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Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination
Yiting Liu1, Katherine S Given2, Danielle E Harlow2
1Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Acta Neuropathologica Communications
|March 26, 2017
Summary
Myelin-specific antibodies found in cerebrospinal fluid of multiple sclerosis (MS) patients cause oligodendrocyte damage and demyelination via complement activation, distinct from NMO pathology. These findings suggest a role for these antibodies in MS lesion formation.
Area of Science:
- Neuroimmunology
- Pathology of Demyelinating Diseases
Background:
- Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands, and lesional IgG deposition are key features of multiple sclerosis (MS).
- The specific targets and pathogenic roles of antibodies in MS are not well understood.
Purpose of the Study:
- To characterize the targets and pathogenic effects of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF.
- To investigate the role of myelin-specific MS rAbs in demyelination and tissue injury using organotypic cerebellar slices.
Main Methods:
- Produced IgG1 monoclonal recombinant antibodies (rAbs) from MS patient CSF.
- Assessed rAb binding to mouse organotypic cerebellar slices and evaluated tissue injury (demyelination, glial/neuronal viability, complement activation) using immunofluorescence microscopy.
- Compared MS rAb effects to an aquaporin-4 (AQP4)-specific rAb from a neuromyelitis optica (NMO) patient.
Main Results:
- MS myelin-specific rAbs bound to oligodendrocyte processes and myelinating axons.
- These MS rAbs induced complement-dependent oligodendrocyte damage and rapid demyelination, with increased microglia activation but unaffected astrocytes, oligodendrocyte progenitors, and neurons.
- In contrast, the NMO AQP4-specific rAb caused astrocyte damage, followed by oligodendrocyte loss, demyelination, microglia activation, and neuronal death.
Conclusions:
- Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in a manner distinct from AQP4-targeted pathology.
- These findings indicate that myelin-specific antibodies play a significant role in the formation of active MS lesions through complement-dependent mechanisms.
