In a discovery that could speed up the treatment of patients with multiple sclerosis (MS), scientists at the University of California, San Francisco discovered an omen in the blood of some people who later developed the disease.
In about 1 in 10 cases of MS, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms arise. These autoantibodies appear to bind to both human cells and common pathogens, possibly explaining the immunological attacks on the brain and spinal cord that are the hallmark of MS.
The findings were published in Nature medicine on April 19.
MS can cause a devastating loss of motor control, although new treatments can slow the progression of the disease and, for example, preserve the patient’s ability to walk. Scientists hope that one day the autoantibodies they have discovered will be detected with a simple blood test, giving patients a head start when it comes to treatment.
“Over the last few decades, there has been a movement in the field to treat MS earlier and more aggressively with newer, more powerful therapies,” said UCSF neurologist Michael Wilson, MD, senior author of the paper. “A diagnostic result like this makes that early intervention more likely, giving patients hope for a better life.”
Linking infections to autoimmune diseases
Autoimmune diseases like MS are thought to result, in part, from rare immune reactions to common infections.
In 2014, Wilson joined forces with Joe DeRisi, PhD, president of Chan Zuckerberg Biohub SF and lead author of the paper, to develop better tools to unmask the culprits of autoimmune diseases. They took a technique in which viruses are engineered to display protein fragments as flags on their surface, called phage display immunoprecipitation sequencing (PhIP-Seq), and further optimized it to detect autoantibodies in human blood.
PhIP-Seq detects autoantibodies against more than 10,000 human proteins, enough to investigate almost any autoimmune disease. In 2019, they successfully used it to discover a rare autoimmune disease that appeared to arise from testicular cancer.
MS affects more than 900,000 people in the United States. Its early symptoms, such as dizziness, twitching, and fatigue, may resemble other conditions, and diagnosis requires careful analysis of brain MRIs.
The scientists reasoned that the phage display system could reveal the autoantibodies behind the immune attacks of MS and create new opportunities to understand and treat the disease.
The project was led by first co-authors Colin Zamecnik, PhD, a postdoctoral researcher in the DeRisi and Wilson laboratories; and Gavin Sowa, MD, MS, former UCSF medical student and now internal medicine resident at Northwestern University.
They teamed up with Mitch Wallin, MD, MPH, of the University of Maryland and lead author of the paper, to look for autoantibodies in the blood of people with MS. These samples were obtained from the U.S. Department of Defense Serum Repository, which stores blood drawn from armed service members when they apply to join the military.
The group analyzed blood from 250 MS patients collected after their diagnosis, as well as samples taken five or more years earlier, when they joined the military. The researchers also looked at comparable blood samples from 250 healthy veterans.
Between the large number of subjects and the before-and-after timing of the samples, it was “a phenomenal cohort of individuals to look at to see how this type of autoimmunity develops over the course of the clinical onset of this disease,” Zamecnik said. . .
A consistent MS signature
Using just a thousandth of a milliliter of blood at a time, scientists thought they would see a jump in autoantibodies when the first symptoms of MS appeared.
Instead, they found that 10% of MS patients had a surprising abundance of autoantibodies years before their diagnosis.
The dozen autoantibodies attached to a chemical pattern that resembled that found in common viruses, including Epstein-Barr virus (EBV), which infects more than 85% of all people, but which in previous studies has been noted as a contributing cause of the disease. EM.
Years before diagnosis, this subset of MS patients had other signs of immune warfare in the brain. Ahmed Abdelhak, MD, a co-author of the paper and a postdoctoral researcher in the lab of Ari Green, MD at UCSF, found that patients with these autoantibodies had elevated levels of neurofilament light (Nfl), a protein that is released when neurons break down. . .
Perhaps, the researchers speculated, the immune system was mistaking friendly human proteins for some viral enemy, leading to a lifetime of MS.
“When we analyze healthy people using our technology, they all seem unique, with their own imprint of immunological experience, like a snowflake,” DeRisi said. “When one person’s immune signature looks like another person’s and stops looking like snowflakes, we start to suspect something is wrong, and that’s what we found in these MS patients.”
A test to accelerate patients towards appropriate therapies
To confirm their findings, the team analyzed blood samples from patients in the UCSF ORIGINS study. All of these patients had neurological symptoms and many, but not all, were diagnosed with MS.
Again, 10% of the patients in the ORIGINS study who were diagnosed with MS had the same pattern of autoantibodies. The pattern was 100% predictive of an MS diagnosis. In both the DoD group and the ORIGINS group, all patients with this autoantibody pattern had MS.
“Diagnosis of MS is not always easy because we haven’t had specific biomarkers for the disease,” Wilson said. “We are excited to have something that can provide more diagnostic certainty at an earlier stage, to have a concrete discussion about whether treatment should be initiated for each patient.”
Many questions remain about MS, ranging from what triggers the immune response in some MS patients to how the disease develops in the other 90% of patients. But researchers believe they now have a definitive sign that MS is brewing.
“Imagine if we could diagnose MS before some patients arrive at the clinic,” said Stephen Hauser, MD, director of the Weill Institute for Neurosciences at UCSF and senior author of the paper. “It improves our chances of moving from suppression to cure.”