B cells have a fundamental role in the pathogenesis of various autoimmune neurological disorders, not only as precursors of antibody-producing cells, but also as important regulators of the T-cell activation process through their participation in antigen presentation, cytokine production, and formation of ectopic germinal centers in the intermeningeal spaces. Two B-cell trophic factors—BAFF (B-cell-activating factor) and APRIL (a proliferation-inducing ligand)—and their receptors are strongly upregulated in many immunological disorders of the CNS and PNS, and these molecules contribute to clonal expansion of B cells in situ. The availability of monoclonal antibodies or fusion proteins against B-cell surface molecules and trophic factors provides a rational approach to the treatment of autoimmune neurological diseases. This article reviews the role of B cells in autoimmune neurological disorders and summarizes the experience to date with rituximab, a B-cell-depleting monoclonal antibody against CD20, for the treatment of relapsing–remitting multiple sclerosis, autoimmune neuropathies, neuromyelitis optica, paraneoplastic neurological disorders, myasthenia gravis, and inflammatory myopathies. It is expected that ongoing controlled trials will establish the efficacy and long-term safety profile of anti-B-cell agents in several autoimmune neurological disorders, as well as exploring the possibility of a safe and synergistic effect with other immunosuppressants or immunomodulators.
During the past three decades, investigations into neuroimmunological diseases of the CNS—and to a lesser degree the PNS—have centered predominantly on the roles of activated, cytotoxic and immunoregulatory T cells rather than B cells. The decision to focus on T cells can probably be attributed to the long-standing observation that the main lymphocytic subset within the lesions in the two most common autoimmune disorders, multiple sclerosis (MS) and Guillain–Barré syndrome, are dominated by T-cell infiltrates. In addition, myelin-specific T cells are responsible for disease transfer in the respective animal models for these conditions. The contribution of activated B cells to these disorders has traditionally been viewed as a secondary consequence of the breakdown of T-cell tolerance. Over the past few years, however, compelling data on the roles of B cells as sensors, coordinators and regulators of the immune response1 have strengthened the view that B cells and autoantibodies are fundamental for activating T cells and/or mediating tissue injury in several disorders of the CNS and PNS. The observation that B-cell depletion is an effective therapy in autoimmune disorders such as rheumatoid arthritis has provided the impetus to explore the functions of B cells in neurological diseases, and has triggered an interest in conducting clinical trials in this area.
This Review focuses on B-cell homeostasis, addresses the roles of B-cell functions in autoimmune neurological disorders, and summarizes the experience to date with anti-B-cell therapies, in particular the B-cell-depleting monoclonal antibody rituximab.
Roles of B cells in the immune response: neurological aspects
In the context of autoimmune neurological disorders, B cells have traditionally been associated with the production of autoantibodies from plasma cells, the end products of B-cell differentiation.2, 3, 4, 5 In several neurological diseases, including myasthenia gravis and certain neuropathies, the autoantibodies are pathogenetic, exerting a direct effect on self antigens either by functioning as neutralizing antibodies or by activating and fixing complement on the targeted tissues (Figure 1A). Autoantibodies and immune complexes can also activate Fc receptors on macrophages or dendritic cells, leading to the production of cytokines, which cause further tissue injury (Figure 1A). In most autoimmune neurological disorders, however, the autoantibodies are directed against cytosolic antigens and might not be directly involved in tissue injury. In such cases, B cells might still participate in the autoimmune process through antibody-independent mechanisms that include antigen presentation, costimulation, cytokine production, and coordination of T-cell functions (Figure 1A–D).4, 6
A proof-of-principle that activated B cells are fundamental for coordinating T-cell functions was provided by the observation that B-cell-depleted mice exhibit a dramatic decrease in numbers of CD4+ and CD8+ T cells, and a tenfold inhibition of memory CD8+ T cells.7, 8 An important function of B cells is their ability to present antigenic peptides, in the context of major histocompatibility complex class II molecules on their surface, to the T-cell receptors of CD4+ cells, leading to expansion of antigen-specific T cells (Figure 1B).1, 2, 3, 4, 5, 6 B cells are 100–1,000 times more potent in antigen presentation than are the other antigen-presenting cells, such as macrophages or dendritic cells,9 and they are especially effective at presenting low concentrations of antigen. Activated B cells are also as efficient as T cells at producing cytokines—most notably interleukins (IL-1, IL-4, IL-6, IL-10, IL-12, IL-23 and IL-16), tumor necrosis factor (TNF) and the chemokines macrophage inflammatory protein 1 (MIP1) and MIP1.10, 11 These inflammatory mediators modulate the migration of dendritic cells, activate macrophages, exert a regulatory role on T-cell functions, and provide feedback stimulatory signals for further B-cell activation (Figure 1C). Some cytokines might theoretically exert an inhibitory role in the immune process, although this has not been clearly established in human diseases.
An additional role of B cells that is relevant to neurology is their involvement in de novo formation and maintenance of ectopic lymphoid structures, a process termed neolymphogenesis.6 This is accomplished through the actions of -lymphotoxin, a TNF family member molecule that is expressed on the surface of B cells (Figure 1D). Ectopic follicular structures are found in the meningeal compartment in patients with various neuroinflammatory conditions, as discussed below. The multiple contributions of B cells to the complexity of the autoimmune process make B cells attractive targets for therapeutic interventions that extend beyond the traditional effects on antibody production.
B-cell maturation and homeostasis
B lymphocytes arise from hematopoietic stem cells in the bone marrow. These cells mature independently of an antigen first into pro-B cells, then into pre-B cells and immature B cells (Figure 2).4, 5 They subsequently enter the antigen-dependent phase in the peripheral lymphoid tissues, where mature-but-naive B cells, after encountering their antigen in the extrafollicular regions of the lymphoid organs, become activated B cells and migrate to the follicular regions. From here, they exit to differentiate into memory B cells, late plasmablasts and plasma cells (Figure 2).1, 2, 3, 4, 5, 6 Specific markers, such as CD20, CD27, BAFF-R (B-cell-activating factor receptor), CD38 and CD138, identify the transitional phases of B cells from stem cells to plasma cells (Figure 2).
The memory B cells, late plasmablasts and long-lived plasma cells migrate not only to the bone marrow, spleen and lymphoid tissues, but also to the brain, where they transform into antibody-secreting cells after encountering their antigen (Figure 3).12 Interactions between the homeostatic chemokines CXC-chemokine ligand (CXCL) 13, CXCL10 and CXCL12 secreted from the endothelial cell wall and their respective receptors on B cells3, 13 are fundamental for B-cell homeostasis not only within the lymphoid follicles but also within the brain. These molecules are upregulated in the brains of patients with MS, allowing the recruitment and transmigration of antibody-producing B cells into the brain.14, 15 B-cell transmigration into the brain is also facilitated by the adhesion molecules very late antigen-4 (VLA-4; also known as integrin -4 or ITA4) and lymphocyte function-associated antigen-1 (LFA-1; also known as integrin -L or ITAL) and their counter-receptors vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) on the endothelial cells.13 In secondary progressive MS, activated B cells form germinal centers not only in the lymphoid tissues but also within the intermeningeal spaces, where they undergo the same stages of differentiation as in the periphery (Figure 3).16, 17 Within these structures, which are observed in 41.4% of patients with secondary progressive MS,17 B cells generate inflammatory mediators that can stimulate plasma cells for in situ production of immunoglobulins. The production of intrathecal immunoglobulins (i.e. the life-long persistent oligoclonal bands) in all forms of MS indicates a central role for activated B cells and plasma cells in this disease.
Two members of the TNF family, BAFF (B-cell-activating factor) and APRIL (a proliferation-inducing ligand), have emerged as crucial factors for B-cell survival, differentiation, germinal center formation and immunoglobulin production.3, 18, 19 BAFF and APRIL are produced by monocytes, macrophages and dendritic cells, and they circulate in trimeric forms. They bind to B cells through three different receptors (Table 1): BAFF-R, BCMA (B-cell-maturation antigen) and TACI (transmembrane activator and calcium modulator and cytophilin ligand interactor). Levels of BAFF-R and APRIL mRNA are increased in the monocytes and B cells of patients with MS20 and in the muscles of patients with inflammatory myopathies (Raju R and Dalakas MC, unpublished data). In MS lesions, BAFF and APRIL are produced by astrocytes, and they promote the in situ survival and clonal expansion of B cells (Figure 3).21, 22 Agents that target BAFF or APRIL might, therefore, exert therapeutic effects in various neurological disorders by suppressing B-cell proliferation.
Various immunomodulatory drugs that are currently used in neurology, such as intravenous immunoglobulin (IVIg), alemtuzumab, cyclophosphamide, mitoxanthrone and natalizumab, can affect some aspects of B-cell function that are relevant to the pathogenesis of neurological disease. New monoclonal antibodies or fusion proteins that specifically target B-cell survival or proliferation are, however, now becoming available. The evidence that B cells have a role in autoimmune neurological disorders is summarized here:
Observations supporting a role for B cells in the pathogenesis of autoimmune neurological disorders.
B cells are clonally expanded within the CNS, producing intrathecal
immunoglobulin (IgG), in various CNS disorders such as multiple sclerosis (MS),
paraneoplastic CNS disorders and stiff-person syndrome
B cells, plasma
cells, myelin-specific IgG and complement are present in the active and chronic
plaques of MS
IgGs specific for myelin oligodendrocyte glycoprotein and
myelin basic protein are detected in the brains of individuals with MS
Memory B cells, along with early, late or short-lived plasmablasts, are
detected in the cerebrospinal fluid and ectopic germinal centers in the meninges
of patients with MS
B cells are required for disease induction by antigenic
peptides in some experimental autoimmune encephalomyelitis and experimental
autoimmune neuritis models, a requirement consistent with the unique ability of
B cells to recognize antigenic conformation
B cells have a role in the
regulation of CNS inflammation
Autoantibodies against glycolipids and
glycoproteins can induce demyelination within the PNS
B-cell activation leads to production of pathologic autoantibodies in myasthenia
Several antibody-mediated neurological disorders have been
successfully treated using plasmapheresis or intravenous immunoglobulin, which
remove autoantibodies or modify the idiotypic repertoire
monoclonal antibodies such as rituximab that deplete B cells can result in
clinical improvement when used in certain CNS or PNS disorders
Agents affecting B-cell survival
Drugs that target BAFF or APRIL, or their receptors BAFF-R, TACI or BCMA, affect B cell survival and differentiation, resulting in reduced numbers of mature B cells in the lymphoid tissues and the circulation (Figure 4).19 Blockade of BAFF-R, TACI or BCMA in mouse models of systemic lupus erythematosus (SLE) not only reduces antibody titers, but also improves animal survival.6, 23, 24 The targeting of BAFF, BAFF-R and APRIL is of therapeutic interest in the neurological context, because these molecules are upregulated in the tissues of patients with autoimmune diseases. A number of agents are currently in phase I–II clinical trials in rheumatoid arthritis and SLE.1, 2, 3, 4, 5, 6, 24 Agents that target BAFF include belimumab, a humanized monoclonal antibody against soluble BAFF, and the BAFF antagonist AMG G23. BR3-Fc is directed against BAFF-R, resulting in blockade of BAFF binding and, subsequently, B-cell reduction. BCMA-IgG is directed against APRIL. The TACI–IgG fusion protein neutralizes BAFF, APRIL and BAFF–APRIL heterodimers. Anti-lymphotoxin- receptor disrupts the architecture in the ectopic germinal centers.
Agents causing B-cell depletion
Drugs directed against the CD20 or CD22 B-cell-surface glycoproteins can coat B cells and thereby cause their depletion (Figure 4). These drugs include: epratuzumab, which blocks CD22 survival signals on immature and mature B cells, as well as on pro-B and pre-B cells; rituximab, which is directed against the CD20 molecule; and occrelizumab, the humanized version of rituximab. In contrast to agents against trophic factors and their receptors, as mentioned above, these drugs deplete B cells but not the antibody-producing plasma cells.1, 2, 3, 4, 5, 6
Anti-B-cell agents in neurology: the role of rituximab
Among all the aforementioned agents, only two, BCMA-IgG and rituximab, have been used in autoimmune neurological disorders. In mice with experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG), BCMA-IgG prevented disease development, improved the strength of already weak animals, depleted the CD19+ B cells in the blood, spleen and lymph nodes, reduced anti-MOG-specific IgG antibody titers, and suppressed inflammation and ongoing demyelination in the brain and spinal cord.25
Rituximab is a chimeric mouse–human monoclonal antibody consisting of human IgG1 and kappa constant regions and a mouse variable region. It was derived from a hybridoma directed at human CD20, a 297-amino-acid transmembrane phosphoprotein that is present on all cells of the B-cell lineage except for stem cells, pro-B cells and plasma cells (Figure 2).1, 2, 3, 4, 5, 6 In contrast to BAFF and APRIL, CD20 is not secreted, and it is not shed or endocytosed when exposed to rituximab.26 The function of CD20 is unclear—it is thought to be involved in B-cell activation and proliferation,1, 2, 3, 4, 5, 6 although CD20 knockout mice do not exhibit B-cell deficits.1, 2, 3, 4, 5, 6, 26 Rituximab is approved for the treatment of rheumatoid arthritis,27 and, as outlined in the sections that follow, its use is currently being explored in a number of autoimmune neurological disorders in which B cells have a role.
