My projects currently focus on the pathways and cell interactions in CD8-mediated and antibody-associated brain diseases. In CD8-mediated brain diseases, cytotoxic T cells (CTLs) infiltrate the CNS and can target different cell types which leads to a variety of clinical diseases, depending on which cells and which regions of the CNS are targeted. Besides Multiple Sclerosis, CD8-mediated responses can be found in a variety of neuroinflammatory conditions. Roughly, these CD8-mediated encephalitides can be divided into three groups; The first are viral encephalitides, in which a cytotoxic T cell mediated response is directed against infected cells. Second, the classical autoimmune paraneoplastic encephalitides with antibodies, against intracellular or intranuclear (i.e anti-hu, anti-Ma2 and anti-Yo) antigens. Here, cytotoxic T lymphocytes (CTLs), primed by a peripheral neoplasm, attack CNS neurons expressing the same antigens (i.c. oncogenes) that are found in the peripheral tumor. Besides these viral and paraneoplastic encephalitis groups, a third group consists of encephalitides with an unknown etiology but a distinct cytotoxic T cell response against CNS neurons. At present we are working on three CD8-mediated diseases: Susac syndrome (Gross et al., Nat Comm 2029), Narcolepsy type I and Rasmussen Encephalitis.
Rasmussen encephalitis (RE), which is seen mostly in children, is an encephalitis with unknown etiology. RE is both the 'index condition' for the study of epilepsies associated with chronic inflammatory processes as well as a prime example of a CTL-mediated encephalitis. RE is a fascinating condition since both seizures and inflammation only are seen in one of two hemispheres. In 2002 (Bien et al., Ann Neurol 2002) we were the first to show that in this disease CTLs attack neurons in the cortex which leads to severe neuronal degeneration and loss. Recently we proposed that in RE, microglial nodule formation provides an environment for the initiation of the CD8+ T-cell cytotoxicity (Tröscher et al, Acta Neuropath 2019), since, in the absence of infiltrating CTLs, small primary microglial nodules form that upregulate molecules such as endosomal Toll-like receptor (TLR) 3 and 7 and cytokines such as IL-18. We think that microglia in these small primary nodules are responding to an abnormal stimulus, such as a pathogen or an autoimmune antigen. Thus, at present we are investigating why these cells are activated, which molecular signature these nodules have and how they evolve into secondary nodules in which CTLs attack neurons.
MRI and Histopathological features of Susac Syndrome (a-c) and RE (d and e). (a) MRI and (b) angiography of a Susac patient displaying snow ball lesions in the corpus callosum and branch retina artery occlusions (BRAO), respectively. (c) Displays a CD8+ T cell (blue) polarizing GrB (turquoise) towards the EC (red) of a microvessel. (d) MRI (right) of a RE patient with hemispherectomy. (e) Histopathology showing a microglial nodule of a RE patient with CD8+/GrB+ T cells (green/white) intermingled with MHC class II (red) expressing microglial cells. In the midst of this, the yellow arrow points at a CD8+ T cell polarizing GrB (white) towards a (blue) neuron (enlarged in the inset). (Wiendl et al., Nat Rev. Neurol 2020)
Our work on these human diseases is complemented by the study of animal models for these diseases. At present we are working on models for Multiple Sclerosis, Paraneoplastic Cerebellar Degeneration and Narcolepsy.
