The blood-brain barrier in neuroimmunology: Tales of separation and assimilation

Abstract

Neuroimmunology is concerned with the relations between the central nervous and immune systems and with the mechanisms that drive those relations. The blood-brain barrier (BBB) employs mechanisms that both separate and connect these two systems. In fact, the relative immune privilege of the central nervous system (CNS) is largely attributable to the BBB's ability to prevent the unregulated exchange of immune cells and their secretions between the CNS and blood. Having separated the two systems, the BBB then participates in mechanisms that allow them to influence, communicate, and interact with one another. Likewise, the BBB itself is influenced by immune events that are occurring in the periphery and in the CNS so that these three components (the BBB, the immune system, and the CNS) form neuroimmune axes that adapt to physiological and pathological conditions. To date, four major themes have emerged by which the BBB participates in these neuroimmune axes. The first of these four, the formation of the barrier, acts to separate the immune and central nervous systems. The other three themes provide mechanisms for re-establishing communication: response of the BBB to immunomodulatory molecules (e.g., prostaglandins, cytokines, chemokines, nitric oxide) secreted by immune and CNS cells; the controlled, regulated exchange of chemokines, cytokines, and immune cells between the CNS and the blood (i.e., transport across the BBB); the secretion of immunomodulatory molecules by the BBB, often in a polarized fashion. Taken together, these mechanisms reveal the BBB to be a dynamic, interactive, and adaptable interface between the immune system and the CNS, separating them on the one hand and fostering their interactions on the other hand, adjusting to physiological changes, while being a target for disease processes. This review examines specific examples by which the BBB plays an interactive, defining role in neuroimmunology.

Keywords: Blood-brain barrier; Brain endothelial cell; Central nervous system; Cytokine; Immune cells; Neuroimmunology; Pericyte.

Figure 1

Illustrates with examples four mechanisms by which the BBB is central to neuroimmune phenomena. The barrier mechanism prevents the unregulated exchange of substances between the brain and the blood; IgG is given as an example. The responder mechanism means that BBB functions are altered by neuroimmune events; the downregulation of the brain-to-blood transporter p-glycoprotein is illustrated. The transporter mechanism allows certain molecules, most notably some cytokines/chemokines, to cross the BBB because of the presence of specific saturable transporter; the transport of TNF is given as an example. The secretor mechanism endows barrier cells with the ability to release immunoactive and immunomodulatory substances in response to neuroimmune events. The release of IL-6 in response to LPS is illustrated.

Figure 2

Integration of the four mechanisms of barrier, responder, transporter, and secretor allows intercellular crosstalk that is important to the adaption of the BBB to the needs of the CNS, adaption to neuroimmune events, and response to disease. The far right panel shows that transport of TNF across the BBB allows blood-borne TNF to interact with microglia, inducing the microglia to release more TNF, which can induce apopotosis in dopaminergic cells at the substantia nigra. The middle panel shows that LPS enhances insulin transport across the BBB by acting indirectly on other cell types, including circulating lymphocytes, to induce them to release substances that then act at the brain endothelial cell. The final panel shows that pericytes induce the insulin transporter in monolayers of brain endothelial cells. It also illustrates that a complex, three step cross-talk between brain endothelial cells pericytes can further induce the LPS-enhanced passage of HIV-1 across the BBB: 1) LPS acts on the luminal side of the brain endothelial cell to 2) induce it to release factors from its abluminal side that act on the pericyte, 3) inducing the pericyte to release substances that then act on the brain endothelial cell to accelerate HIV-1 passage across the BBB.