Immune cells enter the central nervous system (CNS) from the circulation under normal conditions for immunosurveillance and in inflammatory neurologic diseases. This review describes the distinct anatomic features of the CNS vasculature that permit it to maintain parenchymal homeostasis and which necessitate specific mechanisms for neuroinflammation to occur. We review the historical evolution of the concept of the blood-brain barrier and discuss distinctions between diffusion/transport of

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... es and migration of cells from the blood to CNS parenchyma. The former is regulated at the level of capillaries, whereas the latter takes place in postcapillary venules. We summarize evidence that entry of immune cells into the CNS parenchyma in inflammatory conditions involves 2 differently regulated steps: transmigration of the vascular wall into the perivascular space and progression across the glia limitans into the parenchyma. FIGURE 4. Multistep paradigm for leukocyte entry to the central nervous system (CNS). In the first step of neuroinflammation circulating, immune cells engage in a multistep interaction with CNS microvascular endothelial cells that they cross by either transcellular or paracellular routes. After passing through the endothelial basement membrane (EBM), they reach the perivascular space (PVS). After additional activation triggers that are probably provided by perivascular macrophages or dendritic cells, MMP-2 and MMP-9 are produced and allow the second-step immune cell entry across the glia limitans or pavenchymal basement membrane (PBM) into the CNS parenchyma.