Infiltration of inflammatory cells through brain endothelium.

The blood-brain barrier (BBB) restricts exchanges of soluble factors and cells between the blood and the brain, thus playing a crucial role in maintenance of cerebral homeostasis. It is composed of the endothelial cells that line the cerebral capillaries. Cerebral capillaries have a number of distinctive morphological characteristics, including the presence of tight intercellular junctions. Also, the cerebral capillaries are surrounded by astrocytic projections that exert a positive regulatory effect on BBB tightness. One effect of the BBB is that the number of leukocytes that patrol the central nervous system is far lower than in peripheral organs. Nevertheless, massive leukocyte infiltration occurs in some disease states: for instance, numerous activated leukocytes are found in the cerebral parenchyma in patients with multiple sclerosis, and HIV encephalitis is probably due to passage of HIV-infected monocytes through the BBB. Compelling evidence has been obtained that the perivascular astrocytes and microglial cells, as well as the cerebral endothelial cells, locally produce inflammatory cytokines that increase BBB permeability. Advances have also been made in the identification of leukocyte adhesion molecules expressed at the surface of cerebral endothelial cells. Expression of these molecules is induced by inflammatory cytokines. Interactions between these adhesion molecules and their leukocyte ligands may induce modifications within endothelial cells, including cytoskeleton reorganization and opening of intercellular junctions, which may allow leukocytes to cross the BBB. It is to be hoped that the new insights gained into the mechanisms of leukocyte penetration through the BBB may help to develop novel treatment strategies for neuroinflammatory disorders.