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


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.


Multiple sclerosis (MS) is an immune-mediated disease of the CNS of unknown aetiology. Strong evidence supports an association between immune gene polymorphisms and susceptibility to MS1. MS has been associated with inflammatory T helper (TH) cell profiles and T cells play key roles in adoptive transfer models of demyelinating disease; therefore, historically, the emphasis of MS research has been on T cells. However, evidence has accumulated, especially over the past 10–15 years, that strongly implicates the involvement of B cells in the pathogenesis of MS. Indeed, some of the most effective approved therapies for MS target B cells. However, the precise role of B cells in the evolution of the disease remains unclear and a greater understanding of their roles is needed to refine therapeutic approaches.

In this article, we review what is known about the involvement of B cells in MS pathophysiology and examine the mechanisms of action of B cell-targeted therapies, the effects of pan-lymphocyte-depleting therapies on B cells and the effects of the immune reconstitution strategy autologous haematopoietic stem cell transplantation (AHSCT) on B cells in the treatment of MS. We consider how these therapeutic effects will inform us about the involvement of B cells, with the potential for the refinement of therapeutics.

B cell basics

B cell development

B cells progress through a number of developmental stages (Supplementary Figure 1). They develop from the lymphoid progenitor lineage, which derives from haematopoietic stem cells in the bone marrow. Following the productive rearrangement of the immunoglobulin heavy chain (that is, the production of a DNA sequence that is translated into a full-length and correctly structured protein), pro-B cells proliferate and rearrange their immunoglobulin κ light chain as they develop into immature B cells2. These immature B cells pass through a negative selection process that removes autoreactive clones3. Selected B cells then leave the bone marrow and evolve through transitional (T1 and T2) B cell stages into mature follicular and marginal zone B cells within the peripheral lymphoid organs (the spleen, lymph node and tonsils)4,5,6,7,8.

In the marginal zone and lymphoid follicles, mature B cells differentiate into memory B cells, plasmablasts and plasma cells, which are the immunoglobulin-producing cells. Here, further negative selection mechanisms remove clones that have dysfunctional B cell receptor (BCR) rearrangements or a high affinity for self-antigens, which could initiate autoimmune disease9. A balance between cell proliferation and programmed cell death ensures the homeostasis of circulating memory B cells and bone marrow-resident, long-lived plasma cells9.

Essentials of B cell function

B cells play various roles (Supplementary Figure 1) in mediating humoral immunity and take part in cellular immunity in the adaptive immune system and at the interface of the innate and adaptive immune systems. BCRs and Toll-like receptors expressed by B cells recognize the components of pathogens. Antigenic stimulation and T cell-derived signals promote B cell activation and differentiation into plasma cells that produce protective immunoglobulins. However, plasma cells can also produce autoantibodies that can be pathogenic and associated with autoimmune disease.

Memory B cells participate in the development of cellular immunity in various capacities. First, they can serve as antigen-presenting cells (APCs) for T cells, whereby antigen and the major histocompatibility complex (MHC) expressed by B cells deliver the so-called ‘signal 1’ required for T cell activation. Second, as part of their APC role, B cells express co-stimulatory molecules that engage with appropriate co-stimulatory receptors on T cells to deliver the so-called ‘signal 2’ required for effective T cell activation. Co-stimulatory signals are important for the differentiation of CD4+ TH1 and TH2 cells10. Third, activated B cells release a range of cytokines, including IL-6, tumour necrosis factor (TNF) and granulocyte–macrophage colony-stimulating factor (GM-CSF), that can increase T cell and myeloid cell activation and further contribute to B cell proliferation and differentiation.

B cell-mediated immune regulation

B cells can regulate humoral and cellular immunity through the release of anti-inflammatory cytokines, including IL-10, transforming growth factor-β (TGFβ), granzyme B and IL-35 (refs11,12). Various regulatory B (Breg) cell subsets have been described that can suppress inflammatory immune responses. CD19+CD24HiCD38Hi transitional B cells (henceforth referred to as transitional B cells) and CD19+CD24+CD27+ B cells (the human equivalent of murine B10 cells) are the primary producers of IL-10. An in vitro study has shown that CD19+CD24+CD27+ B cells are more efficient than transitional B cells at suppressing CD4+ T cell proliferation and the expression of IFNγ and IL-17 (ref.13). The same study demonstrated that both subsets of Breg cells release IL-10 and TNF and yet CD19+CD24+CD27+ B cells express higher amounts of TGFβ1 and granzyme B, suggesting that the mechanism of immunosuppression differs between the subsets13.

In one experimental model of autoimmune arthritis, mice that were deprived of IL-10-producing regulatory B cells exhibited worse arthritis than wild-type animals; the numbers of inflammatory TH1 and TH17 T cells were increased in B cell-deficient mice and the number of Foxp3+ T regulatory cells was reduced14. These findings illustrate the protective effect of IL-10-producing Breg cells. This protective role has also been demonstrated in experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmunity that is commonly used to study MS15,16. In this study, a deficiency of TGFβ1-producing B cells exacerbated the susceptibility to EAE; this effect depended on failure of myeloid dendritic cell activation to be downregulated, which in turn increased the encephalitogenic responses of TH1/TH17 cells17.

B cells in multiple sclerosis

B cell abnormalities

Several abnormalities in the function of peripheral blood-derived B cells have been identified in MS (Supplementary Fig. 1). Abnormalities in the cytokine profiles of naive and memory B cells have been observed in patients with MS18. In particular, activated B cells from patients with MS produce excessive amounts of the cytokines TNF, lymphotoxin-α, IL-6 and GM-CSF18,19,20. The details of the mechanisms that underlie B cell cytokine dysregulation, including transcriptional and epigenetic regulation, and the research progress and challenges in this area have been reviewed elsewhere21.

In addition to, and independent of, inflammatory cytokines, B cells in patients with MS produce some as yet unidentified secretory factors that are toxic to oligodendrocytes22 and neurons23. Furthermore, one study has shown that memory B cells can drive the spontaneous proliferation of self-reactive CD4+ T cells from people with MS, an observation that provides fascinating insight into the complex interplay between B cells and T cells24.

