatiramer acetate increases phagocytic activity of human monocytes in vitro and in multiple sclerosis patients. PLoS One 7, e51867 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Sellner, J. et al. Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis. Clin. Exp. Immunol. 173, 381–389 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Ayers, C. L. et al. Modulation of immune function occurs within hours of therapy initiation for multiple sclerosis. Clin. Immunol. 147, 105–119 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Ireland, S. J. et al. The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis. JAMA Neurol. 71, 1421–1428 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Ahn, Y. H. et al. Glatiramer acetate attenuates the activation of CD4+ T cells by modulating STAT1 and -3 signaling in glia. Sci. Rep. 7, 40484 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Watson, C. M., Davison, A. N., Baker, D., O’Neill, J. K. & Turk, J. L. Suppression of demyelination by mitoxantrone. Int. J. Immunopharmacol. 13, 923–930 (1991).

    Article  PubMed  CAS  Google Scholar 

  176. Fox, E. J. Mechanism of action of mitoxantrone. Neurology 63 (Suppl. 6), S15–S18 (2004).

    Article  PubMed  CAS  Google Scholar 

  177. Chan, A., Weilbach, F. X., Toyka, K. V. & Gold, R. Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients. Clin. Exp. Immunol. 139, 152–158 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Putzki, N. et al. Mitoxantrone does not restore the impaired suppressive function of natural regulatory T cells in patients suffering from multiple sclerosis: a longitudinal ex vivo and in vitro study. Eur. Neurol. 61, 27–32 (2009).

    Article  PubMed  CAS  Google Scholar 

  179. Vogelgesang, A., Rosenberg, S., Skrzipek, S., Bröker, B. M. & Dressel, A. Mitoxantrone treatment in multiple sclerosis induces TH2-type cytokines. Acta Neurol. Scand. 122, 237–243 (2010).

    Article  PubMed  CAS  Google Scholar 

  180. Bar-Or, A. et al. Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology 81, 552–558 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Bar-Or, A., Pachner, A., Menguy-Vacheron, F., Kaplan, J. & Wiendl, H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs 74, 659–674 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Bar-Or, A. et al. Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens. Neurol. Neuroimmunol. Neuroinflamm. 2, e70 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Gandoglia, I. et al. Teriflunomide treatment reduces B cells in patients with MS. Neurol. Neuroimmunol. Neuroinflamm. 4, e403 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Li, L. et al. The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro. J. Neuroimmunol. 265, 82–90 (2013).

    Article  PubMed  CAS  Google Scholar 

  185. Spencer, C. M., Crabtree-Hartman, E. C., Lehmann-Horn, K., Cree, B. A. & Zamvil, S. S. Reduction of CD8+ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol. Neuroimmunol. Neuroinflamm. 2, e76 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Berkovich, R. & Weiner, L. P. Effects of dimethyl fumarate on lymphocyte subsets. Mult. Scler. Relat. Disord. 4, 339–341 (2015).

    Article  PubMed  Google Scholar 

  187. Longbrake, E. E. et al. Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult. Scler. 22, 1061–1070 (2016).

    Article  PubMed  CAS  Google Scholar 

  188. Michell-Robinson, M. A. et al. Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis. Ann. Clin. Transl. Neurol. 3, 27–41 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Gross, C. C. et al. Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 3, e183 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Wu, Q. et al. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J. Immunol. 198, 3069–3080 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Fleischer, V. et al. Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS. Mult. Scler. 24, 632–641 (2018).

    Article  PubMed  CAS  Google Scholar 

  192. Ghadiri, M. et al. Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol. Neuroimmunol. Neuroinflamm. 4, e340 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Diebold, M. et al. Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis. J. Autoimmun. 86, 39–50 (2018).

    Article  PubMed  CAS  Google Scholar 

  194. Bielekova, B. et al. Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc. Natl Acad. Sci. USA 103, 5941–5946 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Wynn, D. et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 9, 381–390 (2010).

    Article  PubMed  CAS  Google Scholar 

  196. Lin, Y. C. et al. Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis. Ann. Clin. Transl. Neurol. 2, 445–455 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Lin, Y. C. et al. Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination. Neurol. Neuroimmunol. Neuroinflamm. 3, e196 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Niino, M. et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann. Neurol. 59, 748–754 (2006).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  200. 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).

    Article  PubMed  CAS  Google Scholar 

  201. Sellebjerg, F. et al. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology 73, 2003–2010 (2009).

    Article  PubMed  CAS  Google Scholar 

  202. 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).

