EBV reprograms autoreactive B cells as antigen presenting cells in multiple sclerosis

Younis, S.; Rasouli, S.; Loeffler, J. W.; Sattarnezhad, N.; Courtney, Y.; Moutusy, S.; Jahanbani, S.; Pandit, M.; Tomczak, A.; Wong, H. H.; Sharpe, O.; Utz, P. J.; Meffre, E.; Kipp, L. B.; Dunn, J. E.; Lanz, T. V.; Steinman, L.; Robinson, W. H.

doi:10.64898/2026.02.11.701910

bioRxiv · 10.64898/2026.02.11.701910

EBV reprograms autoreactive B cells as antigen presenting cells in multiple sclerosis

Younis, S.·Rasouli, S.·Loeffler, J. W.·Sattarnezhad, N.·Courtney, Y.·Moutusy, S.·Jahanbani, S.·Pandit, M.·Tomczak, A.·Wong, H. H.·Sharpe, O.·Utz, P. J.·Meffre, E.·Kipp, L. B.·Dunn, J. E.·Lanz, T. V.·Steinman, L.·Robinson, W. H.

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Abstract

Summary paragraphMultiple sclerosis (MS) is a chronic autoimmune disease targeting the central nervous system (CNS). MS develops almost exclusively in individuals previously infected with Epstein-Barr virus (EBV)1, yet the mechanisms linking EBV infection to MS pathogenesis remain incompletely defined. Here we characterized EBV-infected B cells in MS and demonstrated that EBV directly infects autoreactive anti-CNS antigen B cells and reprograms them into pro-inflammatory antigen-presenting cells (APCs). EBV B cells in MS were enriched within the CD27CD21low memory B-cell subset and exhibited upregulated B cell activation and APC transcriptional programs. Recombinant antibodies derived from MS blood and cerebrospinal fluid (CSF) EBV B cells bound brain tissue, and several cross-bound both MS-associated autoantigens and Epstein-Barr virus nuclear antigen-1 (EBNA1). In vitro, EBV B cells functioned as APCs that stimulated T peripheral helper cells, with associated activation of EBV- anti-CNS antigen B cells. Collectively, these findings support a mechanistic framework in which EBV infects and transcriptionally reprograms autoreactive anti-CNS antigen B cells into APCs that drive pathogenic anti-CNS antigen T cell and EBV- B cell responses in MS.

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Younis, S., Rasouli, S., Loeffler, J. W., Sattarnezhad, N., Courtney, Y., Moutusy, S., Jahanbani, S., Pandit, M., Tomczak, A., Wong, H. H., Sharpe, O., Utz, P. J., Meffre, E., Kipp, L. B., Dunn, J. E., Lanz, T. V., Steinman, L., Robinson, W. H.. 2026-02-12. EBV reprograms autoreactive B cells as antigen presenting cells in multiple sclerosis. https://doi.org/10.64898/2026.02.11.701910

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