Translational Immunopsychiatry Unit

National Institute Of Mental Health

Investigators

Abstract

The Translational Immunopsychiatry Unit (TIU) is an integrated clinical, basic, and translational research program that identifies, characterizes, and models immunologic factors that causally contribute to neuropsychiatric illness. In the past year, the TIU deployed its ~1.8 million peptide T7 bacteriophage display platform (PanSeq, whereby ~930K peptides encode all human proteins and ~850K encode proteins from over 4,000 bacteria, viruses, fungi, and parasites). The TIU performed ~3,000 PanSeq assays to determine the antibody binding patterns of human subjects with and without neuropsychiatric illness, including schizophrenia spectrum disorders, seronegative autoimmune encephalitis, Down Syndrome, PANDAS, and unspecified neuroinflammatory illnesses. The TIU also actively engaged in developing new approaches to analyzing phage display data. Because PanSeq can only detect one class of antibody (those that bind to linear protein sequences), the TIU also began utilizing whole human protein arrays to evaluate for antibodies that recognize protein shapes (conformational) and molecules added to proteins (post-translational modifications). For this work, the TIU developed a new bioinformatic pipeline that can identify novel autoantibodies in protein array data. The pipeline can also calculate antibody indices to determine when antibodies are being produced in the cerebrospinal fluid (CSF). We intend to publish the code in early fiscal year 2026. Using these approaches, the TIU has identified novel autoantibody or novel autoantibody-disease associations in schizophrenia spectrum disorders, PANDAS, and Down Syndrome. These identified autoantibodies have been validated using the TIU’s nanoluciferase immunoprecipitation system (nLIPS) technology. A primary goal of the TIU is to determine how autoantibodies that target the brain alter perception and behavior. To start, the TIU worked with the Broad Institute to perform single-cell RNA sequencing (scRNA-Seq) and B cell receptor and T cell receptor sequencing (BCR and TCR, respectively) on peripheral blood cells and CSF cells from five individuals with psychosis associated with clinical evidence of immune dysregulation. As BCRs encode antibodies, this work demonstrated the feasibility of identifying antibody genes from patients for cloning human-derived monoclonal autoantibodies (HD-mAbs) that can then be studied in isolation in various experimental systems. Relatedly, the TIU has also made progress developing a system to ferry HD-mAbs across the blood-brain barrier. The TIU has three ongoing projects in schizophrenia spectrum disorders: (1) deep autoantibody profiling, validation, and characterization in a paired biobank of cerebrospinal fluid and blood samples in collaboration with Northwell Health, (2) autoantibody profiling of plasma and post-mortem brains of individuals with schizophrenia, major depressive disorder, and controls in collaboration with the NIMH Human Brain Collection Core (HBCC), and (3) through a Cooperative Research and Development Award with Baylor College of Medicine. This work has yielded the discovery of a novel autoantibody in the cerebrospinal fluid of a woman with a diagnosis of schizoaffective disorder. The subject's autoantibody is specific to a post-translationally modified form of this secreted protein, which regulates the complexity of hippocampal neuron dendrites and has been shown to be differentially expressed in post-mortem brains of victims of suicide. The TIU also has an active program evaluating the antibody repertoire of extant biospecimens from individuals with PANDAS, PANS, and childhood-onset obsessive-compulsive disorder. Over the reporting period, the TIU has also collaborated with investigators across NIH institutes to determine antibody repertoires of their cohorts of interest. Although some of these cohorts are not neuropsychiatric patients, their data expand what we know about antibody repertoires across human variation and disease, and therefore improve our statistical power when analyzing data from neuropsychiatric patients. The TIU’s multi-site Down Syndrome Regression Disorder (DSRD) study continues to be funded by an NIH Bench-to-Bedside Award. The study is in collaboration with the NIMH Autoimmune Brain Disorders Program, NHGRI, Rady Children’s Hospital, UCSD, and Children’s Hospital of Los Angeles. The study has two phases (1) immune profiling and biomarker analysis of extant cerebrospinal fluid from individuals with Down Syndrome with or without regression and (2) prospective clinical phenotyping, neuroimaging, and immune phenotyping of individuals with Down Syndrome Regression Disorder. We have made significant progress towards the completion of phase I of the DSRD study. Specifically, we performed biomarker measurements on CSF from Down Syndrome patients with and without regression. Additionally, we’ve used PanSeq and protein arrays to define the antibody landscape of these disorders. The TIU is extending this DSRD biomarker study to the generation of patient-derived induced pluripotent stem cell lines (iPSCs) to study the cellular pathobiology of DSRD. In particular, the TIU is evaluating the functional consequences of a third copy of both type I interferon receptor genes on iPSC-derived microglia from individuals Down Syndrome with or without regression. Over the past year, TIU clinical research activities were performed under NCT02435810.