Immune reprogramming following B-cell depletion in MS involves NF-κB activation and durable suppression of EBV host-pathogen interaction
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Emerging data supports a durable immune reprogramming effect of B-cell-depleting therapies (BCDT) in relapsing-remitting multiple sclerosis (MS), although the underlying mechanisms remain unclear. We performed immunologic and transcriptomic profiling of repopulating B cells, including single-cell RNA sequencing of paired naïve and memory B cells before and after rituximab (RTX), at a time when peripheral B-cell counts had normalized. Differential expression analysis revealed upregulation of NF-κB-associated genes across naïve and memory B-cell clusters, correlating with increased circulating B-cell activating factor (BAFF). In contrast, repopulating switched memory B cells showed marked downregulation of an Epstein-Barr virus (EBV) lytic-infection gene signature, accompanied by reduced T-cell activation to EBV antigens and to anoctamin-2, a candidate autoantigen. Our findings support a mechanistic link between active EBV replication in memory B cells and autoreactive T-cell responses, a dysregulated immune axis that is attenuated in the reconstituted B-cell compartment.
