UC San Francisco scientists have made a discovery that could accelerate the treatment for multiple sclerosis (MS) patients. They found a sign in the blood of some individuals who eventually developed the disease. These antibodies target the body’s own proteins and are present years before any symptoms of MS appear, occurring in about 1 in 10 cases.The immune attacks on the brain and spinal cord that are characteristic of MS could be related to autoantibodies that target human cells and common pathogens. These findings were reported in Nature Medicine on April 19. MS can cause a significant loss of motor control, but new treatments can slow the progression of the disease and help preserve a patient’s ability to walk. The researchers are hopeful that the autoantibodies they discovered could one day be identified through a simple blood test, allowing patients to receive treatment earlier. In recent years, there has been a shift in the field towards treating MS at an earlier stage.”Newer and more powerful therapies can be more aggressively implemented,” explained Dr. Michael Wilson, a neurologist at UCSF and one of the senior authors of the study. “Obtaining a diagnostic result like this increases the likelihood of early intervention, providing hope for a better quality of life for patients.”
The connection between infections and autoimmune diseases has been established, with conditions such as MS believed to be a result of rare immune responses to common infections. In 2014, Dr. Wilson and Dr. Joe DeRisi, President of the Chan Zuckerberg Biohub SF and another senior author of the study, collaborated to develop improved tools for identifying the responsible agents.The researchers focused on autoimmune diseases, using a method that involves engineering viruses to display protein fragments on their surface. This technique, called phage display immunoprecipitation sequencing (PhIP-Seq), was further refined to screen human blood for autoantibodies.
PhIP-Seq is capable of detecting autoantibodies against over 10,000 human proteins, making it suitable for investigating a wide range of autoimmune diseases. In 2019, the researchers successfully utilized this method to identify a rare autoimmune disease associated with testicular cancer.
Multiple sclerosis (MS) affects over 900,000 people in the US and its early symptoms, such as dizziness, spasms, and fatigue, can be similar to other conditions.The identification, characterization, and diagnosis of multiple sclerosis (MS) require a thorough analysis of brain MRI scans. The scientists believed that the phage display system could uncover the autoantibodies responsible for the immune attacks in MS and open up new possibilities for understanding and treating the disease. Leading the project were Colin Zamecnik, PhD, a postdoctoral researcher in DeRisi’s and Wilson’s labs, and Gavin Sowa, MD, MS, a former UCSF medical student who is now an internal medicine resident at Northwestern University. They collaborated with Mitch Wallin, MD, MPH, from the University of Maryland, who is a senior author of the paper, to hunt for autoantibodies.The researchers examined blood samples from 250 people with MS that were obtained from the U.S. Department of Defense Serum Repository. This repository stores blood samples from military applicants. The blood samples from the MS patients were collected after their diagnosis, as well as from five years prior to their military enlistment. The researchers also studied blood samples from 250 healthy veterans for comparison. The large number of subjects and the timing of the samples provided a valuable cohort for the study of how this particular aspect of the immune system is linked to MS.”Zamecnik said that the signature of MS develops gradually over the clinical onset of the disease.”
Distinctive Features of MS
By analyzing a small amount of blood from each time point, the researchers expected to see an increase in autoantibodies as the first signs of MS appeared. Instead, they discovered that 10% of MS patients had a notable abundance of autoantibodies years before being diagnosed. These autoantibodies all adhered to a chemical pattern resembling that of common viruses, such as Epstein-Barr Virus (EBV), which infects over 85% of the population.yet has been identified in previous studies as a possible cause of MS.
This group of MS patients displayed signs of immune activity in the brain years before their diagnosis. Ahmed Abdelhak, MD, co-author of the study and a postdoctoral researcher in the UCSF lab of Ari Green, MD, observed that patients with these autoantibodies showed increased levels of neurofilament light (Nfl), a protein released when neurons deteriorate.
The researchers speculated that the immune system might be confusing harmless human proteins with a viral threat, potentially triggering MS over a person’s lifetime.
“When we examine healthy individuals using our technology. DeRisi explained that everyone has a unique immunological experience, likening it to a snowflake. He mentioned that when a person’s immunological signature starts resembling someone else’s, rather than being unique like a snowflake, it suggests that something may be wrong, as observed in the MS patients.
The team conducted further analysis on blood samples from patients in the UCSF ORIGINS study to validate their findings. These patients presented neurological symptoms, and some of them eventually received an MS diagnosis. Around 10% of the patients in the study did not go on to be diagnosed with MS.The ORIGINS study found that all patients diagnosed with MS had the same autoantibody pattern, which was 100% predictive of an MS diagnosis. Both the Department of Defense group and the ORIGINS group showed that every patient with this autoantibody pattern had MS. According to Wilson, diagnosing MS can be challenging due to the lack of disease-specific biomarkers. Having a diagnostic tool that can provide more certainty earlier on is promising, as it allows for a more informed discussion about treatment options for each patient. Many unanswered questions about MS still exist, such as the cause of the immune response in some MS patients.The researchers have found a definitive sign that MS is developing in the majority of patients. They are optimistic that this discovery could lead to earlier diagnosis and improved chances of finding a cure. Stephen Hauser, MD, director of the UCSF Weill Institute for Neurosciences, expressed the importance of being able to diagnose MS before patients reach the clinic, as it could increase the likelihood of finding a cure.
