Skip to main content

Advertisement

Log in

B cells in multiple sclerosis — from targeted depletion to immune reconstitution therapies

  • Review Article
  • Published:

From Nature Reviews Neurology

View current issue Sign up to alerts

Abstract

Increasing evidence indicates the involvement of B cells in the pathogenesis of multiple sclerosis (MS), but their precise roles are unclear. In this Review, we provide an overview of the development and physiological functions of B cells and the main mechanisms through which B cells are thought to contribute to CNS autoimmunity. In MS, abnormalities of B cell function include pro-inflammatory cytokine production, defective B cell regulatory function and the formation of tertiary lymphoid-like structures in the CNS, which are the likely source of abnormal immunoglobulin production detectable in the cerebrospinal fluid. We also consider the hypothesis that Epstein–Barr virus (EBV) is involved in the B cell overactivation that leads to inflammatory injury to the CNS in MS. We also review the immunological effects — with a focus on the effects on B cell subsets — of several successful therapeutic approaches in MS, including agents that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab), agents that less specifically deplete lymphocytes (alemtuzumab and cladribine) and autologous haematopoietic stem cell transplantation, in which the immune system is unselectively ablated and reconstituted. We consider the insights that these effects on B cell populations provide and their potential to further our understanding and targeting of B cells in MS.

Key points

  • Accumulating neuropathological, serological and immune cellular evidence strongly suggests that B cells are involved in the pathophysiology of multiple sclerosis (MS).

  • Specific B cell subsets seem to be involved in MS as antigen-presenting cells and pro-inflammatory cytokine-producing cells; other B cell subsets serve as anti-inflammatory regulatory cells.

  • The persistently active infection of B cells with Epstein–Barr virus could lead to CNS damage; however, the causative role of the virus in MS remains controversial.

  • Treatments that target B cells are effective in MS, which strongly suggests the involvement of B cells in disease pathophysiology.

  • Autologous haematopoietic stem cell transplantation is known to have regenerative effects on T cells and limited evidence indicates that the treatment leads to repopulation with predominantly naive B cells.

  • The effects of therapies on B cell subsets provide insight into the roles of B cell populations in disease; further immunological studies are required to improve our understanding of these roles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1: B cell inflammatory infiltrates in multiple sclerosis.
Fig. 2: Model of the involvement of Epstein–Barr virus in the pathogenesis of multiple sclerosis.
Fig. 3: Effects of multiple sclerosis treatments on lymphocyte levels and B cell markers.

Similar content being viewed by others

References

  1. Sawcer, S., Franklin, R. J. & Ban, M. Multiple sclerosis genetics. Lancet Neurol. 13, 700–709 (2014).

    CAS  PubMed  Google Scholar 

  2. Hardy, R. R. & Hayakawa, K. B cell development pathways. Annu. Rev. Immunol. 19, 595–621 (2001).

    CAS  PubMed  Google Scholar 

  3. Brink, R. & Phan, T. G. Self-reactive B cells in the germinal center reaction. Annu. Rev. Immunol. 36, 339–357 (2018).

    CAS  PubMed  Google Scholar 

  4. Busslinger, M. Transcriptional control of early B cell development. Annu. Rev. Immunol. 22, 55–79 (2004).

    CAS  PubMed  Google Scholar 

  5. Chung, J. B., Silverman, M. & Monroe, J. G. Transitional B cells: step by step towards immune competence. Trends Immunol. 24, 343–349 (2003).

    CAS  PubMed  Google Scholar 

  6. Tierens, A., Delabie, J., Michiels, L., Vandenberghe, P. & De Wolf-Peeters, C. Marginal-zone B cells in the human lymph node and spleen show somatic hypermutations and display clonal expansion. Blood 93, 226–234 (1999).

    CAS  PubMed  Google Scholar 

  7. Dono, M. et al. Heterogeneity of tonsillar subepithelial B lymphocytes, the splenic marginal zone equivalents. J. Immunol. 164, 5596–5604 (2000).

    CAS  PubMed  Google Scholar 

  8. Pillai, S., Cariappa, A. & Moran, S. T. Marginal zone B cells. Annu. Rev. Immunol. 23, 161–196 (2005).

    CAS  PubMed  Google Scholar 

  9. Mayer, C. T. et al. The microanatomic segregation of selection by apoptosis in the germinal center. Science 358, eaao2602 (2017).

    PubMed  PubMed Central  Google Scholar 

  10. Zouali, M. B lymphocytes–chief players and therapeutic targets in autoimmune diseases. Front. Biosci. 13, 4852–4861 (2008).

    CAS  PubMed  Google Scholar 

  11. Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).

    CAS  PubMed  Google Scholar 

  13. Hasan, M. M. et al. CD24hiCD38hi and CD24hiCD27+ human regulatory B cells display common and distinct functional characteristics. J. Immunol. 203, 2110–2120 (2019).

    CAS  PubMed  Google Scholar 

  14. Carter, N. A. et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J. Immunol. 186, 5569–5579 (2011).

    CAS  PubMed  Google Scholar 

  15. 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). One of the earliest definitive demonstrations of the importance of Breg cells in experimental inflammatory CNS disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ray, A., Mann, M. K., Basu, S. & Dittel, B. N. A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Neuroimmunol. 230, 1–9 (2011).

    CAS  PubMed  Google Scholar 

  17. Bjarnadottir, K. et al. B cell-derived transforming growth factor-beta1 expression limits the induction phase of autoimmune neuroinflammation. Sci. Rep. 6, 34594 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Li, R. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 7, 310ra166 (2015). An important study that demonstrated the existence of a functionally specialized B cell subset that exhibits an inflammatory role mediated via effects on monocyte and macrophage activation.

    PubMed  Google Scholar 

  21. Li, R., Patterson, K. R. & Bar-Or, A. Reassessing B cell contributions in multiple sclerosis. Nat. Immunol. 19, 696–707 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. Jelcic, I. et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell 175, 85–100.e23 (2018). An elegant series of cellular and molecular experiments that demonstrated that B cell–T cell crosstalk is pivotal in the pathophysiology of CNS inflammation in MS.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Okada, Y. et al. Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production. J. Autoimmun. 88, 103–113 (2018).

    CAS  PubMed  Google Scholar 

  26. Knippenberg, S. et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J. Neuroimmunol. 239, 80–86 (2011).

    CAS  PubMed  Google Scholar 

  27. Kim, Y. et al. Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis. J. Neuroinflammation 15, 300 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cencioni, M. T., Ali, R., Nicholas, R. & Muraro, P. A. Defective CD19+CD24hiCD38hi transitional B-cell function in patients with relapsing-remitting MS. Mult. Scler. https://doi.org/10.1177/1352458520951536 (2020).

    Article  PubMed  Google Scholar 

  29. Thompson, A. J., Reingold, S. C. & Cohen, J. A., International Panel on Diagnosis of Multiple Sclerosis. Applying the 2017 McDonald diagnostic criteria for multiple sclerosis — Authors’ reply. Lancet Neurol. 17, 499–500 (2018).

    PubMed  Google Scholar 

  30. Villar, L. M. et al. Intrathecal IgM synthesis predicts the onset of new relapses and a worse disease course in MS. Neurology 59, 555–559 (2002).

    CAS  PubMed  Google Scholar 

  31. Villar, L. M. et al. Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis. Ann. Neurol. 53, 222–226 (2003).

    CAS  PubMed  Google Scholar 

  32. Obermeier, B. et al. Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat. Med. 14, 688–693 (2008). This study was the first to demonstrate that CSF IgG proteomes match, to a large extent, with the corresponding IgG transcriptome from CSF B cells, confirming that these cells are the source of IgG oligoclonal bands, strongly suggesting their involvement in the pathogenesis of MS.

    CAS  PubMed  Google Scholar 

  33. Esiri, M. M. Immunoglobulin-containing cells in multiple-sclerosis plaques. Lancet 2, 478 (1977).

    CAS  PubMed  Google Scholar 

  34. Prineas, J. W. & Wright, R. G. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab. Invest. 38, 409–421 (1978).

    CAS  PubMed  Google Scholar 

  35. Esiri, M. M. Multiple sclerosis: a quantitative and qualitative study of immunoglobulin-containing cells in the central nervous system. Neuropathol. Appl. Neurobiol. 6, 9–21 (1980).

