Multiple sclerosis may begin with the death of myelin-producing brain cells

By John Murphy, MDLinx
Published December 17, 2015

Key Takeaways

A first-of-its-kind discovery may explain the pathogenesis of multiple sclerosis (MS): The death of myelin-producing oligodendrocytes triggers a response against myelin, which leads to neuronal damage and symptoms of MS, according to an article published online December 14, 2015 in the journal Nature Neuroscience.

“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 study co-senior author Brian Popko, PhD, the Jack Miller Professor of Neurological Disorders at the University of Chicago, in Chicago, IL.

“Protecting these cells in susceptible individuals might help delay or prevent MS," he added. To that end, the investigators are now developing special nanoparticles to halt this reaction (even after the loss of oligodendrocytes), with a goal to treating MS in humans.

Although MS is a common neurological disorder that affects an estimated 2.5 million people worldwide, the origin of the autoimmune response against myelin—the characteristic feature of the disease—remains unclear.

To investigate whether the death of myelin-producing oligodendrocytes could cause this autoimmune response, Dr. Popko and co-senior author Stephen Miller, PhD, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, in Chicago, IL, and their teams developed a genetically-engineered mouse model that allowed them to target oligodendrocytes.

By specifically killing oligodendrocytes in the mice, the team observed MS-like symptoms that affected the ability of the creatures to walk. After this initial event, the central nervous systems of the mice regenerated their oligodendrocytes, enabling them to walk again. But about 30 weeks later, the MS-like symptoms came back with a vengeance.

The current understanding of MS—the “outside-in” hypothesis—is that an event outside of the nervous system triggers the disease in susceptible individuals who may have a genetic predisposition. In these individuals, the T 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 this new study offers evidence that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly, even in the absence of apparent signs of inflammation. If oligodendrocytes die, demyelination occurs.

This “inside-out” hypothesis suggests that the immune system perceives myelin components as antigens, and it reacts automatically. The immune system’s erroneous attack on myelin antigens leads secondarily to inflammation and demyelination in the CNS, initiating MS.

In humans, MS could develop years after an initial insult triggers oligodendrocyte death. Possible initial insults that cause oligodendrocyte death include developmental abnormalities, viruses, bacterial toxins, or environmental pollutants, the researchers suggested.

“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.

The researchers have also used their MS mouse model to begin testing new drugs against progressive disease. In this study, the investigators administered specially developed nanoparticles that created tolerance to the myelin antigen and prevented progressive MS from developing.

“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,” Dr. Miller said. His team originated this nanoparticle technology and has licensed it to Cour Pharmaceutical Development Company, which is developing it for human trials in autoimmune disease.

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