B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas

Nat Clin Pract Neurol. 2008;4(10):557-567.

Summary and Introduction

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 response^[1] 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.

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Table 1. B-cell Trophic Factors and Their Receptors in Autoimmune Neurological Disorders
B-cell trophic factor	Receptors	Functions of trophic factor	Evidence for roles in neurological disorders
BAFF	BAFF-R BCMA TACI	Promotes B-cell survival and differentiation, sustains germinal centers, and enhances immunoglobulin production Promotes lymphocyte maturation and immunoglobulin production Stimulates plasma cell survival and IgM production	Upregulated in the brain of patients with MS; produced by astocytes in vitro; BAFF mRNA and BAFF-R are upregulated in the brains of patients with MS; BAFF mRNA is increased in the muscles of patients with inclusion body myositis
APRIL	TACI BCMA	Stimulates plasma cell survival and IgM production	TACI mRNA is upregulated in the brain and monocytes of patients with MS; TACI is produced by astrocytes of patients with MS

Abbreviations: APRIL = a proliferation-inducing ligand; BAFF = B-cell-activating factor; BAFF-R = BAFF receptor; BCMA = B-cell-maturation antigen; MS = multiple sclerosis; TACI = transmembrane activator and calcium modulator cytophilin ligand interactor.

Box 1. 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 T-cell-dependent B-cell activation leads to production of pathologic autoantibodies in myasthenia gravis Several antibody-mediated neurological disorders have been successfully treated using plasmapheresis or intravenous immunoglobulin, which remove autoantibodies or modify the idiotypic repertoire New therapeutic monoclonal antibodies such as rituximab that deplete B cells can result in clinical improvement when used in certain CNS or PNS disorders

Table 1. B-cell Trophic Factors and Their Receptors in Autoimmune Neurological Disorders
B-cell trophic factor	Receptors	Functions of trophic factor	Evidence for roles in neurological disorders
BAFF	BAFF-R BCMA TACI	Promotes B-cell survival and differentiation, sustains germinal centers, and enhances immunoglobulin production Promotes lymphocyte maturation and immunoglobulin production Stimulates plasma cell survival and IgM production	Upregulated in the brain of patients with MS; produced by astocytes in vitro; BAFF mRNA and BAFF-R are upregulated in the brains of patients with MS; BAFF mRNA is increased in the muscles of patients with inclusion body myositis
APRIL	TACI BCMA	Stimulates plasma cell survival and IgM production	TACI mRNA is upregulated in the brain and monocytes of patients with MS; TACI is produced by astrocytes of patients with MS

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