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Acta Neuropathol. 2015 Dec;130(6):765-81. doi: 10.1007/s00401-015-1500-6. Epub 2015 Oct 28.

Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants.

Author information

1
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
2
Neuroscience Program, University of Colorado Denver, Aurora, CO, USA.
3
Department of Ophthalmology, University of Colorado Denver, Aurora, CO, USA.
4
Department of Neurology, University of Colorado Denver, Aurora, CO, USA. greg.owens@ucdenver.edu.

Abstract

B cells are implicated in the etiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.

KEYWORDS:

Autoimmunity; Demyelination; Monoclonal antibody; Multiple sclerosis; Neuroimmunology; Spinal cord slice cultures

PMID:
26511623
PMCID:
PMC4655138
DOI:
10.1007/s00401-015-1500-6
[Indexed for MEDLINE]
Free PMC Article
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