Abstract The unequivocal success of B-cell–depleting agents in reducing magnetic resonance imaging and clinical activity in therapeutic trials indicates that B cells play a vital role in mediating the clinical course of relapsing multiple sclerosis (MS). Although no agent that specifically targets B cells has yet been approved for clinical use, all existing disease-modifying therapies (DMTs) for MS modulate B-cell immunity to some degree. This review examines the effects of MS DMTs on B-cell immunity. Most MS DMTs induced a relative decrease in circulating memory B cells with concomitant expansion of circulating B-cell precursors and/or naive B cells. B-cell function was also altered; most DMTs induced B-cell production of the anti-inflammatory cytokine interleukin 10 while inhibiting B-cell expression of proinflammatory cytokines. The commonalities in the effects of approved DMTs on B-cell phenotype and function among treated patients with MS are striking and suggest that effects on B cells underlie part of their efficacy. More complete understanding of how the existing DMTs modulate B-cell immunity may identify future targets for therapeutic intervention. Introduction Multiple sclerosis (MS) has been considered an autoimmune disease of the adaptive immune system. The main cells of the adaptive immune system are T and B lymphocytes. The disease had been thought to be mediated primarily by T lymphocytes (T cells) because of many factors, including the fact that T lymphocytes greatly outnumber B lymphocytes within MS lesions and that T cells, but not B cells, fully transfer the main animal model experimental autoimmune encephalomyelitis (EAE) to naive recipient animals. However, B-cell–depleting agents that act via lysis of CD20+ B cells have now been found in several clinical trials1-3 to ameliorate clinical and radiologic MS manifestations. In contrast, trials eliminating T cells using monoclonal antibodies (mAbs) have been less successful. Clinical trial results have reignited scientific interest in B cells as being primary mediators of MS pathogenesis. Phase 2 clinical trials of the chimeric anti-CD20 mAb rituximab revealed a rapid and sustained 10-fold reduction in contrast-enhancing magnetic resonance imaging (MRI) lesions compared with placebo.1 Moreover, recent phase 3 trials of the humanized anti-CD20 mAb ocrelizumab found MRI activity in patients with relapsing MS to be reduced by approximately 95% compared with those treated with high-dose interferon beta 1α.2 Another anti-CD20 mAb, ofatumumab, had similar notable benefits on MRI in early-phase studies.4 Overall, studies of B-cell depletion using anti-CD20 mAbs in relapsing MS have been unequivocally positive, with results equivalent to those of the strongest disease-modifying therapies (DMTs) available. More than a dozen DMTs approved by the US Food and Drug Administration (FDA) for the treatment of relapsing MS are now in clinical use. None were designed to target B cells, but all affect the B-cell compartment to varying degrees, which may contribute to their efficacy. A summary of approved DMTs for MS and their effects on B-cell immunity appears in the Table. These agents affect B cells by several unique mechanisms (Figure). Understanding these effects may provide insight into the role(s) of B cells in MS pathogenesis. In this article, we examine the existing FDA-approved DMTs for MS from the perspective of their effect on B cells and humoral immunity. For comparison, we also discuss the anti-CD20 mAbs rituximab and ocrelizumab because these were designed to directly target B cells. Interferons Interferon beta was the first DMT found to be effective in MS. Currently, there are 5 formulations of this drug in use, which vary in dose, frequency, and route of administration. From the beginning, it was evident that interferon beta was multifaceted in its effects on MS. In general, interferon beta antagonizes the proinflammatory milieu by inhibiting expression of proinflammatory molecules while increasing production of anti-inflammatory factors and inhibiting leukocyte trafficking. These effects are partly mediated by B cells. Indeed, work in animals5 suggests that B cells play a necessary role in mediating interferon beta efficacy; when EAE was induced in B-cell–deficient mice, the therapeutic effect of interferon beta was lost. Perhaps counterintuitively, interferon beta induces expression of the B-cell survival factor