Rituximab in autoimmune neurological disorders
In MS, B cells and antibodies are involved to varying degrees at different stages of the disease and in different subgroups of MS. In the I–IV classification of Lucchineti, for example, pattern II is characterized by prominent lymphocytic and macrophagic infiltrates, complement activation and deposits of immunoglobulins.28 Additional evidence supporting an antibody-mediated process in patients with MS includes accumulations of clonally expanded B cells in the MS plaques; intrathecal production of IgG bands from oligoclonal populations of B cells; autoantibodies against MOG in actively demyelinating lesions; ectopic lymphoid tissue in the intermeningeal spaces; and upregulation of BAFF and APRIL.17, 21, 22, 28, 29, 30, 31
In patients with MS, 24 weeks of treatment with rituximab was shown to deplete B cells from the cerebrospinal fluid (CSF) and to suppress B-cell activation, but it did not affect the intrathecal synthesis of oligoclonal IgG bands derived from long-lived plasma cells.32 In a phase II, controlled, multicenter clinical trial of 104 patients with relapsing–remitting MS, a 58% relative reduction in the proportion of patients who experienced a relapse was noted after 24 weeks of therapy. A significant reduction in the mean number of gadolinium-enhancing MRI lesions (the study's primary end point), was also observed in the treated patients compared with the placebo group (P <0.0001).33>Neuromyelitis optica
Neuromyelitis optica (NMO) is an inflammatory CNS disorder that affects the optic nerves and the spinal cord. It typically presents with myelitis and optic neuritis, and is characterized by varying degrees of sensory motor disturbances, bladder–bowel dysfunction and visual loss. In NMO, autoantibodies, collectively termed NMO-Ig, bind to cerebral microvessels.35 The main target antigen of these autoantibodies is the aquaporin-4 water channel. NMO-Ig is derived from peripheral B cells, activates complement, and has been implicated in the induction of inflammatory demyelination and necrosis in the endothelial cells of the spinal cord.35 Patients with NMO experience frequent relapses, and the disease is associated with high morbidity. Some acute flare-ups can respond to plasmapheresis, although the disease responds poorly to immunotherapies overall.
In an open-label study, six out of eight patients with NMO became relapse-free after a year of rituximab treatment, with a decline in relapse rate from 26 to zero attacks per year. In addition, seven of the patients showed a substantial improvement in their Expanded Disability Status Scale (EDSS) score.36 In a retrospective review of 34 patients from two different centers, rituximab significantly lowered the relapse rate compared with pretreatment data, and stabilized or improved the EDSS scores in 91% of the patients.37, 38
Paraneoplastic neurological disorders
Patients with paraneoplastic neurological disorders have circulating antibodies against a variety of antigens that are expressed in both brain and cancer cells. There is evidence that B cells, plasma cells and cytotoxic T cells cross the blood–brain barrier, and antibodies are synthesized intrathecally. In paraneoplastic opsoclonus–myoclonus, the number of clonally expanded B cells within the CSF correlates with clinical severity.39 Rituximab, as an add-on therapy to IVIg or adrenocorticotropic hormone (ACTH), improved the ataxia severity scores, ameliorated myoclonus and reduced the rate of clinical relapse in 81% of 16 children with opsoclonus–myoclonus, and selectively reduced the numbers of clonally expanded B cells in the CSF.40 In addition, the required ACTH dose was reduced by 51% after rituximab treatment.
Chronic autoimmune neuropathies
The chronic autoimmune neuropathies include a spectrum of predominantly demyelinating neuropathies, the most common of which are chronic inflammatory demyelinating neuropathy (CIDP), multifocal motor neuropathy (MMN) and IgM anti-myelin-associated glycoprotein (IgM-MAG) neuropathies. Evidence for a role for B cells in the pathogenesis of these conditions includes the deposition of immunoglobulins and complement on the patients' nerves, and the presence of complement-fixing antibodies against MAG and gangliosides.41, 42 In an open series of 21 patients with IgM antibodies to gangliosides, rituximab improved symptoms in 61% of the patients 6 months after therapy, and the benefits were maintained for up to 2 years with repeated infusions.43 The IgM antibody titers dropped by 36% in the first year and by 57% in the second. Rituximab has also been reported to be effective in some patients with MMN or CIDP.44, 45 In another study, rituximab improved the symptoms in six out of nine patients with IgM-MAG neuropathy, and reduced IgM-MAG titers by a mean of 52% from baseline,46 prompting a placebo-controlled study. In 26 randomized patients, rituximab significantly improved disability scores and reduced IgM-MAG titers after 8 months.47 Rituximab is the first drug to demonstrate efficacy in a randomized trial in this particular neuropathy.
