T cell cytotoxicity in inflammatory brain disease

T-lymphocyte mediated brain inflammation is the hallmark of a large number of putative autoimmune or virus induced diseases of the central nervous system. So far most of our knowledge on the mechanisms of T-cell mediated brain inflammation is derived from studies of the subset of Class II MHC restricted CD4+ T- lymphocytes. Recent studies, however, indicated that Class I MHC restricted cytotoxic T-cells may play a prominent role in the pathogenesis of these diseases. Aim of the present project is to elucidate the contribution of such cytotoxic CD8+ T-cells in the pathogenesis of a variety of human inflammatory brain diseases, such as multiple sclerosis, paraneoplastic diseases of the nervous system, acute disseminated leucoencephalomyelitis, Rasmussen`s encephalitis as well as different virus induced disorders of the central nervous system. By quantitative technologies we will determine the relative contribution of Class I restricted T-cells to the global inflammatory process. In addition we will further analyze the mechanisms, responsible for tissue damage in these diseases by studying the direct interaction of cytotoxic T-cells with target cells in the nervous system and by defining the local expression of toxic molecules, produced by cytotoxic T-cells and activated macrophages / microglia cells within the lesions by confocal laser microscopy. These studies may lead to the identification of new therapeutic targets for human inflammatory brain diseases.

The aim of this project was to elucidate the contribution of a subset of T lymphocytes, the cytotoxic CD8 + T-cells, in the pathogenesis of a variety of human inflammatory brain diseases, such as multiple sclerosis, paraneoplastic diseases (a neurological disease which can occur due to the presence of a tumor), Rasmussen encephalitis (a form of childrens epilepsy which in addition to seizures show inflammation in the brain) as well as different virus induced disorders of the central nervous system. We studied the presence and localisation of these cytotoxic T-cells in autopsy brains from patients with these different diseases by light microscopy and fluorescence confocal laser microscopy. We found that in all of these diseases most of the lymphocytes which enter the central nervous system are indeed these CD8 + T lymphocytes. Investigation of a specific cytotoxic substance produced by these cells (the so-called granzyme-B) revealed that in many cases lymphocytes which produce this granzyme-B can attach to cells, release this granzyme-B and in this way kill these target cells. As an example, in cytomelovirus infected brain, clusters of these granzyme-B positive lymphocytes were gathered around cytomegalovirus infected cells. In Rasmussen encephalitisbrains we could find these Granzyme-B positive cells attached to both neurons and astrocytes, cells which help the neurons to function properly. These findings are important because this knowledge can be used for therapeutic treatment, for instance by treatment with drugs which suppress the activity of these cytotoxic T lymphocytes or can prevent entry of these cells into the brain.