B-cell–activating factor of the tumor necrosis factor (TNF) family (BAFF).5,6 Some authors have found a corresponding increase in the numbers of circulating B cells among patients treated with this DMT, although the literature is not unanimous on this point.5,7 BAFF promotes survival of B cells at and beyond the transitional (CD19+ CD24hi CD38hi) stage of development,8 and this subpopulation was preferentially increased in the circulation of interferon beta–treated patients compared with treatment-naive and glatiramer-treated patients. Meanwhile, there was a decrease in the proportion of circulating class-switched memory B cells.5 A higher proportion of newly released B cells was found in interferon beta–treated patients, supporting evidence of a shift toward less mature circulating B cells in this patient population.9 In addition to its effects on B-cell maturation and survival, interferon beta affects B-cell function. It downregulates costimulatory molecules, including CD40 and CD80.10 As a result, B cells that have been exposed to interferon beta are less efficient antigen-presenting cells than untreated B cells and are less able to induce T-cell proliferation.11,12 B-cell cytokine production is also affected by interferon beta; in general, proinflammatory cytokines, including interleukin (IL) 1β and IL-23, are inhibited, whereas the anti-inflammatory and immunomodulatory cytokine IL-10 is upregulated in B cells.5,11,12 Supernatants from interferon beta–treated B cells suppressed T-cell differentiation into TH17 cells, a T-cell subpopulation thought to be pathogenic in MS.12 Despite this widespread immunomodulation, interferon beta treatment causes functional immunosuppression in patients. After more than 2 decades of clinical use in MS, serious opportunistic infections have not been observed, and treated patients mount normal immune responses to vaccines.13 Glatiramer Acetate Glatiramer acetate is a synthetic peptide designed to resemble the putative autoantigen myelin basic protein. Glatiramer acetate biases T cells toward an immunoregulatory phenotype, which is thought to be its main mechanism of action. However, animal and human data indicate that glatiramer acetate also affects B cells, reducing proinflammatory cytokine production while increasing regulatory cytokines. It also alters the distribution of circulating B-cell phenotypic subsets. The effects of glatiramer acetate on B cells have been studied using the animal model EAE. Treatment of C57BL/6 female mice with glatiramer acetate led to lower expression levels of the costimulatory molecules CD80 and CD86 (but not major histocompatibility complex II) by B cells when compared with control animals treated with ovalbumin. Glatiramer acetate did not alter total B-cell numbers in these mice.14 Adoptive transfer of B cells from glatiramer acetate–treated mice ameliorated incidence and severity of EAE in recipient mice compared with mice receiving B cells from control-treated donors.15 Moreover, glatiramer acetate did not ameliorate EAE in B-cell–deficient mice, which suggests that B cells are necessary for the mechanism of action of glatiramer acetate in this model system.15 The B-cell effect was mediated in part by selectively increasing IL-10 production and inhibiting proinflammatory cytokines, including IL-17, IL-6, and TNF-α.14,15 Expression of the B-cell survival factor BAFF was downregulated by glatiramer acetate.14 A cross-sectional study16 compared circulating B-cell phenotypes and cytokine production in glatiramer acetate–treated patients with MS vs treatment-naive patients with MS and healthy controls (HCs). B cells from glatiramer acetate–treated patients had impaired proliferation and proinflammatory cytokine production (lymphotoxin and, transiently, IL-6) in vitro. At baseline, the B cells from patients with MS produced less of the regulatory cytokine IL-10 than the B cells from HCs. After a mean of 3 years of glatiramer acetate treatment, production of IL-10 increased to levels comparable to those of HCs.16 Immunophenotyping of B cells from glatiramer acetate–treated patients has been inconclusive. One study16 reported a decreased total number of circulating CD19+ B cells with relative expansion of the naive (CD27− IgD+) cohort and a relative decrease of CD27hi plasmablasts and memory B cells, but these results have not been universally found.7 B10 cells, a subset of B cells that spontaneously produce