Schizophrenia is a severe neuropsychiatric disorder whose etiology and biological heterogeneity remain poorly understood. Immune dysregulation has long been implicated, but the breadth and clinical significance of autoantibody responses remain unclear beyond rare individual examples. Here we use Rapid Extracellular Antigen Profiling-a proteome-scale assay for autoantibodies against extracellular and secreted proteins-to profile 352 individuals with schizophrenia and 971 community controls. We find that schizophrenia is marked by a striking elevation in extracellular autoantibody burden, present near disease onset, and approaching nearly twice control levels in the most severely ill patients. This burden increases with age in a pattern that diverges from controls and targets central nervous system antigens, including neuroactive receptors, neuronal ion channels, proteins involved in synaptic function, and blood-brain barrier integrity. Autoantibodies against blood-brain barrier antigens impair barrier function ex vivo and are associated with broader central nervous system autoreactivity, supporting a model in which barrier disruption promotes loss of tolerance to brain antigens. At the clinical level, higher baseline autoantibody burden predicts reduced responsiveness to the antipsychotic risperidone, suggesting that autoantibodies contribute to treatment resistance. Together, these findings identify humoral autoimmunity as a pervasive component of schizophrenia and imply that therapies that reset humoral immunity or reduce autoantibody burden may benefit patients beyond those with currently recognized antibody-mediated syndromes. ### Competing Interest Statement A.M.R. is an inventor of a patent application assigned to Yale University describing the REAP technology (patent number: WO2021189053A1). In addition, A.M.R. is the founder and a director of Seranova Bio, the commercial licensee of REAP. S.M.C., L.F., B.S.M. are employees of Seranova Bio. J.R.J. K.N., U.A., D.A., S.M.Y., B.M.S., N.H., R.W.T and D.C.G.. declare no competing interests.

T cells do the heavy lifting when it comes to the anti-tumor action of checkpoint immunotherapy. But do antibodies play a role too? That’s the question @yile_dai looked to answer in his thesis work, out today in @Nature! 🧵below https://t.co/VgTByRKRCX https://t.co/74qbyuU3hD

Comprehensive profiling of Ixodes scapularis antigens reveals that tick bites induce antivector immunity linked to acquired tick resistance.