Schizophrenia affects millions of people worldwide, yet its biological origins are poorly defined. Genetics and disruptions to brain development are known to increase risk, but researchers still do not fully understand the molecular and cellular processes that produce the disorder's hallmark symptoms.
That uncertainty has important consequences. Although antipsychotic medications help many people with this disorder, treatment responses vary widely, and a substantial proportion of patients remain resistant to existing therapies. The search for the biological mechanisms underlying schizophrenia could pave the way for more effective, personalized treatments.
In a recent preprint posted to bioRxiv, researchers in Dr. Aaron Ring’s lab in the Translational Science and Therapeutics Division investigated the role of immune dysfunction, specifically from proteins called autoantibodies, in schizophrenia. The work was led by Dr. Jillian Jaycox, a recent MD/PhD graduate from the Ring laboratory, in collaboration with Dr. Katlyn Nemani and Dr. Donald Goff in the New York University Department of Psychiatry.
“For a long time, we've observed abnormal immune responses in schizophrenia, for example elevated inflammation in the blood and cerebrospinal fluid as well as higher rates of autoimmune diseases and severe infections” said Dr. Jaycox. “Yet, whether the immune system is actively driving the disease or is just an innocent bystander has remained unclear.”
Antibodies recognize and bind to specific antigens - proteins or other biological structures - and tag them for the immune system to attack. While most antibodies bind to foreign antigens, like those on pathogens, and protect from harmful invaders, autoantibodies bind to antigens on human cells, where they can drive inflammation and the destruction of healthy cells. Autoantibodies can have additional functional effects. For example, through binding a receptor or its ligand, autoantibodies can block or activate a biological pathway, akin to the effect of gain- or loss-of-function genetic mutations. So far, Dr. Ring’s lab has detected hundreds of these functional autoantibodies that modify disease outcomes in cancer, COVID19, and autoimmunity.
The inspiration to explore autoantibodies in schizophrenia came from a separate group of diseases called autoimmune encephalitis, where autoantibodies targeting specific brain receptors cause psychosis and neurological deficits. These diseases provided proof of principle for the drastic biological effects of autoantibodies in the brain. Could a similar mechanism be at play in schizophrenia?
To answer this question, the researchers profiled autoantibodies against up to 6,000 human proteins using Rapid Extracellular Antigen Profiling (REAP), a technology invented in Dr. Ring’s lab, in 352 people with schizophrenia and 971 community controls. The schizophrenia cohort included people at different stages of illness and treatment, ranging from newly diagnosed, treatment-naïve patients to individuals with chronic psychosis.
The results revealed a striking pattern: people with schizophrenia had markedly higher levels of autoantibodies than community controls, even after adjusting for differences in demographics and medical comorbidities. And the number of autoantibodies correlated with disease severity and duration – people with more advanced disease had more autoantibodies.
“We discovered roughly 90 autoantibody reactivities that were enriched in schizophrenia,” Jaycox noted. “Interestingly, these autoantibodies are biased toward binding central nervous system antigens, including neuroactive receptors, neuronal ion channels, synaptic proteins, and blood-brain barrier components.”
To determine whether these autoantibodies were affecting vital biological functions, the team performed an ex vivo assay assessing blood-brain barrier integrity in the presence of purified bulk antibody from schizophrenia patients with or without blood brain barrier-directed autoantibodies. They observed increased permeability of molecules across the blood brain barrier model exposed to schizophrenia samples with the blood brain barrier targeting autoantibodies. They also found that patients with blood brain barrier targeted autoantibodies tended to have more autoantibodies recognizing central nervous system proteins overall. Together, the results suggest a mechanism where autoantibodies binding the blood brain barrier contribute to barrier dysfunction and expose the immune system to otherwise hidden antigens in the central nervous system, thereby driving broader autoantibody responses in the brain.
Jaycox commented, “While we know these autoantibodies bind 90 different protein targets, many of which are expressed in the brain, we don't yet understand most of the functions of the autoantibodies, like whether they block or activate a receptor or drive a specific flavor of inflammation. To understand how these autoantibodies might be driving disease, decoding autoantibody function is the next big question for us.”
The study also evaluated if autoantibody burden prior to treatment is related to the effectiveness of the antipsychotic Risperidone in a longitudinal trial of treatment-naïve, early disease patients. The research team observed that patients with higher autoantibody burden at baseline had worse treatment responses, suggesting that autoantibodies may contribute to treatment resistance. If future studies establish a causal relationship, therapies that reduce autoantibody levels could become a promising strategy for treating schizophrenia.
“The potential of this work to provide new answers to patients with schizophrenia and their families has been our primary driving force over the past five years,” Jaycox reflected. With clinical trials to reduce antibodies and the cells that produce them now underway, “we are excited to see where this research leads us.”
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Aaron Ring contributed to this research.
The spotlighted research was funded by the Mark Foundation for Cancer Research, the Pew Charitable Trust, the Anderson and Bezos families, the Yale Medical Scientist Training Program, the National Institutes of Health, and the PANDAS Network.
Nemani K, Jaycox JR, Akcan U, Schuman BM, Yeon SM, Hararo N, Qin K, Notestine AA, Carroll SM, McKenzie BS, Furchtgott L, Lahti AC, Tsien RW, Agalliu D, Goff DC, Ring AM. 2026. High prevalence of CNS-directed autoantibodies in patients with schizophrenia. bioRxiv. doi: 10.64898/2026.05.04.722731
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.