Autoantibody Discovery in Neuropsychiatric Disease

2020 Scientific Innovations Award
Samuel J. Pleasure, M.D., Ph.D.
University of California, San Francisco

The global incidence of schizophrenia is 1 percent and of psychotic syndromes 3.4 percent. The U.S. economic burden of schizophrenia is projected as $16 trillion for 2010-30 including the cost attributable to unemployment. Despite this, over the past three decades the FDA has only approved a single new first-in-class medication for schizophrenia, and current therapies are purely symptomatic and not disease modifying. The discovery of anti-NMDA receptor (NM DAR) encephalitis provided a conceptual model for autoantibody-mediated psychotic disorders since, in early stages, it recapitulates many of the positive symptoms of schizophrenia. NM DAR antibodies inhibit NMDAR function and can reproduce the neurobehavioral syndrome in animal models. The recognition that this highly treatable disease, as well as other autoantibody-mediated causes of encephalitis, can mimic psychotic disorders has increased calls to screen acute-onset first episode psychosis patients with lumbar puncture for evidence of neuroinflammation. Two studies assessing the diagnostic yield of this approach found that known autoantibodies were either rare or absent in this population. Yet, there was evidence for antibody production within the brain in between 7-10% of patients, indicating that a significant proportion of psychotic individuals may harbor CNS antibodies targeting unknown antigens. In addition, there is evidence from a Danish population-based study that serious infections are associated with an increased risk of Schizophrenia.

In order to identify previously uncharacterized autoantibodies associated with psychosis we have developed new molecular approaches to comprehensively identify autoantigenic targets and antiviral antibodies in 1) steroid-responsive encephalitis patients with psychiatric symptoms and unidentified autoantibodies and 2) two well phenotyped schizophrenia cohorts. This combined approach will allow us to identify novel anti-neural antibodies in patients with psychosis, as well as to identify with a rapid approach any evidence of anti-viral antibodies in the same patients. If we are successful in this proposal, we will directly test the proposition that a minority of schizophrenia patients have an autoimmune association with their schizophrenia and identify antibodies that may be causative of symptoms in these patients.

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