The role of cell adhesion molecules in the movement of activated T cells and natural killer cells across the blood-CNS barrier. (a) Tethering through the interaction of glycosylated PSGL-1 on leukocytes and P-selectin on endothelial cells. (b) Rolling of leukocytes along endothelial cells. (c) Integrin activation on leukocytes. (d) Firm adhesion through the interaction of α4β1-integrin and vascular cell adhesion molecule-1 expressed on the endothelial cell layer. (e) Paracellular movement of immune cells into CNS parenchyma (extravasation). (f) Presence of leukocytes in CNS parenchyma. (g) Once in CNS parenchyma, leukocytes increase in number by clonal expansion and then attack the entire supramolecular complex of myelin. This includes (i) a critical antibody response to various myelin proteins and lipids, (ii) initiation of the complement cascade and T and natural killer cell attack of certain key portions of various myelin antigens and (iii) release of cytokines, notably tumour necrosis factor, which stimulates macrophages, microglia and astrocytes, to produce nitric oxide [45].