In multiple sclerosis, barriers
that guard the brain become leaky, allowing some disease-causing immune cells
to invade. Now scientists have identified a key molecule in the process that helps
B cells breach the barriers.
ALCAM, a protein produced by
B cells, helps the immune cells sneak into the central nervous
system, researchers report November
13 in Science Translational Medicine.
Tests in mice and in artificial human brain barriers show that B cells without
ALCAM, or activated leukocyte cell adhesion molecule, had trouble getting
through the brain’s barriers. And in mice with a disease with some characteristics
similar to MS, blocking ALCAM seemed to alleviate the disease’s severity. These
early results indicate that the protein may be a good target for new treatments
for multiple sclerosis in people, the researchers say.
“This is a very important
puzzle piece in how we understand multiple sclerosis,” says David Leppert, a
neurologist at the University Hospital Basel in Switzerland who was not
involved in the work. “How it translates into clinical applications is yet
Worldwide, over 2.3 million people have multiple sclerosis, including nearly 1 million adults in the United
States. Scientists think that rogue immune cells invade the brain and strip
away the protective coating on nerve cells — leading to neurological issues and physical
disability as the disease progresses. There’s no cure, and treatments don’t
work for advanced stages of multiple sclerosis.
Scientists have developed over
a dozen medications to treat MS symptoms (SN: 11/29/17),
one of which uses antibodies to destroy the body’s B cells. But that approach
weakens patients’ immune systems, opening the door
for future infections or cancer. In the new study, the researchers are instead focusing
on preventing disease-causing B cells from entering the brain.
“We’re trying to block
specific molecules that promote migration of immune cells into the brain, but
leave the immune surveillance of the rest of the body intact,” says neuroscientist
Alexandre Prat of the University of Montreal Hospital Research Centre. “In
order to migrate into the brain, the B cell needs ALCAM. If you block ALCAM,
you block the progression of the disease.” Prat and his colleagues previously tested this idea with T cells, another type of immune cell implicated in MS, but
found that ALCAM isn’t involved in helping these cells infiltrate the brain.
Prat and his team gave the
mice antibodies that attack ALCAM. While blocking the protein slowed the
progression of the mice’s disease, it didn’t prevent its onset. Mice with more
severe cases of the disease also had more B cells in their brains, suggesting
that disease severity is related to the amount of B cell infiltration into the
The researchers also tested
the molecular mechanism using artificial human brain barriers called Boyden
chambers as stand-ins for real human brains. The scientists grew cells, taken from
the barriers that protect the brain in humans, on a
mesh filter. Most of the B cells that got through the artificial barriers had
ramped up ALCAM production. Blocking ALCAM reduced the number of B cells that made
it across, though it’s unclear how the protein may help these cells traverse that
Tests with the artificial human barriers also suggested
that B cells tend to cross at a different entry point in humans than in mice. Twice
as many B cells broke through an artificial version of the blood-meningeal
barrier — near the protective membranes surrounding the outside of the brain —
than the artificial blood-brain barrier around blood vessels that penetrate
deeper into the brain.
In brain samples from MS patients, the
scientists also saw B cells with elevated ALCAM near the membranes surrounding
the brain and in the brain lesions that characterize multiple sclerosis.
A hypothetical drug blocking ALCAM, if it
works in people, may decrease the flow of disease-causing immune cells that get
into the brain and wreak havoc, Prat says. “There’s an unmet need in the field
of multiple sclerosis,” he says. “We still have no medication to really control
the progressive phase of the disease,” when the disease can cause severe
physical disability and neurological deterioration.