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

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA

    Jacqueline R. Rivas, Sara J. Ireland, William H. Rounds, Joseph Lim, Jordan Johnson, Denise M. O. Ramirez, Ann J. Ligocki, Ding Chen, Alyssa A. Guzman, Benjamin M. Greenberg, Ann M. Stowe & Nancy L. Monson

  2. Department of Pathology, UT Southwestern, Dallas, TX, USA

    Rati Chkheidze & Charles White III

  3. Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Mark Woodhall & Patrick Waters

  4. Department of Biomedical Sciences, University of Chicago, Chicago, IL, USA

    Patrick C. Wilson

  5. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Eric Meffre

  6. Department of Clinical Science, UT Southwestern, Dallas, TX, USA

    Lindsay G. Cowell

  7. Department of Immunology, UT Southwestern, Dallas, TX, USA

    Nancy L. Monson

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  1. Jacqueline R. Rivas
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Correspondence to Nancy L. Monson.

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Conflict of interest

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

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Rivas, J.R., Ireland, S.J., Chkheidze, R. et al. Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathol 133, 43–60 (2017). https://doi.org/10.1007/s00401-016-1627-0

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  • DOI: https://doi.org/10.1007/s00401-016-1627-0

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