Fixing Leaky Blood-Brain Barrier May Help Treat Multiple Sclerosis


In multiple sclerosis, immune cells break through the blood-brain barrier and attack nerve cells.

New video footage is now revealing the paths those cells use to breach this barrier—some slip through weak spots in the barrier, while others travel in tiny particles across the cells that make up this barrier—and giving scientists ideas about how to stop the cells from entering the brain.

In the healthy central nervous system, the blood-brain barrier is constructed from a tightly packed layer of endothelial cells that line blood vessels, keeping viruses and toxins that are circulating in the bloodstream from slipping into the brain and/or spinal cord. In people with MS, this barrier becomes more porous, and immune cells slip past and attack the myelin that surrounds nerve cells.

Using new microscopy techniques that allow researchers to visualize contacts between endothelial cells in the spinal cord of living mice, Dritan Agalliu, PhD, assistant professor of pathology & cell biology (in neurology and pharmacology) at Columbia, examined the contact points between the barrier’s endothelial cells in a strain of mice with a condition similar to MS.

"The first thing we found is that contacts between endothelial cells—the so-called tight junctions—break down very early in the course of MS, before we see any clinical manifestations,” said Dr. Agalliu, whose findings were reported in Cell Reports. “This is the first in vivo evidence that blood-brain barrier dysfunction is an early and prominent feature of the disease.”

Dr. Agalliu also saw that immune cells were able to exploit loose junctions to cross the barrier and enter the brain. One type of immune cell, Th17, slips through the loosened cell junctions, while another immune cell, Th1, is transported across the endothelial cell via small vesicles and released into the central nervous system. In mice lacking these specialized vesicles, few Th1 cells are found in the central nervous system of mice with MS, reducing their symptoms.

“Tightening loose junctions and targeting this transportation system across the damaged blood-brain barrier could potentially prevent both types of immune cells from entering the nervous system and reduce or halt disease progression,” Dr. Agalliu said.

Dr. Agalliu’s team has already identified one way in which the blood-brain barrier could be repaired in MS. In a study published in the January 2017 issue of the Proceedings of the National Academy of Sciences, they found that Wnt signaling, which is important for the formation of the blood-brain barrier, can partially restore blood-brain barrier function in MS by reducing the number of vesicles that transport Th1 lymphocytes and by blocking expression of proteins that allow immune cells to bind to blood vessels. However, the experiments also revealed that Wnt signaling alone is not sufficient to restore damaged junctions between endothelial cells in mice with MS.

In a follow-up study published this month in Neuron, Dr. Agalliu’s team discovered that endothelial cells produce large amounts of a Wnt inhibitor, Apcdd1, during development of the blood-retina barrier (a close cousin to the blood-brain barrier). Eliminating the inhibitor in mice caused the barrier to form prematurely, and increasing Apcdd1 delayed development of the barrier. They also found that Apcdd1 is expressed in blood vessels that have a leaky barrier, in both human and mouse MS.

“If we could eliminate Apcdd1, we might be able to increase Wnt activity in endothelial cells and fully repair the damaged barriers in diseases like MS,” Dr. Agalliu said.

“Many current MS therapies only target the immune system,” Dr. Agalliu said, “and though that may help alleviate symptoms, it won’t stop disease progression, because other inflammatory factors will still enter the brain through the barrier, triggering a cascade of pathologies that are independent of T cells. These new studies suggest that we need to focus on vascular function as well as immune function to effectively treat MS in the future.”


The Cell Reports study is titled "Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation."

Other authors: Sarah E. Lutz (CUIMC and University of Illinois at Chicago), Julian R. Smith (CUIMC), and Dae Hwan Kim, Carl V.L. Olson, Kyle Ellefsen, Jennifer M. Bates, and Sunil P. Gandhi (all University of California, Irvine).

The research was supported by the NIH (R01 HL116995, R56 MH109987, R01 MH112849, P30 CA62203, and S10 RR027050); the National Multiple Sclerosis Society (RG4673A1/1 and FG2035-A-1); the Leducq Foundation; a gift from John Castle to Columbia University's Department of Neurology, Stroke Division; UC Irvine Undergraduate Research Opportunity fellowships; a Searle Scholar Award; and a Klingenstein Fellowship.