Subtle Myelin Damage May Occur Before Inflammatory Reactions in MS, Study Suggests

Subtle changes in myelin, the protective layer of nerve fibers, may be an early event in multiple sclerosis (MS) prior to the inflammatory reaction, a new University of Calgary study shows.

The study, “Biochemically altered myelin triggers autoimmune demyelination,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).

An immune attack against myelin is a central event in MS and leads to inflammation. However, the cause of this autoimmune reaction is still unknown.

The conventional view is that MS starts from the “outside in,” referring to the fact that immune cells enter the brain and cause myelin damage. However, other studies support the theory that subtle alterations in myelin within the brain precede inflammatory reactions.

“In the field, the controversy about what starts MS has been brewing for more than a decade. In medical school, I was taught years ago that the immune attack initiates the disease. End of story,” Peter Stys, MD, the study’s senior author, said in a press release. Stys is a professor of neurology at UCalgary’s Cumming School of Medicine.

“However, our findings show there may be something happening deeper and earlier that damages the myelin and then later triggers the immune attacks,” he said.

To test their view on what drives MS, scientists used a mouse model called cuprizone autoimmune encephalitis, which induces a mild myelin injury, involving biochemical changes — this model is believed to mimic the earliest stages of the disease.

They coupled administration of cuprizone, a compound that reacts with copper, with immune stimulation and found that in these animals the initial slight myelin damage was followed by lesions involving inflammatory demyelination, or loss of myelin.

Researchers also found that myelin damage that was either too limited or too extensive failed to trigger severe pathology. Importantly, inhibiting enzymes called PADs, which change myelin structure and correlate with MS lesion severity, eased the immune attack and brain inflammation. This result was confirmed in in vitro experiments.

“Our experiments show, at least in this animal model, that a subtle early biochemical injury to myelin secondarily triggers an immune response that leads to additional damage due to inflammation. It looks very much like an MS plaque,” Stys said.

He emphasized that although these findings do not prove this is the way that human MS develops, they strongly suggest that this is a potential mechanism of disease initiation.

Overall, the study “potentially reconciles conflicting theories about MS pathogenesis and provides a strong rationale for investigating myelin as a primary target for early, preventative therapy,” the researchers wrote in the study.

The team is now testing strategies to stop demyelination to see if that could decrease or stop the secondary autoimmune response.

“This research opens a whole new line of thinking about this disease,” Stys said. “Most of the science and treatment for MS has been targeted at the immune system, and while anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stages of the disease when most disability happens.”

Funding for the study was provided by the Brain and Mental Health Strategic Research Fund, an initiative of the office of the vice president (research) at UCalgary.

“The MS study shows the potential of brain and mental health scholars to expand capacity by tapping into new approaches for conducting research,” said Ed McCauley, PhD, UCalgary’s vice president (research).