    CAS  PubMed  Google Scholar 

  36. 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 

  37. Bevan, R. J. et al. Meningeal inflammation and cortical demyelination in acute multiple sclerosis. Ann. Neurol. 84, 829–842 (2018).

    CAS  PubMed  Google Scholar 

  38. 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).

    PubMed  Google Scholar 

  39. 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 

  40. Choi, S. R. et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 135, 2925–2937 (2012).

    PubMed  Google Scholar 

  41. Androdias, G. et al. Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann. Neurol. 68, 465–476 (2010).

    CAS  PubMed  Google Scholar 

  42. Haider, L. et al. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain 139, 807–815 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. DeLuca, G. C. et al. Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology. Brain 136, 1025–1034 (2013).

    PubMed  Google Scholar 

  44. Magliozzi, R. et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann. Neurol. 68, 477–493 (2010).

    CAS  PubMed  Google Scholar 

  45. Gardner, C. et al. Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats. Brain 136, 3596–3608 (2013).

    PubMed  Google Scholar 

  46. Magliozzi, R. et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann. Neurol. 83, 739–755 (2018).

    CAS  PubMed  Google Scholar 

  47. 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 

  48. 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).

    CAS  PubMed  Google Scholar 

  49. 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 

  50. Barnett, M. H. & Prineas, J. W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).

    PubMed  Google Scholar 

  51. Sabatino, J. J. Jr., Probstel, A. K. & Zamvil, S. S. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat. Rev. Neurosci. 20, 728–745 (2019).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

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

    CAS  PubMed  Google Scholar 

  55. 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 

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

    Google Scholar 

  57. Schafflick, D. et al. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat. Commun. 11, 247 (2020). A study that exploited the latest technological advances in single-cell transcriptomics to simultaneously examine blood and CSF cell composition in patients with MS, which revealed compartmentalized T cell and B cell interactions that experiments in an animal model confirmed as functionally relevant in CNS inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ramesh, A. et al. A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Proc. Natl Acad. Sci. USA 117, 22932–22943 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).

    CAS  PubMed  Google Scholar 

  60. Drayton, D. L., Liao, S., Mounzer, R. H. & Ruddle, N. H. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344–353 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kim, H. J. et al. Epstein-Barr virus-associated lymphoproliferative disorders: review and Update on 2016 WHO classification. J. Pathol. Transl. Med. 51, 352–358 (2017).

    PubMed  PubMed Central  Google Scholar 

  63. Munger, K. L. & Ascherio, A. Prevention and treatment of MS: studying the effects of vitamin D. Mult. Scler. 17, 1405–1411 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Almohmeed, Y. H., Avenell, A., Aucott, L. & Vickers, M. A. Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One 8, e61110 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Aloisi, F., Serafini, B., Magliozzi, R., Howell, O. W. & Reynolds, R. Detection of Epstein-Barr virus and B-cell follicles in the multiple sclerosis brain: what you find depends on how and where you look. Brain 133, e157 (2010).

    PubMed  Google Scholar 

  66. Serafini, B. et al. Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J. Neuropathol. Exp. Neurol. 69, 677–693 (2010).

    CAS  PubMed  Google Scholar 

  67. Veroni, C., Serafini, B., Rosicarelli, B., Fagnani, C. & Aloisi, F. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. J. Neuroinflammation 15, 18 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Tzartos, J. S. et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 78, 15–23 (2012).

    CAS  PubMed  Google Scholar 

  69. Peferoen, L. A. et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain 133, e137 (2010).

    PubMed  Google Scholar 

  70. Mancuso, R. et al. Detection of viral DNA sequences in the cerebrospinal fluid of patients with multiple sclerosis. J. Med. Virol. 82, 1051–1057 (2010).

    CAS  PubMed  Google Scholar 

  71. Willis, S. N. et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 132, 3318–3328 (2009).

    PubMed  PubMed Central  Google Scholar 

  72. Lassmann, H., Niedobitek, G., Aloisi, F. & Middeldorp, J. M., NeuroproMiSe EBV Working Group. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue – report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 134, 2772–2786 (2011).

    PubMed  PubMed Central  Google Scholar 

  73. Cocuzza, C. E. et al. Quantitative detection of Epstein-Barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis. PLoS One 9, e94497 (2014).

    PubMed  PubMed Central  Google Scholar 

  74. Lunemann, J. D. et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J. Exp. Med. 205, 1763–1773 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Angelini, D. F. et al. Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 9, e1003220 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. van Nierop, G. P. et al. Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients. Acta Neuropathol. 134, 383–401 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Cencioni, M. T. et al. Programmed death 1 is highly expressed on CD8+ CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus. Immunology 152, 660–676 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Pittet, C. L., Newcombe, J., Antel, J. P. & Arbour, N. The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD-L1 levels on CNS cells. Glia 59, 841–856 (2011).

    PubMed  PubMed Central  Google Scholar 

  79. Bar-Or, A. et al. Epstein-Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends Mol. Med. 26, 296–310 (2020).

    CAS  PubMed  Google Scholar 

  80. 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).

    CAS  PubMed  Google Scholar 

  81. Staun-Ram, E. & Miller, A. Effector and regulatory B cells in multiple sclerosis. Clin. Immunol. 184, 11–25 (2017).

    CAS  PubMed  Google Scholar 

  82. Beers, S. A., Chan, C. H., French, R. R., Cragg, M. S. & Glennie, M. J. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin. Hematol. 47, 107–114 (2010).

    CAS  PubMed  Google Scholar 

  83. Tipton, T. R. et al. Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies. Blood 125, 1901–1909 (2015).

    CAS  PubMed  Google Scholar 

  84. Moreno Torres, I. & Garcia-Merino, A. Anti-CD20 monoclonal antibodies in multiple sclerosis. Expert Rev. Neurother. 17, 359–371 (2017).

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008). Seminal clinical trial evidence of the efficacy of B cell depleting therapy in MS.

    CAS  PubMed  Google Scholar 

  87. 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 

  88. Svenningsson, A. et al. Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally. Neurol. Neuroimmunol. Neuroinflamm 2, e79 (2015).

    PubMed  PubMed Central  Google Scholar 

  89. Komori, M. et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann. Clin. Transl. Neurol. 3, 166–179 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  91. 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 

  92. Sacco, K. A. & Abraham, R. S. Consequences of B-cell-depleting therapy: hypogammaglobulinemia and impaired B-cell reconstitution. Immunotherapy 10, 713–728 (2018).

    CAS  PubMed  Google Scholar 

  93. Myhr, K.-M., Torkildsen, Ø., Lossius, A., Bø, L. & Holmøy, T. B cell depletion in the treatment of multiple sclerosis. Expert Opin. Biol. Ther. 19, 261–271 (2019).

    CAS  PubMed  Google Scholar 

  94. van de Veerdonk, F. L. et al. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum. 63, 1507–1516 (2011).

    PubMed  Google Scholar 

  95. Nissimov, N. et al. B cells reappear less mature and more activated after their anti-CD20-mediated depletion in multiple sclerosis. Proc. Natl Acad. Sci. USA 117, 25690–25699 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Quan, C. et al. The immune balance between memory and regulatory B cells in NMO and the changes of the balance after methylprednisolone or rituximab therapy. J. Neuroimmunol. 282, 45–53 (2015).

    CAS  PubMed  Google Scholar 

  97. Maurer, M. A. et al. Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity. J. Clin. Invest. 122, 1393–1402 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. 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 

  100. 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 

  101. 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 

  102. Topping, J. et al. The effects of intrathecal rituximab on biomarkers in multiple sclerosis. Mult. Scler. Relat. Disord. 6, 49–53 (2016).

    PubMed  Google Scholar 

  103. Sorensen, P. S. & Blinkenberg, M. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther. Adv. Neurol. Disord. 9, 44–52 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Klein, C. et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. mAbs 5, 22–33 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  107. Laurent, S. Effect of ocrelizumab on B and T cell immune repertoires in patients with relapsing multiple sclerosis. Mult. Scler. 23, 85–426 (2017).