Several studies have also indicated the dysfunction of Breg cells in MS. In vitro, B cells that derive from people with MS exhibit deficient IL-10 production when stimulated with CD40L in comparison with B cells from matched healthy controls25. In people with MS, IL-10-producing Breg cells are reduced during disease relapse compared with in remission26 and this reduction is associated with a reduction in the ratio of naive to memory Breg cells, suggesting an enrichment of functional Breg cells in the naive subset. Similarly, low numbers of transitional Breg cells have been observed during MS relapse when compared with numbers of these cells during remission, suggesting that a reduction in B cell-dependent regulation is involved in inflammatory clinical disease27. Finally, a study published in 2020 demonstrated that, in addition to producing low levels of IL-10, transitional B cells from patients with MS are defective in the suppression of TH1 cell effector functions28.

Taken together, the evidence suggests that, within the B cell pool, the memory subset harbours most of the potentially pathogenic MS-associated cells. However, deficiencies in protective (anti-inflammatory or regulatory) B cells in other subsets could be equally important in the pathophysiology of MS and further investigation is needed to fully understand the contributions of different B cell populations.

Neuropathological evidence

Abnormalities in the quantity and quality of immunoglobulins in the cerebrospinal fluid (CSF) are classic pathological features of MS. In >90% of patients with MS, the CSF is positive for immunoglobulin G (IgG) oligoclonal bands, a long-known and still useful diagnostic biomarker29. Immunoglobulin M (IgM) oligoclonal bands are detected less frequently but are associated with a worse disease course30 and therefore have prognostic value31. In a key study, a comparison of the immunoglobulin transcriptomes of B cells with the corresponding immunoglobulin proteomes in patients with MS demonstrated that intrathecal B cells are the source of immunoglobulin oligoclonal bands in the CSF32.

B cells have long been recognized as a subset of infiltrating cells in brain and spinal cord lesions in MS. Initially, these cells were identified mainly in perivascular cuffs and were rarely seen to spread into the parenchyma33,34,35. Subsequently, B cell accumulation within the meningeal and perivascular immune cell infiltrates has been demonstrated36 (Fig. 1). These abnormalities are accentuated in a subgroup of patients who have a high level of brain inflammation, extensive and active subpial grey matter demyelination, and a rapidly progressive clinical disease course, suggesting that B cell accumulation causes or contributes to the worse clinical course36,37,38,39,40,41,42,43. In particular, meningeal inflammation has been associated with a gradient of neuronal, astrocyte and oligodendrocyte loss from the surface inwards, accompanied by microglial activation in subpial grey matter lesions that is greatest in the most external cortical layers and lower in the inner layers close to the white matter44. Changes in mRNA levels in the meninges were similar to changes in protein levels in the CSF, suggesting that immune infiltrates in the subarachnoid space — in particular those that are rich in B cells — release inflammatory and/or cytotoxic mediators into the CSF, creating an intracerebral milieu that sustains chronic compartmentalized inflammation and also directly mediates or exacerbates cortical pathology and disease progression45,46.

Fig. 1: B cell inflammatory infiltrates in multiple sclerosis.

a | Immune infiltrates accumulate in meningeal lymphoid-like structures (top) and perivascular regions (bottom) and CD20+ B cells and plasmablasts are present in the cerebrospinal fluid (CSF). b | Immunostaining of a post mortem brain section from an individual with multiple sclerosis shows that CD20+ B cells and CD3+ T cells accumulate in meningeal lymphoid structures. c | Immunostaining for myelin oligodendrocyte glycoprotein (MOG), a marker of myelin in white and grey matter, suggests that infiltration of CD20+ B cells and CD3+ T cells into the meninges (asterisk) is associated with subpial cortical grey matter lesions. d | Immunofluorescent staining shows that CD20+ B cells and CD3+ T cells accumulate in perivascular inflammatory infiltrates. e | Immunostaining for MOG suggests that infiltration of CD20+ B cells and CD3+ T cells into the perivascular spaces (asterisk) is associated with white matter demyelination. H&E, haematoxylin and eosin; LFB, Luxol fast blue.

Furthermore, a study of brain biopsy samples from patients with a recent diagnosis of MS showed that actively demyelinating cortical lesions that contain perivascular immune infiltrates are common in early MS and are associated with meningeal inflammation47. Autoantibodies to myelin oligodendrocyte glycoprotein (MOG) are also present in these lesions, suggesting that myelin is disrupted around axons in acute MS lesions48. Studies of MS lesion subtypes49 suggest that antibody-dependent mechanisms are crucial in MS pathogenesis in a subgroup of patients (type II pattern). However, this pattern could be common to all plaques and just reflect a specific stage of development50 and B cells could contribute to MS pathogenesis not only by producing antibodies but also through their capacity to release inflammatory factors and their antigen-presenting function. Subsequent studies have shown that autoantibodies to MOG are detectable in a subset of people with MS but are also associated with a wide spectrum of CNS disorders for which the term MOG spectrum disorders has been proposed51.

Analysis of the immunoglobulin variable region gene repertoire of B cells that were isolated from MS lesions and the CSF of people with MS revealed high levels of clonally expanded memory B cells with extensive somatic mutations, which indicates antigen-driven B cell activation rather than a random bystander response52,53,54. Furthermore, the same antigen-experienced clones can be found in meningeal immune cell infiltrates, the CSF and perivascular parenchymal lesions55, suggesting that the same initial B cell activation and clonal expansion event led to the invasion of different areas throughout the CNS. Indeed, high-throughput sequencing of IgG heavy chain variable region repertoires in patients with MS56 has demonstrated that B cell clones are bidirectionally exchanged between the CNS and the periphery and that affinity maturation occurs on both sides of the blood–brain barrier56.

In two studies published in 2020, single-cell transcriptomic approaches were used to investigate abnormalities in CSF and blood leukocytes in MS57,58. The first study identified various T cell subset changes in the CSF of patients with MS, including the enrichment of T follicular helper cells, which support B cell function. This observation suggests that high levels of T follicular helper cells in the CNS could promote B cell maturation and accumulation57. In the second study, single-cell RNA sequencing of paired CSF and blood samples from people with MS and healthy controls58 revealed the differential expression of several genes that encode cytokines and chemokines and the activation of nuclear factor κB signalling and cholesterol synthesis pathways in memory B cells in MS. Furthermore, single-cell immunoglobulin sequencing revealed clonally expanded, somatically hypermutated IgM and IgG1 B cells in the CSF that were associated with acute inflammation58. Taken together, these data indicate a skewing of CNS B cells towards an inflammatory phenotype and provide evidence that cross-talk with T cells promotes the differentiation of B cells to plasmablasts and plasma cells as well as the production of abnormal immunoglobulins.

