Editorial [ Hot Topic: The Blood-Brain Barrier as a Cause of Disease (Executive Editor: William A. Banks) ]

Over 100 years ago, experiments were conducted that showed an inability of selected blood-borne substances to enter the central nervous system (CNS). These experiments served as the basis of the concept of a blood-brain barrier (BBB). Research in subsequent decades expanded our understanding of the blood-brain barrier. The last 40 years in particular has elucidated the ultrastructural basis for the restrictive aspects of the BBB, shown that the BBB is endowed with a myriad of transporters, is composed of endothelial, epithelial, and tanycytic arms, regulates the flux of immune cell trafficking into the brain, and secretes a wide number of substances [1]. Transport systems supply the brain with glucose, amino acids, vitamins, electrolytes, and minerals and remove from the brain toxins, both endogenous and exogenous. The BBB regulates an exchange of informational molecules between the CNS and peripheral tissues. The BBB secretes prostaglandins, nitric oxide, and cytokines into both the blood and the CNS. All these activities of the BBB are themselves regulated and slave to the needs of the CNS. They help the CNS maintain the homeostatic and nutritive environment critical to survival and provide mechanisms for communication between the brain and peripheral tissues. As such, the BBB is not simply a barrier, but a regulatory interface between the CNS and blood. What happens when some complex function of the BBB fails? Could dysregulation of a function of the BBB cause disease? The role of the BBB in diseases of the CNS has long been appreciated. However, its roles have generally been viewed either in terms of drug delivery across the BBB or as the BBB being targeted by disease processes. But the complexity and importance of the BBB makes it clear that dysregulation or failure of its processes or an inability to respond to the needs of the CNS could lead to disease states. In such a case, the BBB itself becomes the therapeutic target. This special issue examines some of the conditions in which BBB dysfunction seems to play a primary causal role in disease. Although this has been a neglected view, there are clear precedents to such a concept. Disruption of BBB integrity with extremely high blood pressures leads to hypertensive encephalopathy [2] and a deficiency of glucose transporters at the BBB underlies a familial form of mental retardation [3]. This issue also explores the physiological and pathological underpinnings which may predispose the BBB to be a seat of disease. Multiple sclerosis has long been viewed as a classic disease of the BBB [4]. Invasion of the CNS by immune cells is key to the pathophysiology of multiple sclerosis. However, the immune cells do not “leak” across a disrupted BBB. Even in advanced disease, the trafficking of immune cells into the CNS is a highly regulated, multi-staged process, termed diapedesis. Understanding this process will lead to better treatments for multiple sclerosis, as has already occurred with the introduction of anti-alpha 4-integrins. Whereas this improved understanding may help us to keep immune cells out in multiple sclerosis, it may also help us to get more immune cells into the brain; the latter would be desirable after bone marrow transplantation for the treatment of lysosomal storage diseases [5]. We now know that immune cell trafficking occurs normally in healthy adults as part of immunosurveillance. This mostly occurs at the post-capillary venule. Thus, a type of regional specification of the BBB architecture is illustrated. This is recapitulated by pericyte specification in that arteriolar, but not capillary pericytes, typically possess alpha smooth muscle actin [6]. The BBB also shows variation among brain regions in susceptibility to disruption in diabetes [7] and the rate at which informational molecules such as cytokines are transported across the BBB [8]. A disease in which the BBB was thought to be relatively preserved is diabetes mellitus. However, this has changed dramatically in recent years [9]. As reviewed by Huber, several BBB transporters are now known to be altered, including p-glycoprotein and those for insulin and leptin [10]. Huber's review emphasizes recent findings that the vascular BBB also becomes disrupted with time, especially to the smaller vascular marker molecules such as sucrose and inulin. Susceptibility of the BBB to disruption shows a high degree of regional susceptibility in diabetes, again demonstrating that all regions of the BBB are not identical.......