In patients with multiple sclerosis (MS), a restricted pool of B cells are shared between the cerebrospinal fluid (CSF) and blood, according to a new study. Sequencing of IgG heavy chain genes was used to identify B-cell repertoires, and revealed clonally related B-cell populations on both sides of the blood–brain barrier. Moreover, diversification of different B-cell populations occurred in the blood versus the CSF, indicating that the autoimmune response to CNS antigens is triggered and driven in both the brain and the periphery.