B cells as therapeutic targets in autoimmune neurological disorders

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.     

Evolution of Anti-B Cell Therapeutics in Autoimmune Neurological Diseases

B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurological disorders, acting as antigen-presenting cells facilitating antibody production but also as sensors, coordinators, and regulators of the immune response. In particular, B cells can regulate the T cell activation process through their participation in antigen presentation, production of proinflammatory cytokines (bystander activation or suppression), and contribution to ectopic lymphoid aggregates. Such an important interplay between B and T cells makes therapeutic depletion of B cells an attractive treatment strategy. The last decade, anti-B cell therapies using monoclonal antibodies against B cell surface molecules have evolved into a rational approach for successfully treating autoimmune neurological disorders, even when T cells seem to be the main effector cells. The paper summarizes basic aspects of B cell biology, discusses the roles of B cells in neurological autoimmunities, and highlights how the currently available or under development anti-B cell therapeutics exert their action in the wide spectrum and immunologically diverse neurological disorders. The efficacy of the various anti-B cell therapies and practical issues on induction and maintenance therapy is specifically detailed for the treatment of patients with multiple sclerosis, neuromyelitis-spectrum disorders, autoimmune encephalitis and hyperexcitability CNS disorders, autoimmune neuropathies, myasthenia gravis, and inflammatory myopathies. The success of anti-B cell therapies in inducing long-term remission in IgG4 neuroautoimmunities is also highlighted pointing out potential biomarkers for follow-up infusions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01196-w.     

The natural history of B cells

Multiple sclerosis is a common neurological disorder that represents a significant source of disability. B cells have recently emerged as a novel therapeutic target for multiple sclerosis. The natural development of B cells is characterized by an antigen-independent phase that occurs in the bone marrow and an antigen-dependent phase that takes place in the peripheral lymphoid tissue. The stage of B-cell development can be identified by the presence of specific cell surface markers. Checkpoints are in place to prevent self-reactive B cells from further development and activation. Some self-reactive B cells are able to escape these checkpoints, resulting in a loss of tolerance. B cells may contribute to systemic autoimmunity and the development of autoimmune disease via cytokine production, antigen presentation, and complement activation. In addition, B cells may trigger autoimmune disease via molecular mimicry, which occurs when a single B-cell receptor recognizes both a non-self antigen molecule and a self-molecule. Accumulating data suggest that ectopic proliferation of B cells in the central nervous system may also play a role. Further research is needed to elucidate the pathology of B cells and their role in central nervous system autoimmune diseases, including multiple sclerosis.     

B-cell-targeted treatment for multiple sclerosis: mechanism of action and clinical data

Strategies for treating autoimmune disorders are increasingly employing targeted therapies rather than non-specific, multitargeted treatments. Accumulating evidence on the involvement of B lymphocytes in the pathophysiology of autoimmune demyelinating disease has led to a renewed interest in B cells as potential therapeutic targets. In particular, antigen presentation between B cells and T cells, increased trafficking of B cells across the blood-brain barrier, and autoantibodies produced by plasma cells may contribute to the pathophysiology of autoimmune disorders such as multiple sclerosis. Several B-cell-targeted, depletion therapies are currently in development, including rituximab, epratuzumab, diphtheria toxin-single chain Fv (DC2219), belimumab, atacicept, abatacept, and abetimus sodium. Of these agents, only rituximab and abatacept have been evaluated in multiple sclerosis patients. Preliminary results of a phase II trial of rituximab in multiple sclerosis suggest that rituximab is well tolerated and significantly reduces the number of gadolinium enhancing lesions over 24 weeks of treatment. Results of an exploratory analysis suggest the potential promise of abatacept 10 mg/kg for multiple sclerosis. It is expected that future clinical trials will establish a role for B-cell-targeted therapies in the treatment of multiple sclerosis and other autoimmune neurological diseases. This article describes the mechanism of action behind B-cell-targeted depletion therapies in development and reviews available clinical data.     

Pathogenetic role of autoantibodies in neurological diseases

Autoreactive B cells and antibodies can be detected in a variety of neurological diseases. Their causative role has been established in some disorders and they are obviously involved in the pathogenesis of others. Some mechanisms engendering B-cell autoimmunity in animal models have been shown to operate in humans. Factors that determine B-cell immune-response patterns and the effector pathways have been identified. B-cell responses to CNS-restricted autoantigens are governed by distinctive immune reactions. Evidence has accumulated that the CNS is a permissive and, under inflammatory conditions, even a B-cell-supporting micro-environment. Data from human and animal experiments have enhanced our understanding of B-cell physiology in health and neurological disease, which has relevant diagnostic and therapeutic implications.     

Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody that depletes CD20(+) B cells, has demonstrated efficacy in peripheral neurological diseases. Whether this efficacy can be translated to neurological diseases of the central nervous system with possible autoimmune B-cell involvement remains unknown. OBJECTIVE: To determine the effect of rituximab on cerebrospinal fluid B cells in patients with multiple sclerosis. DESIGN: Four patients with primary progressive multiple sclerosis were treated with rituximab. Cerebrospinal fluid and peripheral blood B-cell subsets were identified by flow cytometry from each patient before and after rituximab treatment. RESULTS: The B cells in cerebrospinal fluid were not as effectively depleted as their peripheral blood counterparts. Rituximab treatment temporarily suppressed the activation state of B cells in cerebrospinal fluid. The residual B cells underwent expansion after rituximab treatment. CONCLUSION: The effect(s) of rituximab on the cerebrospinal fluid B-cell compartment is limited in comparison with the effect(s) on the B cells in the periphery, but this finding will need to be confirmed in a larger group of MS patients.     

Movement disorders of autoimmune origin

In recent years there has been renewed interest in the role of autoimmunity in many neurological disorders such as multiple sclerosis and neurodegenerative diseases. Research advances in this field have led to the discovery of new potential therapeutic strategies. There are, however, only a few neurological disorders in which an autoimmune origin has been adequately documented and definitely confirmed. The most important neurological diseases causing movement disorders in which an autoimmune basis has been demonstrated are summarized in this review. The possible role of immunity with the most frequent movement disorders such as parkinsonism or dystonia is also commented. Received: 22 July 1998 Accepted: 17 August 1998     

Cerebrospinal fluid CD19+ B‐cell expansion in N‐methyl‐D‐aspartate receptor encephalitis

There is increasing interest in the role of autoantibodies in acquired autoimmune central nervous system disorders. N‐methyl‐d ‐aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis defined by the presence of autoantibodies that bind to the NMDAR. Although there is evidence of NMDAR antibody pathogenicity, it is unclear which treatment results in the best outcome. We measured the proportion of B‐cells in the cerebrospinal fluid of two children with NMDAR encephalitis (a 6‐year‐old male and a 4‐year‐old female), one in the acute phase and one in the relapsing phase. The proportion of CD19⁺ B‐cells in both children was greater than 10%, significantly higher than seen in non‐inflammatory neurological disorders (<1%). This finding supports the use of drugs, such as rituximab, that deplete B‐cells in severe or refractory cases of NMDAR encephalitis, and lends further support to the humoral autoimmune hypothesis in NMDAR encephalitis.     

B-cell depletion abrogates T cell-mediated demyelination in an antibody-nondependent common marmoset experimental autoimmune encephalomyelitis model

CD20-positive B-cell depletion is a highly promising treatment for multiple sclerosis (MS), but the mechanisms underlying therapeutic effects are poorly understood. B cells are thought to contribute to MS pathogenesis by producing autoantibodies that amplify demyelination via opsonization of myelin. To analyze autoantibody-nondependent functions of B cells in an animal model of MS, we used a novel T cell-driven experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys (Callithrix jacchus). In this model, demyelination of brain and spinal cord white and gray matter and the ensuing neurological deficits are induced by immunization with peptide 34 to 56 of myelin/oligodendrocyte glycoprotein (MOG34-56) in incomplete Freund's adjuvant. Although autoantibodies do not have a detectable pathogeniccontribution in the model, depletion of B cells with monoclonal antibody 7D8, a human IgG1κ monoclonal antibody against human CD20, suppressed clinical and pathological EAE. In B cell-depleted monkeys, the activation of peptide-specific Th17-producing and cytotoxic T cells, which in previous studies were found to play an essential role in disease induction, was impaired. Thus, we demonstrate a critical antibody-nondependent role for B cells in EAE, that is, the activation of pathogenic T cells.     

