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Acta Neuropathol Commun. 2017 Mar 24;5(1):25. doi: 10.1186/s40478-017-0428-6.

Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination.

Author information

1
Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
2
Department of Cell and Developmental Biology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
3
Program in Neuroscience, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
4
Department of Ophthalmology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
5
Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA. greg.owens@ucdenver.edu.

Abstract

Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies remain poorly characterized. We produced IgG1 monoclonal recombinant antibodies (rAbs) from clonally-expanded plasmablasts recovered from MS patient CSF. Among these were a subset of myelin-specific MS rAbs. We examined their immunoreactivity to mouse organotypic cerebellar slices by live binding and evaluated tissue injury in the presence and absence of human complement. Demyelination, glial and neuronal viability, and complement pathway activation were assayed by immunofluorescence microscopy and compared to the effects of an aquaporin-4 water channel (AQP4)-specific rAb derived from a neuromyelitis optica (NMO) patient. MS myelin-specific rAbs bound to discrete surface domains on oligodendrocyte processes and myelinating axons. Myelin-specific MS rAbs initiated complement-dependent cytotoxicity to oligodendrocytes and induced rapid demyelination. Demyelination was accompanied by increased microglia activation; however, the morphology and survival of astrocytes, oligodendrocyte progenitors and neurons remained unaffected. In contrast, NMO AQP4-specific rAb initiated complement-dependent astrocyte damage, followed by sequential loss of oligodendrocytes, demyelination, microglia activation and neuronal death. Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in organotypic cerebellar slices, which are distinct from AQP4-targeted pathology, and display seminal features of active MS lesions. Myelin-specific antibodies may play an active role in MS lesion formation through complement-dependent mechanisms.

KEYWORDS:

Antibodies; Complement; Cytotoxicity; Demyelination; Myelin; Oligodendrocytes

PMID:
28340598
PMCID:
PMC5366134
DOI:
10.1186/s40478-017-0428-6
[Indexed for MEDLINE]
Free PMC Article

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