B cell depleting therapies have been effective in the treatment of Multiple Sclerosis (MS), yet to date little is known about how B cells promote disease pathogenesis. B cells can be found invading the meninges around the brain and spinal cord in MS, where they cluster in association with T cells. These meningeal B cells clusters are often adjacent to demyelinating lesions suggesting this may be a site where B cells are exerting their pathogenic effects. The purpose of this thesis was to understand the contribution of meningeal B cells to central nervous system (CNS) autoimmunity, by characterizing their phenotype and determining their susceptibility to B cell depletion. Using an animal model of MS, immunofluorescence analysis, flow cytometry, or single-cell sequencing analysis was used to analyze B cells within the inflamed CNS. Interestingly, while anti-myelin T cells were readily identified in the inflamed CNS, anti-myelin B cells were excluded from this site. Non-specific B cells within the CNS were phenotypically unique from naïve B cells, exhibiting a non-classical activation status. Following treatment with anti-CD20, B cells were rapidly depleted in peripheral tissues such as the blood, lymph node and spleen, while depletion in the CNS was delayed. Following treatment there was minimal evidence that anti-CD20 accessed meningeal B cells directly, but rather that depletion was indirect and the result of ongoing turnover of the meningeal population and elimination of the peripheral pool from which it is sustained. Depleting B cells from the CNS resulted in significantly less demyelination and T cell accumulation within meningeal clusters. This suggests that B cells may be required to help with T cell reactivation within the meninges, and that depletion of B cells over time prevents ongoing local pathology. Collectively, this thesis elucidates the phenotype of B cells within the inflamed CNS of anti-myelin autoimmunity, supporting a role for their involvement in disease pathogenesis. By selectively targeting pathogenic populations of B cells this will help minimize the adverse effects that exist with current complete B cell depletion therapies
