Acta Neuropathologica

, Volume 130, Issue 6, pp 765–781

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

  • Kevin Blauth
  • John Soltys
  • Adeline Matschulat
  • Cory R. Reiter
  • Alanna Ritchie
  • Nicholas L. Baird
  • Jeffrey L. Bennett
  • Gregory P. Owens
Original Paper

DOI: 10.1007/s00401-015-1500-6

Cite this article as:
Blauth, K., Soltys, J., Matschulat, A. et al. Acta Neuropathol (2015) 130: 765. doi:10.1007/s00401-015-1500-6

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

Multiple sclerosis Monoclonal antibody Demyelination Autoimmunity Neuroimmunology Spinal cord slice cultures 

Supplementary material

401_2015_1500_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOCX 21 kb)
401_2015_1500_MOESM2_ESM.jpg (89 kb)
Supplemental Fig. 1. Superbiochip array slides were deparaffinized and immunostained as described in the methods section. rAb immunostaining is in green, DAPI is in blue. Scale bar = 100 µm. (a) MS04-2 # 30 peripheral reactivity was punctate and often associated with epithelia. (b) MS05-3 # 38 peripheral reactivity was punctate in esophagus and pancreas but more ubiquitously expressed in ileum and skin. (c) IC05-2 # 2 reactivity was largely absent in the periphery (JPEG 89 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2015

Authors and Affiliations

  • Kevin Blauth
    • 1
  • John Soltys
    • 1
    • 2
  • Adeline Matschulat
    • 1
  • Cory R. Reiter
    • 1
  • Alanna Ritchie
    • 1
  • Nicholas L. Baird
    • 1
  • Jeffrey L. Bennett
    • 1
    • 2
    • 3
  • Gregory P. Owens
    • 1
  1. 1.Department of NeurologyUniversity of Colorado DenverAuroraUSA
  2. 2.Neuroscience ProgramUniversity of Colorado DenverAuroraUSA
  3. 3.Department of OphthalmologyUniversity of Colorado DenverAuroraUSA