Dissection of Acute and Chronic Pathology in Autoimmune Encephalitis Using a Highly Defined Human Stem Cell-Derived Co-Culture System
Anti-NMDAR (N-methyl-D-aspartate receptor) encephalitis (NMDARE), the most common form of autoimmune encephalitis, is caused by antibodies targeting the GluN1 subunit of NMDARs leading to inflammation in the central nervous system (CNS). NMDARE is characterized by psychiatric and neurological symptoms and often affecting children and young adults. One of the most prevalent, but poorly understood aspects of NMDARE, are the long-term neurological sequelae for which there are no therapeutic options.
Advancements in human pluripotent stem cell (hPSC) technology offer a unique opportunity to the neuroimmunology field to study autoimmunity-induced inflammation in human, disease relevant cells of the CNS. This project will focus on the application of a state-of-the-art hPSC-based co-culture system using highly defined hPSC-derived cortical neurons, astrocytes, and microglia. By combining hPSC-based co-cultures with single cell RNA-seq following incubation with anti-NMDAR antibodies, this study aims to identify both the signalling pathways involved in acute and chronic inflammation and identify the specific role of individual cell types that drive chronic inflammation. CRISPR/Cas gene-editing leading to the knockout of specific subunits of the NMDAR in distinct cell-populations will allow for the validation of key drivers of inflammation following binding of anti-NMDAR antibodies to CNS cells. In summary, this project will aim to answer two key questions in the field of autoimmune encephalitis, namely what cell-nonautonomous signalling pathways drive the pathogenesis of NMDARE in the acute phase and what drives chronic inflammation following anti-NMDAR antibody binding.