IL-10, have not been found to be altered by glatiramer acetate treatment.16 B-cell immunomodulation by glatiramer acetate may have functional implications; in a small study,13 patients with MS taking glatiramer acetate had reduced serologic responses to influenza virus vaccines compared with HCs and patients with MS taking interferon beta. Fingolimod Fingolimod was the first oral DMT approved for MS. It appears to act primarily by sequestration of lymphocytes within secondary lymphoid structures via its modulation and functional inhibition of 4 of the 5 known sphingosine-1-phosphate (S1P) receptors. Both T and B lymphocytes expressing S1P receptors normally exit secondary lymphoid tissues along a S1P chemical gradient. However, on in vivo phosphorylation, fingolimod acts as a functional mimic of S1P, leading to downregulation of receptors on T and B cells and retention of these otherwise unaltered lymphocytes in lymphoid tissues. Fingolimod can cross the blood-brain barrier, and speculation exists that it may also have direct effects within the central nervous system (CNS). Fingolimod decreases the absolute numbers of circulating B and T cells.17 However, it does not affect all lymphocyte subsets equally. Among T cells, it preferentially retains naive and central memory T cells, whereas effector memory T cells are relatively spared from retention in lymphoid tissues and increase proportionally in the circulation.18 Among B cells, there is a relative increase in the proportion of circulating immature and naive B cells, determined by the presence of κ-deleting recombination excision circles, with concurrent decreases in the proportion of memory cells.17,19 Expression of the costimulatory molecule CD80 was decreased in B cells from fingolimod-treated patients when compared with untreated patients with MS. Moreover, when stimulated ex vivo, B cells from fingolimod-treated patients produced significantly less TNF-α and more IL-10 than those from untreated patients.17 In a randomized trial of vaccination, fingolimod-treated patients were able to mount immune responses against both novel (influenza) and recall antigens (tetanus) and achieved seroprotection according to standard definitions. However, the magnitude of the immune response was significantly less than for placebo-treated patients, indicating that fingolimod blunted the humoral immune response.20 Dimethyl Fumarate Dimethyl fumarate is immunomodulatory on many levels. Known effects include antioxidant function, neuroprotection, and reduction of certain peripheral immune populations.21 Immunomodulatory effects of dimethyl fumarate appear most pronounced among T cells, but there is a modest decrease in the numbers of circulating B cells in patients taking the drug.22,23 The functional implications of this decrease have not yet been reported. To our knowledge, no published studies have yet examined the vaccine response in patients with MS taking dimethyl fumarate. Teriflunomide Teriflunomide inhibits dihydro-orate dehydrogenase, an enzyme necessary to support rapid cellular proliferation. It is thought to affect MS by inhibiting the proliferation of pathogenic lymphocytes. Both B and T cells use dihydro-orate dehydrogenase; research24 has found dose-dependent inhibition of both B- and T-cell proliferation on treatment with teriflunomide without affecting cell activation or viability. In animal models of MS, fewer B and T cells infiltrated into the CNS of teriflunomide-treated animals compared with untreated animals.25 Little in vivo work has addressed the effects of teriflunomide on B cells. In general, teriflunomide-treated patients with MS mounted an effective immune response to influenza vaccines, but patients taking the 14-mg dose had a weaker response to certain viral strains when compared with the 7-mg dose or to interferon beta–treated patients.13 Of note, healthy individuals given teriflunomide for 1 month were able to mount an adequate immune response to the neoantigens in rabies vaccines.26 Natalizumab Natalizumab is a monoclonal antibody against α4-integrin (VLA-4), which is found on many leukocyte subtypes, is upregulated on lymphocyte activation, and is important for transmigration into areas of inflammation. Inhibiting VLA4 via natalizumab impedes the recruitment of immune cells into the CNS. Natalizumab is a potent medication, reducing the annualized relapse rate by 68% and decreasing the number of new or enlarging