Immune System Error: How Antibodies in Multiple Sclerosis Mistake Their Targets
Researchers at HSE University and the Institute of Bioorganic Chemistry of the Russian Academy of Sciences (IBCh RAS) have studied how the immune system functions in multiple sclerosis (MS), a disease in which the body's own antibodies attack its nerve fibres. By comparing blood samples from MS patients and healthy individuals, scientists have discovered that the immune system in MS patients can mistake viral proteins for those of nerve cells. Several key proteins have also been identified that could serve as new biomarkers for the disease and aid in its diagnosis. The study has been published in Frontiers in Immunology. The research was conducted with support from the Russian Science Foundation.
Multiple sclerosis (MS) is a disease in which the immune system mistakenly attacks the myelin sheath that surrounds nerve fibres. Myelin can be thought of like the insulation around electrical wires: when it deteriorates, signals between neurons are transmitted less effectively. This leads to difficulties with movement, vision, speech, and memory. The disease progresses in waves, with periods of exacerbation followed by remission; however, over time, the damage accumulates and may lead to disability. Diagnosing multiple sclerosis is challenging, as symptoms vary from patient to patient, and there are still no reliable biomarkers for a definitive diagnosis.
The causes of the immune system's malfunction are not yet fully understood, but scientists believe that viral infections may play a role. To gain deeper insight into the immune response in the disease, scientists from HSE University–St Petersburg and the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences conducted a study comparing the antibodies of patients with multiple sclerosis to those of healthy individuals. The researchers used PhIP-Seq, a technology that identifies the antigens against which an individual already has antibodies.
Antigens are foreign molecules that trigger an immune response. They are found on the surfaces of bacteria, viruses, and other cells, prompting the immune system to respond by producing antibodies.
Antibodies are proteins produced by the immune system to combat antigens. Antibodies act like 'keys' that recognise and bind to 'locks'—antigens—in order to neutralise them or mark them for destruction by other immune cells.
PhIP-Seq not only identifies the antibodies but also determines which proteins they interact with. This enables the creation of a detailed profile of the immune response, revealing the specific targets the immune system is attacking.
Igor Eliseev
'We selected about a thousand proteins capable of triggering an autoimmune response and fragmented them into small overlapping peptides—short chains of amino acids that make up proteins. Using genetic engineering, these peptides were then displayed on bacteriophages, with each phage presenting a specific peptide on its surface,' explains Igor Eliseev, Academic Supervisor of the Computational Biology and Bioinformatics Master's programme at the HSE Campus in St Petersburg. 'The modified phages were then added to the patients’ blood samples. If antibodies in the blood recognised specific peptides, they bound to the phages, forming complexes. Next, we extracted these complexes and analysed which proteins triggered the immune response.'
PhIP-Seq helped identify autoantibodies—antibodies that mistakenly target the body’s own proteins. The scientists found that in MS patients, the immune system reacts particularly strongly to the SPTAN1 protein, which plays a crucial role in the structure of nerve cells, as well as to the viral protein LMP1, which is associated with the Epstein–Barr virus (EBV). In patients with aggressive forms of MS, the immune response was even broader, with cross-reactivity causing the immune system to attack both viral proteins and the body’s own tissues. Put simply, the immune system behaved as though it were confusing viral proteins with the body’s own proteins.
'Our study showed that autoimmune antibodies in multiple sclerosis respond to a broad range of proteins,' explains Yakov Lomakin, Project Head and Senior Research Fellow at IBCh RAS. 'This indicates reduced specificity: instead of precisely targeting one protein, the antibodies bind to various targets, making the immune response chaotic and destructive.'
During the experiment, the scientists tested whether a combination of several proteins could serve as a biomarker for the disease. They found that testing for four antigens—SPTAN1, PTK6, PRX (nervous system proteins), and LMP1 (an EBV protein)—can distinguish MS patients from healthy individuals with high accuracy. These findings can not only improve diagnosis but also pave the way for new treatment approaches, such as targeted therapies that block misguided immune responses.
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