Live Analysis of the Role of B cells in Experimental Autoimmune Encephalomyelitis

During the last years it has become increasingly clear that autoantigen-specific B cells play a pathogenic role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). However, their exact mode of action is still a matter of debate. Understanding the mechanisms of B cell contribution to the pathogenesis of MS is crucial for the development of novel specific and efficient therapies. Here we used intravital two-photon microscopy (2PM) to track myelin-reactive T and B cells during EAE development induced by recombinant rat myelin oligodendrocyte glycoprotein (rrMOG). We demonstrate that the presence of autoimmune B cells accelerated the invasion of pathogenic T cells into the central nervous system (CNS), resulting in an earlier clinical manifestation of the disease. Our data strongly suggest that MOG-specific B cells were dispensable for the priming of autoimmune T cells in the secondary lymphoid organs. Furthermore, we demonstrate that B cells did not infiltrate the CNS and therefore could not be held responsible for antigen presentation in the CNS and the re-activation of effector T cells. Instead, our data provide evidence that autoantibodies are the pathogenic “weapon” of autoimmune B cells. MOG-specific B cells deficient in the transcription factor XBP-1 and so unable to secrete antibodies had no pathogenic effect on the EAE development. Furthermore, an intravenous transfer of anti-MOG antibody mimicked the disease-promoting effect of B cells. By 2PM we could demonstrate that the anti-myelin antibody accumulated in the meningeal phagocytic cells which are situated at a strategically favorable anatomical location at the boundary between the periphery and the CNS, with access to peripheral circulating encephalitogenic T cells and possibly to endogenous myelin antigens. In summary, our study provides evidence that autoantibodies produced by MOG-specific B cells accelerate the disease onset of EAE by playing a critical role in the initiation of effector T cells invasion into the CNS