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 White, Benjamin M. Greenberg, Patrick Waters, Lindsay G. Cowell, Ann M. Stowe, Nancy L. Monson

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-18
Number of pages18
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Oct 11 2016

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Keywords

  • Antigen receptor genetics
  • Autoantibody
  • B cell
  • Multiple sclerosis
  • Plasmablast

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Rivas, J. R., Ireland, S. J., Chkheidze, R., Rounds, W. H., Lim, J., Johnson, J., Ramirez, D. M. O., Ligocki, A. J., Chen, D., Guzman, A. A., Woodhall, M., Wilson, P. C., Meffre, E., White, C., Greenberg, B. M., Waters, P., Cowell, L. G., Stowe, A. M., & Monson, N. L. (Accepted/In press). Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathologica, 1-18. https://doi.org/10.1007/s00401-016-1627-0