EBV reprograms autoreactive anti-CNS B cells as antigen presenting cells in multiple sclerosis

Multiple 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 CD27⁺CD21^low 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). <i>In vitro</i>, 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.