Autoantibody deposition in the neurovasculature promotes interferon-⍺ release to drive neuropsychiatric lupus 3619

Description Up to 80% of patients with lupus develop CNS manifestations, ranging from anxiety to overt psychosis. While studies have shown an increase in interferon-alpha (IFNα) in patients, the mechanisms behind neuropsychiatric lupus (NPSLE) remain unclear. The Sle1,yaa accelerated mouse model of lupus exhibits anxiety and fatigue-like behaviors, and has increased sera autoantibodies. In the brain, they express “patches” of interferon-stimulated genes (ISGs), with prominence in the hippocampus. This spatiality implicates a local IFNα source and functional detriments to proximal neurons. In the CNS vasculature, Sle1,yaa mice have more antibody deposits compared to B6 mice, with C3 colocalization as they age. This occurs at low levels by P10 – preceding the rise in IFNα levels. This indicates that immune complex deposition could be upstream of IFNα signaling in the CNS. In a transfer study, serum from Sle1,yaa mice was injected into the lateral cerebroventricles of P1 wild-type pups, then retro-orbitally weekly after weaning age. Mice receiving Sle1,yaa serum developed anxiety and showed immune complexes and ISG expression near cerebral ventricles. Areas of ISGs also show greater Iba1+ microglia activation and less proliferative neuron progenitors. This strengthens the hypothesis that autoantibody deposition drives IFNα activity to harm neuron function. This body of work will provide insight into targetable pathways for NPSLE and other neuropsychiatric diseases in autoimmunity. Funding Sources NIH T32 AI007529-25 Topic Categories Neuroimmunology (NEUR)