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To further study the impact of B cell\u2013derived cytokines on neuronal function, we performed patch-clamp recordings on human iPSC-derived neurons. Coculture with proinflammatory human B cells led to depolarization and aberrant firing. Pretreatment of proinflammatory B cells with a Bruton\u2019s tyrosine kinase inhibitor (BTKi), reported in patients to beneficially affect disability progression even in the absence of inflammatory relapse activity, prevented neuronal impairment and inhibited LT\u03b1 release from B cells. Blocking LT\u03b1, tumor necrosis factor receptor 1 (TNFR1), or receptor-interacting protein kinase 1 or 3 also prevented neuronal impairment, but blocking TNF\u03b1 or LT\u03b2 had no such effect. Neuronal impairment was reversible by BTKi or blockage of LT\u03b1, and this reversibility was dependent on the activity of acid sphingomyelinase. In pwMS, LT\u03b1 correlated with elevated neurofilament light chain (NfL) abundance in CSF, and anti-CD20 B cell\u2013depletion therapy led to a reduction in circulating LT\u03b1, supporting the role of B cells as a regulator for LT\u03b1. These findings highlight the negative impact of B cell\u2013derived LT\u03b1 on neurons and suggest potential treatment avenues for MS-associated neuronal injury.<\/jats:p>","DOI":"10.1126\/scitranslmed.adx2652","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:58:20Z","timestamp":1761760700000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Bruton\u2019s tyrosine kinase inhibitors rescue neuronal impairment caused by B cell\u2013mediated lymphotoxin-\u03b1 release"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3556-125X","authenticated-orcid":true,"given":"Josef","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Neurology, Research Center for Immunotherapy (FZI) and Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Centre of the Johannes Gutenberg 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