Unlocking the immune and epigenetic enigma of PANS/PANDAS: Integrating clinical T cell signatures, autoantibody profiles, and microbial dysbiosis with in vitro mechanistic studies using advanced multiplex technology, Raman microscopy and machine learning
Lead supervisor: Professor Karl Morten
Co-supervisor: Professor Michael Dustin
Commercial partner: Virax Biolabs
Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Paediatric Autoimmune Psychiatric Disorders Associated with Streptococcal Infections (PANDAS) are severe childhood disorders characterised by the abrupt onset of debilitating neuropsychiatric symptoms, including obsessive-compulsive disorder (OCD) and tics. These conditions are understood as immune-mediated responses, frequently triggered by infections. A recent landmark study provided robust evidence of extensive immune, epigenetic and metabolic dysregulation in PANS patients. Specifically, RNA sequencing showed upregulated ribosomal biogenesis, translational processes, and RNA methyltransferase pathways, alongside downregulated mitochondrial activity, protein kinase signalling, and critical immune functions including phagocytosis and neutrophil degranulation. PANS patient peripheral blood mononuclear cells (PBMC) also showed blunted TNF and IL-6 responses to Toll-like receptor (TLR) stimulation, indicating impaired innate immune function. Crucially, intravenous immunoglobulin (IVIG) treatment was shown to reverse these dysregulated molecular pathways, highlighting their involvement in pathogenesis.
This DPhil studentship offers an opportunity to dissect these specific PANS patient-derived molecular signatures. Our aims are to identify novel biomarkers, elucidate precise immunopathogenic mechanisms and inform targeted therapies, addressing a critical unmet need in paediatric neuroimmunology. This project is relevant to the MRC remit for understanding disease mechanisms, developing objective diagnostics, and translating research into tangible health benefits for children suffering from a complex immune-mediated disease.
The project will profile PBMCs from PANS/PANDAS patients and matched healthy controls (recruited by Professor Rajat Gupta, Department of Paediatric Neurology at Birmingham Children's Hospital, who will oversee clinical aspects and patient interaction). This profiling will use Virax Biolabs cutting-edge multiplex platform combining high sensitivity ELISpot/FluoroSpot for T cell function (assessing responses to candidate microbial pathogens and neuronal self-antigens like dopamine D1/D2 receptors, lysogangliosides and glycolytic enzymes) with Flow Cytometry for T cell phenotyping. For Virax Biolabs, this collaboration offers expansion of their multiplex platform into a complex, unmet medical area, identifying specific biomarker panels for PANS/PANDAS with significant commercial potential and enhancing their platform’s capabilities through access to patient data and academic expertise.
Novel Raman microscopy techniques (developed with Professor Michael Dustin at the Kennedy Institute, University of Oxford) will enable real-time metabolic profiling of single immune cells via heavy isotope labelling in mixed cell populations. This will be used to directly probe the downregulated mitochondrial activity and potential glycolytic dysregulation observed in PANS within patient immune cells. In addition, Professor Dustin can assist in the design of substrates for selective activation of T cells, monocytes, B cells, NK cells, and dendritic cells with respective physiological ligands. Complex Raman data will be analysed using advanced machine learning (Dr. Tjeerd Old Scheper at Oxford Brookes University). Concurrently, LC-MS/MS metaproteomics will be used to identify active microbial signatures in throat/faecal samples. Access to Dr Bela Paizs’ metabolite discovery programmes at the Rosalind Franklin Institute will provide further metabolomics expertise. The academic leads (Professor Morten, Professor Dustin, Dr Scheper, Dr Paizs and Professor Gupta) will gain access to a complex patient cohort, cutting-edge technologies and interdisciplinary collaboration with a view to generating high-impact publications and future funding by applying their respective expertise to a pressing clinical problem.
Apply using course: DPhil in Women's and Reproductive Health
