A media alert for the journal Cell.
EMBARGOED RELEASE
Media Contact: Joseph Caputo | Cell Press
617-397-2802 | jcaputo@cell.com | press@cell.com
STRICTLY UNDER EMBARGO UNTIL 12:00PM NOON ET (US) ON THURSDAY, SEPTEMBER 10,
2015
Region(s) of Interest: United States, Massachusetts; Argentina, Buenos Aires
Institution(s): Brigham & Women's Hospital; Harvard Medical School; Raul Carrea Institute for
Neurological Research; Universidad de Buenos Aires
Melatonin Explains the Mystery of Seasonal Multiple Sclerosis Flare-Ups
Seasonal flare-ups in patients with multiple sclerosis are caused by plummeting levels of melatonin in
the spring and summer, according to research published September 10 in Cell. The study reveals that
relapses in patients with this autoimmune disorder are much less frequent in the fall and winter, when
levels of the so-called darkness hormone are at their highest, but the reverse is true in the spring and
summer seasons.
Moreover, treatment with melatonin improved clinical symptoms in a mouse model of multiple
sclerosis by restoring a healthy balance of immune cells called T lymphocytes. The findings, which
resulted from a collaboration between American and Argentinian scientists, could potentially lead to
the development of novel treatments for a broad range of autoimmune disorders.
"Our work may provide an answer for the seasonal paradox by identifying melatonin, whose levels are
regulated by seasonal fluctuations in day length, as an additional regulator of the immune response in
multiple sclerosis," says study author Francisco J. Quintanta of the Ann Romney Center for
Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School. "The implication
is that molecules activating melatonin signaling may represent new targets for therapeutic
immunomodulation in multiple sclerosis and potentially other inflammatory diseases."
Multiple sclerosis is a nervous system disorder thought to be triggered by T cells that destroy the
myelin sheath--the material that surrounds and protects nerve cells. This damage slows down or
blocks messages between the brain and the body, leading to symptoms such as visual disturbances,
muscle weakness, trouble with coordination and balance, and thinking and memory problems. In
addition to genetic factors, the disease is influenced by environmental factors such as infections,
sodium intake, smoking, and vitamin D levels.
In particular, vitamin D has been considered as a factor that could potentially contribute to the
seasonal flare-ups that have been observed in patients with multiple sclerosis for decades. Not only
does the vitamin affect immune responses, but its synthesis is triggered by sun exposure and exhibits
large seasonal fluctuations. However, these observations pose a paradox: vitamin D is expected to
reduce the frequency of relapses in the spring and summer due to its anti-inflammatory effects, but
that's exactly when clinical symptoms are at their worst.
To solve this seasonal paradox, Quintana and study authors Mauricio Farez and Jorge Correale of
the Raúl Carrea Institute for Neurological Research (FLENI) in Argentina set out to identify additional
environmental factors that could play a role. They quickly zeroed in on melatonin because levels of
the hormone, which regulates circadian rhythms and immune responses, fluctuate with the seasons.
In support of this idea, the researchers discovered a negative relationship between melatonin levels
and clinical relapses in 139 patients with multiple sclerosis. Because melatonin production is
stimulated by darkness, levels of the hormone peaked in the fall and winter. Meanwhile, there was a
32% reduction in the number of relapses in the fall and winter compared to the spring and summer.
The findings demonstrate that higher melatonin levels in the darker months are associated with an
improvement in clinical symptoms.
To test if melatonin plays a causal role in relapses, the researchers gave daily injections of the
hormone to mice with an autoimmune disease that recapitulates key features of multiple sclerosis.
Not only did melatonin treatment improve clinical symptoms, it also restored a healthy balance of T
cells in the brain, spinal cord, and several immune organs. The hormone reduced levels of harmful T
cells called Th17 cells, which are known to play a major role in the development of multiple sclerosis.
At the same time, melatonin treatment stimulated an increase in regulatory T cells, which keep Th17
activity in check.
"The main strength of the study is that we demonstrate with great detail the mechanisms used by
melatonin to modulate the immune system. In addition to this, we show the effects of melatonin in an
animal model of multiple sclerosis, human cells and patients, connecting basic research with clinical
work," Farez says. "Nonetheless, our work is entirely based in patients from one particular setting and
location--Buenos Aires, Argentina--and further work in other centers and with larger cohorts should be
done to confirm and extend our findings in other regions with genetically distinct populations."
Because melatonin exerted its effects on T cells by activating pathways previously implicated in
inflammatory bowel disease and autoimmune colitis, the same mechanisms may play a role in a
broad range of autoimmune disorders. Moreover, seasonal flare-ups have also been observed in
patients with lupus and rheumatoid arthritis, hinting at broader possible implications of the study.
"Several melatonin-derived drugs have been used or tested in humans for other conditions such as
insomnia," Farez says. "These drugs could potentially be repurposed to modulate inflammation in
multiple sclerosis and other inflammatory conditions."
The researchers are currently working on a pilot clinical trial to study the effect of targeting melatonin
signaling in patients with multiple sclerosis. They are also investigating additional mechanisms of
action and examining whether low melatonin levels increase the risk of developing the disease.
Although the findings provide strong basic and epidemiological evidence for the role of melatonin in
the seasonality of multiple sclerosis flare-ups, the interplay between melatonin and other wellrecognized seasonal factors such as vitamin D remains to be seen.
"In the future, melatonin or its derivatives may be used in patients with multiple sclerosis after
appropriate clinical trials are conducted," Quintana says. "However, extreme caution should be
exercised because our data do not show that melatonin or its analogs are effective in treating multiple
sclerosis. Until a clinical trial is conducted and an appropriate drug and dosage is established, it is not
recommended to use melatonin for the treatment of multiple sclerosis."
###
This study was supported by the Allende Foundation, the Multiple Sclerosis International Federation,
Biogen Idec, Novartis Argentina, Merck Serono Argentina, the National Institutes of Health, the
National Multiple Sclerosis Society, and the International Progressive MS Alliance.
Cell, Farez et al.: "Melatonin Contributes to the Seasonality of Multiple Sclerosis
Relapses"http://dx.doi.org/10.1016/j.cell.2015.08.025.
In online coverage, please mention the journal Cell and link to the paper
at http://www.cell.com/cell/abstract/S0092-8674(15)01038-7.
Related Files:

This Dropbox contains a PDF of the paper
proof: https://www.dropbox.com/sh/d8vzc6sjtvzs67f/AAD2rRwBD8EGMkJi1V-zESBDa?dl=0
Author Contacts:
Francisco J. Quintana, PhD
Brigham and Women's Hospital
Phone: +1 617-525-5317
FQUINTANA@partners.org
Mauricio Farez
Raúl Carrea Institute for Neurological Research (FLENI)
+ 54 11-5777-3200 ext. 2704 / 2708
mfarez@fleni.org.ar
Media Contacts:
Haley Bridger
Brigham and Women's Hospital
o: 617-525-6383
c: 978-807-5302
hbridger@partners.org
Matías Alurraldea
malurralde@alurraldejasper.com