MRI lesions by 83% vs placebo in clinical trials.27 Among lymphocytes, VLA-4 is expressed at higher levels on B cells than on T cells.28 Inhibiting VLA-4 selectively on B cells led to amelioration of the clinical severity of murine EAE and decreased accumulation of B cells, TH17 T cells, and macrophages within the CNS.29 Natalizumab treatment frequently leads to a corresponding peripheral leukocytosis, with circulating B lymphocytes being disproportionately elevated relative to other cell types.30,31 This expansion is partly owing to an influx of newly produced cells; circulating B-cell precursors are increased in treated patients.31,32 B-cell homeostasis is also affected. The proportion of circulating regulatory, memory, and marginal zone–like B cells increases, whereas the relative frequency of naive B cells decreases.33-35 This finding may be due to decreased retention of B cells within the secondary lymphoid organs. Meanwhile, plasma levels of IgG and IgM (produced by mature plasma cells) actually decrease during natalizumab therapy.36 Notwithstanding the increase in circulating B cells, there is decreased B-cell activity within the CNS compartment during natalizumab therapy. There are fewer B cells detectable in the cerebrospinal fluid (CSF) of natalizumab-treated compared with untreated patients with MS.37 The CSF-restricted oligoclonal bands indicate excess humoral immunity in the CNS compartment and are present in more than 90% of patients with MS. Once present, they typically persist throughout the lifetime of the disease. Of interest, natalizumab decreases or eliminates CSF-restricted oligoclonal bands in 16% to 55% of patients.38,39 This phenomenon has not been reported after other MS disease-modifying therapies. Natalizumab-treated patients are able to mount an immune response to vaccines, but this response may be attenuated compared with controls.13 Further study is needed because existing data are conflicting and reflect only small numbers of patients. Alemtuzumab Alemtuzumab is a humanized anti-CD52 mAb that rapidly eliminates CD52-expressing cells from the circulation via antibody-dependent cell-mediated cytotoxicity, complement-mediated cytolysis, and induction of apoptosis. CD52 is expressed at high levels by B and T cells and at lower levels by other circulating immune cells, including natural killer cells, monocytes, macrophages, and dendritic cells.40 Alemtuzumab is administered yearly as a series of infusions; it effectively eradicates the adaptive immune system, which slowly reconstitutes in the ensuing months to years. Total B-cell counts return to baseline levels by 3 months after alemtuzumab treatment and increase to 165% of baseline levels by 12 months after treatment.41 In contrast, CD4+ T-cell counts do not reattain baseline levels even at 5 years after initial alemtuzumab infusion. After alemtuzumab infusion, B-cell reconstitution is driven by differentiation of precursor cells from the bone marrow, and there is upregulation of the B-cell survival factor BAFF.41 Thus, 1 month after infusion, recent bone marrow emigrants are detected with high frequency in the circulation. This population subsequently matures and differentiates into naive B cells; this naive B-cell subtype is disproportionately represented in the circulation beginning at 3 months after alemtuzumab treatment. In contrast, there is a prolonged depletion of memory B cells after alemtuzumab treatment.41 CD52 is expressed on a subset of plasma cells,42 but patients treated with alemtuzumab retained circulating antibodies against previously administered vaccines and common viruses.43 In a small cohort of 24 alemtuzumab-treated patients with MS, there was an adequate antibody response to T-cell–dependent recall antigens (diphtheria and tetanus toxoids and pertussis vaccine), T-cell–dependent novel antigens (meningococcus vaccine), and T-cell–independent antigens (pneumococcal vaccine), even early after alemtuzumab infusion.13 Mitoxantrone Mitoxantrone is a synthetic anthracenedione agent that has anticancer and immunosuppressive activities. Mitoxantrone was approved by the FDA in 2000 for worsening relapsing-remitting MS, secondary progressive MS, and progressive relapsing MS. Its use carries the major health risk of cardiomyopathy, necessitating regular cardiac monitoring and a limitation on lifetime cumulative dose. Risk of acute myelogenous leukemia is also increased. With the arrival