Scientists find a missing link between Epstein-Barr virus and multiple sclerosis

The findings were published Feb. 5 in Nature Immunology. The study shows that people with MS have higher levels of certain CD8+ "killer" T cells. These immune cells normally destroy infected or damaged cells. Some of the elevated killer T cells specifically respond to EBV, suggesting the virus may help set off the harmful immune activity seen in MS.

For years, scientists have known that EBV is closely linked to MS. The virus infects about 95% of adults and is found in nearly everyone who eventually develops the disease.

"Looking at these understudied CD8+ T cells connects a lot of different dots and gives us a new window on how EBV is likely contributing to this disease," said senior author Joe Sabatino, MD, PhD, an assistant professor of Neurology and a member of the UCSF Weill Institute for Neurosciences.

Why the Immune System Attacks in MS

Multiple sclerosis occurs when the immune system mistakenly attacks myelin, the protective layer surrounding nerve fibers in the brain and spinal cord. Over time, this damage leads to worsening neurological problems.

Until now, much of MS research has centered on CD4+ T cells. These cells help organize immune responses but do not directly kill other cells. CD4+ T cells are easier to study in animal models, which has left CD8+ killer T cells less explored despite their potential importance.

Sabatino's team set out to study these killer T cells directly in people.

Comparing Blood and Cerebrospinal Fluid

The researchers examined blood and cerebrospinal fluid (CSF) from 13 individuals with MS or early signs of the disease. They also studied samples from five people without MS.

Their analysis focused on CD8+ T cells that recognized specific proteins found in these fluids. In participants without MS, these immune cells appeared in similar numbers in both the blood and CSF.

The pattern was very different in people with MS. In those patients, the protein recognizing CD8+ T cells were between 10 and 100 times more concentrated in the CSF than in the blood. This striking imbalance pointed to unusual immune activity inside the central nervous system.

Viral Activity Inside the Nervous System

EBV itself was detected in the CSF of most participants, regardless of whether they had MS. Some EBV genes were active in these samples. One gene stood out because it was active only in people with MS. This finding suggests the gene may help drive the heightened immune response that defines the disease.

The results add to growing evidence that EBV plays a role in autoimmune illness. In addition to MS, the virus has been linked to lupus, rheumatoid arthritis, and long COVID.

Potential Paths Toward New Treatments

Because of the strong association between EBV and MS, some researchers have already started testing treatments that aim to target the virus directly.

"The big hope here is that if we can interfere with EBV, we can have a big effect, not just on MS but on other disorders, and improve the quality of life for many, many people," Sabatino said.

Additional UCSF authors on the study include Fumie Hayashi, Kristen Mittl, Ravi Dandekar, Josiah Gerdts, Ebtesam Hassan, Ryan D. Schubert, Lindsay Oshiro, Rita Loudermilk, Ariele Greenfield, Danillo G. Augusto, Gregory Havton, Shriya Anumarlu, Arhan Surapaneni, Akshaya Ramesh, Edwina Tran, Kanishka Koshal, Kerry Kizer, Isabelle J. Fisher, Tiffany Cooper, Meagan Harms, Refujia Gomez, University of California, San Francisco MS-EPIC Team, Claire D. Clelland, Bruce A. C. Cree, Stephen L. Hauser, Jill A. Hollenbach, Michael R. Wilson, and Scott S. Zamvil. For other authors, please see the study.

The study was funded by the National Institutes of Health (grants K08NS107619, R01AI158861, R01AI169070, R01AI169070, R35NS111644, and R21AI142186).