Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody

Charles L. Howe; Allan J. Bieber; Arthur E. Warrington; Larry R. Pease; Moses Rodriguez

doi:10.1016/j.nbd.2003.09.002

Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody

Charles L. Howe, Allan J. Bieber, Arthur E. Warrington, Larry R. Pease, Moses Rodriguez

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	120-131
Number of pages	12
Journal	Neurobiology of Disease
Volume	15
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2003.09.002
State	Published - Feb 2004

Keywords

Apoptosis
Autoantibody
Demyelinating disease
Glia
Multiple sclerosis
Myelin

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2003.09.002

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title = "Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody",

abstract = "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.",

keywords = "Apoptosis, Autoantibody, Demyelinating disease, Glia, Multiple sclerosis, Myelin",

author = "Howe, {Charles L.} and Bieber, {Allan J.} and Warrington, {Arthur E.} and Pease, {Larry R.} and Moses Rodriguez",

note = "Funding Information: This work was supported by National Multiple Sclerosis Society grants PP0893 (CLH) and RG 3172-A-6 (MR), National Institutes of Health grants NS24180, NS32129, NS40209, and HD07447-10R, as well as by the generous support of Mr. and Mrs. Eugene Applebaum and Ms. Kathryn Peterson.",

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doi = "10.1016/j.nbd.2003.09.002",

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AU - Rodriguez, Moses

N1 - Funding Information: This work was supported by National Multiple Sclerosis Society grants PP0893 (CLH) and RG 3172-A-6 (MR), National Institutes of Health grants NS24180, NS32129, NS40209, and HD07447-10R, as well as by the generous support of Mr. and Mrs. Eugene Applebaum and Ms. Kathryn Peterson.

PY - 2004/2

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N2 - 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.

AB - 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.

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Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody

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Keywords

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