    Google Scholar 

  108. Gingele, S. et al. Ocrelizumab depletes CD20+ T cells in multiple sclerosis patients. Cells 8, 12 (2018).

    PubMed Central  Google Scholar 

  109. Gingele, S., Skripuletz, T. & Jacobs, R. Role of CD20+ T cells in multiple sclerosis: implications for treatment with ocrelizumab. Neural Regen. Res. 15, 663–664 (2020).

    PubMed  Google Scholar 

  110. Bar-Or, A. et al. B cells, T cells and inflammatory CSF biomarkers in primary progressive MS and relapsing MS in the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Trial (1635). Neurology 94, 1635 (2020).

    Google Scholar 

  111. Derfuss, T. & al. Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions. ECTRIMS Online Library. https://onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/279399/tobias.derfuss.serum.immunoglobulin.levels.and.risk.of.serious.infecti (2019).

  112. Teeling, J. L. et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J. Immunol. 177, 362–371 (2006).

    CAS  PubMed  Google Scholar 

  113. Bleeker, W. K. et al. Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody. Br. J. Haematol. 140, 303–312 (2008).

    CAS  PubMed  Google Scholar 

  114. Bar-Or, A. et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: the MIRROR study. Neurology 90, e1805–e1814 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hauser, S. L. et al. Ofatumumab versus teriflunomide in multiple sclerosis. N. Engl. J. Med. 383, 546–557 (2020).

    CAS  PubMed  Google Scholar 

  116. 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 

  117. Benson, M. J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).

    CAS  PubMed  Google Scholar 

  118. Dillon, S. R., Gross, J. A., Ansell, S. M. & Novak, A. J. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat. Rev. Drug Discov. 5, 235–246 (2006).

    CAS  PubMed  Google Scholar 

  119. Gross, J. A. et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity 15, 289–302 (2001).

    CAS  PubMed  Google Scholar 

  120. 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 (2008).

    CAS  PubMed  Google Scholar 

  121. 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).

    PubMed  Google Scholar 

  122. 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).

    CAS  PubMed  Google Scholar 

  123. Rip, J., Van Der Ploeg, E. K., Hendriks, R. W. & Corneth, O. B. J. The role of Bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit. Rev. Immunol. 38, 17–62 (2018).

    PubMed  Google Scholar 

  124. Montalban, X. et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N. Engl. J. Med. 380, 2406–2417 (2019).

    CAS  PubMed  Google Scholar 

  125. Torke, S. et al. Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol. 140, 535–548 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Investigators, C. T. et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008).

    Google Scholar 

  127. Cohen, J. A. et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380, 1819–1828 (2012).

    CAS  PubMed  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Coles, A. J. et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology 89, 1117–1126 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Havrdova, E. et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 89, 1107–1116 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Jones, J. L. & Coles, A. J. Mode of action and clinical studies with alemtuzumab. Exp. Neurol. 262 (Pt A), 37–43 (2014).

    Google Scholar 

  132. Jones, J. L. et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 133, 2232–2247 (2010).

    PubMed  Google Scholar 

  133. Hu, Y. et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 128, 260–270 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Xia, M. Q., Hale, G. & Waldmann, H. Efficient complement-mediated lysis of cells containing the CAMPATH-1 (CDw52) antigen. Mol. Immunol. 30, 1089–1096 (1993).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  136. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

  139. von Essen, M. R. et al. Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis. Brain 142, 120–132 (2019).

    Google Scholar 

  140. Wiendl, H. et al. Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab. Neurol. Neuroimmunol. Neuroinflamm. 7, e635 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ruck, T. et al. ALAIN01 — Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential. BMC Neurol. 16, 34 (2016).

