Danger Signals
As we have seen in previous sections, the innate immune system can discriminate between foreign and self molecules with the help of PRRs. However, many of the PAMPs recognised by PRRs are also expressed on harmless, beneficial microbes. It is therefore important for the immune system to know when actual damage has been inflicted to the host, indicating the presence of a pathogen. In this way the immune system resembles a beekeeper that knows that the bees (pathogens) are there but will do nothing and keep on smiling until he gets stung!
This discrimination between healthy and damaged self can be mediated by "danger signals" or damage-associated molecular patterns (DAMPs). DAMPs are self, or endogenous, proteins and molecules that either escape from the damaged cell or are produced outside the cell as a consequence of proteins escaping. Examples of intracellular molecules that turn into DAMPs after their escape include adenosine-5'-triphosphate (ATP), uric acid and DNA. Hyaluronic acid, fibrogen, and heparan sulphate are, on the other hand, examples of DAMPs produced when self molecules leak out from damaged cells. It is not only invasive pathogens that can damage cells. DAMPs are also released in response to, for example, burns, excessive cold, radiation, oxygen or nutrient deprivation and autoimmune destruction; conditions many times simply referred to as "cell stress".
Take a closer look at danger signals in action (click link to activate zoom). Here you see dendritic cells (DCs) stretching out their long arms through the epithelium to sample the environment (read more about this in the Linker module). The middle DC has sensed a bacterium via one of its many PRRs and some signalling pathways have been triggered as you can see by the glowing arm. But have you noticed how the right DC is glowing all over, signifying its complete activation? What is the difference? The clue is found to the far right where a pathogenic bacterium has damaged an epithelial cell. The cell content is leaking out and reaching the DC. Some of the escaping molecules will be DAMPs that bind to PRRs on the DC causing its complete activation, others activate the immune system by binding to other receptors like complement or prostanoid receptors. In this way DAMPs help controlling the elimination of the correct microbe at the correct time.