Multiple sclerosis and the blood-central nervous system barrier

Abstract

The central nervous system (CNS) is isolated from the blood system by a physical barrier that contains efflux transporters and catabolic enzymes. This blood-CNS barrier (BCNSB) plays a pivotal role in the pathophysiology of multiple sclerosis (MS). It binds and anchors activated leukocytes to permit their movement across the BCNSB and into the CNS. Once there, these immune cells target particular self-epitopes and initiate a cascade of neuroinflammation, which leads to the breakdown of the BCNSB and the formation of perivascular plaques, one of the hallmarks of MS. Immunomodulatory drugs for MS are either biologics or small molecules, with only the latter having the capacity to cross the BCNSB and thus have a propensity to cause CNS side effects. However, BCNSB penetration is a desirable feature of MS drugs that have molecular targets within the CNS. These are nabiximols and dalfampridine, which target cannabinoid receptors and potassium channels, respectively. Vascular cell adhesion molecule-1, present on endothelial cells of the BCNSB, also serves as a drug discovery target since it interacts with α4-β1-integrin on leucocytes. The MS drug natalizumab, a humanized monoclonal antibody against α4-β1-integrin, blocks this interaction and thus reduces the movement of immune cells into the CNS. This paper further elaborates on the role of the BCNSB in the pathophysiology and pharmacotherapy of MS.

Figure 1

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].