    PubMed  PubMed Central  Google Scholar 

  142. Giovannoni, G. et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 362, 416–426 (2010).

    CAS  PubMed  Google Scholar 

  143. Comi, G. et al. MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study. J. Neurol. 260, 1136–1146 (2013).

    CAS  PubMed  Google Scholar 

  144. Giovannoni, G. et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet. Neurol. 10, 329–337 (2011).

    CAS  PubMed  Google Scholar 

  145. De Stefano, N. et al. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets. Mult. Scler. 24, 222–226 (2018).

    PubMed  Google Scholar 

  146. Leist, T. P. et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 13, 257–267 (2014).

    CAS  PubMed  Google Scholar 

  147. Freedman, M. S. et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult. Scler. J. Exp. Transl. Clin. 3, 2055217317732802 (2017).

    PubMed  PubMed Central  Google Scholar 

  148. Giovannoni, G. Cladribine to treat relapsing forms of multiple sclerosis. Neurotherapeutics 14, 874–887 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Beutler, E. Cladribine (2-chlorodeoxyadenosine). Lancet 340, 952–956 (1992).

    CAS  PubMed  Google Scholar 

  150. Comi, G. et al. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis. Mult. Scler. Relat. Disord. 29, 168–174 (2019).

    PubMed  Google Scholar 

  151. Stuve, O. et al. Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers. Ther. Adv. Neurol. Disord. 12, 1756286419854986 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ceronie, B. et al. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J. Neurol. 265, 1199–1209 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Baker, D. et al. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol. Neuroimmunol. Neuroinflamm 4, e360 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. Rejdak, K., Stelmasiak, Z. & Grieb, P. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult. Scler. Relat. Disord. 27, 117–120 (2019).

    PubMed  Google Scholar 

  155. Swart, J. F. et al. Haematopoietic stem cell transplantation for autoimmune diseases. Nat. Rev. Rheumatol. 13, 244–256 (2017).

    CAS  PubMed  Google Scholar 

  156. Marmont, A. M. Immune ablation followed by allogeneic or autologous bone marrow transplantation: a new treatment for severe autoimmune diseases? Stem Cell 12, 125–135 (1994).

    CAS  Google Scholar 

  157. Muraro, P. A. et al. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat. Rev. Neurol. 13, 391–405 (2017).

    CAS  PubMed  Google Scholar 

  158. Burt, R. K. et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 313, 275–284 (2015).

    PubMed  Google Scholar 

  159. Muraro, P. A. & Abrahamsson, S. V. Resetting autoimmunity in the nervous system: The role of hematopoietic stem cell transplantation. Curr. Opin. Invest. Drugs 11, 1265–1275 (2010).

    CAS  Google Scholar 

  160. Atkins, H. L. et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 388, 576–585 (2016).

    PubMed  Google Scholar 

  161. Abrahamsson, S., Mattoscio, M., Muraro P. A. in Multiple Sclerosis Immunology - A Foundation for Current and Future Treatments (ed Gran B. & Yamamura T.) Ch. 19, 401-431 (Springer-Verlag, 2013).

  162. Mancardi, G. & Saccardi, R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 7, 626–636 (2008).

    PubMed  Google Scholar 

  163. Saccardi, R. et al. A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper. Mult. Scler. 18, 825–834 (2012). This study provided the key concept and high-level protocol for randomized controlled trials of AHSCT compared with best standard therapy, a design that has been adopted by subsequent trials, including BEAT-MS and STAR-MS.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Saccardi, R. et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 105, 2601–2607 (2005).

    CAS  PubMed  Google Scholar 

  165. Mancardi, G. L. et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult. Scler. 18, 835–842 (2012).

    CAS  PubMed  Google Scholar 

  166. Burt, R. K. et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA 321, 165–174 (2019). First proof-of-principle, randomized controlled trial that demonstrated superior clinical efficacy of AHSCT compared with standard disease modifying therapy in patients with MS.

    PubMed  PubMed Central  Google Scholar 

  167. Sormani, M. P. et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology 88, 2115–2122 (2017).

    PubMed  Google Scholar 

  168. Muraro, P. A. et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J. Exp. Med. 201, 805–816 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Muraro, P. A. et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J. Clin. Invest. 124, 1168–1172 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Harris, K. M. et al. Extensive intrathecal T cell renewal following hematopoietic transplantation for multiple sclerosis. JCI Insight 5, e127655 (2020). The first high-resolution description of the reconstitution of TCR repertoires in the blood and CSF of patients with MS who underwent AHSCT and the first report of extensive ablation of pre-therapy T cell clones in both blood and CSF, which persisted for the 4-year duration of follow-up.

