Wistar researchers (L-R) Drs. Samantha Soldan and Paul Lieberman CREDIT The Wistar Institute

Samantha Soldan, PhD, has demonstrated how B cells infected with the Epstein-Barr virus (EBV) can contribute to a pathogenic, inflammatory phenotype that contributes to multiple sclerosis; the group has also shown how these problematic B cells can be selectively targeted to reduce the damaging autoimmune response of multiple sclerosis.

EBV — a usually inactive or latent herpes virus — affects most of the human population; more than 90% of people carry the virus as a passive, typically symptomless infection. However, EBV infection has been linked to several diseases, including multiple sclerosis, an incurable, chronic autoimmune disease that causes the body’s immune system to attack the myelin sheath of neurons in the brain and nervous system. Because myelin sheathing facilitates fast, nervous system signalling (the fatty insulation of myelin along a neuron’s axon allows electrical impulses to travel through neuronal networks faster), its degradation can cause a wide variety of symptoms in both type and severity that may include motor control disruption, sensory issues, and speech difficulties.

Though researchers know that EBV can contribute to the development of multiple sclerosis, the exact mechanisms by which it does so aren’t completely understood. The research team analyzed spontaneous lymphoblastoid cell line (SLCL) cell samples from a healthy control group; a group of patients with active multiple sclerosis (as opposed to so-called stable multiple sclerosis; the disease is characterized by unpredictable periods of flare-ups and eased symptoms); and a group of patients with stable multiple sclerosis. 

B cells are crucial cells of the immune system that help regulate the body’s immune responses; they have also been implicated in autoimmune conditions due to their role as mediators, of which biological signals warrant immune response. And B cells, when infected with EBV, become immortalized — that is, the cells are no longer constrained by senescence, so they can continue to divide an indefinite number of times — as “lymphoblastoid cell lines,” or LCLs. This immortalized B cell state can occur spontaneously within the body due to EBV infection, which is how the Lieberman lab was able to extract immortalized SLCL samples for study from the different patient groups. 

Having obtained the matched samples, Dr. Lieberman and his team conducted genetic analyses of the SLCLs and confirmed that the MS-positive sample groups showed greater expression of genes associated with lytic EBV (“lytic” describes when latent viruses like EBV become active); they also saw increased inflammatory signaling and expression of the FOXP1 protein, the latter of which was shown to promote lytic EBV gene expression. As a whole, the group’s findings suggested a mechanism of lytic EBV in MS that promoted inflammation and disease. 

Diving further, Lieberman’s group tested several antiviral compounds on all SLCL groups and found that one, TAF, reduced lytic EBV gene expression without killing the cells. TAF also significantly reduced the expression of inflammatory cytokines like IL-6 in the SLCLs from the patients with active MS. Finally, when cultured SLCLs from active MS, stable MS, and controls were administered TAF in the presence of antiviral T cells, the T cell response (a major factor in the autoimmune dysfunction of MS) was reduced in SLCLs from patients with MS but not reduced in the control SLCLs — an indication that TAF treatment has potential as a selectively cytotoxic anti-lytic treatment for MS.

“Our work with these SLCLs shows that the problematic inflammation signaling from lytic EBV can be selectively targeted in a way that demonstrably reduces damaging immune responses,” said Dr. Lieberman. “We’re excited about expanding this concept further; we have the potential to see whether TAF or other inhibitors of EBV might be a viable treatment for multiple sclerosis that can stop the autoimmune damage without causing wide-ranging and dangerous cell death.” 

The test was developed using an existing diagnostic procedure as its basis and has the potential to be applied in clinical trials that target the Epstein Barr Virus

A team of research scientists at Trinity College Dublin have developed a new and unique blood test to measure the immune response to the Epstein Barr Virus (EBV) which is the leading risk factor for developing multiple sclerosis (MS). Their findings are published in the journal Neurology Neuroimmunology and Neuroinflammation and have implications for future basic research in further understanding the biology of EBV in MS, but also has the potential to be applied in clinical trials that target the virus.

MS is a chronic neurological disease with no known cure. It affects approximately three million people worldwide and is the second leading cause of disability in young adults. There is a pressing need for better treatments.

A range of viruses relating to MS have been studied in the past but none have had such compelling evidence as EBV. The question the team considered was why do some people have known MS have a rogue immune response to EBV, a common viral infection that is generally asymptomatic? 

