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  • Review Article
  • Published:

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

Nature Reviews Neurology volume 17, pages 399–414 (2021)Cite this article

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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.

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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.

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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.

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Authors and Affiliations

  1. Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK

    Maria T. Cencioni, Miriam Mattoscio, Roberta Magliozzi & Paolo A. Muraro

  2. Department of Neurology, University of Verona, Verona, Italy

    Roberta Magliozzi

  3. Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Amit Bar-Or

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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.

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Correspondence to Paolo A. Muraro.

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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.

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

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

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

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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

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