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 TH17 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, TH17 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 TH17 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 TH17 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 TH17 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 TH17 cells. The researchers surmise that a key protein in the clock network binds to the NFIL3 gene to keep the production of TH17 cells synchronized with periods of light and darkness. And the team found that normal mice produce less NFIL3, and thus more TH17 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 TH17 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 TH17 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."
ScienceNOW, the daily online news service of the journal Science