The remarkable success of anti-CD20 B cell depletion therapies in reducing the 
burden of multiple sclerosis (MS) disease has prompted significant interest in 
how B cells contribute to neuroinflammation. Most focus has been on identifying 
pathogenic CD20+ B cells. However, an increasing number of studies have also 
identified regulatory functions of B lineage cells, particularly the production 
of IL-10, as being associated with disease remission in anti-CD20-treated MS 
patients. Moreover, IL-10-producing B cells have been linked to the attenuation 
of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal 
model of MS. In addition to IL-10-producing B cells, antibody-producing plasma 
cells (PCs) have also been implicated in suppressing neuroinflammation. This 
review will examine regulatory roles for B cells and PCs in MS and EAE. In 
addition, we speculate on the involvement of regulatory PCs and the cytokine 
BAFF in the context of anti-CD20 treatment. Lastly, we explore how the 
microbiota could influence anti-inflammatory B cell behavior. A better 
understanding of the contributions of different B cell subsets to the regulation 
of neuroinflammation, and factors that impact the development, maintenance, and 
migration of such subsets, will be important for rationalizing next-generation B 
cell-directed therapies for the treatment of MS.