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Meningeal inflammation, as a clinical feature of multiple sclerosis (MS), is associated with worse clinical disease outcomes. In both relapsing and secondary progressive MS and the experimental autoimmune encephalomyelitis (EAE) MS model, the meninges have been found to contain ectopic lymphoid follicles enriched with B cells. The metabolic requirement of meningeal B cell function in MS or EAE is not well elucidated. Using 7-Tesla MRI brain scans of MS patients and leptomeningeal enhancement as a marker, we found a correlation between meningeal inflammation and metabolites of the arginine/polyamine pathway, a finding recapitulated in EAE. Ornithine Decarboxylase (ODC1), the rate limiting enzyme for polyamine biosynthesis, as well as polyamine metabolism was diminished in the dura meningeal B cells from mice with MOG induced EAE mice as compared to naïve controls. Pharmacological inhibition of ODC1 restricted meningeal T cells but promoted meningeal B cell proliferation. B cell-specific deletion of ODC1 resulted in expansion of B cells with age-associated B cell-like phenotype (CD11cCD21/35CD23IgD), an increase in MOG-specific IgG in the brain, reduction of hippocampal synaptic density, and exacerbated disease in the MOG EAE model. Together, these findings demonstrate a divergent role of polyamines in regulating B and T cell responses in the meninges during autoimmunity.