Background: T-cells reactive against the neuronal antigen beta-synuclein induce cortical grey matter inflammation accompanied by partially reversible neuronal damage.
Hypothesis: We hypothesize that the recovery potential of the cortical grey matter upon immune attack is dictated by crucial checkpoints that can be functionally modulated.
Strategy: We will employ an integrative approach based on multiscale imaging, cellular and molecular profiling and genetics in order to define the checkpoints which determine if the grey matter tissue regenerates from the acute inflammatory bout or becomes irreversibly damaged.
The focus of this proposal is the regenerative potential of the CNS grey matter. This will be tested in a novel Lewis rat model for acute autoimmune grey matter inflammation induced by beta-synuclein-specific T cells. The beta-synuclein-specific T cells almost exclusively enter the CNS grey matter of the spinal cord and in particular the brain cortex where they become activated upon auto-antigen encounter and induce a severe local inflammatory process. This T-cell driven inflammation of the grey matter is accompanied by significant damage to neuronal structures and the development of paresis of individual limbs, head tilting and ataxia. Clinically the animals recover from the disease. However, the inflammatory lesions and structural changes of the neuropil are only partially reversible. T-cells directed against myelin basic protein induce classical experimental autoimmune encephalomyelitis characterized by inflammation of the spinal cord white matter and ascending pareses. By employing an integrative approach of multiscale imaging, cellular and molecular profiling and genetics we will examine the recovery potential of the CNS grey matter. Furthermore, by exploiting our different autoimmune models we will compare the recovery potential of the CNS grey matter with that of the white matter. The overall aim of our project is to define checkpoints which determine if and when the grey matter tissue can regenerate from the acute inflammatory bout or it becomes irreversibly damaged.