Tertiary lymphoid-like structures

The studies described above have revealed the presence and accumulation of B cells and plasmablasts in the chronically inflamed CNS, possibly through the selective recruitment of differentiated B cells. The long-lived plasma cells that result can persist in the CNS in so-called survival niches that are similar to ectopic follicle-like structures found in chronically inflamed target organs in other autoimmune diseases59. Their appearance resembles secondary lymphoid organs and they are therefore referred to as tertiary lymphoid organs60. The function of these structures is unknown but some evidence suggests that they act as local sites of antigen presentation and lymphocyte activation and differentiation, including B cell maturation steps such as immunoglobulin gene hypermutation and class switch recombination (reviewed in detail elsewhere59). Chemokines that are known to support the formation of such germinal centres, such as CXC-chemokine ligand 13 (CXCL13), CXCL10, lymphotoxin α, IL-6 and IL-10, are present at high levels in the CSF of patients with MS, which is consistent with the formation of tertiary lymphoid-like structures in the leptomeninges46.

The Epstein–Barr virus hypothesis

The cause of B cell overactivation in MS is poorly understood. One study has demonstrated that genetic variation in B cell activating factor (BAFF) causes its abnormal expression, leading to excess B cell activation in MS61. Lymphotropic viruses are also a potential cause of B cell activation — in the context of MS, the Epstein–Barr virus (EBV) is the most strongly implicated and the most extensively investigated virus. A discussion of all viral associations is beyond the scope of this Review but we illustrate the principle with the hypothesis that EBV drives B cell overactivation in people who develop MS (Fig. 2).

Fig. 2: Model of the involvement of Epstein–Barr virus in the pathogenesis of multiple sclerosis.

This model is based on the hypothesis that the Epstein–Barr virus (EBV) causes the activation of infected B cells and their targeting by T cell responses. During primary infection, EBV is transmitted orally and replicates in the oropharyngeal epithelium with a rapid expansion of the viral load (part a). The EBV then colonizes the pharyngeal lymph nodes and infects B cells where it persists for the life of the host as asymptomatic latent infection (latent cycle). The virus produces infectious virions with intermittent reactivation of the lytic cycle that drives the expansion of infected CD27+CD70+ memory B cells. The balance between the latent and lytic cycle depends on the ability of the immune system of the host to generate an appropriate immune response to the EBV infection and the EBV to escape the immune system. The EBV-specific cytotoxic T cell response, including both CD4+ and CD8+ T cells, reduces the expansion of latently infected B cells. Upon the recognition of EBV-infected B cells, CD4+ T helper (TH) cells differentiate and sustain the proliferation and differentiation of cytotoxic CD8+ T cells (CTLs; part b) and contribute to the elimination of EBV-infected cells by producing interferon-γ (IFNγ) and perforin/granzyme (part c). The T cell response controls the infection, but EBV can remain in a latent state in memory B cells for life (part d). If the T cell response does not effectively resolve the EBV infection owing to either insufficient CTL activity (which can result from the overactivity of immune checkpoints such as PD1) or to the ability of the virus to evade the immune system (which it does by producing viral IL-10 (vIL-10) that downregulates cell-surface HLA and modulates the immune response or by inhibiting IFNγ receptor (IFNGR) expression on EBV-infected B cells (part e)), EBV persists and can reactivate (part f). EBV reactivation induces the proliferation of memory B cells, which shed EBV virions and produce inflammatory cytokines. Some evidence suggests that EBV is present in activated memory B cells within follicle-like structures in the leptomeninges in multiple sclerosis (part g). The reactivation of the virus in EBV-infected B cells attracts T cells that enter the CNS across the blood–brain barrier and generate an immune response against EBV without resolving the infection. EBV induces B cell proliferation and the production of inflammatory mediators (tumour necrosis factor (TNF), IL-10, transforming growth factor-β (TGFβ) and IL-6) that cause microglial activation and neuronal injury.

EBV is a human gamma herpesvirus that infects primary B cells and epithelial lineage cells. Approximately 90% of the world’s adult population is seropositive for EBV. Infection is usually benign and asymptomatic, though it can cause infectious mononucleosis syndrome and, far less commonly, it can evolve into lymphoproliferative disorders62. EBV typically persists throughout life in host memory B cells, normally in a latent, inactive state or, less frequently, in a lytic, replicative state, depending on the combination of viral (latent and lytic) gene expression and host (immune surveillance and epigenetic) factors. Strong epidemiological data implicate EBV as a factor in the risk of developing MS, and serological positivity for EBV increases the risk of developing MS63,64; however, the role of EBV infection in the pathogenesis of MS is controversial and the mechanism unknown.

Studies in post mortem brain tissue from people with MS indicate that EBV reactivation can cause CD8+ T cell cytotoxicity against infected B cells and plasma cells in tertiary lymphoid-like follicles and acute lesions65,66,67. In addition, changes in cytokines that are involved in immune surveillance against the virus, such as the overexpression of IFNα, have been detected in active lesions and are associated with the presence of EBV latent proteins68. However, in other studies, EBV has not been detected in CNS tissue from patients with MS, bringing into question the notion that EBV acts directly as a pathogen within the target organ69,70,71. The discrepancies in these studies could be partially explained by technical differences in tissue preservation that might alter the quality of proteins and RNA72. Alternatively, the control of EBV replication by the immune system could be dysfunctional within the CNS, a hypothesis supported by evidence of low titres of antibodies to EBV in the CSF of people with MS70,73. However, in a transcriptomic study published in 2020, the interrogation of RNA sequencing libraries for human viral transcripts, including EBV, in B cells from the CSF of people with relapsing–remitting MS, no viral transcripts were found58. This study included a relatively small number of patients (n = 12) and therefore confirmatory studies are needed.

Several studies have been conducted to characterize T cell reactivity to EBV in the blood. EBV antigen-specific CD4+ T cells are detectable in the blood of patients with MS and these cells have the potential to cross-react with myelin antigen and produce inflammatory cytokines74. CD8+ T cells specific to EBV lytic antigens are also increased in patients with active MS75. Studying EBV antigen-specific T cell responses in the CNS is more difficult because of the limited access to tissue, but the phenotypes and functional profiles of T cells in post mortem brain tissue and in vitro cell co-culture experiments in one study showed that CD8+ T cells from CSF derived from patients with MS could recognize autologous EBV-infected B cells76. EBV-specific CD8+ T cells express programmed cell death protein 1 (PD1), which has a central role in immune tolerance by inducing the apoptosis of cytotoxic T cells, and the expression of PD1 in CD8+ T cells is higher in patients with stable MS than in those with inflammatory-active MS. These observations suggest that the suppression of cytotoxic responses against viruses, including EBV, is associated with the attenuation of inflammation and, accordingly, CNS disease remission77. Furthermore, immunohistochemical analysis of post mortem brain tissue has demonstrated that the expression of PDL1, the main receptor for PD1, is higher in MS lesions than in control tissue from individuals without CNS disease and this expression co-localized with astrocyte or microglia/macrophage cell markers78. Taken together, these observations suggest that the PD1–PDL1 axis modulates cytotoxic T cell responses against EBV in MS and could therefore be implicated in the pathogenesis of MS and/or be harnessed therapeutically.

Although knowledge of the relationship between EBV and MS is incomplete and, in some areas, controversial, a model that includes EBV provides a plausible hypothesis to explain B cell overactivation in MS. The relationship of EBV with MS has been reviewed in more detail elsewhere79.

B cell-targeted therapy in MS

The involvement of B cells in the pathogenesis of MS has long been suggested by immunoglobulin abnormalities, including oligoclonal bands, in the CNS. However, only in recent years have treatments that target B cells, including rituximab, ocrelizumab, ofatumumab, atacicept and Bruton tyrosine kinase (BTK) inhibitors, been tested in MS in clinical trials and two of these treatments have been approved — ocrelizumab and ofatumumab. Below, we summarize the key results from the pivotal trials of these treatments and discuss the immunological effects of these therapies on B cell subsets and B cell-related biomarkers. Disease-modifying treatments for MS that do not specifically target B cells but might also have effects on B cell function (for example, dimethyl fumarate, teriflunomide, IFNβ, glatiramer acetate, natalizumab and fingolimod) have been reviewed elsewhere80,81 and are therefore not discussed here.


Rituximab is a mouse–human chimeric anti-CD20 monoclonal antibody that is licensed for the treatment of some haematological cancers (non-Hodgkin B cell lymphoma and chronic lymphocytic leukaemia), rheumatoid arthritis and granulomatosis with polyangiitis. CD20 is expressed in cells of the B cell lineage, including pre-B cells, naive B cells and memory B cells. The mechanisms by which rituximab depletes B cells include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC)82,83,84.

Summary of clinical evidence

Pivotal studies of the intravenous administration of rituximab in MS include a phase I open-label trial in relapsing–remitting MS85, a phase II study in relapsing–remitting MS86 and a phase II/III study in primary progressive MS87. Phase I/II studies have also been done to investigate the intrathecal administration of rituximab in secondary progressive MS88,89. The trials demonstrated that treatment with rituximab reduced relapses in relapsing–remitting MS and attenuated the worsening of disability in a subset of patients with primary progressive MS.

Immunological effects

After the administration of rituximab, a dose-dependent depletion of circulating CD20+ B cells rapidly ensues and persists for several months. A small subset of CD20+CD3+ T cells is also depleted by rituximab in patients with MS90. The function of this T cell population is unknown but they have been proposed as contributors to the pathogenic process in MS, in which case their depletion could partly account for the action of CD20-targeted therapies90.

The patients with relapsing–remitting MS who received rituximab in the phase I trial exhibited a near-total B cell depletion (~99.8%) in the circulation by week 2 that was sustained at week 48 (ref.85). The reconstitution of B cells was slow and reached a mean of only 34.5% of baseline levels by week 72. Most of the re-populating B cells were naive (CD27). Serum levels of IgM, IgA and IgG were tested in some treated patients and did not decrease below the lower limit of normal by week 72 (ref.85).

Similarly, in the phase II trial, patients with relapsing–remitting MS who were treated with rituximab exhibited a rapid and near-complete (>95%) depletion of circulating B cells at 2 weeks after the first course of treatment and substantial depletion persisted until week 24; B cells reconstituted to ~30% of baseline levels by week 48. Serum levels of immunoglobulin were measured at baseline, at 24 weeks and 48 weeks after treatment, and at the time of any relapse; levels were below the lower limit of normal in 7.9% of patients who received rituximab compared with 3.0% of patients who received placebo86. The median serum levels of IgM, IgG and IgA across all participants remained above the lower limit of normal for the duration of the trial but individual levels of IgM were abnormally low in 22.4% of patients who received rituximab and in 8.6% of patients who received placebo. The minimal effect on serum immunoglobulin levels is explained by the fact that rituximab and other CD20-targeted treatments do not directly deplete plasma cells because these cells do not express CD20 (except a small population of CD20+ plasmablasts)91. However, long-term treatment with anti-CD20 agents can cause hypogammaglobulinaemia and the attendant increased risk of severe infections (reviewed elsewhere92). Overall, the beneficial effects of B cell depletion achieved with rituximab and without a reduction in plasma cell number or in the levels of circulating antibodies supports the notion that B cell subsets play a causative role in inflammation in MS.

