ORLANDO—Two great mysteries of multiple sclerosis (MS) pathology are—Why don’t the demyelinated lesions surrounding the ventricle continue to spread throughout the entire white matter and destroy it, and why isn’t repair to the areas of demyelination more vigorous? These questions were posed by Cedric Raine, PhD, DSc, a Professor in the Departments of Pathology and Neuroscience as well as in the Saul R. Korey Department of Neurology at Albert Einstein College of Medicine, Yeshiva University, Bronx, New York.

In MS, distinctive large periventricular lesions arise in the white matter. What amazes Dr. Raine is that these lesions arise and progress to a certain size—then stop. According to Dr. Raine, who made his remarks at the 19th Annual Conference of the Consortium of Multiple Sclerosis Centers, “There is nothing in this world to say why they shouldn’t have taken over the whole white matter. But the fact that they stop at such a sharp edge means that there must be a mechanism in place that stops them from growing.”

That the lesions cease progression hints at a regulatory mechanism capable of starting, and eventually stopping, the growth of the lesion, he believes. Growth can also resume from lesion edges with each relapse and each period of disease worsening, noted Dr. Raine. “Then again, it stops, and again it’s telling you that there are regulatory mechanisms in place that stop the disease process from wiping out all myelin in the white matter.” Although there is a mechanism halting lesion progression, Dr. Raine observed, the lesions themselves do not repair very well. Remyelination does occur and may be extensive during acute MS exacerbations, but it does not repair the lesion completely and much of it is transient.

ON THE EDGE

The future of MS research lies in identifying these regulatory mechanisms and flaws in the repair mechanisms, believes Dr. Raine. His research team has focused on these two avenues for the past three years. Their work indicates that “most of the clues come from looking at the very, very edge of the established lesion.” Indeed, there is only an extremely narrow area 50 microns wide that divides completely demyelinated from normal-appearing white matter, which indicates to Dr. Raine the existence of molecular pathways controlling events at this zone. What is striking to the researchers is that microglial cells appear to determine the edge of the chronic lesion and have a negative effect on remyelination yet a positive effect on progression—a double-edged sword, according to Dr. Raine.

Research is focused on the edge of the lesion, a tiny zone only 10 to 50 microns wide, which separates the myelin-producing oligodendrocytes from the lesion, but “they don’t get the opportunity to enter the lesion and do their stuff,” said Dr. Raine. Microglial cells apparently have the ability to prevent inward migration of repair mechanisms yet also curtail outward progression of the lesion.

THE IMMUNE BRAIN

Associated with developing lesions are class II major histocompatibility complex molecules and a group of proinflammatory cytokines that mediate the immune system. As the investigators have found, oligodendrocytes around active lesions can proliferate and demonstrate the ability to express a wide variety of immune-system molecules such as the chemokine receptor CXCR2 implicated in migration and positioning. This capacity “speaks heavily of them having the potential to remyelinate if ever allowed to,” noted Dr. Raine. “The picture isn’t as bleak as I’ve painted at the outset; there are prospects for remyelination. We just have to understand which mechanisms are stopping these genes from being switched on and [preventing] tissue recovery.”

The key to MS is understanding the interaction of the brain cells of the MS patient with the immune system. During the past 10 years, Dr. Raine and his colleagues have found that many molecules produced and presented on the surface of brain cells are identical to molecules of the immune system and allow for communication between the two systems. This interaction can be good or it can be bad, offered Dr. Raine, and falls under the rubric of the “innate immune system.” As he explained, the brain has its own immune system and even a healthy brain can interact, at a certain level, with the immune system. However, the MS brain can interact at a much higher level with the immune system because acquired damage induces activation of molecular pathways within astrocytes, microglial cells, oligodendrocytes, and white matter—molecules typically only expressed in the immune system and not in the healthy brain. Accordingly, the potential for interaction with the immune system is quite high in the MS patient’s central nervous system.

And again, that can be good or that can be bad. The interaction can be proinflammatory or it can be anti-inflammatory, depending on disease stage or stage of lesion formation, Dr. Raine noted. An expanding lesion will show proinflammatory activity and a resolving lesion will show anti-inflammatory molecules involved in regulation of the immune system. Earlier research conducted in his laboratory demonstrated the ability of brain cells to express these molecules, the ability for the brain to remyelinate, and the survival of the oligodendrocytes in some MS lesions. “Everybody thought until 10 to 20 years ago the oligodendrocyte was completely wiped out in MS and there was no hope of repair or proliferation of the surviving cells,” recounted Dr. Raine. “That’s now known through our work not to be so. And oligodendrocytes can actually proliferate in certain stages of the disease and can repair the lesion, but the problem is that because of the ongoing inflammation in the brain the cells eventually get wiped out.” The key to remyelination of the MS brain is suppression: “Anything you can do to suppress the expanding immune response in the brain will have a beneficial effect on the ability of the oligodendrocytes to repair the myelin that has been damaged. The oligodendrocytes have all the molecules needed for repair, if they can just be allowed to express and put them into working order.”

NR

—Heidi W. Moore

Suggested Reading
Arnett HA, Fancy SP, Alberta JA, et al. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science. 2004;306:2111-2115.
Omari KM, John GR, Sealfon SC, Raine CS. CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain. 2005;128(pt 5):1003-1015.
Zhao C, Fancy SP, Kotter MR, et al. Mechanisms of CNS remyelination—the key to therapeutic advances. J Neurol Sci. 2005;233:87-91.

Return to table of contents