Acta Neuropathologica

, Volume 133, Issue 1, pp 43–60 | Cite as

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients

  • Jacqueline R. Rivas
  • Sara J. Ireland
  • Rati Chkheidze
  • William H. Rounds
  • Joseph Lim
  • Jordan Johnson
  • Denise M. O. Ramirez
  • Ann J. Ligocki
  • Ding Chen
  • Alyssa A. Guzman
  • Mark Woodhall
  • Patrick C. Wilson
  • Eric Meffre
  • Charles WhiteIII
  • Benjamin M. Greenberg
  • Patrick Waters
  • Lindsay G. Cowell
  • Ann M. Stowe
  • Nancy L. MonsonEmail author
Original Paper


Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.


Plasmablast Multiple sclerosis Autoantibody B cell Antigen receptor genetics 



The authors would like to thank the patients and healthy donors who gave samples for this study. This project was funded by the UT Southwestern CONQUER program and a grant from the National MS Society. Angela Mobley assisted with flow cytometry and sorting and Genevieve Konopka provided the SH-Sy5y cells. Betty Diamond at the Hofstra Northwell School of Medicine Department of Molecular Medicine provided the lupus control antibodies. We also thank E. Sally Ward at Texas A&M University for helpful discussion of this manuscript.

Compliance with ethical standards

Conflict of interest

Nancy Monson reports patent US 8,394,583 B2 on MSPrecise™, a diagnostic tool for predicting conversion to MS.

Supplementary material

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Supplementary material 1 (DOCX 34 kb)
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Supplementary material 2 (PDF 43866 kb)
401_2016_1627_MOESM3_ESM.pptx (93 kb)
Supplementary material 3 (PPTX 92 kb)
401_2016_1627_MOESM4_ESM.docx (33 kb)
Supplementary material 4 (DOCX 33 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jacqueline R. Rivas
    • 1
  • Sara J. Ireland
    • 1
  • Rati Chkheidze
    • 2
  • William H. Rounds
    • 1
  • Joseph Lim
    • 1
  • Jordan Johnson
    • 1
  • Denise M. O. Ramirez
    • 1
  • Ann J. Ligocki
    • 1
  • Ding Chen
    • 1
  • Alyssa A. Guzman
    • 1
  • Mark Woodhall
    • 3
  • Patrick C. Wilson
    • 4
  • Eric Meffre
    • 5
  • Charles WhiteIII
    • 2
  • Benjamin M. Greenberg
    • 1
  • Patrick Waters
    • 3
  • Lindsay G. Cowell
    • 6
  • Ann M. Stowe
    • 1
  • Nancy L. Monson
    • 1
    • 7
    Email author
  1. 1.Department of Neurology and NeurotherapeuticsUT SouthwesternDallasUSA
  2. 2.Department of PathologyUT SouthwesternDallasUSA
  3. 3.Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
  4. 4.Department of Biomedical SciencesUniversity of ChicagoChicagoUSA
  5. 5.Department of ImmunobiologyYale University School of MedicineNew HavenUSA
  6. 6.Department of Clinical ScienceUT SouthwesternDallasUSA
  7. 7.Department of ImmunologyUT SouthwesternDallasUSA

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