Targeting EBV-infected B-cells may help prevent or treat MS: Study
Researchers ID possible way infection could set the stage for disease
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- Epstein-barr virus (EBV) infection is a major risk factor for multiple sclerosis (MS).
- EBV tricks self-reactive B-cells into becoming activated in the brain, causing MS-like inflammation.
- Targeting EBV-infected B-cells could prevent or treat multiple sclerosis.
When immune B-cells mistakenly recognize the body’s own nerve tissue, they can shut themselves down to prevent damage, but infection with the Epstein-Barr virus (EBV) can trick B-cells into surviving and becoming activated in the brain instead of being eliminated by normal immune safety mechanisms, according to a study.
These self-reactive B cells can then drive inflammatory damage similar to the lesions seen in multiple sclerosis (MS), suggesting a potential mechanism by which EBV infection may lead to the development of MS, researchers said.
“Experts in the field mostly agree that both B cells and Epstein-Barr virus are somehow involved in the disease, but there is no consensus about how. The model that emerges from the work of our team is very simple and therefore very persuasive,” Nicholas Sanderson, PhD, co-author of the study at University Hospital Basel and the University of Basel in Switzerland, said in a university news story. “In a nutshell, we suggest that virus-infected B cells cause the lesions.”
The study, “Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation,” was published in Cell.
B-cells play key role in MS-driving inflammation
In MS, the immune system launches an inflammatory attack that targets the myelin sheath, a fatty covering around nerve fibers that helps them send electrical signals. Damage to myelin disrupts nerve signaling, ultimately leading to MS symptoms.
The causes of MS are not fully understood. It’s been established that B-cells, a type of immune cell, play a key role in MS-driving inflammation. It’s also been established that infection with EBV — a virus that causes infectious mononucleosis and other nonspecific childhood illnesses — is a significant risk factor for MS.
It’s not clear exactly how EBV infection leads to MS. However, researchers know the virus mainly infects B-cells, and some think the infection may alter B-cell activity in a manner that sets the stage for MS to develop. The new study, done mainly in mouse models, lends credence to this idea.
Viral protein produced by EBV mimics activity of gatekeeper protein
Each B-cell is equipped with a unique molecular receptor that binds to a specific target. Normally, B-cells target infectious viruses or bacteria, but some B-cells are accidentally made with receptors that recognize the body’s own tissue.
The researchers found that when a viral infection occurs in the brain, many B-cells move from the blood into the brain to fight the infection. Some of these B-cells possess receptors that can recognize components of the myelin sheath. But instead of attacking myelin, these self-targeting B cells quickly die off.
This rapid death of self-targeting cells is a feature of the immune system’s normal quality-control mechanisms. When a B-cell’s unique receptor engages its target, the cell doesn’t go on the attack right away. Instead, it requires additional activation signals from T-cells, another type of immune cell, to remain active, like an assassin checking in with his handler before pulling the trigger.
If the T-cells are themselves activated by a genuine immune threat, they can provide a set of confirmation signals, one of the most important being via a protein called CD40L, which allows the B-cell to survive and become activated. But if the B-cell does not receive the CD40L signal from T-cells, this will trigger the self-reactive B-cell to die.
In their study, the researchers found that a viral protein produced by EBV, called LMP1, mimics the activity of CD40L. As such, when EBV-infected B-cells with receptors that can target myelin enter the brain, they don’t require T-cell help to prevent them from dying off, allowing them to survive and go on the attack.
We have identified a series of events including EBV infection that has to happen in a clearly defined sequence to cause localized inflammation in the brain. While this is not fully explaining all aspects of MS, it might be the spark that ignites chronic inflammation in the brain.
In mouse models, these self-targeting B-cells ultimately caused nerve damage similar to that seen in people with MS, and analyses of B-cells from a few MS patients found similar molecular anomalies.
This mechanism could help explain how EBV sets the stage for MS, the researchers said, and it lends credence to the idea that MS may be treatable or preventable by targeting EBV-infected B-cells.
“The role of EBV in MS has been quite mysterious for a long time. We have identified a series of events, including EBV infection, that must occur in a clearly defined sequence to cause localized inflammation in the brain. While this is not fully explaining all aspects of MS, it might be the spark that ignites chronic inflammation in the brain,” said Tobias Derfuss, MD, study co-author at University Hospital Basel and the University of Basel.
