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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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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