of newer and safer DMTs for MS, the use of mitoxantrone has diminished. Mitoxantrone acts by intercalating into DNA, which causes strand breaks; it also inhibits topoisomerase II. These 2 actions impart potent cytotoxic effects, which target replicating cells. Mitoxantrone affects numerous cell types, suppressing proliferation of T cells, B cells, and macrophages and leading to cell death primarily via apoptosis. Mitoxantrone has been reported to preferentially affect B cells.44 On ex vivo stimulation, B cells from untreated patients with MS produce less of the regulatory cytokine IL-10 than matched HCs but more of the proinflammatory cytokine lymphotoxin. When patient B cells were studied 4 weeks after administration of mitoxantrone, IL-10 increased and lymphotoxin decreased compared with pretreatment levels. Mitoxantrone treatment also led to a reduction in the proportion of CD27+ memory B cells in peripheral blood.45 Rituximab and Ocrelizumab Rituximab and ocrelizumab target CD20, a surface marker expressed throughout much of the B-cell lineage, including pre-B cells and mature B cells. Rituximab is a chimeric mouse and human mAb, whereas ocrelizumab is humanized. On binding CD20, the antibodies induce antibody-dependent cell-mediated cytotoxicity, complement-mediated cytolysis, and activation of apoptotic pathways with subsequent depletion of the circulating CD20+ B-cell lineage.46 Terminally differentiated, antibody-producing plasma cells and very early B-cell precursors are spared. Early-phase clinical trials of rituximab supported a causal role for B cells in relapsing MS by revealing significant reductions in contrast-enhancing brain lesions.3 Ocrelizumab reduced MRI activity by approximately 95% in patients with relapsing MS in 2 recent large, phase 3 clinical trials.2 Trials testing these medications in progressive MS yielded less strong results; subgroup analyses suggested that rituximab might benefit patients with primary progressive MS who were younger and/or had gadolinium-enhancing MRI lesions at baseline.47 There was a modest but statistically significant decrease in MS progression in patients with primary progressive MS treated with ocrelizumab in the phase 3 ORATORIO clinical trial.48,49 To date, the latter is the only DMT to have met its primary end point in a trial in primary progressive MS. Eliminating B cells that produced granulocyte-macrophage colony-stimulating factor may be an important mechanism for B-cell depletion therapies. This unique subpopulation of memory B cells was recently identified and found to be abnormally increased among patients with MS. These cells inhibit IL-10 production and support a proinflammatory myeloid response. The increased proportion of these proinflammatory B cells found in patients with MS normalized on reconstitution of B cells after therapeutic depletion.50 In addition to eliminating circulating B cells, rituximab depletes B cells from the CSF in patients with MS.51 IgG indexes and the numbers of oligoclonal bands in CSF were not affected at 6 months after initiation of rituximab treatment; however, the cytokines CXCL13 and CCL19 were decreased.52 These cytokines are not typically produced by B cells but play a role in B-cell chemoattraction and the organization of lymphoid follicles. Of interest, ectopic lymphoid follicles containing B cells have been detected in the meninges of patients with MS, and their presence correlates with worse disease.53 The levels of circulating immunoglobulins, especially IgM, may decrease with long-term rituximab treatment. Vaccination studies have not been performed in patients with MS, but among patients taking rituximab for other reasons (eg, rheumatoid arthritis, lymphoma), there was an attenuated humoral response to the influenza vaccine.13 Vaccination with live viruses is contraindicated with rituximab. Ocrelizumab is a newly developed agent. Vaccine efficacy in ocrelizumab-treated patients has not yet been reported but will likely be similar to that of rituximab. Conclusions Recent clinical trials of rituximab and ocrelizumab have reiterated the importance of B cells in mediating the clinical course of MS. Anti-CD20 mAbs specifically target B cells, but none of these have yet been approved by the FDA or European Medicines Agency for MS treatment. All of the currently approved DMTs also affect B-cell immunity to varying degrees. Indeed, the commonalities may yield valuable insight