== MOG-specific antibodies partially restored susceptibility to rhMOG-induced EAE in BMHC II/mice.(A) Sera were obtained from BMHC II/and BMHC II+/+mice on day 14 after immunization with MOG p3555, rmMOG, or rhMOG. susceptibility in BMHC II/mice. In the absence of antibodies, IgHMOG-memmice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal folliclelike structures were observed in IgHMOG-memmice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B celltargeted therapies. Evidence supports roles for B cells and antibodies in the pathogenesis of multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disease (von Bdingen et al., 2011). B cells and plasma cells are frequently observed in active inflammatory MS lesions, and myelin-specific antibodies have been detected in FSCN1 areas of CNS demyelination (Meinl et al., 2006). Identification of oligoclonal antibodies in cerebrospinal fluid is also used to confirm the diagnosis of MS (Blennow et al., 1994). Further, it has been suggested that the meningeal B cell follicles detected in progressive MS may contribute to detrimental humoral immunity (Magliozzi et al., 2007). Although it was the emphasis on humoral autoimmunity that provided the impetus to test B cell depletion in MS, the clinical benefit observed in recent clinical MS trials that tested anti-CD20 agents was not associated with reduction in serum or cerebrospinal fluid Ig titers, and oligoclonal antibodies were unchanged (Cross et al., 2006;Martin et al., 2009). Besides serving as the source for antibody-secreting plasma cells, B cells express MHC class II (MHC II) molecules constitutively, and via up-regulation of co-stimulatory molecules, they can participate as APCs for activation of antigen (Ag)-specific T cells (Lanzavecchia, 1985;van der Veen et al., 1992;Constant et al., 1995b). In this regard, reduction of proinflammatory Th17 cells has been observed in CD20-mediated B cell depletion in MS (Bar-Or et al., 2010). Together, these observations suggest that, independent of their potential Esmolol humoral participation, there is prominent cellular involvement of B cells in MS pathogenesis. Distinguishing the separate cellular and humoral contributions of B cells in the pathogenesis of MS, and in its model experimental autoimmune encephalomyelitis (EAE), has been challenging. As myelin-specific T cells are essential for initiation of CNS inflammation and clinical manifestations, EAE is T cell dependent (Zamvil and Steinman, 1990). Esmolol B cells are not required in many EAE models, in particular those that are Esmolol induced by encephalitogenic peptides of myelin proteins. In this regard, immunization with myelin oligodendrocyte glycoprotein (MOG) peptide 3555 (p3555) induces EAE in B celldeficient mice and does not elicit strong humoral responses in WT mice (Fillatreau et al., 2002;Lyons et al., 2002). In contrast, immunization of WT mice with recombinant human MOG (rhMOG) protein induces B cell activation and production of anti-MOG antibodies, which are pathogenic only in association with T cellmediated CNS inflammation (Lyons et al., 2002;Oliver et al., 2003;Marta et al., 2005). As B celldeficient mice are resistant to EAE induced by immunization with rhMOG, this model is considered both T cell and B cell dependent. Therefore, this EAE model is well suited to evaluate the dual cellular and humoral roles of B cells in CNS autoimmunity. It is recognized that B cells are capable of processing native Ags and are very efficient APCs when they recognize the same Ag as the responding T cells (Constant et al., 1995a,b). When MOG-specific BCR knockin.