Timing is everything. Infection-fighting TH17 cells (green) in the intestine cause disease when the body clock is disrupted
Jet
lag, shift work, and even late nights staring at your tablet or
smartphone may be making you sick. That's because the body's internal
clock is set for two 12-hour periods of light and darkness, and when
this rhythm is thrown off, so is the immune system. One reason may be
that the genes that set the body clock are intimately connected to
certain immune cells, according to a new study.
The finding “was a happy accident," says Lora Hooper, an immunologist
at the University of Texas Southwestern Medical Center in Dallas. She
and her colleagues were studying NFIL3, a protein that guides the
development of certain immune cells and turns on the activity of others.
The gene for this protein is mutated in some human patients with
inflammatory bowel disease, and mice lacking the gene for NFIL3, the
team found, had more so-called T
H17 cells in their intestines.
These cells are a type of immune cell known as a T cell. They get
their name from a signal they produce, called interleukin 17, which
tells other T cells to increase the immune response. In normal numbers, T
H17
cells, which live in the intestines, help the body fight bacterial and
fungal infections. But when there are too many, the immune defense
begins to cause illness rather than prevent it. Boosting NFIL3 levels in
T cells growing in lab cultures resulted in fewer of them turning into T
H17
cells, the researchers found, suggesting that the protein's job is to
prevent T cells from going into that area of specialization. The absence
of the protein, the team concluded, leads to runaway T
H17 activity.
At this point, the researchers had no reason to suspect a connection
to our body’s internal timekeeping system—also known as our circadian
clock—which responds to daily cycles of light and dark. But as they
continued to explore the connection between NFIL3 and T
H17
cells, they found that some of the proteins produced by the body’s
"clock genes” attach to the NFIL3 genes. What's more, cultured cells and
mice whose clock genes were experimentally tampered with produced fewer
T
H17 cells. The researchers surmise that a key protein in the clock network binds to the NFIL3 gene to keep the production of T
H17 cells synchronized with periods of light and darkness. And the team found that normal mice produce less
NFIL3, and thus more T
H17 cells, during the day than at night.
In a final experiment, the researchers gave the mice jet lag. "We
didn't fly them anywhere," Hooper jokes. Instead, the team shifted the
rodents' light/dark cycles by 6 hours every 4 days. "It would be like
flying from the U.S. to Europe, India, and Japan and spending 4 days in
each country," she explains.
Mice with altered light cycles had nearly twice as many TH17 cells in their spleens and intestines, compared with mice having a normal day, the team reports online today in
Science.
The jet-lagged mice also mounted a stronger inflammatory response to
irritation by an experimental chemical—a test used to gauge
immune-system sensitivity that hints the animals may be more prone to
inflammatory disease.
The finding adds to a growing body of research showing that a healthy
pattern of light and dark, sleeping and waking, is essential to keep
the immune system in balance, Hooper says. She notes that inflammation
is the basis of many chronic disorders, such as heart disease, asthma,
chronic pain, and many things ending in "-itis," like bursitis and
dermatitis. Inflammatory conditions are more prevalent in developed
countries, where people's circadian rhythms are chronically disrupted.
Even people who don't work shifts or cross time zones still wake and
sleep out of sync with light and darkness, Hooper says. "We all have
screwed up light cycles. We stay up late, keep the lights on, look at
our lit-up iPhones at 2 a.m."
Immunologist Dan Littman of New York University in New York City
finds the results in cultured cells convincing. He cautions, though,
that the neatly defined pathway from clock gene to T
H17
suppression might not be so tidy in a living animal. "Even if NFIL3 is
involved in the way they show, circadian disruption affects many other
things." Stress hormones, gut bacteria, and the actions of other types
of T cells may also account for the effects of the experimental jet lag,
he says.
Littman also notes that the increased inflammation in the jet-lagged
animals was a response to an induced chemical irritation, and more
research is needed to prove a link to inflammatory or autoimmune
disease.
Hooper agrees that the present study is probably the tip of the
iceberg, and more research will yield deepening insight into the
relationship between immune cells circadian rhythms. She is hoping to
collaborate with other researchers to determine if T
H17 cells
are increased in humans with chronically altered light cycles. For now,
she says, she tries to keep her own sleeping patterns more aligned with
nature, starting by limiting exposure to artificial light at night. "I
turn off the lights, I draw the curtains, and I keep my iPhone off."
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Tuesday, November 12, 2013
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