The Scientist: NewsBlog:
Breaching the blood-brain barrier
Posted by Edyta Zielinska
[Entry posted at 23rd March 2009 04:21 PM GMT]
Researchers have identified a novel mechanism by which immune cells wiggle their way across the blood-brain barrier in diseases such as multiple sclerosis (MS). A type of T-cell involved in autoimmune disease leads the way, entering the brain and perhaps priming the blood-brain barrier's membrane to attract other immune cells -- opening the door for those cells to do their inflammatory damage, according to a study published online yesterday (Mar 22) in Nature Immunology.
The blood-brain barrier is a selectively permeable interface between brain tissue and circulating molecules and cells. For years, researchers studying MS have used a mouse model of the disease, experimental autoimmune encephalomyelitis (EAE), to try to untangle how immune cells make their way across the blood-brain barrier to initiate inflammation in the brain. Federica Sallusto at the Institute for Research in Biomedicine in Switzerland and her colleagues attacked the problem by looking at one likely candidate: a recently-discovered T-cell called Th-17 that plays an important role in mediating autoimmune diseases. Th-17's physiological mechanism is still unknown, and its role in MS inflammation has been controversial. Sallusto and her team knocked out a receptor on Th-17's surface that helps direct its movement, and found that the knockout mice didn't develop EAE. The researchers also traced the path of Th-17 cells expressing the receptor, CCR6, in normal brains. CCR6's ligand, they observed, was highly expressed in an area of the brain called the choroid plexus -- suspected as an entry-point for inflammatory immune cells -- suggesting that the trafficking receptors lead Th-17 cells there. Normal brains express CCR6's ligand, and Th-17 cells may even enter the brain as part of routine immuno-surveillance, Sallusto explained. In the study, Sallusto's group used Th-17 cells which had been exposed to a myelin protein to make them reactive against the myelin in brain tissue. Once the primed Th-17 cells entered the brain, they initiated an inflammatory response, recruiting other immune cells to cross the blood-brain barrier. The researchers suspect that the Th-17 cell inflammatory reaction acts to weaken the blood-brain barrier by stimulating the surface of capillary epithelia to express adhesion molecules, the first step of immune cell entry from blood to tissue. Th-17 cells may also release cytokines, which attract other inflammatory cells to the area. Patients with MS are generally treated with factors that block inflammatory cells from entering the brain, but many of these drugs dampen cells that are necessary for fighting normal infection and have numerous side-effects. If the CCR6 and its ligand work similarly in humans, blocking the process could inhibit the first stage of inflammation in MS, the researchers suggest. "Certainly, further functional studies on human Th-17 cells are necessary here," said Linker. One caveat, said Sallusto, is that while such a strategy might help prevent recurring MS, in which the patient suffers flares or relapses of inflammation, it may not help patients with full blown MS, since CCR6's job is to facilitate initial access to the brain. Related stories: [24th April 2007] [16th December 2008] [May 2007] |
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Nice
by Donald Duck
[Comment posted 2009-03-23 20:36:23]
[Comment posted 2009-03-23 20:36:23]
Interesting. Makes sense, but still interesting.
The nature of the blood-brain barrier and its functional implications.
by Les Simpson
[Comment posted 2009-03-23 15:17:25]
[Comment posted 2009-03-23 15:17:25]
Capillaries are the sole means by which oxygen and nutrient substrates are delivered to tissues so the capillary wall acts as a size-dependent filter. The capillary wall comprises a basement membrane lined by endothelial cells.
Although the brain capillaries have endothelial cells with tight junctions, in order to perform their usual function, at some stage the tight junctions must break down, temporarily.
The most permeable capillaries have fenestrated endothelium as in the renal glomerulus and in the third ventricle so the basement membrane is the only barrier.
In 1980 I proposed that basement membranse have the property of thixotropic gels and thus exhibit pressure-dependent permeability. The effects were demonstrable by increasing blood viscosity which increased the size of the proteins in the urine. The general concept was that the membrane was a gel through which water and small molecules passed without change in the membrane. But large molecules (and cells ) had to have sufficient kinetic energy to dislodge the gel units which were replaced after the molecule passed. A German time-lapse cinematograph showed a white cell push a pseudopodium through a basement membrane and the cell followed, showing the hour-glass shape as it traversed the membrane. No breach in the membrane could be demonstrated after the cell passed through the membrane, indicating its self-repair. Warfel and Hull have reported similar observations.
It is possible that the immune-related breaches of the BBB may relate to a viscosity-related rise in intra-capillary pressure.
Although the brain capillaries have endothelial cells with tight junctions, in order to perform their usual function, at some stage the tight junctions must break down, temporarily.
The most permeable capillaries have fenestrated endothelium as in the renal glomerulus and in the third ventricle so the basement membrane is the only barrier.
In 1980 I proposed that basement membranse have the property of thixotropic gels and thus exhibit pressure-dependent permeability. The effects were demonstrable by increasing blood viscosity which increased the size of the proteins in the urine. The general concept was that the membrane was a gel through which water and small molecules passed without change in the membrane. But large molecules (and cells ) had to have sufficient kinetic energy to dislodge the gel units which were replaced after the molecule passed. A German time-lapse cinematograph showed a white cell push a pseudopodium through a basement membrane and the cell followed, showing the hour-glass shape as it traversed the membrane. No breach in the membrane could be demonstrated after the cell passed through the membrane, indicating its self-repair. Warfel and Hull have reported similar observations.
It is possible that the immune-related breaches of the BBB may relate to a viscosity-related rise in intra-capillary pressure.
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