They show that signs of multiple sclerosis appear in the blood several years before the first symptoms appear.

A team of scientists from the University of California, San Francisco (USA) has discovered a precursor in the blood of some people who subsequently developed multiple sclerosis (MS) that could speed up treatment for patients with the disease.

In about 1 in 10 cases of multiple sclerosis, the body begins to produce a characteristic set of antibodies against its own proteins several years before symptoms appear. These autoantibodies appear to bind to both human cells and common pathogens, possibly explaining the immune attacks on the brain and spinal cord that characterize multiple sclerosis.

MS can cause a devastating loss of motor control, although new treatments may slow the progression of the disease and, for example, preserve a patient’s ability to walk.

In the study, published in the journal Nature Medicine, the scientists hope that the autoantibodies they discovered could one day be detected using a simple blood test, giving patients an advantage in treatment. “In recent decades, there has been a trend to treat multiple sclerosis earlier and more aggressively with newer and more powerful treatments,” said UCSF neurologist and lead author of the paper Michael Wilson.

“A diagnostic result like this makes early intervention more likely, giving patients hope for a better life,” he added.

Relationship between infections and autoimmune diseases

Autoimmune diseases such as multiple sclerosis are thought to be caused in part by rare immune responses to common infections. In 2014, Wilson joined forces with Joe DeRisi, president of Chan Zuckerberg Biohub SF and lead author of the paper, to develop better tools for identifying the culprits of autoimmune diseases.

They took a method by which viruses are engineered to display flag-like protein fragments on their surface, called phage display immunoprecipitation sequencing (PhIP-Seq), and optimized it for detecting autoantibodies in human blood. PhIP-Seq detects autoantibodies against more than 10,000 human proteins, enough to study virtually any autoimmune disease. In 2019, they successfully used it to detect a rare autoimmune disease that appears to arise from testicular cancer.

Multiple sclerosis affects more than 900,000 people in the United States. Its early symptoms, such as dizziness, cramping and fatigue, can resemble other conditions, and its diagnosis requires careful analysis of MRI scans of the brain. Scientists believed that the phage display system could identify the autoantibodies responsible for the immune attacks of multiple sclerosis and create new opportunities for understanding and treating the disease.

The researchers obtained samples from the U.S. Department of Defense Serum Repository, which stores blood taken from military personnel when they apply to join the military. The team analyzed blood from 250 patients with multiple sclerosis collected after diagnosis, as well as samples taken five or more years earlier when they enlisted in the military.

The researchers also analyzed matched blood samples from 250 healthy veterans. Given the large number of subjects and the timing of the before-and-after sampling, this was a “phenomenal cohort of people who could see this type of autoimmunity develop during the clinical onset of this disease,” Zamecnik says.

Consistent MS Signature

Using just a thousandth of a milliliter of blood at a time, the scientists believed they would see an increase in autoantibodies when the first symptoms of multiple sclerosis appeared. However, they found that 10 percent of patients with multiple sclerosis had a surprising number of autoantibodies in the years before diagnosis.

These dozen autoantibodies had a chemical structure similar to that of common viruses, such as the Epstein-Barr virus (EBV), which infects more than 85 percent of the population and has, however, been identified in previous studies as one of the causes of MS.

Years before diagnosis, this subgroup of MS patients had other signs of immune warfare in the brain. Dr. Ahmed Abdelhak, a co-author of the paper and a postdoctoral fellow in Dr. Ari Green’s laboratory at the University of California, San Francisco, found that patients with these autoantibodies had increased levels of neurofilament light (Nfl), a protein that is released when neurons are destroyed.

Perhaps, the researchers speculated, the immune system mistook friendly human proteins for some kind of viral enemy, leading to lifelong multiple sclerosis. “When we analyze healthy people with our technology, each person appears unique, with their own imprint of immunological experience, like a snowflake. It’s when one person’s immunological signature resembles that of another, and they stop looking like a snowflake, that’s when we start to suspect something is wrong, and that’s what we find in patients with multiple sclerosis,” DeRisi said.

A test that will help patients choose the appropriate treatment.

To confirm their findings, the team analyzed blood samples from patients participating in the UCSF ORIGINS study. All of these patients had neurological symptoms, and many, but not all, were diagnosed with multiple sclerosis.

Again, 10 percent of patients in the ORIGINS study diagnosed with multiple sclerosis had the same set of autoantibodies. This pattern was 100% predictive of a diagnosis of multiple sclerosis. In both the DoD and ORIGINS groups, all patients with this autoantibody pattern had multiple sclerosis.

“The diagnosis of multiple sclerosis is not always easy because we do not have specific biomarkers for the disease. “We’re pleased that we have something that can provide more diagnostic confidence sooner to have a specific discussion about whether to initiate treatment for each patient.” Wilson concluded.