MS therapy may work in part by lowering EBV immune response

Anti-CD20 therapies, a type of treatment approved for multiple sclerosis (MS), may be highly effective in MS partly because they reduce the immune system’s ongoing response to the Epstein-Barr virus (EBV), a well-established risk factor for MS.

That’s according to a study involving nearly 200 people that found that MS patients receiving anti-CD20 therapies had significantly fewer immune T-cells that specifically recognize EBV than patients who had not yet started treatment and healthy people.

Also, the longer people had been receiving the treatment, the lower their levels of certain EBV-targeting T-cells tended to be.

Together, the findings suggest “that reduced EBV-reactive T-cell responses” may contribute to the “high clinical efficacy of [anti-CD20 therapies seen] in this [study],” researchers wrote.

The study, “The influence of anti-CD20-directed B cell depletion across different agents on Epstein-Barr virus-specific humoral and cellular immunity in patients with multiple sclerosis,” was published in the Journal of Neuroinflammation.

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Anti-CD20 therapies target key protein on B-cells

EBV is an extremely common virus, best known for causing infectious mononucleosis, or mono. After infection, the virus remains in the body for life, mainly inside B-cells, which are the immune cells responsible for producing antibodies. EBV infection is considered a major risk factor for MS, although exactly how the virus contributes to the disease remains poorly understood.

B-cells are also implicated in the abnormal immune responses that damage the nervous system in MS, making them an important treatment target. Disease-modifying therapies such as Ocrevus (ocrelizumab), Kesimpta (ofatumumab), and Briumvi (ublituximab-xiiy) are known as anti-CD20 therapies because they target the CD20 protein on the surface of B-cells, promoting their death.

Because B-cells are also the main reservoir for EBV, depleting them may reduce cells harboring the virus and alter the immune response against it. This has been “proposed as a potential mechanism underlying the remarkable clinical efficacy of [anti-CD20 therapy] in MS,” the researchers wrote, although “substantial knowledge gaps remain.”

To learn more, a team of researchers in Germany analyzed blood samples from 183 people enrolled at a single German hospital between October 2025 and January 2026. These included 54 people with MS receiving anti-CD20 therapy, 22 with newly diagnosed MS who had not yet started treatment, and 107 age- and sex-matched healthy people.

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Treated patients had fewer EBV-specific T-cells than healthy controls

Among treated MS patients, 48.1% were on Ocrevus, 37% on Kesimpta, and 14.8% on Briumvi. They had been living with MS for a median of 9.1 years and had received anti-CD20 treatment for a median of 1.7 years.

Anti-CD20 treatment was very effective, without any signs of disability worsening or new lesions on MRI, and a median of zero relapses per year.

Treated patients had significantly fewer EBV-specific T-cells than healthy controls. These included CD8-positive T-cells, which recognize and destroy virus-infected cells (median, 0.2% vs. 1.29%, respectively), and CD4-positive T-cells, which help coordinate antiviral immune responses (median, 0.01% vs. 0.02%).

The effect also appeared relatively specific to EBV: T-cell responses to other infectious agents were largely similar between treated patients and controls

Also, longer anti-CD20 treatment was significantly associated with fewer EBV-specific CD8-positive T cells, while disease duration was not.

“No significant associations were observed with [CD4-positive] T-cell responses,” the team wrote.

Moreover, newly diagnosed patients who had not yet received treatment had EBV-specific T-cell numbers similar to healthy controls and significantly more EBV-specific CD8-positive T-cells than treated patients. This supported an association between B-cell-depleting treatment and the reduced EBV-specific T-cell response.

Given the differential effects of B-cell depleting agents on reducing EBV-specific T-cell levels, future studies should elucidate whether the depletion of specific T-cells is associated with the clinical effectiveness of the drugs.

Antibodies against the virus, however, showed a different pattern. All treated patients had antibodies against two EBV proteins, EBNA1 and VCA, with levels significantly higher than in healthy controls. In untreated patients, antibody levels were generally similar to those in healthy people.

This is not necessarily surprising despite the loss of antibody-producing B-cells. B-cells can mature into long-lived plasma cells that produce high amounts of antibodies, and these cells are largely spared by anti-CD20 therapies. That means established antibody responses can persist even after circulating B-cells have been depleted.

Anti-CD20 therapies are “associated with selectively lower EBV-specific T-cell levels, while general T-cell functionality was preserved,” the researchers wrote. “In contrast, the [antibody] response to EBV is far less affected,” suggesting that “the significance of EBV-specific T-cell reactivity may be greater than that of [antibody] immunity.”

Differences were also seen among the three therapies. Counts of EBV-specific CD8-positive T-cells were significantly lower with Ocrevus than Kesimpta (median, 0.08% vs. 0.54%). Cell counts with Briumvi were also lower than with Kesimpta, but the difference was not statistically significant.

The researchers cautioned, however, that the small treatment groups limit conclusions about differences between therapies and warrant further investigations.

“Given the differential effects of B-cell depleting agents on reducing EBV-specific T-cell levels, future studies should elucidate whether the depletion of specific T cells is associated with the clinical effectiveness of the drugs,” the researchers wrote.