Animal Model Provides Clues into Multiple Sclerosis’s Heterogeneity

by Kayt Sukel

December 16, 2008

Multiple sclerosis (MS) is a chronic, debilitating neurological disorder characterized by seemingly random tissue damage across the nervous system. But a new study by researchers at the University of Maryland School of Medicine and Washington University in St. Louis offers clues to understanding the disease’s innate heterogeneity—its apparently diverse effects.

Many researchers believe that inflammation causes MS symptoms such as numbness, balance problems and cognitive decline. This inflammation results in T cells, a kind of white blood cell, attacking tissue in the brain and spinal cord. What symptoms a person develops, as well as how quickly the disease progresses, depends largely on where that damage occurs.

“One of the hallmarks of the disease is that there is substantial heterogeneity,” says Jeffrey Cohen, a clinical neurologist at the Cleveland Clinic. “Superficially, we tend to think that lesions in MS occur randomly. But, in fact, there are probably specific biologic factors that determine why lesions occur in different locations in different people.”

Most people with MS have damage to the spinal cord and white matter of the brain. Some develop damage in the cerebellum, which results in a more progressive form of the disease. Scientists have not uncovered the mechanism that underlies these differences. But John H. Russell, a professor of developmental biology at Washington University, and colleagues published a study in the Oct. 27 issue of the Journal of Experimental Medicine that pinpoints a potential biologic factor for MS’s heterogeneity. Their work suggests a protein called interferon-gamma (IFN-gamma) may play a role in determining which parts of the nervous system come under attack.

Proteins influence the outcome

Russell’s group examined mice with experimental autoimmune encephalomyelitis (EAE), an MS-like disease that leads to significant inflammation in the brain. The researchers compared diseased mice that had IFN-gamma receptors with mice bred to lack these receptors and discovered that the protein influenced where brain damage would occur.

“What we found was that if mice made T cells in the absence of IFN-gamma, the T cells would attack the cerebellum and brain stem,” says Russell. But in mice that had intact IFN-gamma receptors, the disease would target the spinal cord.

After eliminating other proteins and demonstrating that IFN-gamma was the cause, Russell and colleagues then took the experiment a step further. The group knew that if they transferred IFN-gamma to normal animals with the MS-like disease, they would develop damage to the spinal cord. What they didn’t know was what would happen if they mixed cells that produced IFN-gamma with those that did not.

They found that by increasing the ratio of cells that could not produce IFN-gamma, animals were more likely to get the disease in the cerebellum and brain stem.

“By mixing the ratio, we could predict whether the animal would get damage in the cerebellum and brain stem or the spinal cord,” he says. “This suggests that interferon is somehow protective for the cerebellum.”

Russell says these studies are merely a first step to understanding what underlies MS’s heterogeneity.

Integrating knowledge for future research

Richard Ransohoff, a researcher at the Cleveland Clinic who studies the causes of brain inflammation in people with multiple sclerosis, says that Russell and colleagues have come up with a new concept about the role of IFN-gamma in experimental autoimmune encephalomyelitis that deserves further exploration. But he cautions that the mechanisms that underlie EAE—and, by proxy, MS—are complicated. He suggests that Russell’s findings be integrated with the many previous studies on IFN-gamma, some of which have offered different results, to find common ground.

“If we could integrate those results with the data shown here, we may find the next step,” he says. “What’s needed is a review of all these atypical models of EAE, where the lesions affect the brain stem instead of the spinal cord, to see if there is a previously undiscovered common thread that gives us a pointer for future research.”