    Article  PubMed  CAS  Google Scholar 

  203. 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).

    Article  PubMed  CAS  Google Scholar 

  204. Planas, R., Jelči, 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).

    Article  PubMed  CAS  Google Scholar 

  205. Börnsen, L. et al. Effect of natalizumab on circulating CD4+ T-cells in multiple sclerosis. PLoS One 7, e47578 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Warnke, C. et al. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult. Scler. 21, 1036–1044 (2015).

    Article  PubMed  CAS  Google Scholar 

  207. Saraste, M., Penttilä, T. L. & Airas, L. Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells. Neurol. Neuroimmunol. Neuroinflamm. 3, e292 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Kimura, K. et al. Disrupted balance of T cells under natalizumab treatment in multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 3, e210 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Mameli, G. et al. Natalizumab therapy modulates miR-155, miR-26a and proinflammatory cytokine expression in MS patients. PLoS One 11, e0157153 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Serpero, L. D. et al. Fingolimod modulates peripheral effector and regulatory T cells in MS patients. J. Neuroimmune Pharmacol. 8, 1106–1113 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Claes, N. et al. Compositional changes of B and T cell subtypes during fingolimod treatment in multiple sclerosis patients: a 12-month follow-up study. PLoS One 9, e111115 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Muls, N., Dang, H. A., Sindic, C. J. & van Pesch, V. Fingolimod increases CD39-expressing regulatory T cells in multiple sclerosis patients. PLoS One 9, e113025 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Mazzola, M. A. et al. Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation. J. Neuroinflammation 12, 245 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Blumenfeld, S., Staun-Ram, E. & Miller, A. Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with multiple sclerosis. J. Autoimmun. 70, 40–51 (2016).

    Article  PubMed  CAS  Google Scholar 

  215. Miyazaki, Y. et al. Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis. Clin. Immunol. 187, 95–101 (2018).

    Article  PubMed  CAS  Google Scholar 

  216. Ghadiri, M. et al. Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod. Mult. Scler. 23, 1225–1232 (2017).

    Article  PubMed  CAS  Google Scholar 

  217. Jones, J. L. et al. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc. Natl. Acad. Sci. USA 110, 20200–20205 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Thomas, K., Eisele, J., Rodriguez-Leal, F. A., Hainke, U. & Ziemssen, T. Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS. Neurol. Neuroimmunol. Neuroinflamm. 3, e228 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Gross, C. C. et al. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 3, e289 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Cox, A. L. et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35, 3332–3342 (2005).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  222. Hill-Cawthorne, G. A. et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 83, 298–304 (2012).

    Article  PubMed  Google Scholar 

  223. 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 naïve B cells. Am. J. Transplant. 12, 1784–1792 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Zhang, X. et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J. Immunol. 191, 5867–5874 (2013).

    Article  PubMed  CAS  Google Scholar 

  225. Wilk, E. et al. Depletion of functionally active CD20+ T cells by rituximab treatment. Arthritis Rheum. 60, 3563–3571 (2009).

    Article  PubMed  CAS  Google Scholar 

  226. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Studer, V., Rossi, S., Motta, C., Buttari, F. & Centonze, D. Peripheral B cell depletion and central proinflammatory cytokine reduction following repeated intrathecal administration of rituximab in progressive Multiple Sclerosis. J. Neuroimmunol. 276, 229–231 (2014).

    Article  PubMed  CAS  Google Scholar 

  228. Dall’Era, M. et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 56, 4142–4150 (2007).

    Article  PubMed  CAS  Google Scholar 

  229. van Vollenhoven, R. F., Kinnman, N., Vincent, E., Wax, S. & Bathon, J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum. 63, 1782–1792 (2011).

    Article  PubMed  CAS  Google Scholar 

  230. Ma, N. et al. BAFF suppresses IL-15 expression in B cells. J. Immunol. 192, 4192–4201 (2014).

    Article  PubMed  CAS  Google Scholar 

  231. Munafo, A., Priestley, A., Nestorov, I., Visich, J. & Rogge, M. Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers. Eur. J. Clin. Pharmacol. 63, 647–656 (2007).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amit Bar-Or.

Ethics declarations

Competing interests

A.B.-O. has consulted for multiple entities involved in B cell–targeting therapies and has received consulting fees and/or grant support from Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis and Sanofi-Genzyme. R.L. and K.R.P. have nothing to disclose.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, R., Patterson, K.R. & Bar-Or, A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol 19, 696–707 (2018). https://doi.org/10.1038/s41590-018-0135-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-018-0135-x

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing