Involvement of Junctional Adhesion Molecules in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

In the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) leukocyte migration into the central nervous system (CNS) has been defined as key-event. Circulating leukocytes enter the CNS by crossing either the highly specialized endothelium forming the blood–brain-barrier (BBB) or the epithelium establishing the blood–cerebrospinal fluid barrier (BCSFB). Junctional adhesion molecule (JAM)-A is expressed in tight junctions of both barriers as well as by different leukocyte subsets while JAM-B is exclusively expressed by endothelial cells. Both JAM-A and JAM-B have been implicated in leukocyte adhesion and diapedesis across endothelial barriers of peripheral vascular beds. We detected an up-regulation of JAM-A during inflammatory conditions of MOGaa35–55-induced EAE in the BBB vasculature, BCSFB epithelium, and on microglial cells. At sites of leukocyte infiltration JAM-A was exposed on the luminal side of BBB endothelial cells, indicating an active involvement in leukocyte extravasation. In JAM-A−/− mice MOGaa35–55-induced EAE was milder and delayed compared to wildtype littermates. These findings were accompanied by a reduction of infiltrating leukocytes into the spinal cord, while MOG-specific T cell priming was not affected. Investigations of the BBB integrity in the absence of JAM-A using primary mouse brain microvascular endothelial cells (pMBMECs) revealed monolayer maintenance and a role for JAM-A in monocyte diapedesis but not of encephalitogenic T cells across pMBMECs in vitro. The importance of JAM-A in monocyte migration was confirmed by the presence of fewer infiltrating monocytes but not T cells in the CNS of JAM-A−/− mice compared to wildtpye littermates during EAE. So far our data demonstrate a role for JAM-A in EAE pathogenesis by specifically regulating monocyte but not T cell recruitment across the inflamed BBB. In ongoing studies we investigate the role of JAM-B in the pathogenesis of EAE.