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 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.
Nat Clin Pract Neurol. 2008;4(10):557-567. © 2008 Nature Publishing Group
Cite this: B Cells As Therapeutic Targets In Autoimmune Neurological Disorders - Medscape - Oct 01, 2008.