As discussed above, abnormalities of B cells in MS include a propensity to produce excess pro-inflammatory cytokines, such as TNF, lymphotoxin, IL-6 and GM-CSF, and insufficient anti-inflammatory cytokines (IL-10). The effect of rituximab is thought to be mediated by various cell-dependent mechanisms, including the suppression of APC function, the depletion of pro-inflammatory memory B cells, a decrease in cytokine production, and possibly the prevention of lymphoid neogenesis93. In more detail, B cell depletion with rituximab affected B cell–T cell interactions in patients with MS in whom the proliferation of CD4+ and CD8+ T cells and the T cell expression of IFNγ and IL-17 in T cells were reduced19,94. Anti-CD20 therapy in patients with MS also decreased pro-inflammatory myeloid cell responses, attributable to the depletion of GM-CSF-producing B cells20. Myeloid cells remained less pro-inflammatory even when the B cell population reconstituted, possibly reflecting changes in STAT5 and STAT6 signalling and in GM-CSF to IL-10 cytokine ratios in the reconstituted B cells20.

The analysis of B cells in people with MS who had received rituximab demonstrated that the repopulating B cells were enriched in transitional and mature naive B cell subsets with a high expression of activation markers but repopulation patterns varied at the individual level95. Further studies into B cell compartment reconstitution after rituximab treatment for neuromyelitis optica spectrum disorders and peripheral autoimmune conditions have confirmed the predominance of naive and Breg cells over memory B cells in the repopulated B cell pool96,97. However, B cell depletion with CD20 antibodies caused the exacerbation of MOG35–55 peptide-induced EAE98,99 and this exacerbation was associated with an increased production of pro-inflammatory TNF by CD11b+ APCs, suggesting that the depletion of Breg cell subsets could accentuate disease by removing the Breg control of inflammatory cells99. These contrasting observations raise the concern that the total B cell depletion that affects the subsets of Breg cells could be ineffective or even counter-productive in some clinical settings.

Though CD20 antibodies efficiently deplete circulating B cells, they do not efficiently cross the blood–brain barrier and, therefore, upon intravenous administration, they are expected to be less effective at depleting CNS-resident memory B cells, which are the origin of abnormal intrathecal immunoglobulin production in MS. However, in one study in patients with MS who were receiving intravenous rituximab, both B cell and T cell numbers in the CSF were significantly reduced after therapy100. This effect indirectly suggests that B cells support T cell recruitment into the CNS through mechanisms that take place in the peripheral lymphoid system. This mechanism could involve a contribution of B cells to the activation and proliferation of pathogenic T cells through antigen presentation and/or the release of pro-inflammatory cytokines. The notion of a cytokine-mediated effect is supported by data from studies in EAE in which the depletion of IL-6-producing B cells ameliorated disease as well as from studies in patients with MS in whom rituximab treatment reduced the production of IL-6 and IL-17 (ref.101).

In a trial of intrathecal administration of rituximab102, levels of BAFF — which regulates B cell survival, development and differentiation, the size of the peripheral B cell pool and production of immunoglobulins — were drastically decreased in the CSF, whereas levels in the serum increased. CD20+ and CD19+ cells were depleted in the periphery but no significant change in the levels of these cells was seen in the CSF, possibly because B cell counts were too low to enable the detection of changes102.


Ocrelizumab is a humanized monoclonal antibody that is approved for the treatment of active relapsing–remitting MS and primary progressive MS. Like rituximab, it selectively targets CD20, which is expressed on pre-B cells and mature naive and memory B cells but not on lymphoid stem cells or plasma cells103. Ocrelizumab binds with high affinity to the large extracellular loop of CD20, a different but overlapping epitope from that to which rituximab binds84. Ocrelizumab induces B cell depletion via similar mechanisms to rituximab, including ADCC (to a greater extent than rituximab) and CDC (to a lesser extent than rituximab)82,104.

Summary of clinical evidence

In two essentially identical randomized phase III trials (OPERA I and OPERA II)105, ocrelizumab was shown to be more effective than subcutaneously administered IFNβ1a in patients with relapsing–remitting MS. The clinical benefits of ocrelizumab treatment were also observed in patients with primary progressive MS in the ORATORIO study, a phase III, placebo-controlled trial106. Based on these trials, ocrelizumab has been approved for the treatment of relapsing–remitting MS and primary progressive MS.

Immunological effects

As with rituximab, the radical depletion of B cells occurs within 2 weeks after the first ocrelizumab infusion85,105. Preliminary analysis of blood from a small group of participants in the OPERA I trial indicated that a small number of B cells remain detectable in the peripheral circulation after treatment with ocrelizumab, characterized by a memory class-switched profile with a low diversity of BCRs107. CD20-expressing T cells, which one study has suggested make up nearly 20% of all CD20-expressing cells (including B cells), are efficiently depleted in addition to B cells108, suggesting that the clinical efficacy of ocrelizumab might not only be mediated by effects on B cells109. The longitudinal analysis of the CSF before and after ocrelizumab treatment has been presented in abstract form and reveals reductions in the CSF levels of B cells, T cells and CXCL13 (ref.110).

Although plasma cells are not directly targeted by ocrelizumab, data from the pivotal trials of ocrelizumab and their extensions reveal that, as with rituximab92, immunoglobulin levels can be reduced during long-term treatment (mean 5.5 years) and could be associated with serious infections, particularly if IgG levels are low111; this risk warrants further investigation. Detailed studies of B cell reconstitution in patients with MS who have been treated with ocrelizumab are awaited.

The mechanisms that mediate the clinical effects of ocrelizumab in primary progressive MS are unknown, particularly as many other therapeutics have failed in this form of the disease. Most speculation has focused on the possibility that CD20+ B cell (and T cell) depletion could dampen the ‘smouldering’ inflammatory activity in primary progressive MS. However, some investigators have21 suggested that the mechanisms are not solely anti-inflammatory but also involve a reduction of neurotoxic factors produced by B cells22,23.


Ofatumumab is a fully human monoclonal antibody that binds to a small-loop epitope of CD20 close to the cell surface and induces both CDC and ADCC even when the expression of CD20 is low112,113.

Summary of clinical evidence

Completed clinical trials of ofatumumab in patients with MS are the phase IIb double-blind MIRROR study114 and the phase III trials of ofatumumab versus teriflunomide ASCLEPIOS I and II115. In August 2020, ofatumumab was approved by the FDA for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing–remitting MS and active secondary progressive MS.

