A protein helps disease-causing immune cells invade MS patients’ brains

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 another question.”

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 brain.

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 barrier.

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.