Patho-mechanisms of autoantibodies in CNS autoimmunity

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This project focuses on the question of what role CNS-specific autoantibodies play in the pathogenesis of CNS autoimmunity. B cells and autoantibodies are in the focus of research since an anti-CD20 antibody (rituximab) showed unexpected efficiency in the treatment of Multiple sclerosis (MS). How the B cells contribute to the disease pathogenesis is still incompletely understood. When following myelin oligodendrocyte glycoprotein (MOG)-reactive T and B cells during the course of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, we recently found that the presence of MOG-specific B cells significantly accelerated the entry of these pathogenic T cells into the CNS resulting in an earlier onset and increased severity of clinical disease in so-called regular EAE or a disease manifestation in subclinical EAE (Flach et al. PNAS 2016). Furthermore, we found that these effects were not mediated by the B cells per se but instead by B cell-derived autoantibodies. In the proposed research project we now aim to elucidate the mechanisms of how the autoantibodies exert their pathogenic function within the CNS. The following not mutually exclusive mechanisms might contribute to the observed clinical effects: 1) CNS-specific antibodies can enhance demyelination by opsonizing myelin for the destruction by myeloid effector cells or antibody-dependent cellular cytotoxicity (ADCC). 2) The immune complexes can bind to resident CNS cells (e.g. astrocytes or microglia), thereby triggering a release of pro-inflammatory factors that lead to an attraction of immune cells from the blood circulation. 3) Antibodies can target brain antigens in the CNS to local antigen-presenting phagocytes. The uptake of the antibody/antigen complexes can increase antigen presentation and consecutive T cell (re)activation. In our previous studies we found that in the presence of MOG-specific autoantibodies the T-cell activation levels within the CNS tissue were elevated (Flach et al. PNAS 2016). However, how exactly autoantibodies mediate T-cell activation in the CNS and which pathomechanism contributes to the tissue damage during the autoimmune process is still not clear. We therefore will address these questions by (i) following the autoantibodies and the autoimmune process in vivo using intravital 2-photon laser scanning microscopy; (ii) tracking T-cell activation in the context of local APCs using suitable biosensor-carrying animals; (iii) testing different autoantibody properties/specificities for their T-cell-activation-enhancing / demyelinating potential; (iv) evaluating the role of the different Fc receptors on distinct CNS cell populations; (v) creating transgenic mouse models with novel T- and B-cell reactivities; and (vi) testing the potential of human autoantibodies derived from patient sera / cerebrospinal fluids to accelerate and aggravate EAE.