How multiple sclerosis harms a brain long before symptoms appear

By the time patients start seeking care for multiple sclerosis (MS), the disease has already been damaging their brains for years. But until recently, scientists didn’t understand which brain cells were being targeted or when the injury began.

Now, by analyzing thousands of proteins found in the blood, scientists at UC San Francisco have created the clearest picture yet of when the disease attacks the myelin sheath that covers the nerve fibers. It shows that the immune system begins attacking the brain even earlier than previously had been thought.

The findings appear in Nature Medicine.

The study measured debris from these attacks in a person’s blood, along with the signals that coordinate the immune system to go on the attack. It lays out, for the first time, the sequence of events that eventually lead to the disease.

The discovery could lead to new ways to diagnose multiple sclerosis—and possibly one day prevent it.

MS first attacks the fatty myelin sheath, and a year later, it’s possible to see the breakdown of nerve fibers themselves.

Among the many immune signaling proteins that were elevated in the early stage of the disease, one protein stood out: IL-3. It plays an important role in this early phase when the central nervous system is suffering significant damage, but the patient doesn’t yet feel it. IL-3 is known for recruiting immune cells to the brain and spinal cord, where they attack nerve cells.

“We think our work opens numerous opportunities for diagnosing, monitoring, and possibly treating MS,” said Ahmed Abdelhak, MD, assistant professor of Neurology at UCSF, and the first and co-lead author of the paper. “It could be a gamechanger for how we understand and manage this disease.”

Researchers analyzed more than 5,000 proteins in blood samples from 134 people with MS, both before and after their diagnosis. These samples were provided by the U.S. Department of Defense Serum Repository, which stores samples from armed service members when they apply to join the military. The samples are then available for study decades afterward, by which time some of the people may have gone on to develop MS.

Seven years before a person’s diagnosis, they saw a spike in a protein called MOG, which stands for myelin oligodendrocyte glycoprotein and indicates damage to the insulation around the wires of the nervous system. A year after the MOG spike appeared, they saw a spike in another protein called neurofilament light chain, which indicates damage to the wires themselves.

During this time, IL-3 and some related proteins that orchestrate an immune reaction appeared in the blood.

The team identified about 50 proteins that herald future disease, and they have submitted a patent application for a diagnostic blood test using the top 21 of them.

Ari Green, MD, chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology and senior author of the paper, said the study offers the hope of prevention and it gives a deeper understanding of what leads to the development of symptoms in MS.

“We now know that MS starts way earlier than the clinical onset, creating the real possibility that we could someday prevent MS—or at least use our understanding to protect people from further injury.”