ARTICLE IN BRIEF
Investigators identified an antibody in the serum of MS patients that targeted a brain protein — contactin-2/transiently expressed axonal glycoprotein (TAG-1) — that seems to trigger gray matter demyelination, and they think it could be a useful new model for targeted therapies for multiple sclerosis.
The identification of a protein that can generate a two-hit immune response that leads to gray and white matter damage is now seen as a potent model of multiple sclerosis (MS).
It has long been thought that MS in humans is the result of damage to the white matter fibers of the CNS based on insights from the classic animal model — experimental autoimmune encephalomyelitis (EA) that approximates the symptoms of human MS and has allowed scientists to test theories about the autoimmune disease and experimental treatments. In the EAE model, the inflammation is restricted to the white matter.
The EAE animal model has clearly helped elucidate molecular mechanisms in CNS tissue injury, but the growing evidence suggests that a big part of the MS puzzle is missing. There is growing support for abundant gray matter pathology as well, according to a report published last spring in the Proceedings of the National Academy of Sciences (PNAS).
Tobias Derfuss, MD, and his colleagues at the Max Planck Institute of Neurobiology in Germany, identified an antibody in the serum of MS patients that targeted a brain protein — contactin-2/transiently expressed axonal glycoprotein (TAG-1). The protein was named for its transient appearance in axons during development.
Dr. Derfuss and his colleagues thought that the pattern of this distribution may have something to do with MS, which is why they focused attention on the protein. When they injected the protein subcutaneously in mice, the immune response made the cortex more permeable to myelin oligodendrocyte glycoprotein antibodies that in turn induced gray matter demyelination.
The European team said that the finding suggests that a contactin-2 specific T-cell response contributes to the gray matter pathology that occurs in MS. The investigators mined human brain tissue from MS patients and controls looking for antibody reactivity against select glycoproteins. They discovered that contactin-2/TAG-1 was recognized by both autoantibodies and T-helper cells.
“No one has ever tried this before,” wrote Bruce D. Trapp, PhD, and Richard A. Rudick, MD, both of the Cleveland Clinic, in an Oct. 8 New England Journal of Medicine editorial on the clinical implications of the PNAS paper.
WHAT CAUSES THE DEMYELINATION
Results from the European study suggest that “immune-mediated inflammation targeted at the protein contactin-2 on or near gray matter endothelial cells opens the blood-brain barrier or alters endothelial cells in the gray matter, permitting effectors of demyelination (such as antibodies to myelin proteins) to gain access to gray matter,” Drs. Trapp and Rudick wrote in their editorial.
Advances in imaging technology are now confirming that these gray matter lesions are common in MS. “Gray matter pathology could be as much as white matter pathology but we have not been able to see it or measure it in living patients,” said Dr. Trapp, in an interview with Neurology Today. “And we have overlooked gray matter demyelination in the pathologenesis of the disease.”
“When MRI was developed and applied to MS the bright lesions on the scan were scattered around the ventricles and white matter,” said Dr. Rudick. “There are no observable lesions in the gray matter using standard procedures.” Today, scientists are developing imaging markers to reveal gray matter damage and these findings are changing the landscape of research and hopefully the development of new treatments, he added.
Dr. Rudick and colleagues at the Cleveland Clinic, who have been following 85 MS patients and healthy controls since 2000, reported in the July 15 Journal of Neurological Science that the gray matter volume in patients decreases over time. Early in the disease, Dr. Rudick said, gray matter volume loss proceeds three times faster in patients than in controls.
As the disease progresses — and the symptoms worsen — “the rate of atrophy in patients increases to 14 times that seen in unaffected people,” Dr. Rudick added. “What's more, gray matter atrophy correlates with physical disability and cognitive disability more strongly than white matter atrophy.”
As the evidence for this two-hit hypothesis strengthens, scores of laboratories are trying to find imaging tools to identify gray matter pathology and develop therapies that slow or stop the cortical degeneration. The therapies now in development target white matter pathology. And scientists still have to figure out the relationship between the inflammation in the white matter and the cortical damage.
• Derfuss T, Parikh K, Meinl E, et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci USA
• Rudick RA, Trapp BD.Gray-matter injury in multiple sclerosis. N Engl J Med
• Rudick RA, Lee JC, Nakamura K, Fisher E. Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS. J Neurol Sci
• Fisher E, Lee JC, Rudick RA, et al.Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol