Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody

• Published in: Neurobiology of disease Vol. 15; no. 1; pp. 120 - 131
• Main Authors: Howe, Charles L, Bieber, Allan J, Warrington, Arthur E, Pease, Larry R, Rodriguez, Moses
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2004; Elsevier
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; Animals; Antibodies - immunology; Antibodies - pharmacology; Antibodies - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Autoantibody; Calcium Channels - drug effects; Calcium Channels - metabolism; Cardiovirus Infections - drug therapy; Cardiovirus Infections - immunology; Caspase 3; Caspases - drug effects; Caspases - genetics; Caspases - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - immunology; Demyelinating disease; Glia; Humans; Hydrogen Peroxide - pharmacology; JNK Mitogen-Activated Protein Kinases; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Mice; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Myelin; Myelin Proteins - immunology; Myelin Sheath - drug effects; Myelin Sheath - immunology; Nerve Degeneration - drug therapy; Nerve Degeneration - immunology; Nerve Degeneration - pathology; Oligodendroglia - drug effects; Oligodendroglia - immunology; Rats; Signal Transduction - drug effects; Signal Transduction - immunology; Stem Cells - drug effects; Stem Cells - immunology; Tumor Necrosis Factor-alpha - pharmacology; Demyelinating disease; Autoantibody; Multiple sclerosis; Glia; Myelin; Apoptosis
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2003.09.002

Stabilizing the survival of oligodendrocytes and oligodendrocyte precursors within and near lesions in patients suffering from multiple sclerosis (MS) and other demyelinating diseases is an important therapeutic goal. Previous studies have identified a human-derived monoclonal IgM antibody designated rHIgM22 that induces remyelination in a mouse model of MS. We provide evidence that this antibody, directed against myelin, induces antiapoptotic signaling in premyelinating oligodendrocytes and reduces caspase-3 activation and caspase gene expression in mice undergoing antibody-induced remyelination. This effect was dependent on calcium entry via CNQX-sensitive channels and on lipid raft integrity, and was correlated with suppression of JNK signaling. We conclude that rHIgM22 may induce remyelination via rescue of oligodendrocytes, and suggest that such autoantibody-mediated signaling may have important therapeutic implications for a variety of neurological diseases, including stroke and Alzheimer's disease.