Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by inflammation manifesting in multiorgan damage 1, 2, 3. Beyond hallmark dermatological findings such as the malar rash and severe renal involvement in lupus nephritis, patients with SLE can also develop neurological and psychiatric symptoms. In the central nervous system (CNS), the disease impact spans from constitutional symptoms like fatigue (in up to 80% of patients) to anxiety, seizures, or psychosis 4, 5, 6, 7. This constellation of neurological symptoms constitutes an especially challenging subset of lupus, coined neuropsychiatric SLE (NPSLE). Because of the complexity of NPSLE and unknowns in its underlying pathophysiology, diagnosis and therapeutic management have remained difficult. With growing understanding of the interactions between neuro-resident and systemic immune populations, we are starting to better characterize key contributors to NPSLE. This review will highlight an integrative mechanism by which immune complexes in the neurovasculature activate complement and drive a type I interferon response by glial cells in the brain.