Breaching the blood-brain barrier

[Guest guest]

Breaching the blood-brain barrier

Posted by Edyta Zielinska

[Entry posted at 23rd March 2009 04:21 PM GMT]

View comment(1) | Comment on this news story

http://www.the-scientist.com/blog/display/55517/

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 choroid plexus is a doorway

into the brain for T lymphocytes.

Image: Elston/

LifeSpan BioSciences, Inc.

" This study certainly refines our understanding on how inflammatory cells cross

the blood-brain barrier, " said clinical immunologist Ralf Linker at St

f-Hospital/Ruhr-University Bochum, who was not involved in the research.

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:

Blood-brain barrier bypassed

[24th April 2007]

MS drug sickens patient...again

[16th December 2008]

The Art of Adapting to MS

[May 2007]