Immunological effects

The pivotal trials demonstrated that ofatumumab depletes B cells in a dose-dependent manner; B cell counts were between <2% and 25% of baseline levels at week 12. The time to onset of repopulation was lengthened by a higher dose of the drug. At the last follow-up time point (132 weeks), the repletion of CD19+ B cells to the normal reference range had occurred in 64–74% of patients across the ofatumumab treatment groups114. However, detailed information about the effects of ofatumumab on B cell populations is awaited.


Atacicept is a human recombinant fusion protein that comprises the ligand portion of a receptor for B lymphocyte stimulator and a proliferation-inducing ligand, which are important cytokines for B cell maturation, proliferation and survival116. In contrast to anti-CD20 therapies, atacicept affects only mature naive B cells and B cells in the late stages of development, including antibody-secreting cells, and spares B cell progenitors and memory B cells117,118,119. Consequently, the survival of short-lived plasma cells and serum immunoglobulin levels are reduced with atacicept treatment as documented in healthy volunteers and patients with systemic lupus erythematosus or rheumatoid arthritis120,121,122.

All trials of atacicept in MS have been halted because an unexpected increase in disease activity was observed during treatment116. One plausible suggested reason for the observed effect is that the preferential diminishing of naive B cells and plasmablasts and the relative sparing of memory cells, which are the probable disease-promoting B cell subset in MS, exacerbated an imbalance of pro-inflammatory cytokines21.

Bruton tyrosine kinase inhibitors

Bruton tyrosine kinase (BTK) is critically involved in B cell receptor signalling and, consequently, in B cell activation, and activates myeloid cells via the Fc receptor. The observation of abnormal BTK activity in autoimmune diseases has prompted the development of BTK inhibitors as potential therapeutics123. The oral BTK inhibitor evobrutinib has been tested in MS in a phase II trial124. The treatment reduced MS lesion activity and the study met the primary MRI endpoint but significant effects were not seen on key secondary endpoints, including the annualized relapse rate and change in disability.

The effects of BTK inhibitors on lymphocyte subsets in this trial were not reported but the immunological effects of evobrutinib have been studied in the EAE mouse model. Multiple effects on B cells were observed, including the inhibition of activation, cytokine release and APC function125.

Overall, BTK inhibition is an attractive strategy for the therapeutic targeting of B cells without their depletion. Therapeutics in this class could become an important alternative for patients whose immunoglobulin levels are reduced by B cell depleting therapy. Further trials of BTK inhibitors are expected to investigate the clinical efficacy of these drugs.

Non-specific lymphocyte depletion

Some highly effective treatments for MS deplete all lymphocytes and consequently affect B cell numbers and functions. In the sections below, we discuss the effects that these therapies have with a focus on their effects on B cells.


Summary of clinical evidence

Alemtuzumab is a humanized monoclonal CD52 antibody approved for the treatment of active relapsing–remitting MS. Its approval was based on findings that it reduces relapse rates to a greater extent than IFNβ in treatment-naive patients with active MS (demonstrated in the CAMMS232 and CARE-MS I trials)126,127 and in patients who experienced a relapse while on previous treatment (demonstrated in the CARE-MS II trial)128. Treatment with alemtuzumab also reduced the sustained accumulation of disability progression126,128. The durability of efficacy has been demonstrated over 5 years of follow-up without continuous treatment129,130. The efficacy of alemtuzumab has largely been attributed to the long-lasting drug-induced T cell lymphopenia and the homeostatic changes it induces131,132.

Immunological effects

Alemtuzumab induces the rapid depletion of CD52-expressing leukocytes (mainly T cells and B cells, with transient effects on neutrophils, monocytes, eosinophils, basophils and natural killer cells) through antibody-dependent133 and complement-dependent cytolysis134, followed by reconstitution that starts within a few days after each treatment cycle. After a single course of alemtuzumab, B cell counts recover to the lower limit of normal after ~8 months, whereas T cell subsets do not normalize for up to 3 years135.

At 1 month after treatment, transitional type 1 immature B cells (CD19+CD23CD27) constitute the majority of the B cell pool and the levels of BAFF increase and remain high until at least 12 months after treatment136. BAFF is critical for the transition of immature B cells into mature naive B cells (CD19+CD23+CD27), which account for most of the B cell population at 3 months after treatment and ultimately hyper-populate the peripheral circulation; their levels reach 165% of baseline levels at 12 months after treatment. By contrast, the repletion of memory B cells is slow and their levels reach only 25% of baseline at 12 months after treatment136. Levels of CD19+CD24hiCD38hi Breg cells increase substantially at 6 months and 9 months after treatment compared with their pre-treatment levels, suggesting that B cell regulation is preferentially restored27.

In comparison with B cells, T cells reconstitute more slowly — CD8+ T cells return to baseline levels by 12 months after treatment and CD4+ T cells remain below baseline levels at 12 months. During the repopulation phase, the proportion of the memory T cell population that are T regulatory cells (CD4+CD25high T cells) is higher than before treatment137,138 and the proportion of TH17 and TH1 cells is lower138. The findings of a study published in 2019 suggest that a population of pro-inflammatory T cells that express CD20 and are present at high levels in the blood and CSF of patients with MS is depleted after treatment with alemtuzumab139.

Differences in the repopulation of T cell and/or B cell subsets, such as different ratios of naive and memory T cell and B cell subsets, are an attractive explanation for differences in clinical efficacy and in the occurrence of secondary autoimmunity among patients after treatment with alemtuzumab. However, a study published in 2020 investigated this possibility and found no evidence for a correlation between clinical outcomes and lymphocyte dynamics140. The effects of alemtuzumab on B cells in the CSF are also poorly understood; additional insight could be gained by testing the hypothesis that the long-term clinical effects observed after alemtuzumab treatment are partly mediated by the prevention of B cell-related immune pathology in the CNS compartment, including the formation of tertiary lymphoid-like structures141.


Cladribine is a synthetic purine analogue (2-chlorodeoxyadenosine) that selectively depletes lymphocytes but spares innate immune cells. The drug can be administered orally or intravenously and the oral preparation is approved for the treatment of highly active relapsing–remitting MS.

Summary of clinical evidence

Oral cladribine was approved for the treatment of highly active relapsing–remitting MS based on the phase III CLARITY trial and its extension study, which showed that cladribine effectively reduced relapses, disability progression and MRI activity when compared with placebo142,143,144,145. The ORACLE study has also shown that cladribine effectively reduces the rate of conversion to MS in patients with a first demyelinating episode146,147.

