Original Article

Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid†

  1. Gregory P. Owens PhD1,‡,
  2. Jeffrey L. Bennett MD, PhD1,2,‡,
  3. Hans Lassmann MD3,
  4. Kevin C. O'Connor PhD4,
  5. Alanna M. Ritchie BS1,
  6. Andrew Shearer BS1,
  7. Chiwah Lam BS1,
  8. Xiaoli Yu PhD1,
  9. Marius Birlea MD1,
  10. Cecily DuPree MS1,
  11. R. Anthony Williamson PhD5,
  12. David A. Hafler MD4,
  13. Mark P. Burgoon PhD1,
  14. Don Gilden MD1,6,*

Article first published online: 19 MAR 2009

DOI: 10.1002/ana.21641

Issue

Annals of Neurology

Annals of Neurology

Volume 65, Issue 6, pages 639–649, June 2009

Additional Information

How to Cite

Owens, G. P., Bennett, J. L., Lassmann, H., O'Connor, K. C., Ritchie, A. M., Shearer, A., Lam, C., Yu, X., Birlea, M., DuPree, C., Williamson, R. A., Hafler, D. A., Burgoon, M. P. and Gilden, D. (2009), Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Annals of Neurology, 65: 639–649. doi: 10.1002/ana.21641

Author Information

  1. 1

    Department of Neurology, University of Colorado Denver School of Medicine, Denver, CO

  2. 2

    Department of Ophthalmology, University of Colorado Denver School of Medicine, Denver, CO

  3. 3

    Center for Brain Research, Medical University of Vienna, Vienna, Austria

  4. 4

    Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

  5. 5

    Calmune Corporation, San Diego, CA

  6. 6

    Department of Microbiology, University of Colorado Denver School of Medicine, Denver, CO

  1. ‡

    Gregory Owens and Jeffrey Bennett contributed equally to this work.

*Department of Neurology, University of Colorado Denver School of Medicine, 12700 East 19th Avenue, Mail Stop B182, Aurora, CO 80045

  1. †

    Potential conflict of interest: Nothing to report.

Publication History

  1. Issue published online: 25 JUN 2009
  2. Article first published online: 19 MAR 2009
  3. Accepted manuscript online: 19 MAR 2009 12:00AM EST
  4. Manuscript Accepted: 9 JAN 2009
  5. Manuscript Revised: 19 DEC 2008
  6. Manuscript Received: 27 OCT 2008

Funded by

  • Public Health Service. Grant Numbers: NS32623, EY014573, NS041549
  • National Multiple Sclerosis Society. Grant Number: RG3908

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Abstract

Objective

Intrathecal IgG synthesis, persistence of bands of oligoclonal IgG, and memory B-cell clonal expansion are well-characterized features of the humoral response in multiple sclerosis (MS). Nevertheless, the target antigen of this response remains enigmatic.

Methods

We produced 53 different human IgG1 monoclonal recombinant antibodies (rAbs) by coexpressing paired heavy- and light-chain variable region sequences of 51 plasma cell clones and 2 B-lymphocyte clones from MS cerebrospinal fluid in human tissue culture cells. Chimeric control rAbs were generated from anti-myelin hybridomas in which murine variable region sequences were fused to human constant region sequences. Purified rAbs were exhaustively assayed for reactivity against myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein by immunostaining of transfected cells expressing individual myelin proteins, by protein immunoblotting, and by immunostaining of human brain tissue sections.

Results

Whereas humanized control rAbs derived from anti-myelin hybridomas and anti-myelin monoclonal antibodies readily detected myelin antigens in multiple immunoassays, none of the rAbs derived from MS cerebrospinal fluid displayed immunoreactivity to the three myelin antigens tested. Immunocytochemical analysis of tissue sections from MS and control brain demonstrated only weak staining with a few rAbs against nuclei or cytoplasmic granules in neurons, glia, and inflammatory cells.

Interpretation

The oligoclonal B-cell response in MS cerebrospinal fluid is not targeted to the well-characterized myelin antigens myelin basic protein, proteolipid protein, or myelin oligodendrocyte glycoprotein. Ann Neurol 2009;65:639–649

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