Researchers link the “clock” hormone melatonin to seasonal MS relapses
Multiple sclerosis (MS) relapse activity follows the seasons; MS attacks are generally more frequent in the spring and summer and quiet down in the fall and winter. Although the reason for this seasonal pattern is unknown, one hypothesis suggests that a factor provoked by the environment that rises and falls with the time of year may be responsible. Recently, an international team of scientists from Argentina and the United States identified a possible candidate; the hormone melatonin, whose levels peak over the fall/winter months and then drop off in the spring/summer.
Produced by a tiny gland in the brain called the pineal gland, melatonin is released into the bloodstream in response to a dark environment: melatonin release begins in the evening, rises overnight, and diminishes in the morning. In addition to daily cycling, overall melatonin levels in the body also fluctuate seasonally as the lengths of the days and nights change. Melatonin release is critical to regulating the body’s internal clock and helping to regulate the immune system.
It was this immune system link that interested the team of researchers. In a study published in the journal Cell, the researchers set out to determine if low levels of melatonin in the spring and summer can help explain why MS relapses are more frequent during that time of year.
The study was a collaborative effort between two teams; the first based at the Raúl Carrea Institute for Neurological Research in Buenos Aires, and the second at the Ann Romney Center for Neurologic Diseases in Boston.
The researchers began the study by corroborating the work of previous researchers showing that MS relapses fluctuate with the seasons. They documented the pattern of relapses across time in a group of 139 participants, all of whom had relapsing remitting MS.
Next, the researchers measured participants’ melatonin levels by measuring a melatonin byproduct. They determined whether there was a relationship between the amount of melatonin present in a participant’s body and MS relapse activity.
The study then shifted to the laboratory, where researchers set about testing whether melatonin could influence the MS disease process at the cellular level. The researchers gave melatonin to mice with an MS-like disease and measured the hormone’s impact on MS-like symptoms and immune cell behavior. They focused on two immune cell subtypes: pro-inflammatory Th17 immune cells – known contributors to MS pathology – and immune cells secreting an anti-inflammatory molecule called IL-10, used by the body to keep other aggressive immune cells at bay.
A final set of cell culture experiments determined melatonin’s impact on the development of both Th17 immune cells, as well as a specific subclass of immune cells called Tr1. Tr1 immune cells secrete the anti-inflammatory molecule IL-10 and are thought to protect against damaging inflammation.
In keeping with findings from previous work, participants had a 32% reduction in the number of relapses during the fall and winter months. Participant melatonin levels were also highest during these two seasons. When the data was combined, a clear picture emerged – more melatonin was associated with fewer relapses and fewer new symptoms. Older symptoms were also less likely to worsen.
When mice with an MS-like disease were given melatonin, their clinical symptoms improved. In particular, melatonin dampened the number of pro-inflammatory Th17 cells while simultaneously increasing the number of immune cells secreting the anti-inflammatory molecule IL-10.
In cell culture, melatonin further blocked the development of Th17 immune cells, and boosted the growth of anti-inflammatory Tr1 immune cells that release the IL-10 molecule.
The authors provide strong evidence that melatonin protects against MS relapses, decreasing the number and severity of relapses during the fall and winter months. This protective effect is diminished in spring and summer as melatonin levels subside.
As the authors state, the hormone, released in response to darkness, represents another environmental factor with a strong MS impact, and goes a long way to explaining why MS activity changes with the seasons. Whether melatonin also protects against first developing MS remains to be seen.
At a cellular level, melatonin alters the immune system, blocking the development of harmful pro-inflammatory Th17 cells, while simultaneously giving a boost to anti-inflammatory Tr1 cells. It is this shift in equilibrium, from an aggressive to a more subdued immune system, that the authors think is responsible for melatonin’s protective effect.
Though the findings are exciting, the authors do urge caution. As they make clear, melatonin acts on a variety of cell types in the body, not just those of the immune system. These interactions are often complex and still not well understood. While melatonin is an early candidate as a therapeutic option for MS, it still requires rigorous testing to reveal its mechanisms of action and determine its safety and efficacy.
Farez MF et al. (2015). Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. Cell. 162(6): 1338-52.