Translational Immunopsychiatry Unit

National Institute Of Mental Health

Investigators

Abstract

The Translational Immunopsychiatry Unit (TIU) opened in late August of 2022 with just Drs. Chris Bartley and Sam Listwak. In year one, the TIU has made tangible progress towards an integrated research ecosystem: (1) Personnel: Over the last year the TIU has expanded from 2 to 11 members, including a summer student, two post-bacs, a graduate student, a post-doc, a biologist, a biochemist, a bioinformaticist, and clinical research coordinator. (2) Partners & Collaborations: a. Human Brain Collection Core (HBCC), NIMH - The TIU has engaged the HBCC in a hypothalamic single cell sequencing project to determine the identities and map the circuitry of cells that express a novel psychosis-associated hypothalamic autoantigen. This protein is unstudied and not expressed in rodents. b. Pediatric Autoimmune Brain Disorders Program (ABDP), NIMH - The ABDP is led by Dr. Gena Mooneyham, M.D. who refers patients for TIU research, including a young woman with acute psychosis in whom a genetic variant in the immune gene TBK1 was identified. We identified a glial autoantibody in this patient and are characterizing the genetic variant. The TIU also co-sponsored an ADBP Bench-to-Bedside research application for immunophenotyping in Down Syndrome Regression Disorder. c. Dr. Avindra Nath, M.D. - Clinical Director of NINDS Dr. Bartley was made an Associate Investigator on Dr. Nath's 15N0125 protocol. d. Dr. Anthony Zoghbi, M.D. - Dr. Zoghbi is a geneticist and associate professor at Baylor College Medicine. He has established a collection of hundreds of biospecimens from atypical and cognitively impaired schizophrenia spectrum disorder patients. He is formally collaborating with the TIU for to perform deep antibody profiling in his research cohort. e. Dr. James Bourne, Ph.D. - The TIU is collaborating with Dr. Bourne to evaluate the anatomic expression of neural autoantigens in relevant models. (3) Assay Development: a. Nanoluciferase immunoprecipitation system (nLIPS): The TIU has built a modified, and more sensitive (down to 2pg of antibody) version of LIPS for antibody validation. b. PanSeq: the TIU has designed a PepSeq library that leverages DNA-barcoded peptides and next-generation sequencing to deeply profile antibody repertoires. We call it PanSeq because the design is comprised of 1,708,000 64-amino acid peptides that encode all human proteins, all theoretical human splice variants due to a single intron retention or exon exclusion event, human endogenous retroviruses, antigens from all pathogenic bacteria, viruses, and all annotated and validated antigens from parasites, and fungi. (4) Cerebrospinal fluid (CSF) Autoantibodies Validated by the TIU using nLIPS: a. RPL4 (anti-ribosomal) antibodies were validated in the CSF of a woman diagnosed with bipolar disorder, who was re-diagnosed with seronegative autoimmune encephalitis 3 years later. Antibodies targeting other ribosomal subunits (P0, P1, and P2) are known biomarkers of systemic lupus erythematosus, but anti-RPL4 antibodies have not been described. This may represent a rare case of isolated neuropsychiatric lupus. b. The TIU also validated the protein target of an autoantibody that was identified in the CSF of a woman who was diagnosed with schizoaffective disorder at 14-years-old. Up to 2% of patients with SSDs have anti-WM autoantibodies (PMID: 35606187), but schizophrenia spectrum patients have not bee systematically screened for this autoantigen. (5) Bioinformatics: a. PairSeq: As a post-doc, Dr. Bartley developed a novel bioinformatic method for analyzing phage display antibody profiling data (PairSeq) that was most recently used to identify an antibody signature that predicts a future diagnosis of multiple sclerosis (MS) (under review, PMID: 37205595). PairSeq will be evolved for PepSeq (above) using machine learning. (6) Talks: Since opening the TIU, Dr. Bartley has been invited to speak at: the Academy of Consult Liaison Psychiatry, the Broad Institutes Schizophrenia Spectrum Biomarker Consortium Meeting and their Stanley Center Biennial Symposium, and Children's National Hospital. He has been invited to deliver clinical grand rounds at Loma Linda, the NIH, Northwell Health, Tufts Medical Center, and University of Connecticut. He was also invited to speak internationally at the Neuroscience School of Advanced Studies Brain-Immune Interactions Workshop in Switzerland and the upcoming International Society of PsychoNeuroEndocrinology (ISPNE) meeting in London.