Stiff-person syndrome (SPS) is a rare but often misdiagnosed CNS disorder that is clinically characterized by stiffness and rigidity in the limbs and paraspinal muscles, intermittent superimposed muscle spasms, and heightened sensitivity to external stimuli. The majority of patients with SPS have antibodies against glutamic acid decarboxylase (GAD) or GABARAP, a linker protein responsible for -aminobutyric acid receptor clustering.48 Anti-GAD antibodies are synthesized intrathecally, and oligoclonal bands are commonly detected in the CSF.49 In one case report, rituximab was effective at reducing stiffness and increasing mobility 2 months after the treatment was initiated, and resulted in disappearance of GAD antibodies and normalization of the electromyogram.50 The first double-blind controlled study using rituximab to treat SPS has now been completed at the NIH, and the results are currently being analyzed.
There are three main subsets of inflammatory myopathies: polymyositis, dermatomyositis and inclusion body myositis. In all these forms of the disease, B cells and plasma cells are present in the muscle tissues, and in dermatomyositis immunoglobulins are deposited on endomysial capillaries.51 In 10 patients with polymyositis or dermatomyositis who had responded poorly to current therapies, rituximab increased or normalized muscle strength in 8 cases. Serum levels of creatine kinase and the required prednisone dose were concurrently reduced.52, 53 A multicenter NIH-sponsored clinical trial of rituximab is now ongoing for the treatment of polymyositis and dermatomyositis. The drug has not yet been tested in inclusion body myositis.
Myasthenia gravis is a prototypic B-cell-mediated autoimmune disease caused by pathogenetic antibodies against the muscle acetylcholine receptors. Evidence from around 20 case reports suggests that rituximab is effective in most patients, but a controlled study has not yet been done.54, 55, 56, 57
Effect of rituximab on circulating B cells, autoantibodies and immunoglobulin levels
In general, 1 month after rituximab infusion, circulating B cells become undetectable, and their numbers remain low for at least 6 months. The cells start reappearing slowly thereafter, but even after 10 months their numbers remain below baseline.3 The circulating memory CD20+CD27+ B cells are also depleted, and their levels remain low until month 8 (Figure 5). The B cells in the follicular splenic regions are preferentially affected, being depleted by 90%, compared with 25% depletion of marginal-zone B cells.6 The germinal-center B cells are resistant to rituximab, even though they express CD20, possibly reflecting an inability of the antibody to access the intravascular spaces within the lymphoid tissues, or different sensitivities of B cells according to the local lymphoid microenvironment.6 Stem cells in the bone marrow that do not express CD20 are also spared, thereby allowing the generation of new naive B cells.58
Rituximab is not expected to affect the levels of antibodies produced by plasma cells, although some reductions in these levels have been noted. In rheumatoid arthritis, for example, the titers of rheumatoid factor were shown to decrease two-to-threefold,58, 59 and in IgM-MAG neuropathy by 30–50%, after treatment with rituximab.45, 47 Such reductions can probably be attributed to depletion of CD27+ memory B cells, the precursors of short-lived plasma cells.4 As the CD27+ memory B cells reappear, so do the short-lived plasma cells.60 Given that the reconstituting B cells are naive cells with a new and diverse immunoglobulin rearrangement pattern,4, 58, 59 it might take some time for them to be restimulated by the original antigen, hence the slow re-emergence of serum antibody titers. Antibody titers might therefore fall after rituximab treatment, and rebound slowly at a rate controlled by the replenishment of memory and short-lived plasma cells.60 Interestingly, after several years of treatment, the antibody titers against anamnestic antigens, such as tetanus toxoid, remain stable.59 This finding suggests that rituximab might have differential effects on 'autoreactive' B cells and their corresponding short-lived plasma cells, compared with 'non-self-reactive' B cells and their corresponding longer lived plasma cells, which are responsible for post-vaccination responses.6 A recent study supports different roles for B cells and longer lived plasma cells in protective immunity.61
Dosing, tolerance, safety and combination therapy
Rituximab can be administered intravenously at a dose of 375 mg/m2, given weekly for 4 weeks, or in two 1 g infusions, given at fortnightly intervals (total 2 g). The average half-life of the drug after completion of an infusion is 21 days. The infusions can be repeated after 6–12 months, at a point when B cells start rebounding or when the patient has relapsed. The drug is generally very well tolerated, although mild hypotension can be observed in some patients, necessitating the discontinuation of antihypertensive drugs on the day of the infusions. Anaphylactic or skin reactions can occur in rare cases, but these respond to intravenous methylprednisolone. Premedication with antihistamine is desirable to prevent the occurrence of such reactions.
