ABSTRACT
The inflammatory process that leads to demyelination and axonal injury in patients with relapsing multiple sclerosis (MS) has been shown to be closely linked to the infiltration of leukocytes into the central nervous system (CNS)1-3. The accumulation of lymphocytes and monocytes in the CNS is a highly regulated process involving factors that promote migration across the blood-brain barrier and that support leukocyte proliferation and survival within the CNS3. The expression of activated adhesion molecules on the surface of lymphocytes and monocytes is required for migration across the blood-brain barrier. One such adhesion molecule is α4β1 integrin, a glycoprotein expressed on the surface of activated lymphocytes, monocytes, mast cells, macrophages, basophils and eosinophils (but not neutrophils)4. A major ligand for α4β1 integrin is vascular cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells (including those of the brain and spinal cord blood vessels)4,5. Expression of both α4β1 integrin and VCAM-1 has been shown to be increased in chronic MS plaques5. Under the control of proinflammatory cytokines, activation of
α4β1 integrin and its interaction with VCAM-1 mediates the adhesion and passage of activated lymphocytes and monocytes into inflamed areas of the CNS4,6-8. The interaction of α4β1 integrin with additional ligands, such as fibronectin4 and osteopontin9, may modulate survival, priming or activation of leukocytes that have gained access to CNS parenchyma, further contributing to the inflammation cascade.