Treating autoimmune demyelination by augmenting lymphocyte apoptosis in the central nervous system

The elimination of autoreactive T cells from the central nervous system (CNS) by apoptosis plays an important role in switching off autoimmune attack. B-cell apoptosis in the CNS probably also has a key role in downregulating autoimmunity. Augmenting lymphocyte apoptosis in the CNS is a potential strategy for treating autoimmune CNS diseases such as multiple sclerosis. These strategies involve modulation of the physiological pro-apoptotic and anti-apoptotic pathways that control lymphocyte fate in the CNS. In the case of T cells, apoptosis can be augmented by enhancing activation-induced T-cell apoptosis through the CD95 (Fas) pathway and by inhibiting costimulation-induced anti-apoptotic pathways mediated through BCL-2 and BCL-X L.     

Invited article: inhibition of B cell functions: implications for neurology

B cells are involved in the pathophysiology of many neurologic diseases, either in a causative or contributory role, via production of autoantibodies, cytokine secretion, or by acting as antigen-presenting cells leading to T cell activation. B cells are clonally expanded in various CNS disorders, such as multiple sclerosis (MS), paraneoplastic CNS disorders, or stiff-person syndrome, and are activated to produce pathogenic autoantibodies in demyelinating neuropathies and myasthenia. B cell activating factor (BAFF) and a proliferating inducing ligand (APRIL), key cytokines for B cell survival, are strongly unregulated in MS brain and in muscles of inflammatory myopathies. Modulation of B cell functions using a series of monoclonal antibodies against CD20+ B cells or the molecules that increase B cell survival, such as BAFF/APRIL and their receptors BAFF-R, TACI, and BCMA, provide a rational approach to the treatment of the aforementioned neurologic disorders. In controlled studies, rituximab, a B cell-depleting monoclonal antibody, has been encouraging in MS and paraproteinemic anti-MAG demyelinating neuropathy, exerting long-lasting remissions. In uncontrolled series, benefit has been reported in several disorders. B cell depletion is a well-tolerated therapeutic option currently explored in the treatment of several autoimmune neurologic disorders.     

Autoantibodies against heterogeneous nuclear ribonucleoprotein B1 in CSF of MS patients

Heterogeneous nuclear ribonucleoproteins (hnRNPs) play an important role as the autoantigens in certain autoimmune disorders including neurological diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis and paraneoplastic neurological syndromes. To clarify their implication in multiple sclerosis (MS), we assayed antibodies (Abs) against hnRNP A and B proteins in sera and cerebrospinal fluid (CSF) of MS patients and compared the results with 25 patients with other neurological diseases (ONDs). Using recombinant hnRNP A1, A2, and B1 proteins and Western blotting for the assay, we found Abs against hnRNP B1 in CSF from 32 of 35 MS patients (91.4%) but not in any sera or CSF of the 25 OND patients. Most notably, no Abs against hnRNP B1 were found in sera of all 22 MS patients examined. Although Abs against hnRNP A1 and A2 were concomitantly found in CSF reacting with B1, their incidence and immunoreactivity were lower or weaker than those of anti-hnRNP B1 Abs. There was no correlation between the reactivity of CSF with hnRNP B1 and CSF parameters-such as the number of the cells and the IgG level-or clinical parameters-such as duration of illness and disease activity. The selective generation of Abs against hnRNP B1 in CSF was shown to be highly specific for MS, which makes them a disease marker.     

Synthesis of anti-acetylcholine receptor antibodies by CD5- B cells from peripheral blood of myasthenia gravis patients

An increased frequency of CD5⁺ B cells (or, according to a new nomenclature, B 1 cells) has been detected in the peripheral blood of a proportion of patients with myasthenia gravis (MG), as in some other autoimmune diseases. To elucidate the pathogenic significance of this B-cell subset in myasthenia gravis, mononuclear cells from the peripheral blood of six MG patients were separated into T and B lymphocytes by a magnetic cell separation procedure employing superparamagnetic microbeads (MACS). Subsequently, the B-cell fraction was depleted of CD5⁺ B cells in a second separation. The resulting purified CD5^– B-cell fraction was cultured alone or with the addition of autologous T cells. Anti-acetylcholine receptor (AChR) synthesis by CD5^– B cells in cultures with T cells was significantly increased by pokeweed mitogen (176 ±130 fmol/ml per week/2 × 10⁵ B cells) compared with unfractionated cells (75 ± 101) or CD5^– B cells alone (19 ± 4). These results demonstrate that in MG anti-AChR are synthesized, at least in part, by CD5^– B cells which are dependent on T cells. Although this does not exclude the existence of AChR-specific CD5⁺ B cells, it provides evidence against a pivotal role of this B-cell subset in anti-AChR synthesis.     

