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Many patients suffering from autoimmune diseases, such as systemic lupus erythematosus (SLE), experience neuropsychiatric symptoms. How does the peripheral immune system impact the brain, when the protective blood-brain barrier (BBB) usually remains intact? Using advanced microscopy, we recently discovered that autoantibodies localized inside neurons in brains of mice with SLE-like disease. We hypothesize that these cell-penetrating autoantibodies cross the BBB, enter neurons, and elicit direct damage to these sensitive and long-lived cells. This potentially provides a new therapeutic target in neuropsychiatric SLE, and more broadly for autoimmune CNS disorders.