EBV can trick the immune system to attack myelin in at-risk individuals
Study shows how a common virus and genetic risk factors interact to trigger MS
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- Multiple sclerosis risk increases with Epstein-Barr virus infection and HLA-DR15 genetic variant.
- EBV infection causes B-cells with HLA-DR15 to "display" myelin proteins, triggering immune attacks.
- Understanding this mechanism may lead to new treatment strategies for multiple sclerosis.
A history of the Epstein-Barr virus (EBV) appears to alter the immune systems of people with specific genetic traits, causing their own cells to mistakenly flag brain proteins as dangerous threats, according to a new study.
This discovery offers insight into how these risk factors — viral infection and genetics — interact to contribute to the development of multiple sclerosis (MS), and could pave the way for new treatment strategies, researchers said.
“Our study shows how the most important environmental and genetic risk factors can contribute to MS and trigger an autoimmune response that targets myelin components in the brain,” Roland Martin, MD, who led the study at the University of Zurich, said in a university news story. “Our findings reveal mechanisms that could be targeted by new therapies.”
The study, “EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation,” was published in Cell.
The role of myelin in autoimmune attacks
In MS, the immune system launches an inflammatory attack in the brain and spinal cord that damages healthy myelin, a fatty substance essential for proper nerve functioning.
The causes of this self-targeting immune attack aren’t fully understood, but several risk factors have been identified. One of the strongest risk factors for MS is a history of EBV infection. Genetics is also thought to play a role.
EBV is best known as the cause of infectious mononucleosis, but it also causes a lot of non-specific childhood illnesses. Almost every adult has been infected with EBV at some point.
A large body of data has shown that EBV infection is a key risk factor for MS. In fact, many scientists think MS can develop only in people who have been infected with EBV. However, exactly how the infection leads to MS is poorly understood, and it’s not clear why only a small fraction of EBV-infected people develop the condition.
EBV primarily infects immune cells known as B-cells. One theory suggests that EBV infection may alter B-cell activity, predisposing an individual to MS. In this study, scientists found that EBV infection can alter the activity of a B-cell protein called the human leukocyte antigen (HLA).
The HLA protein acts like a display case for the immune system: pieces of infectious viruses and bacteria are loaded onto HLA on the surface of cells, allowing the immune system to identify threats.
Depending on a person’s genetics, there are many different variants of HLA, known as haplotypes. Previous research has shown that people with a specific HLA haplotype known as HLA-DR15 are at increased risk of developing MS.
Viral infection triggers a display of myelin
In the study, the researchers found that when B-cells with the HLA-DR15 haplotype are infected with EBV, their HLA molecules begin to display different molecules, including pieces of myelin basic protein (MBP), a key component of myelin. Healthy B-cells that aren’t infected with EBV, by contrast, did not display this myelin protein on their HLA molecules.
The scientists’ initial experiments were done using cell models, but they also analyzed brain tissue from four MS patients who had the HLA-DR15 haplotype. Consistent with the lab experiments, the researchers found EBV-infected B-cells with MBP displayed on their HLA molecules in human tissue.
In cell experiments using immune cells from MS patients, the researchers demonstrated that T-cells — one of the primary types of cells that recognize the proteins displayed by HLA — can respond to the myelin protein presented by EBV-infected B-cells.
Collectively, these data suggest that, in individuals with the HLA-DR15 haplotype, EBV may prime B-cells to display healthy myelin proteins erroneously, signaling other immune cells to launch an attack on myelin. This mechanism could help explain how both genetics and viral infection interact to affect MS risk, the researchers said.
“These data identify a novel mechanism of how EBV infection may contribute to MS [disease development] in conjunction with the HLA-DR15 haplotype,” they concluded.