The evidence for a role of B cells in multiple sclerosis

Understanding the pathogenesis of complex immunologic disorders such as multiple sclerosis (MS) is challenging. Abnormalities in many different cell types are observed in the immune system and CNS of patients with MS and the identification of the primary and secondary events is difficult. Recent studies suggest that the model of MS as a disorder mediated only by T cells is overly simplistic and propose an important role for B cells in the propagation of the disease. B-cell activation in the form of oligoclonal bands (OCB) production is the most consistent immunologic finding in patients with MS. Notably, markers of B-cell activation within the CSF of patients with MS predict conversion from clinically isolated syndrome to clinically definite MS and correlate with MRI activity, onset of relapses, and disability progression. In addition, the main genetic risk factor in MS is associated with OCB production, and environmental agents associated with MS susceptibility (vitamin D and the Epstein-Barr virus) influence B-cell proliferation and function. Finally, the only cell-specific treatments that are effective in patients with MS are monoclonal antibodies targeting the B-cell antigen CD20, suggesting a potentially causative role for B cells. Based on current evidence there is no longer doubt that B cells are relevant to the etiology and pathogenesis of MS. Elucidating the role of B cells in MS will be a fruitful strategy for disease prevention and treatment.     

The role of IL-15 in central nervous system disorders

IL-15 is a proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, dendritic cells, and activated glial cells. It promotes T-cell proliferation, induction of cytolytic effector cells including natural killer and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. Little information is available on the exact role of IL-15 in the neurological diseases. Microglial cells are the main regulators of both innate and adaptive immune responses in the central nervous system (CNS). IL-15 may be involved in the inflammatory reactions and microglial activation of some common CNS disorders such as multiple sclerosis, Alzheimer's and Parkinson's disease, but its exact role in their pathogenesis is not clear.     

Hashimoto's encephalopathy with selective involvement of the nucleus accumbens: a case report

Hashimoto's encephalopathy (HE) is an acute or subacute relapsing disorder usually affecting euthyroid patients with evidence of autoimmune thyroiditis. The neurological manifestations are non-specific, with subacute cognitive impairment, movement disorders, generalized seizures, focal neurological symptoms such as stroke-like episodes, or psychiatric disturbances. Autoimmune phenomena are likely to play an etiological role. Magnetic resonance imaging (MRI) findings are usually normal or show non-specific changes. We report the case of an 11-year-old girl with autoimmune thyroiditis who presented acutely with a complex neuropsychiatric disorder in association with MRI evidence of focal involvement of the nucleus accumbens (NA). The NA, a ventral striate nucleus, is part of a complex dopaminergic network. Lesions to the NA result in several psychiatric symptoms, such as attention-deficit hyperactivity disorders. In this patient, we observed alternating phases of stupor and hyperkinetic-anxious behavior, with marked instability. The pathogenetic mechanism and the anatomic and functional correlations are briefly discussed.     

New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer's disease: cathepsin inhibitors as potential therapeutics

Endolysosomal proteases such as cysteinyl and aspartyl cathepsins play diverse roles in inflammatory autoimmune diseases, cancers, and neurodegenerative diseases. Cysteinyl cathepsin B and aspartyl cathepsin D levels are markedly elevated in a variety of neurological disorders including Alzheimer's disease (AD), a leading cause of dementia in the elderly. Studies have also shown an increased cathepsin activity in AD patients where senile plaques and neuronal loss are marked features of the disease. Senile plaques contain amyloid-beta (Abeta) peptide, which is produced by proteolytic cleavage of the amyloid precursor protein (APP) by the proteases. In this article, we present the current knowledge of cysteinyl and aspartyl cathepsins in cellular and molecular events that lead to formation of senile plaques in AD. This article also focused on the role of cathepsin inhibitors as disease-modifying treatment strategies that could halt, or even prevent, this devastating neurological disorder.     

Immunotherapies for Neurological Manifestations in the Context of Systemic Autoimmunity

Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example anti-tumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients.     

Potassium channels, memory T cells, and multiple sclerosis.

Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system characterized by demyelination and axonal damage that result in disabling neurological deficits. Here the authors explain the rationale for the use of inhibitors of the Kv1.3 K+ channel in immune cells as a therapy for multiple sclerosis and other autoimmune disorders.