ReviewThe blood–brain barrier and immune function and dysfunction
Introduction
Interactions between the immune system and the central nervous system (CNS) are increasingly recognized. The mechanisms by which the immune system and CNS interact are numerous, but share a common conceptual theme of the transfer of information from one system to the other. Two broad categories of the mechanisms of interaction are nervous transmission and humoral transmission. Afferent and efferent nerves, exemplified by the vagus, form a neuroimmune link between the CNS with peripheral tissues as diverse as the gastrointestinal tract, spleen, and soft palate. Humoral transmission relies on the blood stream to deliver products of the peripheral immune system to the brain and to convey secretions of the brain to elements of the peripheral immune system. However, the circulation through the brain differs from that of most peripheral tissues in that the capillary bed of the brain does not produce an ultrafiltrate (Reese and Karnovsky, 1967, Broman, 1950). This lack of leakage is a main basis underlying the concept of the blood–brain barrier (BBB). This review will concentrate on the role the BBB plays in both separating and conjoining the immune and central nervous systems. It will focus on 4 aspects of BBB–neuroimmune interactions: BBB disruption, cytokine transport across the BBB, immune cell trafficking, and effects of lipopolysaccharide (LPS) on the BBB.
Section snippets
Relevant concepts of the BBB
The BBB can be conceptualized as those mechanisms that control the exchange of substances between the blood and the fluids of the brain. The concept of the BBB arose from studies in the late 19th century that found that basic dyes injected into the blood did not stain the brain and that bile acids produced seizures when directly injected into the brain but not when injected peripherally (Davson, 1967). The dyes and bile acids were prevented from entering the brain because they bound tightly to
Neuroimmune interactions with the BBB
Nearly every category of BBB function is involved with the neuroimmune system. Table 2 lists some examples of these interactions and is by no means exhaustive. As detailed below, these interactions between the BBB and the neuroimmune system are likely involved in physiologic regulation, in adaptions to stress, and in disease processes. Currently, much more is known about how the BBB is involved in or responds to the neuroimmune system than about the consequences of those responses. The rest of
Disruption of the BBB
Early work showed that LPS can disrupt the BBB (Wispelwey et al., 1988). Subsequent studies showed that tumor necrosis factor-alpha (TNF) could mediate some of these actions and likely did so by processes that involved cytoskeletal rearrangement (Quagliarello et al., 1991, Deli et al., 1995). Early work with interleukin-2 (IL-2) suggested it also disrupted the BBB (Ellison et al., 1987), but subsequent work could not replicate this effect of IL-2 (Banks and Kastin, 1992) and suggested that
Cytokine transport across the BBB
Numerous cytokines have been found to be transported across the BBB by saturable transport systems (Banks, 2005, Pan and Kastin, 2008). The BBB has cytokine binding sites that alter intracellular function (receptors) or convey the cytokine across the BBB (transporters). In some cases, the transporter seems to be a product of the same gene encoding for the cytokine receptor involved in activating intracellular machinery. For example, both the p75 and p55 receptor for tumor necrosis factor-alpha
Immune cell trafficking
Passage of immune cells across the BBB depends upon an elaborate interaction between the immune cell and the BBB termed diapedesis. Most studies have not been in normal animals but in models of multiple sclerosis (MS). The most commonly used animal models in the study of MS are those of experimental autoimmune encephalomyelitis (EAE,) which is induced by generating a T-cell-mediated autoimmune response against CNS antigen (Lassmann, 2008). Origins of this model date back to the late 1800s, when
LPS actions at the BBB
LPS has numerous effects on the BBB. Originally, LPS was noted to disrupt the BBB (Wispelwey et al., 1988). Since then LPS has been noted to affect BBB permeability in other ways. It increases absorptive endocytosis, a process that depends on interactions of glycoproteins on the surface of the cell composing the BBB with glycoproteins of the transported moiety (Banks et al., 1999). The human immunodeficiency virus and its surface coat glycoprotein gp120 can enter the brain by this mechanism and
Conclusions
The BBB is intimately involved with the neuroimmune system. Indeed, its physical location divides and so defines these two compartments. Pathological disruption of the BBB by LPS and cytokines was the first clear interaction between the neuroimmune system and the BBB. Other interactions include immune cell trafficking, transport of cytokines, modulation of BBB saturable transport systems and other mechanisms of permeation, and secretion of neuroimmune substances by the BBB. These mechanisms of
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