    PubMed Central  Google Scholar 

  171. Collins, F., Kazmi, M. & Muraro, P. A. Progress and prospects for the use and the understanding of the mode of action of autologous hematopoietic stem cell transplantation in the treatment of multiple sclerosis. Expert Rev. Clin. Immunol. 13, 611–622 (2017).

    CAS  PubMed  Google Scholar 

  172. Farge, D. et al. Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum. 52, 1555–1563 (2005).

    CAS  PubMed  Google Scholar 

  173. Arruda, L. C. M. et al. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv. 2, 126–141 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Alexander, T. et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113, 214–223 (2009).

    CAS  PubMed  Google Scholar 

  175. Karnell, F. G. et al. Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin. Exp. Immunol. 189, 268–278 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Nash, R. A. et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. 72, 159–169 (2015).

    PubMed  PubMed Central  Google Scholar 

  177. Nash, R. A. et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 102, 2364–2372 (2003).

    CAS  PubMed  Google Scholar 

  178. Saiz, A. et al. MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology 56, 1084–1089 (2001).

    CAS  PubMed  Google Scholar 

  179. Openshaw, H. et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol. Blood Marrow Transpl. 6, 563–575 (2000).

    CAS  Google Scholar 

  180. Bowen, J. D. et al. Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results. Bone Marrow Transpl. 47, 946–951 (2012).

    CAS  Google Scholar 

  181. Nash, R. A. et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology 88, 842–852 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. BEAT-MS. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04047628 (2021).

  183. 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 

  184. Villar, L. M. et al. Intrathecal IgM synthesis in neurologic diseases: relationship with disability in MS. Neurology 58, 824–826 (2002).

    CAS  PubMed  Google Scholar 

  185. Mehra, V. et al. Epstein-Barr virus and monoclonal gammopathy of clinical significance in autologous stem cell transplantation for multiple sclerosis. Clin. Infect. Dis. 69, 1757–1763 (2019).

    PubMed  Google Scholar 

Download references

Acknowledgements

M.T.C. and P.A.M. have received support from the National Institute of Health Research (NIHR-EME Project: 16/126/26 to P.A.M.) and the NIHR Biomedical Research Centre funding scheme to Imperial College London. M.T.C. has received support from the Elena Pecci research project and the Fondazione Careggi Onlus (Firenze, Italy). We thank Rui Li and Diego Espinoza for helpful comments on B cell subsets.

Author information

Authors and Affiliations

Authors

Contributions

M.T.C. and P.A.M. conceptualized the manuscript. M.T.C., M.M., R.M. and P.A.M. wrote the initial draft. A.B.O. critically reviewed the manuscript for important intellectual content and edited the manuscript. P.A.M. supervised, reviewed and revised the manuscript.

Corresponding author

Correspondence to Paolo A. Muraro.

Ethics declarations

Competing interests

M.M. discloses travel support and speaker honoraria from Biogen Idec, Genzyme, Merck-Sereno, Novartis, Roche, and Teva and consultation for Celgene, Merck-Serono, Novartis and Roche. A.B.-O. discloses participation as a speaker in meetings sponsored by and receiving consulting fees and/or grant support from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi-Genzyme. P.A.M. discloses travel support and speaker honoraria from unrestricted educational activities organized by Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono, Novartis and Sanofi Aventis, and consultation for Jasper Therapeutics and Magenta Therapeutics. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks J. Laman, M. Weber and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

BEAT-MS: http://www.beat-ms.org

STAR-MS: https://www.sheffield.ac.uk/scharr/research/centres/ctru/starms

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cencioni, M.T., Mattoscio, M., Magliozzi, R. et al. B cells in multiple sclerosis — from targeted depletion to immune reconstitution therapies. Nat Rev Neurol 17, 399–414 (2021). https://doi.org/10.1038/s41582-021-00498-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-021-00498-5

  • Springer Nature Limited

This article is cited by

Navigation