Francisco Quintana

For multiple sclerosis (MS) patients and clinicians alike, there’s been a mystery: Why do symptoms of MS seem to get better in the winter and worse in the summer?

A group led by Francisco Quintana, PhD, of the Ann Romney Center for Neurologic Diseases at BWH, and collaborators has found an explanation that could lead to a deeper understanding of the disease and more targeted treatment options for patients. By first looking broadly at possible environmental factors and then at preclinical models of MS, the research team found that melatonin—a hormone involved in regulating a person’s sleep-wake cycle—may influence MS disease activity. The team reported its findings earlier this month in scientific journal Cell.

“We know that for MS and most autoimmune diseases, both genetic and environmental factors play an important role, but in the last decade or so, most research has focused only on the genetic side of the equation,” said co-corresponding author Quintana. “But we wanted to see what environmental factors would reveal to us about this disease. We knew that MS disease activity changed with the seasons. What we’ve uncovered offers an explanation for why that is the case.”

Working closely with colleagues at the Center for Research on Neuroimmunological Diseases at the Raul Carrea Institute for Neurological Research in Argentina, Quintana and his colleagues found that during the fall and winter, a group of 139 MS patients experienced a significant improvement in symptoms (a phenomenon that’s been observed in previous studies). The team then explored a variety of environmental factors that has been proposed as possibly linked to MS symptoms, including vitamin D levels, UV incidence and upper respiratory tract infections. But the factor that was consistently associated with severity of MS symptoms was melatonin. Melatonin levels are known to correlate with day length; during the longer days of spring and summer, levels are lower and during the shorter days of fall and winter, levels are higher.

The team tested this lead in the lab, studying the role that melatonin may play on a cellular level. Using both preclinical models and human cells, they investigated the effects of melatonin on certain types of cells known to play a role in the immune response that leads to MS symptoms. The team found that melatonin affected the roles of two kinds of cells that are important in MS disease progression: pathogenic T cells, which directly attack and destroy tissue, and regulatory T cells, which are supposed to keep pathogenic T cells in check.

“We found that melatonin has a protective effect,” said Quintana. “It dampens the immune response and helps keep the ‘bad guys,’ or pathogenic T cells, at bay.”

Researchers caution that the work does not mean MS patients should start taking supplements of melatonin—an imperfect drug. Although melatonin is available over the counter, it has significant drawbacks, including causing unwanted drowsiness. Instead, this new approach, which takes its lead from environmental observations, can be seen as a first step toward better and more targeted therapies. The team hopes to tease apart the molecular mechanisms that underlie melatonin’s role in order to develop targeted, non-toxic drugs that are safe and effective with minimal side effects.

“In the future, after appropriate clinical trials are conducted and dosage is established, melatonin or its derivatives may be used in MS patients,” said Quintana. “However, extreme caution should be exercised: additional studies are needed before melatonin or its analogs can be used to treat MS.”

The team is currently working to establish a pilot clinical trial to study the effects of targeting melatonin signaling in MS patients and identify additional mechanisms of action.