Sentries at the gate: chemokines and the blood-brain barrier.

The blood-brain barrier (BBB) isolates the CNS from the rest of the organism. The anatomic foundation of this structure is a syncytium of cerebrovascular endothelial cells sealed together by tight junctions. The endothelial basal lamina, located at the abluminal side of endothelium, borders the perivascular (Virchow-Robin) space. The perivascular space is continuous with the subarachnoid compartment and is itself bordered by the glia limitans, formed by astrocytic and microglial end feet. Within the perivascular space, on either side of the endothelial basal lamina, dwell a unique population of phagocytic cells variously termed perivascular macrophages, perivascular microglia, perivascular cells or pericytes. These cells form a ®rst line of defense once the BBB is breached. Astrocytes are also important for BBB development and function: their processes attach to the basement membrane shared with the endothelial cells and perivascular cells. The close contact between astrocytes and brain endothelial cells suggests that both cell types interact in maintaining the function of the BBB, a bidirectional interaction that is mediated at least in part by cytokine-mediated signaling (Selmaj, 1996; Johansson, 1990). It is known that activated lymphocytes cross the intact BBB in the process of executing immunological surveillance of the CNS. T-cell migration into the normal CNS is antigen nonspeci®c and is contingent solely upon the activation state of the lymphocyte (Hickey et al, 1991; Wekerle et al, 1986). Leukocyte transmigration through a vascular endothelium involves a well-characterized multistep process of cell-cell interactions. Initial interactions between selectins on leukocytes and their receptors on endothelial cells slows down the circulating hematogenous cells, a state termed `rolling'. Rolling is permissive for activation of adhesion molecules (leukointegrins), which promote tight adhesion of leukocytes to vascular endothelium. Finally in ̄ammatory cells migrate through endothelium along concentrations gradients of chemokines (Springer, 1994). Lymphocytes bind to CNS endothelial cells with lower af®nity than to endothelium derived from other organs. After stimulation with proin ̄ammatory cytokines lymphocyte adhesion to cerebrovascular endothelium increases and becomes similar to that observed in other organs (Male et al, 1990). Perhaps, this fact may explain why during CNS in ̄ammatory conditions the BBB endothelium becomes permeable for hematogenous in ̄ammatory cells. Expression of the VLA-4 integrin by CD4 T cells is required for their migration into brain parenchyma in EAE. Moreover, antibodies to VLA-4 and its ligand VCAM-1 ameliorated pathogenicity of encephalitogenic cells in vivo (Baron et al, 1993; Yednock et al, 1992). A great deal of investigation of the BBB in in ̄ammation has focused on EAE. After BBB penetration and local encounter with antigens, lymphocytes initiate in ̄ammatory processes within the CNS parenchyma. It has been shown that there are two stages in homing of T lymphocytes to the CNS during EAE: initial selective and second nonselective, when clinical signs appear (Karin et al, 1993). Only a small number of in ̄ammatory *Correspondence: RM Ransohoff Received 4 August 1999; revised 8 September 1999; accepted 23 September 1999 Journal of NeuroVirology (1999) 5, 623 ± 634 ã