Immune reprogramming following B-cell depletion in MS involves NF-κB activation and durable suppression of EBV host-pathogen interaction

Immune reprogramming following B-cell depletion in MS involves NF-κB activation and durable suppression of EBV host-pathogen interaction | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Immune reprogramming following B-cell depletion in MS involves NF-κB activation and durable suppression of EBV host-pathogen interaction Chiara Starvaggi Cucuzza, Gavin Li, Olga Dethlefsen, Karin Byskata, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8544428/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract 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. Health sciences/Neurology/Neurological disorders/Multiple sclerosis Health sciences/Diseases/Immunological disorders/Autoimmune diseases/Multiple sclerosis Biological sciences/Immunology/Autoimmunity Biological sciences/Neuroscience/Diseases of the nervous system/Multiple sclerosis Biological sciences/Immunology/Neuroimmunology Full Text Additional Declarations Yes there is potential Competing Interest. DG is an employee of Merck AB, Solna, Sweden, an affiliate of Merck KGaA. CS is currently an employee at AstraZeneca, Mölndal, Sweden, but had no disclosures at the time of the contribution to the present work. OT has received compensation for lectures and an advisory board from Merck and Pfizer respectively, which have no relation to the content of this study. TO has received lecture/advisory board honoraria from Merck, Novartis, Biogen and Sanofi, and unrestricted MS research grants from the same companies, none of which have contributed to this study. NR has received a research grant from Pfizer. FP has received research grants from Denka, Janssen, Merck KGaA, Novartis, Pfizer and UCB, and fees for serving on DMC in clinical trials with Lundbeck and Roche, and preparation of expert witness statement for Novartis. All other authors declare no competing interests. Supplementary Files Suppltables.xlsx Supplementary tables 20260107Brepopsupplementary.docx Supplementary figures with legends and supplementary table titles Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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