By the time most people begin seeking help for multiple sclerosis (MS), the disease has already been quietly injuring the brain for years. Until recently, scientists were uncertain which cells were affected first or when the damage actually started.
Tracking the Disease’s Earliest Attacks
Researchers at UC San Francisco have now provided the most detailed timeline yet by analyzing thousands of proteins circulating in the blood. Their findings show that the immune system begins attacking the brain’s protective myelin sheath — the fatty covering that insulates nerve fibers — much earlier than scientists once believed.
The team measured fragments of myelin and other molecules left behind by immune attacks, along with the chemical signals that drive the immune system’s response. This work allowed them to outline, for the first time, the chain of biological events that ultimately leads to the onset of MS.
The discovery opens the door to earlier diagnosis and, in the future, may make prevention possible.
The Body’s Early Warning Signs
The research showed that MS first targets the myelin sheath. About a year later, evidence of damage to the underlying nerve fibers themselves begins to appear.
Among the immune-related proteins that rose during this initial stage, one stood out: IL-3. This molecule plays a central role in the early disease phase, when the central nervous system is already taking significant damage even though patients do not yet experience symptoms. IL-3 helps recruit immune cells into the brain and spinal cord, where they begin attacking nerve tissue.
“We think our work opens numerous opportunities for diagnosing, monitoring, and possibility treating MS,” said Ahmed Abdelhak, MD, assistant professor of Neurology at UCSF, and the first and co-lead author of the paper, which was published in Nature Medicine on Oct. 20. “It could be a gamechanger for how we understand and manage this disease.”
Following Blood Clues Years Before Diagnosis
The researchers analyzed more than 5,000 different proteins in blood samples from 134 individuals who eventually developed MS. These samples came from the U.S. Department of Defense Serum Repository, which stores blood from military applicants. Because the repository holds samples for decades, scientists were able to examine blood drawn years before these individuals were diagnosed.
Seven years prior to diagnosis, the researchers detected a spike in a protein known as MOG (myelin oligodendrocyte glycoprotein), which signals damage to the myelin insulation around nerve fibers. Roughly a year later, they observed a rise in neurofilament light chain, a marker of injury to the nerve fibers themselves.
During this same window, IL-3 and several related immune proteins appeared in the bloodstream, indicating that an immune assault was already underway.
Building the Foundation for a Predictive Blood Test
In total, the team identified about 50 proteins that could serve as early indicators of MS. They have since filed a patent application for a diagnostic blood test based on the 21 most reliable markers.
Ari Green, MD, chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology and senior author of the study, said the findings could reshape how doctors approach prevention and treatment.
“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.”
Authors: Other UCSF authors are Gabriel Cerono, MD, Kiarra Ning, John Boscardin, PhD, The UCSF ORIGINS Study, Christian Cordano, MD, PhD, Asritha Tubati, Camille Fouassier, Eric D. Chow, PhD, Refujia Gomez, Adam Santaniello, Kelsey C. Zorn, MHS, Jill A. Hollenbach, PhD, MPH, Jorge R. Oksenberg, PhD, Bruce A.C. Cree, MD, PhD, MAS, Stephen L. Hauser, MD, Jonah R. Chan, PhD, Sergio E. Baranzini, PhD, Michael R. Wilson, MD, and Ari J. Green, MD. For all authors, see the paper.
Funding: This work was funded in part by the Department of Defense (HT94252310499), the National Institutes of Health (R01 NS105741 R01AG062562 R01AG038791, 1S10OD028511-01, R35NS111644, the Valhalla Foundation, the National MS Society, the Westridge Foundation, the National Multiple Sclerosis Society (RFA-2104-37504, SI-2001-35751), the Water Cove Charitable Foundation, Tim and Laura O’Shaughnessy, and the Littera Family. For all funding and disclosures, see the paper.