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  • Similarly in the EAE model


    Similarly in the EAE model, Chalmin et al. previously demonstrated that EBI2 and CH25H might be responsible for the efficient egress of differentiated Th17 cells from the draining lymph nodes [31]. As discussed above, in active EAE we did not find differences in EAE development and only the transfer model could reveal a role of EBI2 expression on T cells for neuroinflammation [37]. Nevertheless, usage of full EBI2-KO mice may also preclude effects due to developmental MPEP Hydrochloride sale processes with redundant mechanisms in place. Our data [37] as well as previous data of others [7,8] also revealed that the EBI2–7α,25-OHC system may rather have a subdominant role compared to chemokine receptors and their ligands in transmigration or localization in lymphoid tissues. Several groups focused on the expression of EBI2 and of the ligand generating enzymes in astrocytes and macrophages and showed that both cell types express EBI2 as well as the enzymes producing its ligand [[39], [40], [41], [42]]. Furthermore, EBI2 triggering via 7α,25-OHC in astrocytes was shown to inhibit LPS-induced IL-6 secretion and therefore to trigger an anti-inflammatory program [43]. Interestingly, EBI2 was also demonstrated by the same group to protect from lysolecithin-mediated demyelination in mouse ex-vivo models [44].
    Acknowledgments This work was supported by the Deutsche ForschungsgemeinschaftSFB/TR-128 to F.C.K.
    Introduction Dynamic changes in lymphocyte localization are fundamental to the rapid and efficient production of protective antibodies. Antibody responses are initiated by the relocalization of antigen-engaged B cells to the B zone-T zone (B-T) boundary where cognate interactions with T cells drive initial B cell proliferation (Kelsoe and Zheng, 1993, Okada and Cyster, 2006). Proliferating B cell blasts subsequently proceed down one of two independent pathways of migration and differentiation (Jacob et al., 1991, Liu et al., 1991). Responding B cells can migrate from the B-T boundary to extrafollicular areas where they are induced to rapidly expand and differentiate into plasmablasts and plasma cells (MacLennan et al., 2003). These transient antibody-secreting cells provide the most immediate source of antigen-specific antibodies. Alternatively, antigen-engaged B cells can localize in the central, follicular dendritic cell (FDC)-rich region of the follicle to form germinal centers (GCs) (MacLennan, 1994). B cells proliferating in GCs give rise to high-affinity clones and exit the GC as long-lived plasma cells and memory B cells (Manz et al., 2005, O\'Connor et al., 2003). This second GC-dependent pathway of B cell differentiation provides a sustained source of antibodies with enhanced antigen neutralization potential and mediates long-term immunity against reinfection. The early changes in positioning that recruit responding B cells to either the extrafollicular or the GC pathway of antibody production are therefore crucial for coordinating rapid versus long-term humoral responses. Lymphocyte mobility and homing is modulated by the chemoattractant receptor subfamily of G protein-coupled receptors (GPCRs) (Campbell et al., 2003, Rot and von Andrian, 2004). B cell migration and position are controlled to a large extent by the lymphoid chemokines CXCL13, CXCL12, CCL19, and CCL21 and the regulated expression of their receptors CXCR5, CXCR4, and CCR7 (Allen et al., 2004, Forster et al., 1996, Forster et al., 1999, Hargreaves et al., 2001, Nie et al., 2004, Reif et al., 2002). Homing of B cells to B cell follicles is dependent on their expression of CXCR5 (Forster et al., 1996), whereas their movement to the B-T boundary after antigen encounter is directed by the rapid upregulation of CCR7 (Reif et al., 2002). As activated B cells differentiate into plasma cells, they downregulate CXCR5 and CCR7 and upregulate CXCR4, which is critical for their localization in the splenic red pulp and subsequent accumulation in the bone marrow (Hargreaves et al., 2001). Expression of CXCR5 is retained on B cells seeding GCs and, together with CXCR4, mediates the organization of GCs (Allen et al., 2004). Although differential expression of these chemokine receptors on plasma cells and GC B cell plays an important role in the localization of these populations to their distinct microenviroments, it is unclear whether additional factors contribute to the migration of activated B cells to extrafollicular sites versus follicular GCs.