You must know five things about the Epstein-Barr virus (EBV). Why? Because chances are you have it.
Epstein–Barr virus
The Role of Epstein-Barr Virus in Multiple Sclerosis
This week’s “Ask an MS Expert” will cover the most recent evidence regarding the role of the Epstein-Barr virus in triggering multiple sclerosis. Dr. Bruce Bebo, the executive vice president of research programs at the National MS Society, and host Jon Strum will discuss the implications of this information for the MS community and share the Society’s plans for utilizing this new knowledge.
Epstein-Barr Virus and brain cross-reactivity: a mechanism for Multiple Sclerosis
The role that Epstein-Barr Virus (EBV) plays in the development of multiple sclerosis (MS) may be caused a higher level of cross-reactivity, where the body’s immune system binds to the wrong target, than previously thought.
In a new study published in PLOS Pathogens, researchers looked at blood samples from people with multiple sclerosis, healthy people infected with EBV and people recovering from glandular fever caused by recent EBV infection. The study investigated how the immune system deals with EBV infection as part of worldwide efforts to understand how this common virus can lead to the development of multiple sclerosis, following 20 years of mounting evidence showing a link between the two.
While previous studies have shown that antibody responses to one EBV protein — EBNA1 — also recognise a small number of central nervous system proteins, this study found that T-cells, another important part of the immune system that targets viral proteins, can also recognise brain proteins.
A second important finding was that these cross-reactive T-cells can be found in people with MS and those without the disease. This suggests that differences in how these immune cells function may explain why some people get MS after EBV infection.
Dr Graham Taylor, associate professor at the University of Birmingham and one of the corresponding authors of the study, said:
“The discovery of the link between Epstein-Barr Virus and Multiple Sclerosis has huge implications for our understanding of autoimmune disease, but we are still beginning to reveal the mechanisms involved. Our latest study shows that following Epstein-Barr virus infection, there is a great deal more immune system misdirection, or cross-reactivity than previously thought.”
“Our study has two main implications. First, the findings give greater weight to the idea that the link between EBV and multiple sclerosis is not due to uncontrolled virus infection in the body. Second, we have shown that the human immune system cross-recognises a much broader array of EBV and central nervous system proteins than previously thought and that different cross-reactivity patterns exist.
“Knowing this will help identify which proteins are important in MS and may provide targets for future personalised therapies.”
T Cells are involved.
During blood testing, the team also found evidence that cross-reactive T cells targeting Epstein-Barr virus and central nervous system proteins are present in many healthy individuals.
Dr Olivia Thomas from the Karolinska Institute in Sweden and joint corresponding author of the paper said:
“Our detection of cross-reactive T-cells in healthy individuals suggests that these cells’ ability to access the brain is important in MS.
“Although our work shows the relationship between EBV and MS is now more complex than ever, it is important to know how far this cross-reactivity extends to fully understand the link between them.”
Research identifies mechanisms for selective multiple sclerosis treatment strategy
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.”
Multiple Sclerosis – New approach to Epstein-Barr virus and resulting diseases
Exactly 60 years ago, pathologist Anthony Epstein and virologist Yvonne Barr announced the discovery of a virus that has carried their names ever since. The Epstein-Barr virus (EBV) made scientific history as the first virus proven to cause cancer in humans. Epstein and Barr isolated the pathogen, which is part of the herpesvirus family, from tumour tissue and demonstrated its cancer-causing potential in subsequent experiments.
Most people are carriers of EBV: 90% of the adult population are infected with the virus, usually experiencing no symptoms and no resulting illness. Around 50% become infected before the age of five, but many people don’t catch it until adolescence. Acute infection with the virus can cause glandular fever — also known as “kissing disease” — and can put infected individuals out of action for several months. In addition to its cancerogenic properties, the pathogen is also suspected to be involved in the development of autoimmune diseases such as multiple sclerosis.
As yet, no drug or approved vaccination can specifically thwart EBV within the body. Now, a research group from the University of Basel and the University Hospital Basel has reported a promising starting point for putting the brakes on EBV. Their results have been published in the journal Science.
EBV hijacks the metabolism of infected cells
Researchers led by Professor Christoph Hess have deciphered how the immune cells infected with EBV —the so-called B cells — are reprogrammed. Known as “transformation,” this process is necessary for the infection to become chronic and cause subsequent diseases such as cancer. Specifically, the team discovered that the virus triggers the infected cell to ramp up the production of an enzyme known as IDO1. This ultimately leads to greater energy production by the power plants of infected cells: the mitochondria. In turn, this additional energy is needed for the increased metabolism and the rapid proliferation of B cells reprogrammed by EBV in this way.
Clinically, the researchers focused on a group of patients who had developed EBV-triggered blood cancer following organ transplantation. To prevent a transplanted organ from being rejected, it is necessary to weaken the immune system using medications. This, in turn, makes it easier for EBV to gain the upper hand and cause blood cancer, referred to as post-transplant lymphoma.
In the paper, which has now been published, the researchers were able to show that EBV upregulates the enzyme IDO1 already months before post-transplant lymphoma is diagnosed. This finding may help to develop biomarkers for the disease.
Second chance for a failed drug
“Previously, IDO1 inhibitors have been developed in the hope that they could help to treat established cancer — which has unfortunately turned out not to be the case. In other words, there are already clinically tested inhibitors against this enzyme,” explains Christoph Hess. Accordingly, this class of drugs might now receive a second chance in applications aimed at dampening EBV infection and thereby tackling EBV-associated diseases. Indeed, in experiments with mice, IDO1 inhibition with these drugs reduced the transformation of B cells and therefore the viral load and the development of lymphoma.
“In transplant patients, it’s standard practice to use drugs against various viruses. Until now, there’s been nothing specific for preventing or treating Epstein-Barr virus associated disease,” says Hess.