Rituximab has been used in combination with other immunosuppressants, such as corticosteroids, mycophenolate, cyclophosphamide, azathioprine or methotrexate,6, 62 for the treatment of vasculitis and rheumatoid arthritis, without additional complications. This experience differs from that with natalizumab, which requires discontinuation of the other immunosuppressants for 2–3 months before initiating therapy.63 It remains to be determined whether combination therapy will be more effective than monotherapy in difficult neurological cases. Rituximab has been also used effectively in some cases of pediatric SLE in two infusions of 750 mg/m2 administered 2 weeks apart, either alone or in combination with corticosteroids and cyclophosphamide,1 suggesting that it can be used in children with difficult autoimmune neurological disorders.
The resistance of long-lived plasma cells to rituximab probably explains its excellent safety profile, the absence of infections, and the patients' retained ability to produce immunoglobulins and mount an antibody response against anamnestic antigens. In spite of the apparent plasticity of the immune system, which enables it to compensate for the peripherally depleted B cells, vigilance is still required to guard against the possibility of infections in patients receiving repeated doses or concurrent immunosuppressants.3 Such infections might not be limited to common bacterial or viral agents, but might also extend to agents that cause latent infections, such as JC virus or herpesviruses, as has been experienced with natalizumab.63 Rare cases of progressive multifocal leukoencephalopathy have been reported in patients with SLE receiving rituximab, although a cause-and-effect relationship has not been established.64
A consistent observation in many series is the elevation of BAFF levels after rituximab treatment, probably as an inherent compensatory mechanism to drive B-cell production.1, 2, 3, 4, 5, 6 Theoretically, combining rituximab with one of the agents against BCMA or TACI-IgG, which reduce the survival of BAFF-dependent, immunoglobulin-producing, long-lived plasma cells, might have a prolonged effect on B cells and autoantibody levels. Such a combination therapy might be attractive in the future, in view of increased levels of BAFF in autoimmune neurological disorders.
Modes of action of rituximab
Rituximab depletes B cells through three mechanisms (Figure 6): antibody-dependent cellular cytotoxicity, whereby antibody-coated cells bind to the Fc receptors of macrophages or natural killer cells; activating the membrane attack complex on B cells (complement-dependent cytotoxicity); and inducing apoptosis by changing the lipid raft environment on the CD20+ B-cell membrane.1, 2, 3, 4, 5, 6
The most impressive observation in all published series, and from our own experience, is the long-lasting benefit of rituximab, sometimes exceeding 6–8 months after therapy. The degree of clinical response, however, varies from patient to patient, probably reflecting the varying degree of contribution of B cells to the autoimmune process, as discussed earlier. It is difficult to ascertain which of the B-cell functions depicted in Figure 1 is primarily influenced by the drug and is responsible for the noted benefit. Diminished production of pathogenetic autoantibodies might be a contributing factor, but this decrease in production might be insufficient to be clinically meaningful.27, 59 The effects of rituximab on other B-cell functions—effects that include blockade of costimulatory molecules required for clonal expansion of T cells, inhibition of the antigen-presenting role of B cells, suppression of the cytokine network, inhibition of immune complexes, and induction of immunoregulatory T cells—might be more important in explaining the noted clinical benefit. Accordingly, rituximab might be beneficial not only in antibody-mediated disorders of the CNS and PNS, but also in other autoimmune diseases where both B cells and T cells contribute to disease pathogenesis.
Conclusions and future prospects
Anti-B-cell therapy, in particular treatment with rituximab, is a promising approach for immunotherapy of neurological diseases, and it has the potential to produce long-lasting benefits. The reported excellent tolerance of rituximab administered in combination with other immunosuppressants is an important advantage, but close monitoring will be required to promptly identify any long-term sequelae or unforeseen adverse effects. Newer monoclonal antibodies designed to target B-cell survival factors might prove to be even more effective than rituximab, because they can also affect the production of immunoglobulin and antibodies by plasma cells. The B cell is an attractive target for immunotherapeutic interventions, and controlled trials with rituximab and other new agents that work through similar mechanisms are warranted for the treatment of neurological disorders.
