Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody.
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.
Howe
Charles L
CL
Department of Neurology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. howe.charles@mayo.edu
Bieber
Allan J
AJ
Warrington
Arthur E
AE
Pease
Larry R
LR
Rodriguez
Moses
M
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D018188:Cardiovirus Infections / Q000188:drug therapy / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009185:Myelin Proteins / Q000276:immunology; D009186:Myelin Sheath / Q000187:drug effects / Q000276:immunology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000906:Antibodies; D015220:Calcium Channels; D009185:Myelin Proteins; D014409:Tumor Necrosis Factor-alpha; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases