Is immune system linked to the body clock?

“Not sleeping enough can damage your immune system and make you ill,” according to the Daily Mail.

This somewhat sweeping statement is based purely on an animal study looking at how mice body clocks affected their immune systems. The study found that levels of an infection-detecting protein called TLR9 fluctuated throughout the day and that the exact level of this protein influenced how effective a vaccine was in mice. It also influenced the mice’s response to a type of serious infection.

Differences between man and mouse mean more research will be needed to determine if these findings apply to humans. If they do, then it may be possible that certain vaccinations could be administered at specific times of day to make them more effective. However, this approach would need to be tested in humans to be sure that it actually made a meaningful difference to the effectiveness of the vaccines.

The immune system is a complex area, and while this research shed some light on one aspect of the body’s immunity and its ties to the body clock, there’s still much to learn.

Where did the story come from?

The study was carried out by researchers from Yale University School of Medicine and the Howard Hughes Medical Institute in the US. It was funded by the US National Institutes of Health and published in the peer-reviewed scientific journal, Immunity.

When reporting this study both BBC News and the Daily Mail stated that this research was in mice, and gave good summaries of the findings. However, the Mail’s headline claimed that “not sleeping enough can damage your immune system and make you ill”, which the current research does not support. The results of this research in mice should not be interpreted as providing proof that amount of sleep affects illness in humans.

What kind of research was this?

This was animal research looking at exactly how the body clock affects the function of the immune system in mice. The researchers say that previous studies have shown that certain immune system functions and chemicals vary naturally in relation to light and daily rhythms in humans and mice. They say that studies have also suggested that disruptions to normal daily rhythms, such as jet lag or sleep deprivation, may also affect the immune system.

This type of early research will usually use animals such as mice to carry out in-depth investigation of the interaction of basic biological functions, which might be difficult to carry out in humans. Generally, it’s only once researchers have built up a picture of these interactions in mice that they can then carry out further studies to test the findings in humans.

What did the research involve?

The researchers first looked at a group of mice genetically engineered to have defective body clocks and a group of normal mice to identify any differences between the two groups in how their white blood cells (immune cells) responded to invading microorganisms. They found that the differences identified related to a protein called Toll-like receptor 9 (TLR9). This protein recognises DNA from bacteria and viruses, and plays a role in signalling to the immune system to mount an attack on these invading organisms. The researchers then looked at whether the production and function of TLR9 in normal mice varies throughout the day as a result of the body clock cycle (known as the “circadian cycle”).

The researchers then gave mice vaccinations containing molecules that would activate TLR9 and looked at whether mice responded differently to the vaccine according the time of the day it was given. They also looked at whether time of day affected how mice responded to being infected with bacteria in a process known to involve TLR9. The method used involves allowing bacteria from the mouse’s intestines to invade its body cavity. This leads to a condition called sepsis, a strong inflammatory immune system response throughout the body that is harmful to the mice.

What were the basic results?

The researchers found that levels of the protein TLR9 in mice did fluctuate naturally through the day, peaking at set times over a 24-hour cycle.

They found that when they gave mice vaccines that would activate TLR9, the vaccination produced a greater immune response if given at a time of day when TLR9 levels were at their highest. The researchers found that if the mice were infected at a time when TLR9 was at its highest, the mice showed worse signs of sepsis and died earlier than mice infected at the time when TLR9 was at its lowest.

How did the researchers interpret the results?

The researchers concluded that their findings showed a direct link between the body clock and one aspect of the immune system in mice. They said that this may have important implications for how vaccination and immune-system-related therapies are administered in humans.

They also noted that some studies have found that people with sepsis are more likely to die between 2am and 6am. They say that further studies are needed to determine if this may be related to levels of TLR9, and if so whether giving certain therapies during this period could reduce this risk.

Conclusion

This study identifies one way in which the body clock and immune system interact in mice, via a protein called TLR9. The researchers found that fluctuations in this protein throughout the day influenced how effective a certain form of vaccination was in mice, and also influenced the mice’s response to one type of serious infection.

Differences between the species mean more research is needed to determine if these findings also apply to humans. If they do, then vaccinations could be given at specific times of day when they would be most effective. However, this theory needs testing in humans to ensure that it makes a meaningful difference to the effectiveness of the vaccine.

There has also been media speculation that researchers could develop infection-fighting drugs based on these findings. However, this suggestion is premature as researchers first need to confirm that the mechanism identified in this study also applies in humans. Even if it is confirmed, it would still take a great deal of research to develop and test a drug that could capitalise on it.

It’s also worth remembering just how complex the immune system is, and although this research improves our understanding of one aspect (how it is affected by the body clock) there is still much to learn.