How the immune system recognizes danger from non-danger

There are three types of possible relationships between two different organisms: parasitism is when one benefits from the other, but the other is harmed; mutualism is when both benefit from the relationship; and, finally, commensalism is when one organism benefits and the other is neutral (neither harmed or benefitting). There are roughly 10^12 bacteria in our body. These are "commensal" microbes, because they live in our body without harming us. However, our immune system is trained to recognize "self" from "non-self", so a natural question to ask is: how come the immune system doesn't attack the skin and gut microbiota? In the guts especially, how does the immune system know how to distinguish the numerous pathogens we normally ingest through foods from the beneficial microbes that are fundamental in aiding digestion and nutritional assimilation?

It turns out that what the immune system does is far more complex than recognizing self from non-self. It's become a motto of mine, isn't it, how things are always more complicated than we think they are!

"Bacterial associations with their hosts can be beneficial, damaging, or benign, depending on the context and the identity of players. A host determines the balance of non-self elicitors and danger signals to decide when to activate the immune system against pathogenic infection while also maintaining healthy relationships with commensals [1]."

These interactions are mediated through a class of molecules, called "microbe-associated molecular patterns," or MAMPs, that are present in bacteria and are recognized by the host's immune system. Immune models studied in both insects and vertebrates suggest that both MAMP and danger signals are required to trigger a strong immune response, as shown in the figure below [Credit: Science Magazine]:

While both true pathogens and symbiotic microbes present MAMPs molecules, true pathogens also trigger "danger" signals by damaging host cells or secreting molecules that interfere with host biology.

"Studies in insect model systems suggest that the joint presence of both MAMPs and danger signals may be required to launch a true defense response and that insects have mechanisms for disregarding MAMPs presented in the absence of pathological damage to the host."

Interestingly, these findings suggest that rather than being mutually exclusive, MAMPs and danger signals are read together in a combined signal that helps the immune system decide not just whether or not to mount a response, but also the strength of the response itself. This way, the immune system is able to maintain a homeostatic equilibrium in maintaining a healthy level of symbiotic microbes, and also in dosing the strength of immune response.

"Rather than striving to completely eliminate infections, the immune system might manage a persistent infection at a low and nondamaging level. [...] MAMPs indicate the presence of microbes, but if the microbes are doing little or no damage to the host, the cost of immune activity may exceed the benefit of clearing the infection."

Lazzaro, B., & Rolff, J. (2011). Danger, Microbes, and Homeostasis Science, 332 (6025), 43-44 DOI: 10.1126/science.1200486