Neural autoantibodies in the cerebrospinal fluid of individuals with schizophrenia spectrum disorders

Schizophrenia spectrum disorders have substantial genetic liability, but their stable incidence and clinical heterogeneity leave open contributions from non-genetic mechanisms. Though autoimmune encephalitis demonstrates that anti-neural antibodies can cause psychosis, encephalitis antibodies are uncommon in schizophrenia. Here we show that multi-platform autoantigen profiling of cerebrospinal fluid and plasma detects rare, anti-neural autoantibodies in schizophrenia spectrum disorders.

By antibody profiling the cerebrospinal fluid of 32 schizophrenia spectrum participants and 32 neuropsychiatrically unaffected controls by brain tissue immunostaining, immunoprecipitation–mass spectrometry, phage display immunoprecipitation sequencing, and plasma by complementary protein microarrays, we identify three autoantibodies, including to alpha-crystallin B. The anti-alpha-crystallin B antibody preferentially recognizes phosphorylated serine-45 and is absent from the cerebrospinal fluid of individuals with untreated multiple sclerosis, a disease with frequent antibodies to unphosphorylated alpha-crystallin B. These findings do not define autoimmune psychosis as a new disease but support broader autoantibody searches in psychotic disorders.

Thank you to the 15N-00125 study team at NIH for their assistance in the management of the positive control CRYAB case. The authors thank the research subjects and their families for their participation in this study. Funding for this work was provided by NIMH IRP ZIA MH002982, NIMH R01MH122471 (S.J.P., M.R.W., K.C.Z., J.L.D.), NIMH R25MH060482 (C.M.B.), NINDS IRP ZIA NS003130, Brain Research Foundation (S.J.P.), Westridge Foundation (M.R.W.), the Chan Zuckerberg Biohub SF (J.L.D.), and the John A.

Watson Scholar Program, UCSF (C.M.B.). C.M.B. is additionally supported by a Hanna H. Gray Fellowship, Howard Hughes Medical Institute, a President’s Postdoctoral Fellowship Program, the University of California, and a Deeda Blair Research Initiative for Disorders of the Brain.

Sequencing was performed at the UCSF CAT, supported by UCSF PBBR, RRP IMIA, and NIH 1S10OD028511-01 grants. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at UCSF, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. This work utilized the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov).

This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S.