Gene Test May Predict Which MS Patients Will Respond to Interferon-beta Therapy

In multiple sclerosis (MS) patients who do not respond to interferon-beta treatment, autoimmunity may depend on processes that differ from patients helped by this treatment— a finding that could lead both to better therapies and tests that predict a patient’s likely response.

The study, “An interferon-β-resistant and NLRP3 inflammasome–independent subtype of EAE with neuronal damage,” was published in the journal Nature Neuroscience.

Interferon-beta is a first line of therapy to prevent MS flares, but it does not work in sizable groups of patients. Up to now, clinicians and scientists had no way of knowing if a patient would be helped by the treatment or not, and for those unfortunate not to respond, finding that out is long, costly, and detrimental.

Researchers at Duke University in North Carolina turned to a mouse model of an MS-like disease, called experimental autoimmune encephalomyelitis (EAE), to learn more about the different responses.

In an earlier study, the research team — led by Mari Shinohara, an associate professor of immunology at Duke — found that interferon-beta treatment helps to prevent MS relapses by blocking a complex of proteins known as the NLRP3 inflammasome. This structure seemed to trigger processes that allow the immune system to attack the brain.

But the study also revealed that some mice got sick without NLRP3 inflammasome involvement, indicating that different disease routes could lead to autoimmune activation and damage. Interestingly, these mice also did not react to interferon-beta treatment.

The researchers decided to explore exactly how the mice differed. In their new study, they reported that two receptors, called CXCR2 and LTBR, were crucial for promoting disease in interferon-resistant mice. Blocking these two receptors succeeded in doing what the interferon had failed to do — protecting the mice from disease relapses.

“The study shows a really clear molecular mechanism that may explain why some people do not respond to interferon-beta treatment,” Shinohara, the study’s senior author, said in a news release.

But mice and humans do differ, so to explore if the receptors were involved also in human MS, the team used genetic data from another MS study. Comparing gene activity in patients who responded to interferon treatment with those who did not revealed that the genes for these two receptors were more active in non-responders. Higher gene activity can translate to more of the receptors being produced.

Researchers now hope to explore whether the gene activity levels of a patient can tell beforehand whether that person is likely to be helped by interferon treatment.

“Now these patients have to go through all the pain, inconvenience and cost of interferon-beta treatment, only to be told that it doesn’t work for them,” said Shinohara. “So it’s a big problem, and it would be really nice if we could tell upfront which treatment works.”

Dr. Xiaoxia Li with the Cleveland Clinic, who was not involved in the study, highlighted the value of the findings in opening new diagnostic or treatment options.

“This new model gives us opportunities to explore a different disease mechanism that has been elusive to the field thus far,” Li said. “I believe it will have a large impact on both the basic and translational research on multiple sclerosis.”