To answer this, scientists measured the cellular response of MS patients to EBNA-1, a part of the EBV that can mimic the myelin coating of nerves which are the principal site of attack of the immune system in MS. The team found that the immune response is higher to EBNA-1 in people with MS compared to those with epilepsy, or the healthy control group. The team also showed that this cellular response is impacted by currently approved medications for MS which target the immune system, but not the virus. The immune response to EBNA-1 was found to be lower in people who are taking B cell depleting medications compared to people with MS not taking medication and the level recorded was equivalent to healthy controls.  

B cell depleting medications are effective for reducing MS disease activity. It is not known however, how exactly they work. Many people believe that reducing B cells reduces EBV levels, as EBV can lie dormant within B cells. The scientists do not prove this theory, but do show that the immune response to EBV in MS is equal to healthy controls when these medications are used. The team believe that this supports the need for more selective reduction in EBV rather than targeting all B cells. This is of importance as B cells play an important role in fighting infection and an unselective approach can lead to unwanted side effects.

The Trinity researchers are the first team of scientists to capture the immune response to EBNA-1 using whole blood samples carried out exclusively with equipment that is used in the hospital laboratory day to day. This builds on previous research that used extensive pre-processing in research laboratories. We believe this is of importance as it shows the ability for the test to be run elsewhere and at scale without a need for new equipment or personnel. 

This research is important because a standard blood test that was processed in a hospital laboratory provides important information on the immune system’s response to EBNA-1. This response appears to be at the heart of the pathogenesis of MS. The ability to measure this in a scalable test, that was developed using an existing diagnostic test as its basis, has implications for future basic research in further understanding the biology of EBV in MS. But the test also has the potential to be applied in clinical trials that target the virus. This would mean that there is the potential to directly measure the immune response to any potential antiviral treatments, rather than measuring MS outcome measures alone.

Speaking on the potential benefits of this research, Dr Hugh Kearney, Neurologist, School of Medicine, Trinity College and lead author said:

“In the short term the benefit of this research is likely to be for the research community in MS. We believe the approach adopted in this test that uses whole blood samples on a robust hospital-based platform will facilitate adoption in other centres and also replication of the results with a view towards validation. In the medium term, if validated, then this would be of benefit to researchers involved in clinical trials in MS. Long term benefits will be for people with MS, who live with a chronic neurological illness as new treatments tested in clinical trials have the potential to reduce the burden of this potentially disabling disease.

The next step for our team is to develop a longitudinal study. We aim to do this by recruiting newly diagnosed people with MS and measuring this blood test before treatment has started and then repeating the blood test at an interval to show that B cell depletion directly impacts on the cellular response to EBNA-1 in MS.”

The underlying cause of MS has not yet been fully clarified, but a connection with the Epstein-Barr virus (EBV) has long been suspected. In most patients who develop MS, specific immune responses against EBV are detectable, which are also directed against certain structures of the central nervous system and thus contribute to the development of MS. Until now. However, it was unclear why an EBV infection, one of the most common and lifelong persistent viral infections in humans, only leads to MS in a small number of people. A research group at the Centre for Virology led by Elisabeth Puchhammer-Stöckl, in cooperation with a team from the Department of Neurology at the Medical University of Vienna led by Thomas Berger and Paulus Rommer, has now shown that the risk of MS is particularly high in people with a combination of certain host factors and virus variants.

Natural killer cells as a potential protective factor
To be specific, the investigations revealed a greatly increased risk of MS, if, on the one hand, the EBV-specific and autoreactive immune responses are strong and, on the other hand, the patients are unable to control this autoimmunity efficiently. The study authors identified a subgroup of the natural killer cells of the human immune system as a potential key factor for protection against MS. “These immune responses could therefore play a decisive role in the development of future vaccines,” says Hannes Vietzen from the Centre for Virology, first author of the study, describing the new possibilities that arise from the research work with regard to the prevention and early detection of MS. According to the investigations, the development of MS proved to be dependent on certain genetic factors as well as on infection with a specific EBV virus variant, which, according to the laboratory experiments, leads to a significantly weakened immune response against the autoreactive processes and thus contributes to the development of MS. “It may be helpful to analyse the EBV variants detected in these patients in order to identify patients at risk at an early stage,” says Hannes Vietzen in the run-up to further studies that are intended to deepen these findings.

A new study from Harvard University has provided more evidence supporting a link between Epstein-Barr Virus (EBV) infection and multiple sclerosis. MStranslate co-founder and chief science communicator, Brett Drummond, explores the outcomes of this published work in detail and explains why we must remain cautious when interpreting the significances of these findings.