Blood-Brain Barrier Disruption In Multiple Sclerosis
Minagar A, Alexander JS
Mult Scler 2003 Dec;9(6):540-9
Louisiana State University Health Sciences Center, Department of Neurology, Shreveport, LA 71130, USA
The Blood-Brain Barrier (BBB) is a complex organization of Cerebral Endothelial Cells (CEC), Pericytes and their basal lamina, which are surrounded and supported by Astrocytes and PeriVascular Macrophages.
Collectively these cells separate and form the compartments of the Cerebral Vascular space and the Cerebral Interstitium under normal conditions.
Without the BBB, the 'interior milieu' of the Central Nervous System (CNS) would be flooded by Humoral NeuroTransmitters and formed blood elements that upset normal CNS functions and lead to Vascular/Neural Injury.
Dysregulation of the BBB and TransEndothelial migration of activated Leukocytes are among the earliest CerebroVascular abnormalities seen in Multiple Sclerosis (MS) Brains and parallel the release of inflammatory Cytokines/Chemokines.
Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these Cytokines/ Chemokines on Endothelial regulation of BBB components, as well as indirect Cytokine/Chemokine-dependent Leukocyte mediated injury.
Unique Endothelial structural features of the BBB include highly organized Endothelial Tight Junctions, the absence of Class II Major Histocompatibility Complex, abundant Mitochondria and a highly developed transport system in CEC.
Exposure of Endothelium to ProInflammatory Cytokines (IFN-γ, TNF- and IL-1ß) interrupts the BBB by disorganizing cell-cell junctions, decreases the Brain solute barrier, enhances Leukocyte Endothelial Adhesion and migration.
As well as increases expression of Class II MHC and promotes shedding of Endothelial 'MicroParticles' (EMP).
In this review we examine interactions between Cytokines/Chemokines, activated Leukocytes, Adhesion Molecules and activated CEC in the pathogenesis of BBB failure in MS.
Tight Junctional Abnormality In Multiple Sclerosis White Matter Affects All Calibres Of Vessel And Is Associated With Blood-Brain Barrier Leakage And Active DeMyelination
Kirk J, Plumb J, Mirakhur M, McQuaid S
J Pathol 2003 Oct;201(2):319-27
Queen's University of Belfast, School of Medicine Inflammation Research Centre, Northern Ireland, UK
Blood-Brain Barrier (BBB) HyperPermeability in Multiple Sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in MicroVascular Tight Junctions (TJs).
This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage.
Frozen sections from plaque and Normal-Appearing White Matter (NAWM) in 14 cases were studied together with White Matter from six neurological and five normal controls.
Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein Zonula Occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to Fibrinogen leakage.
Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control White Matter.
These were frequent in oil-red O (ORO)(+) active plaques, affecting 42% of vessel segments, but less frequent in ORO(-) inactive plaques (23%), NAWM (13%), and normal (3.7%) and Neurological controls (8%).
A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators.
In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most Fibrinogen leakage.
This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage.
It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage.
TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process.
In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy.
Copyright 2003 John Wiley & Sons, Ltd.
The Complementary Membranes Forming The Blood-Brain Barrier
Hawkins RA, Peterson DR, Vina JR
IUBMB Life 2002 Sep;54(3):101-7
Finch University of Health Science/The Chicago Medical School, Department of Physiology and Biophysics, North Chicago, Illinois 60064-3095, USA
Brain Capillary Endothelial Cells form the Blood-Brain Barrier. They are connected by extensive Tight Junctions, and are polarized into Luminal (Blood-facing) and AbLuminal (Brain-facing) plasma membrane domains.
The polar distribution of transport proteins allows for active regulation of Brain ExtraCellular Fluid.
Experiments on isolated membrane vesicles from Capillary Endothelial Cells of bovine Brain demonstrated the polar arrangement of Amino Acid and Glucose transporters, and the utility of such arrangements have been proposed.
For instance, passive carriers for Glutamine and Glutamate have been found only in the Luminal membrane of Blood-Brain Barrier Cells, while Na-dependent secondary active transporters are at the AbLuminal membrane.
This organization could promote the net removal of Nitrogen-rich Amino Acids from Brain, and account for the low level of Glutamate penetration into the Central Nervous System.
Furthermore, the presence of a gamma-Glutamyl cycle at the Luminal membrane and Na-dependent Amino Acid transporters at the AbLuminal membrane may serve to modulate movement of Amino Acids from Blood-to-Brain. Passive carriers facilitate Amino Acid transport into Brain.
However, activation of the gamma-Glutamyl cycle by increased plasma Amino Acids is expected to generate OxoProline within the Blood-Brain Barrier.
OxoProline stimulates secondary active Amino Acid transporters (Systems A and B(o)+) at the AbLuminal membrane, thereby reducing net influx of Amino Acids to Brain.
Finally, passive Glucose transporters are present in both the Luminal and AbLuminal membranes of the Blood-Brain Barrier.
Interestingly, a high affinity Na-dependent Glucose carrier has been described only in the AbLuminal membrane. This raises the question whether Glucose entry may be regulated to some extent.
Immunoblotting studies suggest more than one type of passive Glucose transporter exist in the Blood-Brain Barrier, each with an asymmetrical distribution.
In conclusion, it is now clear that the Blood-Brain Barrier participates in the active regulation of Brain ExtraCellular Fluid, and that the diverse functions of each plasma membrane domain contributes to these regulatory functions.
Astrocyte-Endothelial Interactions And Blood-Brain Barrier Permeability
J Anat 2002 Jun;200(6):629-38
Centre for NeuroScience Research, King's College London, UK
The Blood-Brain Barrier (BBB) is formed by Brain Endothelial Cells lining the Cerebral MicroVasculature, and is an important mechanism for protecting the Brain from fluctuations in plasma composition.
And, from circulating agents such as NeuroTransmitters and XenoBiotics capable of disturbing Neural function.
The Barrier also plays an important role in the homeostatic regulation of the Brain MicroEnvironment necessary for the stable and co-ordinated activity of Neurons.
The BBB phenotype develops under the influence of associated Brain Cells, especially Astrocytic Glia, and consists of more complex Tight Junctions than in other Capillary Endothelia
And, a number of specific Transport and Enzyme Systems which regulate molecular traffic across the Endothelial Cells.
Transporters characteristic of the BBB phenotype include both uptake mechanisms (e.g. GLUT-1 Glucose carrier, L1 Amino Acid transporter) and efflux transporters (e.g. P-GlycoProtein).
In addition to a role in long-term Barrier induction and maintenance, Astrocytes and other cells can release chemical factors that modulate Endothelial permeability over a time-scale of seconds to minutes.
Cell culture models, both primary and cell lines, have been used to investigate aspects of Barrier induction and modulation.
Conditioned medium taken from growing Glial Cells can reproduce some of the inductive effects, evidence for involvement of diffusible factors.
However, for some features of Endothelial differentiation and induction, the ExtraCellular Matrix plays an important role.
Several candidate molecules have been identified, capable of mimicking aspects of Glial-Mediated Barrier induction of Brain Endothelium; these include TGF-beta, GDNF, bFGF, IL-6 and steroids.
In addition, factors secreted by Brain Endothelial Cells including Leukaemia Inhibitory Factor (LIF) have been shown to induce Astrocytic differentiation. Thus Endothelium and Astrocytes are involved in two-way induction.
Short-term modulation of Brain Endothelial permeability has been shown for a number of small chemical mediators produced by Astrocytes and other nearby cell types.
It is clear that Endothelial Cells are involved in both long- and short-term chemical communication with neighbouring cells, with the PerivVascular End Feet of Astrocytes being of particular importance.
The role of Barrier induction and modulation in normal physiology and in pathology is discussed.