Neuroimmune mechanisms of neuropsychiatric systemic lupus erythematosus

In systemic lupus erythematosus (SLE), chronic autoimmunity and sustained inflammation can lead to the development of neuropsychiatric lupus (NPSLE) in up to 80% of patients. Elevated interferon-alpha (IFNα) is detected in serum and cerebrospinal fluid, making it a major focus in studies investigating the mediators of NPSLE. Others have emphasized the role of autoantibodies, such as anti-dsDNA, which have been shown to cross-react with neurotransmitter receptors and directly damage neurons. In this review, we present an integrative framework in which immune complexes deposited in the neurovasculature trigger local IFNα production in the brain. We discuss how complement activation amplifies inflammation by recruiting monocytes and promoting transcriptional shifts in glial cells toward reactive and neurotoxic states. Together, cellular and soluble immune effectors converge to disrupt neuronal function and drive the behavioral symptoms characteristic of NPSLE. • Type 1 interferon signature in the brain presents in a spatially heterogeneous manner. • Immune complexes are deposited throughout the neurovasculature. • Complement activation recruits monocytes from brain-border tissues. • Glial cells respond to interferon and adopt neurotoxic states.