B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas

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

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.

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Acknowledgments

The author thanks Dr R Raju for performing the B-cell counts in his patients treated with rituximab.

Reprint Address

Marinos C Dalakas, Director of Neuromuscular Division, Thomas Jefferson University, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA; E-mail: marinos.dalakas@jefferson.edu

Neuroinflammation and Neuromuscular Diseases Section, Imperial College London, Burlington Danes Building, Office E412, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; E-mail: m.dalakas@imperial.ac.uk

Cite this: B Cells As Therapeutic Targets In Autoimmune Neurological Disorders - Medscape - Oct 01, 2008.

Summary and Introduction
Roles of B Cells in the Immune Response: Neurological Aspects
B-cell Maturation and Homeostasis
Anti-B-cell Therapy in Neurology: Present and Future
Anti B-cell Agents in Neurology: The Role of Rituximab
Conclusions and Future Prospects
References
Sidebar: Keypoints

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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