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The presence of persistent intrathecal oligoclonal immunoglobulin G (IgG) bands (OCBs) and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Despite extensive investigations, the role of antibodies, the products of mature CD19+ B cells, in disease development is still controversial and under significant debate. Recent success of B cell depletion therapies has revealed that CD20+ B cells contribute to MS pathogenesis via both antigen-presentation and T-cell-regulation. However, the limited effic