Multiple sclerosis (MS) is a disease of mistaken identity that affects some 2.5 million people worldwide. In patients with MS, the body’s own immune system attacks myelin, an essential layer of insulation around nerve fibers. Without myelin, nerve cells misfire, leading to the progressive deterioration of a wide range of body functions. There is no cure for MS, and little is known about what triggers the erroneous self-attack, also known as an autoimmune response.

A new study co-led by scientists from the University of Chicago now sheds light on a possible cause: the death of brain cells that produce myelin. Publishing in the December issue of Nature Neuroscience, Brian Popko, PhD, Jack Miller Professor of Neurological Disorders, and his colleagues found that if these cells were killed, an initial loss of myelin would occur, followed by a period of regeneration that returned nerve function to normal. However, around six months later, immune cells suddenly began attacking myelin.

“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,” said Popko, who served as co-senior author of the study. “Protecting these cells in susceptible individuals might help delay or prevent MS.”

To investigate how MS is triggered, Popko, with collaborator Stephen Miller, PhD, Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, and their teams developed a genetically engineered mouse model that allowed them to target oligodendrocytes, the brain cells that produce myelin. By specifically killing oligodendrocytes, the team observed the loss of myelin and onset of MS-like symptoms. These cells would eventually regenerate and restore nerve function to normal. But about six months later, the MS-like symptoms came barreling back.

“To our knowledge, this is the first evidence that oligodendrocyte death can trigger myelin autoimmunity, initiating inflammation and tissue damage in the central nervous system during MS,” said study co-author Maria Traka, PhD, research associate professor in neurology at the University of Chicago.

Inside-out

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. These confused immune cells enter the brain and begin their mistaken attack on myelin.

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, its components 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.

“It will be exciting to determine the nature of this process in humans—its precise role in MS and whether therapies to prevent it are effective,” Popko said.

Possible causes of oligodendrocyte death are developmental abnormalities, viruses, bacterial toxins or environmental pollutants. In humans, the researchers hypothesize MS could develop years after an initial injury to the brain triggers oligodendrocyte death.

The mouse model also enabled 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. The nanoparticle technology was developed in Miller’s lab and has been licensed to Cour Pharmaceutical Development Company, which is developing the technology for human trials in autoimmune disease.

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

The timing of therapy is important, Popko pointed out.

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

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The study, “Oligodendrocyte death results in immune-mediated CNS demyelination,” was supported by the Myelin Repair Foundation and the National Multiple Sclerosis Society. Additional authors include Joseph Podojil and Derrick McCarthy of Northwestern University.

Miller, a founder and chief of the Scientific Advisory Board of Cour Pharmaceutical, does not receive financial compensation from the company.

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