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2022 is off to a great start for Science as Harvard researchers published a study that potentially solves a longstanding question: Can viral infections cause Multiple Sclerosis (MS)? According to their findings, the answer is yes, we can confidently say that Epstein-Barr Virus (EBV), a long-term suspect for causing this autoimmune disease, is indeed the primary causative agent.
In this blog article, we will talk about EBV and its ties to diseases along with discussing the results from this research, and end with the influence of this research in the future of MS therapeutics.
On Epstein-Barr Virus
The elusive virus in question, Epstein-Barr Virus has been under scientists’ lens since its discovery in 1964. It is a type of herpes virus (Human gammaherpesvirus 4) and its infections are rampant among us– up to 95% of humans are infected by EBV at some point in life. In developing countries, EBV infections are common in children, are less severe, and hence often go unnoticed. In the developed world, EBV infections happen later in life and can cause infectious mononucleosis, infamously known as the “kissing disease”. Mononucleosis lasts for 2-4 weeks in young adults and is characterized by fever, sore throat, and enlargement of lymph nodes. Does not sound scary, does it? Not unless you know that once you are infected by EBV, the virus continues to exist in a latent state in the body for the rest of our lives.
In B cells, EBV can establish a latent infection. This refers to when the viral genome stays active in the cell nucleus and multiplies every time the cell does. Other than B cells, EBV can also infect macrophages, epithelial cells, and lymphocytes. The key points in understanding why EBV is implicated in many cancers and MS are: 1. its latency, and 2. factors/triggers which can activate the latent EBV genome at a later point of life, causing disease.
Cancers (especially blood cancer) and EBV have a long history. It was the first virus shown to be directly involved in cancer. After extensive research over a few decades, the World Health Organization (WHO) declared it as a Class 1 carcinogen. A clear mechanism of its pathogenesis and the reason why only a fraction of cases develop tumors is yet to be elucidated. EBV can generate a wide repertoire of proteins and microRNAs that lead to tumor formation and help in escaping host immune responses. It can also mimic essential proteins associated with activation and proliferation of B cells. Besides cancer and MS, EBV has also been implicated in various autoimmune diseases, for example, systemic lupus erythematosus, and rheumatoid arthritis.
What does the research show?
The researchers performed a commendable feat with an excellent study design: by studying serum of more than 10 million young adults whose blood was tested by the US military, over a period of 20 years. Only the subjects who were not infected by EBV at the time of sampling, were considered for this study. With time, they eventually got infected by EBV which was then correlated with MS onset. Out of 801 MS cases, 800 suffered from MS following an EBV infection. Moreover, the chance of developing MS was 32 times higher in those who had antibodies against EBV as compared to those who didn’t.
The group had previously established a serum protein called sNfL (serum Neurofilament light chain) which correlates with neurological disorders. Here, they checked sNfL levels before, during, and after EBV infection, and noticed that there was a significant rise in sNfL levels after EBV infection – pointing towards EBV originating neurodegeneration. They also checked the serum antibody repertoire against a wide range of proteins from other viruses, including cytomegalovirus (CMV), but found nothing of interest. Additionally, MS patients always had the highest number of antibodies specific to EBV antigens.
Hence, the researchers provided solid proof implicating EBV launches Multiple Sclerosis through this paper.
Connecting the dots
MS is characterized by immune-mediated damage of the myelin sheath of neurons in the brain and the spinal cord, which in turn adversely affects signal transduction between neurons. It has long been suspected that a viral infection triggers the immune cells to attack the myelin sheath and to this date, EBV along with other possible viruses have been under investigation. Before the Harvard study was published, a huge body of research was already pointing towards EBV being in some way a major player in the etiology of MS.
In MS, B cells travel to the brain, cross the highly selective blood-brain barrier, and reside there, gradually increasing their population by converting into plasmablasts- stem cells producing antibodies and giving rise to more stem cells or plasma cells. Here they release autoantibodies targeting myelin proteins. The environment gets complicated as other immune cells like T cells, macrophages, and microglia get involved. The current most effective therapy for treating patients with MS include anti-CD20 antibodies that target B cells (although it has many drawbacks).
Many studies have shown these B cells migrating across the blood-brain barrier are EBV infected. Moreover, a meta-analysis from 2007 showed that 99.5% of the MS patients circulated antibodies against EBV in their serum. This has led to an ongoing debate on the exact mechanism of how EBV infection leads to MS: Is it the molecular similarity between EBV proteins and myelin and axonal proteins that leads to our antibodies formed against EBV proteins, attacking the self? Or is it the tendencies of abnormal behavior shown by EBV infected B cells which attack the myelin sheath? (For an extensive summary on the search of the cause for MS, click here)
EBV gained the reputation of being the problematic child over the years. Due to its abundance, finding out how essential of a causative agent it is for various diseases has been difficult. This breakthrough study surges our confidence than EBV play a pivotal role in causing MS. By virtue of it being a viral disease, it brings hope of eradication with the right vaccine. The long-time research on EBV vaccines so far has proved to be unsuccessful. EBV vaccine’s association with the possibility of completely avoiding MS in the future could lead to an increased funding in this area, hence increasing the chances of obtaining the ideal vaccine.
We still don’t know the detailed mechanism by which EBV causes MS, why only a fraction of the population suffers from it, and why rate of incidence is double in women as of that in men. Research also continues in finding ways of treating patients with MS, one of the prophylactic vaccines from BioNTech that we covered last year holds promise but it remains to be seen if it translates to the clinic.
· Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022 Jan 21. doi: 10.1126/science.abj8222.
Article author: Kevin Merchant. Kevin is a MS student at LMU Munich, Germany, who is passionate about Immunology and writing. He aims to simplify latest research so that it becomes accessible to all.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
Check out Antibuddies’ blog post “The Spoils of Epstein-Barr Virus and Its Role in Multiple Sclerosis”.Tweet