Team finds surprising trigger for multiple sclerosis

A de-myelinated lesion (center) amid a field of normal neurons (green). (Credit: Maria Traka)

The death of brain cells that make the insulation around nerve fibers, called myelin, can trigger symptoms seen in multiple sclerosis (MS), a study with mice shows.

It’s possible to prevent the reaction, even after the death of those brain cells, with specially developed nanoparticle, researchers say. The nanoparticles are being developed for clinical trials that could lead to new treatments—without the side effects of current therapies—in adults.

“Protecting these cells in susceptible individuals might help delay or prevent MS.”

“Although this was a study in mice, we’ve shown for the first time one possible mechanism that can trigger MS—the death of the cells responsible for generating myelin can lead to the activation of an autoimmune response against myelin,” says Brian Popko, a professor of neurological disorders at the University of Chicago and co-senior author of the study. “Protecting these cells in susceptible individuals might help delay or prevent MS.”

Myelin is the insulating sheath around nerve fibers that enables nerve impulses to be transmitted. The death of the cells that make myelin, called oligodendrocytes, can activate the autoimmune response against myelin, which is the main feature of MS.

Oligodendrocytes can possibly be destroyed by developmental abnormalities, viruses, bacterial toxins, or environmental pollutants.

The scientists also developed the first mouse model of the progressive form of the autoimmune disease, which will enable the testing of new drugs against progressive MS. In the study, nanoparticles creating tolerance to the myelin antigen were administered and prevented progressive MS from developing.

Early intervention may be key

The nanoparticle technology was developed in the lab of Stephen Miller, a research professor at Northwestern University Feinberg School of Medicine, and has been licensed to Cour Pharmaceutical Development Company, which is developing the technology for human trials in autoimmune disease.

“We’re encouraged that immune tolerance induced with nanoparticles could stop disease progression in a model of chronic MS as efficiently as it can in progressive-remitting models of MS,” says Miller.

The timing of therapy is important, Popko points out.

“It’s likely that therapeutic strategies that intervene early in the disease process will have greater impact.”

Whole new model of MS

In the experiment, scientists developed a genetically engineered mouse model in which the oligodendrocytes died, affecting the animals’ ability to walk. The central nervous system regenerated the myelin-producing cells, enabling the mice to walk again. But about six months later, the MS-like disease came barreling back. This demonstrated the scientists’ theory that the death of oligodendrocytes can initiate MS. In humans, the scientists posit, the disease develops years after the initial injury to the brain.

The current prevailing theory is that an event outside of the nervous system triggers MS in susceptible individuals who may have a genetic predisposition to the disease. In these individuals, the immune cells that normally fight infections confuse a component of the myelin sheath as foreign.

[Slightest change makes myelin come unglued]

These confused immune cells enter the brain and begin their mistaken attack on myelin, thus initiating MS.

But the new study demonstrates the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart.

The inside-out hypothesis suggests that when myelin falls apart, the products of its degradation are presented to the immune system as foreign bodies or antigens. The immune system then erroneously views them as invaders and begins a full-scale attack on myelin, initiating MS.

Grants from the Myelin Repair Foundation and the National Multiple Sclerosis Society funded the study, which appears in Nature Neuroscience.

Miller, a founder and chief of the scientific advisory board of Cour Pharmaceutical, does not receive financial compensation from the company.

Source: Marla Paul for Northwestern University and Kevin Jiang for the University of Chicago