Immunological effects

Cladribine is a pro-drug and requires intracellular phosphorylation to become chemically active. The active metabolite accumulates in the cell, ultimately leading to apoptosis148,149. It is thought to act as a short-term immunosuppressant that induces a transient depletion of B cells and T cells that is followed by immune reconstitution148,150. Pooled data from CLARITY, CLARITY extension and PREMIERE (Prospective Observational Long-Term Safety Registry of Multiple Sclerosis Patients Who Participated in Cladribine Clinical Trials) indicate that cladribine induces the selective depletion of B cells and T cells. In the lymphocyte-depleted phase after the first treatment cycle, B cell counts were reduced by 70% at 5 weeks, 81–84% at nadir (13 weeks), ~60% at week 24 and ~30% at week 48 (ref.151). These reductions were faster and larger than those for T cells, which reduced by ~50% at week 5, predominantly owing to CD4+ T cell depletion — median CD8+ T cell counts never dropped below the reference range, suggesting that this cell subset is relatively resistant to the lymphodepleting effects of cladribine151. Each treatment cycle is followed by a gradual lymphocyte repopulation. B cells recovered to numbers within the reference range by week 84, ~30 weeks after the last dose of treatment150, whereas the recovery of median CD4+ T cell counts to within the normal range was slower and took up to 96 weeks, ~43 weeks after the last dose of cladribine.

The effects of oral cladribine on the composition and functions of B cell subsets in MS are yet to be examined in depth. One cross-sectional study of 40 patients with relapsing–remitting MS who were at the end of the first cycle of alemtuzumab or injectable cladribine treatment showed that the latter induced a marked depletion of class-switched and un-switched memory B cells to levels comparable with those induced by alemtuzumab but without the severe initial lymphopenia associated with alemtuzumab — grade 3 and 4 lymphopenia occurred in 1.8% of patients who received injectable cladribine but in >80% of those who received alemtuzumab152. The numbers of immature and mature (naive) B cells at 1 year after treatment was higher in patients who received injectable cladribine than in those who received alemtuzumab, suggesting that cladribine depletes memory B cells most strongly152. Interestingly, and providing mechanistic support for these effects, the ratio of deoxycytidine kinase to cytosolic 5′-nucleotidase was reported to be high in B cells in physiological conditions, especially in mature, memory and germinal centre B cells, but not in plasma cells. This observation explains the sensitivity of memory B cells to the effects of cladribine and their substantial and persistent depletion after treatment152. B cells remain substantially below their baseline level until the second treatment cycle with cladribine, whereas they reach baseline levels 6 months after each course of alemtuzumab and increase to well-above baseline levels by the end of years one and two after alemtuzumab cycles153.

Interestingly, cladribine can penetrate the CNS, which is, in principle, desirable for the potential treatment effects on lymphocytes that infiltrate the CNS compartment in MS but, to our knowledge, the effects of oral cladribine on the CNS compartment and the CSF of patients with MS has not been definitively reported. In a study of treatment with an injectable variant of cladribine in 29 treatment-naive patients with relapsing–remitting MS, the CSF of 55% of patients became negative for oligoclonal immunoglobulin bands, suggesting a treatment effect on a biomarker of abnormal B cell and plasma cell activation154.

AHSCT and B cells in MS

AHSCT has been used to treat patients with severe autoimmune diseases, usually when the disease is refractory to conventional therapies155,156. The treatment involves the mobilization of haematopoietic stem cells, the preservation of these cells and their reinfusion after high-dose immunosuppressive conditioning that is achieved with varying degrees of lymphoid and myeloid ablation, depending on the regimen157. This procedure enables immune reconstitution and the changes induced by depletion and repopulation are thought to underlie the durable remission of autoimmune disease.

AHSCT for the treatment of MS

During the past 10–15 years, interest has increased in AHSCT as a treatment option for highly active MS, especially for patients whose disease is refractory to standard therapies157,158. The rationale for the treatment strategy is that immunosuppression or ablation will deplete presumably pathogenic immune cells and the subsequent transplantation of autologous bone marrow-derived haematopoietic stem cells will enable the regeneration of a new, tolerant immune system159. The intensity of the immunosuppressive conditioning treatment varies depending on the specific protocol and ranges from non-myeloablative158 to myeloablative160. The autologous transplantation mostly provides a form of haematopoietic support but might influence the rate and quality of immune reconstitution in ways that are still poorly understood161.

AHSCT has stabilized the clinical course of MS in most patients who have undergone the treatment. This effect has resulted from the suppression of inflammatory disease activity, with well-documented beneficial effects on clinical relapses, brain and spinal cord MRI lesions, and neurological dysfunction quantified by the Expanded Disability Status Scale162,163,164,165,166. A meta-analysis of data from 15 studies of AHSCT in any form of MS published between 1995 and 2016 has shown that AHSCT is most likely to offer an advantageous benefit-to-risk profile for patients with aggressive MS who have a relapsing–remitting course and who have not yet accumulated a high level of neurological disability167.

Regeneration of adaptive immunity

To date, most studies of immune reconstitution after AHSCT in MS have focused on T cells. In one of the first demonstrations of extensive immune regeneration, the expansion of naive T cells in the peripheral circulation was observed in patients with MS 1–2 years after total-body irradiation followed by AHSCT and the repertoire of these T cells was distinct from and more diverse than the pre-treatment repertoire168. Subsequent work has shown that a substantial (median 80%) renewal of the CD4+ TCR clonal composition is detectable 12 months after AHSCT and that this renewal is more extensive than that of the CD8+ TCR clonal composition (median 45%)169.

Longer-term studies of TCR repertoires in blood, combined with extension of the analyses to CSF cells, have revealed that the ablation of pre-therapy T cell clones achieved in the blood at 12 months of follow-up persists after 2 and 4 years of follow-up and is more extensive in the CSF, where it also persists at the same time points, long after the completion of peripheral immune reconstitution170. These observations are consistent with the hypothesis that the beneficial effects of AHSCT are mediated by the combined effects of depletion and reconstitution, possibly including a rebalancing of the pro-inflammatory and tolerogenic arms of immunity171 rather than solely lymphoid ablation. A rebalancing mechanism would explain the long-lasting clinical effects better than would immunosuppression from lymphoid depletion as this mechanism would no longer operate after immune repopulation is complete.

The effects of AHSCT on the B cell compartment in MS have not been investigated in the same depth as the effects on T cells. Given that AHSCT protocols are similar across autoimmune diseases and no major differences in immune reconstitution are expected between patients with different autoimmune diseases, we can gain insight from studies of AHSCT for diseases in which B cells were previously known to be pathogenically relevant such as systemic lupus erythematosus and systemic sclerosis. In both of these diseases, the proportions of naive B cells in the blood were increased after AHSCT172,173,174. In addition, one study of patients with systemic sclerosis showed that the proportion and absolute numbers of IL-10-producing CD24highCD38high Breg cells were increased after AHSCT and higher numbers of these cells were associated with more complete clinical responses173; this observation is relevant to the mechanisms of immune tolerance as it suggests that the effects of AHSCT on Breg cells are clinically relevant and a part of the mode of action.

Current knowledge of the effects of AHSCT on B cells specifically in MS comes only from a mass cytometry study of immune cell reconstitution after AHSCT175. The analysis of blood samples from participants in the HALT-MS trial revealed that B cell numbers are fully reconstituted at 1 year and that, in comparison with baseline before the start of the AHSCT procedure, the proportion of B cells that are circulating naive B cells is high at 1 year and remains high at 2 years after transplantation175. These findings are consistent with trends described in earlier studies in which conventional flow cytometry was used176,177. For the mass cytometry study175 as well as for the previously mentioned studies of TCR repertoire169,170, the low rate of treatment failure in the HALT-MS trial meant that statistical power was not sufficient to make comparisons that would provide conclusive information about the clinical correlations of B cell (or indeed any immune) reconstitution features.

In early studies of AHSCT in MS, the qualitative and quantitative changes of oligoclonal IgG bands in the CSF and serum were analysed. The included samples were obtained after relatively short follow-up periods and these studies demonstrated the persistence of oligoclonal IgG in the CSF177,178,179. In one study, CSF oligoclonal bands persisted in the CSF of two patients at 4 and 6 years after transplantation, indicating that immunoglobulin-producing plasma cells persisted despite high-intensity conditioning and long-term disease remission180. However, in the HALT-MS trial, the number of CSF oligoclonal bands and CSF levels of IgG were substantially reduced at 2 years after AHSCT181. In summary, the available evidence suggests that immune-depleting conditioning followed by AHSCT in patients with MS leads to peripheral reconstitution of a predominantly naive B cell population. Limited observations indicate that oligoclonal bands persist in the CSF for at least 2 years, albeit at lower levels, and underscore the need for further study. Given that the disease stabilizes in the vast majority of patients with MS who undergo AHSCT, the persistence of plasma cells in the periphery and CNS, probably together with some pro-inflammatory B cells, is counterbalanced by the regeneration of a regulatory and/or less pro-inflammatory population of B cells. The rebalancing effects proposed for B cells could work together with the demonstrated effects on T cells and natural killer cells in mediating restored tolerance and account for the high efficacy of the treatment strategy.

Increasing our understanding

Further studies are needed to characterize the effects of AHSCT on the B cell compartment and to improve our understanding of their importance in the mode of action of this treatment strategy. We suggest a variety of experiments (Box 1), all of which could involve comparisons before and after AHSCT and comparison with the effects of other treatments, including targeted B cell depleting therapies such as ocrelizumab or rituximab. These studies should be accompanied by clinical and MRI monitoring during follow-up and should include the provision for sample collection if MS relapses occur in order to capture clinical–immunological correlations.

The strategies outlined will be included in the mechanistic studies in the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) and in the Autologous Stem Cell Transplantation versus Alemtuzumab or Ocrelizumab in Relapsing Remitting MS (STAR-MS) trials, in which AHSCT is compared with high-efficacy standard therapy (including B cell depleting agents)182. In parallel with studies of other components of adaptive and innate immunity, this type of research has the potential not only to improve our understanding of the mode of action of AHSCT but also to conclusively demonstrate the critical involvement of immune abnormalities in the pathogenesis of MS and help define their causes.


Several lines of evidence strongly support the involvement of B cells in the pathogenesis of MS beyond abnormal antibody presence within the CNS of patients. First, pathological studies of human tissue have demonstrated B cell infiltration, particularly in tertiary lymphoid-like structures in the meninges. Second, studies of B cells in the peripheral blood and CSF of patients with MS have demonstrated abnormal inflammatory cytokine production by B cells and excess levels of B cell-relevant chemokines. Third, B cell-depleting therapy (either specifically targeted to B cells or not) is effective in MS and the immunological effects of these therapies are providing insight into the roles of different lymphocyte subsets (Fig. 3).

Fig. 3: Effects of multiple sclerosis treatments on lymphocyte levels and B cell markers.

Bar charts and pie charts provide semi-quantitative indications of the proportions of cell subsets in the population. Charts in the left column indicate pre-therapy levels in patients with multiple sclerosis. Oligoclonal bands (OCBs) are shown as present (+) or absent (–). Levels of other soluble B cell markers and T helper (TH) cells are shown as increased (↑) or decreased (↓). Question marks indicate unknowns. AHSCT, autologous haematopoietic stem cell transplantation; BAFF, B cell activating factor; Breg, B regulatory; CSF, cerebrospinal fluid; CXCL13, CXC-chemokine ligand 13; Treg, T regulatory.

Further studies to examine how the clinical course and response to treatment relate to the levels and activity of key B cell subpopulations and molecules involved in B cell activation and regulation could definitively establish and characterize the role of B cells in MS pathogenesis. The improved knowledge will provide rich opportunities to optimize treatments for MS by more specifically targeting pathogenic mechanisms and sparing protective B cell functions. As different mechanisms could be operating in different forms and stages of MS and in different individuals with MS, the efficacy of treatment strategies that are more selective than the current options might ultimately require stratified or personalized medicine approaches. Until this evolution becomes feasible, less selective B cell-targeted treatment strategies are likely to remain the most effective options for most patients.


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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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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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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).

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