Central nervous system-compartmentalized pathogenic B cells promote neurological inflammation relapses
B cells have emerged as a critical player in autoimmune disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While locally educated B cells with a CNS non-self-reactive immune repertoire are observed at the brain borders, the specific function of these CNS-compartmentalized B cells in the neuroinflammation pathogenesis remains unclear. Here we demonstrated that autoreactive B cells promoted neuroinflammation through local cognate interaction with pathogenic T cells in the meninges. By selectively perturbing B cell compositions in the CNS through intra-cisterna magna injection, we found that CNS-compartmentalized autoreactive T-B interactions drove the influx of pro-inflammatory phagocytes and initiated vascular inflammation responses, which were dependent on the expression of class II major histocompatibility complex molecules. Selective targeting of B cells in the CNS effectively alleviated relapses of neurological inflammation. These findings elucidate the pathogenic functions of CNS-compartmentalized B cells, highlighting their potential as therapeutic targets for relapsing MS. Overall design: We induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice by intravenously transferring pathogenic 2D2 pathogenic T-helper 17 (pTh17) cells. On day 3 following the T cell transfer, we transferred wild type (WT) or myelin oligodendrocyte glycoprotein (MOG)-specific mature naïve B cells into the recipients via intracisternal magna (ICM) injection. Subsequently, on day 6 after the T cell transfer, we collected subdural brain tissues and enzymatically digested them to obtain a single-cell suspension. The harvested cells were then labeled with flow antibodies and hashtag antibodies. We specifically sorted and pooled blood endothelial cells (BECs) (CD45–CD31+) and fibroblasts (CD45–PDPN+) for single-cell RNA sequencing using the 10X Genomics platform.