The role of the disruption of blood brain barrier
in the pathogenesis of Multiple Sclerosis
STAVROS J. BALOYIANNIS
1st Department of Neurology, Aristotelian University, Thessaloniki, Greece

Multiple Sclerosis has been considered for long time as a problematic, polymorphic, multidimensional neurological disease of unknown pathogenetic background. However in the last twenty years a substantial body of evidence, derived mainly from the model of the experimental allergic encephalomyelitis in rodents and the ongoing in vivo and in vitro research, clarified many of the pathogenetic mechanisms associated with the disease, suggesting that a perivascular autoimmune reaction is an early event in the successive phenomena of the pathogenetic cascade of Multiple Sclerosis. Increased permeability of the blood brain barrier is an early and crucial stage, often preceding the clinical manifestations of the disease, resulting in a substantial infiltration of the perivascular space by activated lymphocytes, monocytes, macrophages, chemokines, cytokines and other putative pro-inflammatory factors. The blood brain barrier is a dynamic and plastic anatomical and functional system, which plays, under normal conditions, an important always role, in establishing and maintaining the homeostasis in the central nervous system. The inter endothelial cell tight junctions, sealing the intercellular cleft, with the transmembranous and structural proteins, which are associated with the endothelial cells as well as the basal lamina of the capillaries, constitute structural and functional components of substantial importance, which regulate and control the transport of molecules across the vascular wall by various mechanisms, such as carrier mediated efflux and influx, receptor mediated transcytosis, absorptive mediated trancytosis and passive diffusion of molecular factors. The rough penetration of the blood brain barrier by activated lymphocytes in the initial attack of the multiple sclerosis is a multistep process triggering the perivascular inflammatory reaction resulting in the disintegration of the myelin sheath and the axonal degeneration. On a first step, an initial interaction occurs between the vascular cellular adhesion molecules, expressed by the endothelial cells and the integrins and the adhesion molecules, expressed by activated lymphocytes. On a second step, the extravasated activated lymphocytes pass through the extracellular matrix by virtue of alpha integrin and the matrix metalloproteases (MMP), inducing the complete anatomical and functional disruption of the blood brain barrier, which allows inflammatory cells and molecules to migrate across the vascular wall, gaining access to the white matter and the neuropial space of the central nervous system, therefore attacking subsequently and destroying the myelin sheath, which surrounds the myelinated axons. Induced expression of class II major histocompatibility complex (MHC) molecules, which occurs in macrophages and reactive microglial cells, plays also an important role in cell activation and in the maintenance of the immunologic reactions and further awareness, following the lymphocytic perivascular infiltration. Some predictions of the further course of the Multiple Sclerosis can be made from the range of the disruption of the blood brain barrier, as it is well visualized in the gadolinium enhanced MRI. An early repair of the blood brain barrier is essential in the treatment of Multiple Sclerosis. The administration of glycocorticoids and adrenocorticotrophic hormone temporarily ameliorate the clinical condition of the patients, reducing the perivascular edema by repairing the blood brain barrier partially. There is also a substantial body of evidence that beta interferon, which counteracts soluble mediator effects on tight junction integrity, may be beneficial in the early stage of the disease. Some critical issues in multiple sclerosis therapy may therefore include (a) the protection of the blood brain barrier in the initial stage of the disease by enforcing the action of the vascular cellular adhesion molecules, (b) the protection of the integrity of the basal lamina by anti a- integrin factors and matrix metalloproteinase inhibitors, (c) the inhibition of the VLA-4 molecule, which is claimed to be of crucial importance in the entry of cells in the perivascular neuropial space (d) the blocking of T cell receptor costimulatory proteins and (e) the administration of peroxynitrate scavengers and phosphodiesterase IV inhibitors. Further research on the initial stages of pathogenetic process of Multiple Sclerosis is essential in tracing new pathways for an efficient therapeutic approach of the disease.

Key words: Multiple sclerosis, blood brain barrier, ultrastructure.