Fevers are more than just a symptom of illness or infection, claim researchers; elevated body temperature sets in motion a series of mechanisms that regulate our immune system, they found.
When we are healthy, our body temperature tends to gravitate around a constant
But when our bodies are faced with an infection or virus, body temperature often goes up and we experience fever.
A slight fever is characterized by a minor rise in body temperature to about 38°C (100.4°F), with larger increases to around 39.5°C (103.1°F) counting as "high fever."
When we have the flu, for instance, we may come down with a mild and somewhat uncomfortable fever, driving many of us to seek natural or over-the-counter remedies against it.
Fevers aren't always a bad sign; you may even have heard that mild fevers are a good indication that your immune system is doing its job. But fevers aren't just a byproduct of our immune response.
In fact, it's the other way around: an elevated body temperature triggers cellular mechanisms that ensure the immune system takes appropriate action against the offending virus or bacteria.
So say researchers hailing from two academic institutions in the United Kingdom: the University of Warwick in Coventry and the University of Manchester.
Senior researchers Profs. David Rand and Mike White led teams of mathematicians and biologists to understand what happens at cellular level when fever takes hold.
Their findings, which have recently been published in PNAS, reveal that higher body temperatures drive the activity of certain proteins that, in turn, switch genes responsible for the body's immune response on and off, as required.
A temperature-sensitive signaling pathway
NF-κB are proteins that help to regulate gene expression and the production of certain immune cells.
These proteins respond to the presence of viral or bacterial molecules in the system, and that is when they start switching relevant genes related to the immune response on and off at cellular level.
The researchers note that NF-κB activity tends to slow down the lower the body temperature. But when the body temperature is elevated over the usual 37°C (98.6°F), it tends to become more intense.
Why does this happen? The answer, they hypothesized, might be found by looking at a protein known as A20, encoded by the gene with the same name.
A20 is sometimes hailed as the "
NF-κB switches on the gene that produces A20 protein, but the protein, in turn, regulates NF-κB activity, so that it is appropriately slow or intensive.
The protein that alters temperature reactivity
The researchers involved in the new study wondered whether blocking the expression of the A20 gene would affect the way in which NF-κB functioned.
And, sure enough, they found that in the absence of the A20 protein, NF-κB activity no longer reacted to changes in body temperature, and its activity therefore no longer increased in case of a fever.
These findings might also be relevant to the normal fluctuations in temperature that our bodies undergo every day, and how these may affect our response to pathogens.
As Prof. Rand explains, our body clock regulates our internal temperature and determines mild fluctuations — of about 1.5°C (34.7°F) at a time — during wakefulness and sleep.
So, he says, "[T]he lower body temperature during sleep might provide a fascinating explanation into how shift work, jet lag, or sleep disorders cause increased inflammatory disease."
Although many genes whose expression is regulated by NF-κB were not temperature-sensitive, the researchers found that certain genes — which played a key role in the regulation of inflammation and which impacted cell communication — did, in fact, respond differently to different temperatures.
Together, the findings suggest that developing drugs to target temperature-sensitive mechanisms at cellular level could help us to alter the body's inflammatory response when needed.
"We have known for some time that influenza and cold epidemics tend to be worse in the winter when temperatures are cooler. Also, mice living at higher temperatures suffer less from inflammation and cancer. These changes may now be explained by altered immune responses at different temperatures."
Prof. Mike White