In MS, Genome Map Shows Many Immune Cells Are to Blame

A new study of multiple sclerosis (MS) is upending notions about how the autoimmune disease gets started.

The study of over 100,000 people produced a genomic map of the disease, which revealed that MS begins with dysfunction in many different types of immune cells throughout the bloodstream and brain—not only in lymphocytes, a type of immune cell, as had been thought. The array of dysfunctional cells, in combination, triggers a cascade of events that can lead to brain inflammation and, eventually, nerve cell death.

The study, led by researchers at Columbia University Vagelos College of Physicians and Surgeons on behalf of the International Multiple Sclerosis Genetics Consortium (IMSGC), was published Sept 28. in Science.

“This broader perspective on the widespread dysfunction of the immune system will help scientists identify the best targets and drugs for preventing individuals at risk of MS from developing the disease. In particular, the role of microglia, the brain’s resident immune cell, focuses our attention on this unique aspect of the immune system,” says study leader Philip L. De Jager, MD, PhD, director of the Multiple Sclerosis Center at Columbia University Irving Medical Center.

Background

In MS, the immune system attacks myelin, a fatty substance that protects nerve cells in the brain and spinal cord, which causes symptoms such as vision loss, numbness and tingling, muscle weakness, fatigue, and balance problems. A secondary neurodegenerative process causes accelerated brain atrophy in some patients.

The disease affects nearly 1 million adults in the United States and is up to three times more common in women.

Before genetic studies, researchers were uncertain whether MS begins when immune cells in the bloodstream become activated, enter the central nervous system, and launch an attack on myelin that leads to inflammation or with changes in nerve and myelin cells themselves that then trigger inflammation and an influx of immune cells into the brain.

Study Details

By analyzing the genomes of 115,803 individuals, including 47,429 MS patients and 68,374 healthy individuals, the researchers first identified 233 genetic variants that contribute to the onset of MS.

Then they analyzed the downstream effects of these variants to determine the sequence of molecular events in each immune cell type that eventually perturb the function of these immune cells and make them attack the brain and spinal cord.

What’s New

The new study, the most comprehensive of its kind, shows that MS is triggered predominantly by dysregulated immune cells, both inside and outside the brain, that then cause damage to neurons, astrocytes, and other brain cells.

There was little or no evidence that neurons themselves are involved in triggering the disease.

“It’s now clear that MS is not caused by a single type of immune cell, namely lymphocytes, but rather by a broad dysfunction of the immune system,” says De Jager.

“Lymphocytes are clearly important, but we now have good evidence that most immune cell types, such as natural killer cells, monocytes, and dendritic cells, that move into the brain from the bloodstream, are also involved,” De Jager says. “We also found that the resident immune cells of the brain—the microglia—are involved. It’s a dysregulation of the entire immune system.”

What This Means

Current MS treatments aim to stop brain inflammation after it has already started. “With this new understanding of MS, we have a better idea of what cells and molecules to target early in the disease, before the immune cells attack the brain,” says De Jager, “and that could lead to preventive treatments.

“It will also help us identify healthy individuals who are at high risk of developing MS: They are the most likely to experience a strong, dysregulated inflammatory response against the brain. They would benefit the most from preventive or early treatments with new medications that modulate the immune system in a specific fashion to minimize side effects. Right now, we don’t have a good way to identify these individuals. We basically wait for them to have symptoms and then start therapy.”

Next Steps

“The genes we found in this study account for about half of what makes MS heritable. It’s a lot, but there are probably several hundred more variants to discover by enlarging the sample size of the study,” says De Jager. “This is not the end of MS genetics, but it is a major milestone and will be a reference for years to come that will inform the work of many investigators in the field of MS and beyond.”