B cells have a key role in the pathogenesis of various autoimmune neurological
A number of monoclonal antibodies or fusion proteins directed
against B-cell surface molecules and trophic factors are currently in clinical
The anti-CD20 monoclonal antibody rituximab has shown promise in the
treatment of disorders such as relapsing–remitting multiple sclerosis,
autoimmune neuropathies, neuromyelitis optica, paraneoplastic neurological
disorders, stiff-person syndrome, myasthenia gravis and inflammatory myopathies
Circulating B cells, but not the antibody-producing plasma cells that do not
express CD20, become undetec Table
1 month after rituximab treatment, and levels remain low for at least 6
Despite B-cell depletion, patients do not seem to be prone to common
infections after rituximab treatment
Experience in conditions such as
vasculitis and rheumatoid arthritis indicates that rituximab can be used in
combination with other immunosuppressants
- Hasler P and Zouali M (2006) B lymphocytes as therapeutic targets in systemic lupus erythematosus. Expert Opin Ther Targets 10: 803–815 Article PubMed ChemPort
- Shlomchik MJ et al. (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 1: 147–153 Article PubMed ChemPort
- Dalakas MC (2008) Invited article: inhibition of B cell functions: implications for neurology. Neurology 70: 2252–2260 Article PubMed ChemPort
- Browning JL (2006) B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5: 564–576 Article PubMed ChemPort
- Goldsby RA et al. (2000) Kuby Immunology, edn 4. New York: WH Freeman and Company
- Martin F and Chan AC (2006) B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 24: 467–496 Article PubMed ISI ChemPort
- Yurasov S et al. (2005) Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med 201: 703–711 Article PubMed ISI ChemPort
- Chan OT et al. (1999) A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 189: 1639–1648 Article PubMed ISI ChemPort
- Lanzavecchia A (1990) Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu Rev Immunol 8: 773–793 PubMed ISI ChemPort
- Lund FE et al. (2005) Regulatory roles for cytokine-producing B cells in infection and autoimmune disease. Curr Dir Autoimmun 8: 25–54 PubMed ChemPort
- Duddy ME et al. (2004) Distinct profiles of human B cell effector cytokines: a role in immune regulation. J Immunol 172: 3422–3427 PubMed ISI ChemPort
- Knopf PM et al. (1998) Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells. J Immunol 161: 692–701 PubMed ISI ChemPort
- Alter A et al. (2003) Determinants of human B cell migration across brain endothelial cells. J Immunol 170: 4497–4505 PubMed ISI ChemPort
- Meinl E et al. (2006) B lineage cells in the inflammatory central nervous system environment; migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol 59: 880–892 Article PubMed ChemPort
- Ritchie AM et al. (2004) Comparative analysis of the CD19+ and CD138+ cell antibody repertoires in the cerebrospinal fluid of patients with multiple sclerosis. J Immunol 173: 649–656 PubMed ChemPort
- Serafini B et al. (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14: 164–174 PubMed ISI
- Magliozzi R et al. (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130: 1089–1104 Article PubMed ISI
- Dillon SR et al. (2006) An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 5: 235–246 Article PubMed ISI ChemPort
- Peter HH and Warnatz K (2005) Molecules involved in T–B co-stimulation and B cell homeostasis: possible targets for an immunological intervention in autoimmunity. Expert Opin Biol Ther 5 (Suppl 1): S61–S71 Article
- Thangarajh M et al. (2005) Increased levels of APRIL (a proliferation-inducing ligand) mRNA in multiple sclerosis. J Neuroimmunol 167: 210–214 Article PubMed ISI ChemPort
- Krumbholz M et al. (2005) BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 201: 195–200 Article PubMed ISI ChemPort
- Thangarajh M et al. (2007) A proliferation-inducing ligand (APRIL) is expressed by astrocytes and is increased in multiple sclerosis. Scand J Immunol 65: 92–98 Article PubMed ChemPort
- Kalled SL (2006) Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production. Semin Immunol 18: 290–296 Article PubMed ChemPort
- Stohl W (2004) Targeting B lymphocyte stimulator in systemic lupus erythematosus and other autoimmune rheumatic disorders. Expert Opin Ther Targets 8: 177–189 Article PubMed ISI ChemPort
- Huntington ND et al. (2006) A BAFF antagonist suppresses experimental autoimmune encephalomyelitis by targeting cell-mediated and humoral immune responses. Int Immunol 18: 1473–1485 Article PubMed ChemPort
- Eisenberg R and Albert D (2006) B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus. Nat Clin Pract Rheumatol 2: 20–27 Article PubMed ChemPort
- Edwards JC and Cambridge G (2005) Prospects for B-cell-targeted therapy in autoimmune disease. Rheumatology (Oxford) 44: 151–156 Article PubMed ChemPort
- Lucchinetti C et al. (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47: 707–717 Article PubMed ISI ChemPort
