B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas

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

Anti-B-cell Therapy in Neurology: Present and Future

The evidence that B cells have a role in autoimmune neurological disorders is summarized in Box 1 . 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.

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-β receptor disrupts the architecture in the ectopic germinal centers.

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Figure 4.

Monoclonal antibodies or fusion proteins against B-cell targets. The figure highlights several B-cell molecules and their receptors, which are targeted by nine different monoclonal antibodies or fusion proteins currently in phase I-III clinical trials. Abbreviations: APRIL = a proliferation-inducing ligand; BAFF = B-cell-activating factor; BAFF-R = B-cell-activating factor receptor; BCMA = B-cell-maturation antigen; CTLA4 = cytotoxic T-lymphocyte antigen 4; LTβR = lymphotoxin-β receptor; LTβR-Ig = anti-lymphotoxin-β receptor antibody; MHC-II = major histocompatibility complex class II; TACI = transmembrane activator and calcium modulator and cyclophilin ligand interactor; TCR = T-cell receptor.

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]}

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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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B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Anti-B-cell Therapy in Neurology: Present and Future

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References

Authors and Disclosures

Authors and Disclosures

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Sidebar: Keypoints

Figure 4.

Figure 4.

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