MS risk factor EBV alters the way B-cells move through body: Study
Findings could form the basis for new treatment strategies
The Epstein-Barr virus (EBV) — a well-established risk factor for multiple sclerosis (MS) — is able to alter the movements of infected immune cells, a new study reveals.
The findings shed new light on how EBV may set the stage for MS to develop, and could potentially form the basis for new treatment strategies for MS and other EBV-related diseases, according to researchers.
The study, “Epstein–Barr virus induces aberrant B cell migration and diapedesis via FAK-dependent chemotaxis pathways,” was published in Nature Communications.
Most people infected with EBV by adulthood
EBV is most known for causing infectious mononucleosis, colloquially known as mono. It also commonly causes nonspecific childhood illnesses. About 95% of people in the general population have been infected with EBV by the time they reach adulthood, but most never know they’ve been infected.
Studies have identified EBV as a key risk factor for MS — in fact, there’s evidence MS can only develop in people who are infected with EBV. The specific biological mechanisms that link EBV and MS remain incompletely understood, however.
“Understanding the contribution of EBV to the development of autoimmune diseases, and in particular of multiple sclerosis, is seen as key for the understanding of their pathogenesis [disease development] and the development of targeted therapies,” the researchers wrote.
In MS, the immune system launches an inflammatory attack that damages healthy cells in the brain and spinal cord. While many types of immune cells are involved in this inflammatory attack, B-cells are one type of immune cell known to play a central role.
When EBV enters the body, the virus mainly infects B-cells. In this study, researchers discovered EBV-infected B-cells change their behavior and movements.
B-cells and other immune cells normally reside in the blood or in immune organs called lymph nodes. But when there’s trouble, like an infection or cancer, B-cells turn into homing cells, so named because they rush, or home, to the site of trouble.
Researchers have now found EBV-infected cells produce certain inflammatory molecules that cause infected and non-infected cells to turn into homing cells.
“We were able to show that EBV-infected B cells exhibit characteristics of ‘homing cells,’” Henri-Jacques Delecluse, MD, PhD, co-author of the study at the German Cancer Research Center (DKFZ), said in a press release.
Discovery could lead to therapies to prevent B-cell migration
Through a series of experiments in cell and mouse models, the researchers showed EBV-infected B-cells move to other parts of the body, and they also undergo diapedesis, the process where immune cells squeeze out of blood vessels and move into the body’s tissues.
“We found that EBV infection … confers to these cells the ability to migrate and undergo diapedesis with high efficiency, two cardinal features of homing cells,” the researchers wrote.
This process may allow EBV-infected B-cells to move to the brain — and because B-cells in the brain are known to drive MS, this could potentially set the stage for MS.
Deciphering the reaction cascade that triggers EBV-infected B-cells to enter homing mode offers the possibility of targeted intervention to prevent B-cell migration.
The researchers found the movement of EBV-infected B-cells was governed primarily by two EBV proteins called EBNA2 and LMP1, and by an inflammatory signaling molecule called CCL4, which normally helps immune cells move to sites of infection, but has also been implicated in the development of MS.
“The viral proteins EBNA2 and LMP1 increase the activity of pro-inflammatory [signaling molecules] such as CCL4, which have been shown to be relevant in multiple sclerosis,” Delecluse said. “As a result, the infected B cells divide and swarm out. The EBV-manipulated B cells overcome the barrier of the vascular endothelium [the walls of blood vessels] and penetrate into the brain, among other places.”
The discovery of this pathway opens the possibility of developing therapies to prevent B-cell migration, which could potentially have applications in MS and other EBV-related disorders.
In proof-of-concept experiments in mice, the researchers showed inhibitors of B-cell migration could stop EBV-infected B-cells from getting into the brain, lending credence to this strategy as a potential treatment approach. The researchers stressed further tests are needed to see if this approach can be used safely and effectively in people.
“Deciphering the reaction cascade that triggers EBV-infected B-cells to enter homing mode offers the possibility of targeted intervention to prevent B-cell migration,” said Susanne Delecluse, MD, study co-author at DKFZ. “Using specific inhibitors, we were able to reduce the survival rate of EBV-infected B-cells and prevent them from spreading in the body, including to the brain.”
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