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Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule found on blood-brain barrier endothelial cells (BBB-ECs) that was previously shown to be involved in leukocyte transmigration across the endothelium. In the present study, we found that ALCAM knockout (KO) mice developed a more severe myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE). The exacerbated disease was associated with a significant increase in the number of CNS-infiltrating proinflammatory leukocytes compared with WT controls. Passive EAE transfer experiments suggested that the pathophysiology observed in active EAE was linked to the absence of ALCAM on BBB-ECs. In addition, phenotypic characterization of unimmunized ALCAM KO mice revealed a reduced expression of BBB junctional proteins. Further in vivo, in vitro, and molecular analysis confirmed that ALCAM is associated with tight junction molecule assembly at the BBB, explaining the increased permeability of CNS blood vessels in ALCAM KO animals. Collectively, our data point to a biologically important function of ALCAM in maintaining BBB integrity.

© 2014 WILEY VCH Verlag GmbH Co. KGaA Weinheim. The extravasation of CD4+ effector/memory T cells (TEM cells) across the blood brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM 1 and ICAM 2 are essential for CD4+ TEM cell crawling on the BBB prior to diapedesis. Here we investigated the influence of cell surface levels of endothelial ICAM 1 in determining the cellular route of CD4+ TEM cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions inducing high levels of endothelial ICAM 1 promoted rapid initiation of transcellular diapedesis of CD4+ T cells across the BBB while intermediate levels of endothelial ICAM 1 favored paracellular CD4+ T cell diapedesis. Importantly the route of T cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly a low number of CD4+ TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM 1 and ICAM 2 via an obviously alternatively regulated transcellular pathway. In vivo this translated to the development of ameliorated EAE in ICAM 1null//ICAM 2 / C57BL/6J mice. Taken together our study demonstrates that cell surface levels of endothelial ICAM 1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T cell diapedesis across the BBB.