into the mechanisms of MS pathogenesis. Most DMTs induce a shift in circulating B-cell immunophenotypes, increasing the relative frequency of immature and naive B cells while decreasing the proportion of memory B cells. Increased B-cell production of IL-10 with concurrent suppression of proinflammatory cytokine secretion is another common observation. B cells from DMT-treated patients are generally less able to support a proinflammatory T-cell response. These observations support the contention that memory B cells may mediate MS pathologic findings and that promoting a more immature or regulatory B-cell phenotype is protective. The recent observation that proinflammatory, granulocyte-macrophage colony-stimulating factor–producing memory B cells are dysregulated in MS substantiates this hypothesis.50 Further characterization of circulating memory B cells before and after DMT may lead to the identification of cognate antigenic targets for these cells, which may be especially instructive. Natalizumab is the notable exception to the generalization that approved MS therapies decrease the relative frequency of circulating memory B cells. Indeed, there is a relative expansion of this cell type during natalizumab treatment. However, natalizumab acts via a unique mechanism when compared with the other DMTs. By blocking VLA-4, natalizumab impedes lymphocyte trafficking, including across the blood-brain barrier into the CNS. Increased circulating leukocytes, including memory B cells, are a result. This distinct mechanism of action may explain disparate effects by natalizumab on circulating B-cell phenotypes when compared with the other DMTs. The similarities in B-cell phenotype and function among patients with MS undergoing treatment with a variety of DMTs, each of which has a unique mechanism of action, are striking and suggest that such B-cell effects underlie part of the efficacy of the DMTs. Indeed, research using animal models for MS has found that B cells are necessary to observing a full clinical effect for both interferon beta and glatiramer acetate.5,15 A more complete understanding of how the existing DMTs modulate B-cell immunity may identify future targets for therapeutic intervention. Section Editor: David E. Pleasure, MD. Back to top Article Information Accepted for Publication: October 22, 2015. Corresponding Author: Anne H. Cross, MD, Department of Neurology, Washington University, 660 S Euclid Ave, Campus Box 8111, St Louis, MO 63110. Published Online: December 28, 2015. doi:10.1001/jamaneurol.2015.3977. Author Contributions: Dr Cross had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Both authors. Acquisition, analysis, or interpretation of data: Both authors. Drafting of the manuscript: Both authors. Critical revision of the manuscript for important intellectual content: Both authors. Administrative, technical, or material support: Cross. Conflict of Interest Disclosures: Dr Longbrake reported receiving honoraria for consulting and speaking for Genzyme. Her salary and training are supported by the Sylvia Lawry Physician’s Fellowship of the National MS Society. Dr Cross reported receiving honoraria for consulting or speaking from Abbvie, Biogen, Genzyme/Sanofi, Roche, Teva Neuroscience, Genentech, Mallinckrodt, and Novartis; research support from Biogen, Roche, EMD-Serono, Teva Neuroscience, US Department of Defense, National MS Society USA, and the National Institutes of Health; and additional support in part by the Manny & Rosalyn Rosenthal–Dr John L. Trotter Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. References 1. Hauser SL, Waubant E, Arnold DL, et al; HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.PubMedGoogle ScholarCrossref 2. Hauser SL, Comi GC, Hartung H-P, et al. Efficacy and safety of ocrelizumab in relapsing multiple sclerosis—results of the interferon-beta-1a-controlled, double-blind, Phase III OPERA I and II studies. In: Proceedings from the 31st ECTRIMS Congress; October 7-10, 2015; Barcelona, Spain. Abstract 246. 3. 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JAMA Neurology – American Medical Association
Published: Feb 1, 2016
Keywords: b-lymphocytes,immune response,biological therapy,mitoxantrone,multiple sclerosis,rituximab,glatiramer acetate,alemtuzumab,immune response, humoral,natalizumab,fingolimod,interferon-beta,immunity, humoral,cytokine,interleukin-10,immunity
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