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CNS Lupus is a clinical entity that includes conditions as diverse as cognitive dysfunction and psychosis. It is unanimously agreed that it is a disease difficult to diagnose, difficult to treat and the pathogenesis of which is far from understood. While it is widely appreciated that increased generalized systemic lupus erythematosus (SLE) activity is a major risk factor for neuropsychiatric lupus, systemic activity correlates only poorly with CNS disease and the cascade of events leading to CNS manifestations remains largely unknown. In contrast to multiple sclerosis and experimental autoimmune encephalomyelitis, where type I interferons play a protective role, in lupus type I interferons are thought to drive systemic disease activity. However, the role of type I interferons and their target cells in CNS lupus is largely unexplored. We propose that different manifestations of CNS lupus are driven by distinct pathogenetic mechanisms. While type I interferons alone may be sufficient for certain manifestations of CNS disease, such as cognitive dysfunction, systemic disease activity may disrupt the blood-brain barrier and cause brain infiltration by bone marrow-derived myeloid cells and lymphocytes leading to perivascular and meningeal inflammation and several ill-defined clinical manifestations of CNS lupus. Here we will interrogate the role of type I interferons and distinct brain macrophage subsets in the pathogenesis of CNS lupus in a systematic fashion and at single cell resolution. Our goal is to uncover basic pathogenetic principles underlying different clinical presentations of neuropsychiatric lupus and thus identify diagnostic tools and treatment targets.