The role of B cells in the inflamed central nervous system: antigen presentation and phenotype-related migration

• Antragsteller: Privatdozent Dr. Klaus Lehmann-Horn
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie
• Förderung: Förderung von 2012 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 222193024

Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). Promising clinical trials testing B-cell depleting antibodies in MS have brought B cells into the spotlight. B cells may play a dual role in the pathogenesis of CNS autoimmune disease. Besides serving as the source of plasma cells secreting potentially pathogenic antibodies, they may also contribute to disease development as antigen presenting cells (APC) for activation of autoreactive T cells. In contrast to these pathogenic functions B-cell subsets may exert regulatory properties which are collaterally abolished by therapeutic B-cell depletion - an effect that is not favourable.Activation of T cells occurs in the context of Major histocompatibility complex (MHC) II on APC. Like dendritic cells and macrophages, B cells are professional APC and express MHC II constitutively. The first part of this project aims to elucidate the contribution of B cells to MHC II-restricted antigen presentation in CNS autoimmune disease. Creating a novel transgenic mouse model in which MHC II expression is restricted to B cells, we will test whether antigen presentation by B cells alone is sufficient to initiate the animal model of MS, experimental autoimmune encephalomyelitis (EAE).Data suggest that activated pathogenic B cells specifically migrate into the inflamed CNS, whereas antigen-naïve B cells may regulate autoimmune processes in the periphery. In order to test this hypothesis, in the second aim of this project migration of different B-cell phenotypes will be monitored by in vivo imaging in EAE. Additionally, and based on a potential compartmentalization of pathogenic B-cell function, local (intrathecal) application of B-cell depleting antibodies into mice with EAE will be tested. In case that pathogenic B-cell properties in the CNS can hereby be abrogated while sparing regulatory B cells in the periphery, this approach could constitute a future therapeutic option for MS.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Gastgeber: Professor Dr. Scott Zamvil