RESCUE FROM NEURONAL IMPAIRMENT CAUSED BY B CELL-MEDIATED LYMPHOTOXIN-ALPHA RELEASE

B cell depletion therapy slows disability progression in people with multiple sclerosis (MS), but how B cells drive neuronal injury remains unclear. Here, we investigated the impact of B cell-derived cytokines on human neurons. Human iPSC-derived neurons were cocultured with proinflammatory human B cells and analysed by patch-clamp recordings, which revealed membrane depolarization and abnormal firing patterns. Pretreatment of these B cells with a Bruton's tyrosine kinase inhibitor (BTKi), known to reduce disability progression in MS patients, prevented neuronal dysfunction and suppressed lymphotoxin-α (LTα) release. Neuronal impairment was likewise prevented by blocking LTα, tumor necrosis factor receptor 1 (TNFR1), or receptor-interacting protein kinase 1 or 3 (RIPK1 or 3), whereas blockade of TNFα or LTβ was ineffective. Neuronal damage was reversible by BTKi or LTα blockade, and this reversibility was mediated by acid sphingomyelinase (ASM), an enzyme involved in membrane repair mechanisms. Furthermore, in MS patients, cerebrospinal fluid LTα levels correlated with neurofilament light chain concentration, and anti-CD20-mediated B cell depletion reduced circulating LTα, supporting a central role for B cells in LTα regulation. These findings reveal B cell-derived LTα as a critical mediator of neuronal injury in MS, and show that reversing LTα-induced neuronal dysfunction requires ASM-dependent membrane remodeling. The latter is focus of further investigations in neuronal recovery from inflammatory injury.