T-cells Targeting Epstein-Barr Virus at High Levels in MS Patients
MS link to 'broader' T-cell receptor response to EBV possible
People with multiple sclerosis (MS) have significantly more T-cells equipped with receptors that specifically recognize the Epstein-Barr virus (EBV) than do healthy individuals, a study revealed.
Notably, no such differences were detected for T-cells with receptors specifically against other viruses.
These findings add to previous data highlighting EBV infection as a strong MS risk factor and suggesting immune responses against EBV may drive attacks against myelin. Myelin is the protective sheath around nerve fibers that is progressively lost in MS due to abnormal immune attacks.
The study, “Broader Epstein–Barr virus–specific T cell receptor repertoire in patients with multiple sclerosis,” was published in the Journal of Experimental Medicine.
Epstein-Barr is a common herpes virus that can cause infectious mononucleosis, colloquially called “mono.” After infection, it remains in the body throughout life in a dormant form inside B-cells — a type of immune cell implicated in MS.
Increasing evidence supports that a history of EBV infection “is necessary but not sufficient” for the development of MS, the researchers wrote.
T-cell receptors specifically target Epstein-Barr protein in MS
Prior work has shown that people with MS tend to have increased levels of antibodies against EBV. Antibodies are immune proteins made by B-cells that are able to stick to a specific molecular target, called an antigen, with extreme specificity.
Notably, research suggests that structural similarities between an EBV protein and a brain protein found at the surface of myelin-producing cells can cause B-cells to accidentally attack a person’s own healthy tissue while trying to fight off the virus.
Based on this evidence, researchers in Germany and France, along with colleagues at Roche and Adaptive Biotechnologies, evaluated whether the repertoire of T-cell receptors, or TCRs, was also altered in people with MS.
TCRs are the specialized receptors at the surface of immune T-cells that, like antibodies, recognize a specific antigen. Each T-cell contains TCRs that recognize a single antigen, and the binding between the TCR and its target activates the cell to trigger an immune attack against that antigen.
A battery of studies characterized the TCRs of 1,395 MS patients and 887 people without the disease, used as controls.
Results broadly showed that MS patients had significantly higher levels of TCRs specifically against EBV proteins relative to controls. Notably, levels of TCRs against other viruses — such as SARS-CoV-2, which causes COVID-19, and influenza-A, which causes the flu — were not significantly different between MS patients and controls.
While these findings suggest that “MS patients share a higher prevalence of EBV-specific TCRs,” the researchers wrote, “EBV-specific TCR sequences alone are not sufficient to classify MS patients and discriminate them from controls in form of a biomarker.”
TCR levels also distinguish MS patient among identical twins
In further work, the team analyzed the TCRs of 35 pairs of monozygotic, or “identical,” twins where one twin had MS and the other did not. These results also showed increased EBV-specific TCRs in those with MS, even after accounting for a known history of EBV infection.
Since monozygotic twins are by definition genetically identical and usually have similar experiences in childhood, this suggests that the observed change in EBV-specific TCR repertoire is independent of “known genetic and early environmental factors,” the researchers wrote.
Analyses of MS patients with available treatment data showed that those on Tysabri (natalizumab) — an approved MS therapy that works by trapping immune cells in the lymph nodes — also had a particularly strong T-cell repertoire against EBV, but not other viruses.
Since reducing immune cells in circulation should have the same effect on T-cells, regardless of their target, and EBV-specific T-cells have been reported in the brain and surrounding fluid, these findings are “consistent with an ongoing, potentially compartmentalized immune reaction [in the brain] against EBV in MS patients,” the researchers wrote.
However, there was no clear effect of treatment in patients given interferon products, which are suspected to have antiviral effects, or those on B-cell depleting therapies — indicating that “elevated T cell response might not be dependent on peripheral B cells as an EBV reservoir,” they added.
These findings suggest that MS is not only associated with higher EBV-specific antibody levels, “but also with a broader EBV-specific TCR repertoire, even in monozygotic twin pairs with matching [history of EBV infection], and identical genetics, as well as early childhood environment,” the researchers wrote.
“Future studies should determine whether this broader repertoire against EBV in MS is just a byproduct of a putatively aberrant, immune response, or involved in driving disease [mechanisms],” they added.
The study was partly funded by Roche, which markets B-cell-depleting therapies approved for MS, and Biogen, which markets Tysabri.