- Frohman EM et al. (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354: 942–955 Article PubMed ChemPort
- Cepok S et al. (2005) Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128: 1667–1676 Article PubMed ISI
- Genain CP et al. (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5: 170–175 Article PubMed ISI ChemPort
- Monson NL et al. (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62: 258–264 Article PubMed ISI
- Hauser S et al. (2008) B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med 358: 676–688 Article PubMed ChemPort
- Bar-Or A et al. (2008) Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 63: 395–400 Article PubMed ChemPort
- Jarius S et al. (2008) Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol 4: 202–214 PubMed ChemPort
- Cree BA and Wingerchuk DM (2005) Acute transverse myelitis: is the "idiopathic" form vanishing. Neurology 65: 1857–1858 Article PubMed
- Jacob A et al. (2007) Retrospective analysis of rituximab treatment of 24 patients with neuromyelitis optica [abstract #S32.002]. Neurology 68 (Suppl 1): A206 Article
- Genain C et al. (2007) An open label clinical trial of rituximab in neuromyelitis optica [abstract #S32.001]. Neurology 68 (Suppl 1): A205 Article
- Pranzatelli MR et al. (2004) B- and T-cell markers in opsoclonus–myoclonus syndrome: immunophenotyping of CSF lymphocytes. Neurology 62: 1526–1532 PubMed ChemPort
- Pranzatelli MR et al. (2006) Rituximab (anti-CD20) adjunctive therapy for opsoclonus–myoclonus syndrome. J Pediatr Hematol Oncol 28: 585–593 Article PubMed ChemPort
- Dalakas M and Engel WK (1980) Immunoglobulin and complement deposits in nerves of patients with chronic relapsing polyneuropathy. Arch Neurol 37: 637–640 PubMed ChemPort
- Hays AP et al. (1988) Immune reactive C3d on the surface of myelin sheaths in neuropathy. J Neuroimmunol 18: 231–244 Article PubMed ChemPort
- Pestronk A et al. (2003) Treatment of IgM antibody associated polyneuropathies using rituximab. J Neurol Neurosurg Psychiatry 74: 485–489 Article PubMed ChemPort
- Ruegg SJ et al. (2004) Rituximab stabilizes multifocal motor neuropathy increasingly less responsive to IVIg. Neurology 63: 2178–2179 PubMed
- Levine TD and Pestronk A (1999) IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using rituximab. Neurology 52: 1701–1704 PubMed ISI ChemPort
- Renaud S et al. (2003) Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies. Muscle Nerve 27: 611–615 Article PubMed ChemPort
- Dalakas MC et al. (2007) A double-blind placebo-controlled study of rituximab in patients with anti-MAG antibody-demyelinating polyneuropathy (A-MAG-DP) [abstract #S38.001]. Neurology 68 (Suppl 1): A214 Article
- Raju R et al. (2006) Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 129: 3270–3276 Article PubMed
- Dalakas MC et al. (2001) Stiff-person syndrome: quantification, specificity and intrathecal synthesis of GAD65 antibodies. Neurology 57: 780–785 PubMed ChemPort
- Baker MR et al. (2005) Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry 76: 999–1001 Article PubMed ChemPort
- Dalakas MC and Hohlfeld R (2003) Polymyositis and dermatomyositis. Lancet 362: 971–982 Article PubMed ISI ChemPort
- Noss EH et al. (2006) Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol 33: 1021–1026 PubMed
- Levine TD (2005) Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum 52: 601–607 Article PubMed ISI ChemPort
- Wylam ME et al. (2003) Successful treatment of refractory myasthenia gravis using rituximab: a pediatric case report. J Pediatr 143: 674–677 Article PubMed
- Illa I et al. (2008) Rituximab in refractory myasthenia gravis: a follow-up study of patients with anti-AChR or anti-MuSK antibodies [abstract #P06.001]. Neurology 70 (Suppl 1): A301
- Tandam R et al. (2008) Pilot trial of rituximab in myasthenia gravis [abstract #P06.002]. Neurology 70 (Suppl 1): A301
- Frenay CL et al. (2008) Rituximab for treatment of refractory myasthenia gravis [abstract #S57.003]. Neurology 70 (Suppl 1): A427
- Leandro MJ et al. (2006) Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54: 613–620 Article PubMed ISI ChemPort
- Dorner T (2006) Crossroads of B cell activation in autoimmunity: rationale of targeting B cells. J Rheumatol Suppl 77: 3–11 PubMed
- Pescovitz MD (2006) Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 6: 859–866. Article PubMed ChemPort
- Amanna IJ et al. (2007) Duration of humoral immunity to common viral and vaccine antigens. N Engl J Med 357: 1903–1915 Article PubMed ChemPort
- Keogh KA et al. (2005) Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52: 262–268 Article PubMed ISI
- Kleinschmidt-DeMasters BK and Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353: 369–374 Article PubMed ISI ChemPort
- FDA Public Health Advisory (2006) Life-threatening brain infection in patients with systemic lupus erythematosus after Rituxan (rituximab) treatment. [http://www.fda.gov/cder/drug/advisory/rituximab.htm]
Reference: Marinos C Dalakas. Nature Clinical Practice Neurology (2008) 4, 557-567doi:10.1038/ncpneuro0901