Rasmussen Encephalitis: cause and immune reactions

Rasmussen encephalitis (RE) is a neurological disease with neuropathological hallmarks inflammation, neuronal loss, the presence of microglia activation, microglial nodules and astrogliosis. This disorder furthermore is both the index condition for the study of epilepsies associated with chronic inflammatory processes as well as a prime example of a cytotoxic T cell mediated encephalitis. RE is a fascinating condition since seizures and inflammation only are seen in one of two hemispheres. Although first descripted in 1958, the reasons for the inflammation, seizures and neuronal degeneration are still unknown, however, a number of studies have shown that cytotoxic T cells kill the neurons. In this project we hypothesize that a possible infectious agent or a local mosaic (unihemispheric) genetic mutation leads to an (auto) immune CD8- mediated reaction resulting in neurodegeneration. We aim to investigate the cause of disease in various ways: First, by investigation of the presence of an infectious agent by using a deep sequencing platform for analysis of pathogens. Secondly, we will search for genetic mutations in the brain. A third line of research will provide insight in the mechanisms involved in the attack of neurons by cytotoxic T cells. For the latter we investigate molecular changes in microglial nodules that are mixtures of microglial cells and cytotoxic T cells and thus can be described as local hotspots of innate and adaptive immunity in the brains of RE patients. For this we will use whole genome sequencing, T cell receptor analysis as well as advanced multiplex and RNA imaging techniques. If we find the cause of the disease, this integrated analysis is not only of extreme interest for patients with RE, but also can be used to study other inflammatory diseases with a possible pathogen-induced or genetic mutational background.