Neuroimmune Cascade Linking Systemic Autoimmunity and Psychiatric Disorders

Systemic autoimmune diseases frequently present with psychiatric and cognitive manifestations, yet their pathophysiological link to brain dysfunction remains elusive. We propose a translational framework unifying peripheral immune activation with central neuroinflammation. The cascade begins with IL-6–driven Th17 differentiation, promoting IL-17–mediated disruption of the blood–brain barrier (BBB) through endothelial activation and metalloproteinase release. This gateway allows immune mediators and autoantibodies to access the central nervous system, leading to microglial priming and cytokine amplification (IL-1β, TNF, complement). Sustained microglial activation contributes to synaptic pruning, NMDA receptor hypofunction, and excitatory–inhibitory imbalance, which manifest clinically as affective, cognitive, or psychotic symptoms. Clinical paradigms such as neuropsychiatric lupus and anti-NMDA receptor encephalitis illustrate the spectrum—from acute antibody-mediated encephalitis to low-grade systemic autoimmunity with chronic psychiatric sequelae. Biomarker candidates include serum IL-6/IL-17 levels, CSF/serum albumin ratio, sICAM-1, and microglial PET ligands. Therapeutically, we outline a three-stage model integrating (1) immunomodulation (anti-IL-6, anti-CD20), (2) antioxidant and neuroprotective support (N-acetylcysteine, mitochondrial stabilizers), and (3) neurotransmitter modulation (glutamatergic balancing, ketamine caveats). This Perspective calls for integrative immunopsychiatric trials combining molecular biomarkers, neuroimaging, and psychometric endpoints to test the IL-6/Th17–BBB–microglia axis as a mechanistic bridge between systemic autoimmunity and psychiatric disease.