To protect or to kill: A persisting Darwinian immune dilemma

The immune system, which evolved as a protective system, can paradoxically mediate lethal effects when it is over-activated. These effects can be traced back to infected insects and are mainly mediated by phylogenetically old cytokines that have been found already in starfishes and sponges. We hypothesize that these anti-homeostatic effects are important for restricting the cumulative risk of transmission of highly mutating environmental pathogens that may endanger species, particularly when they start to originate and expand. Considering the Darwinian view that evolution is a permanent process, this anti-homeostatic program is preserved and expressed even when there is no risk for the species. Here, we review these aspects and discuss how evolutionary-imposed anti-homeostatic immune programs are expressed during acute and chronic human diseases, which can be further aggravated in the absence of medical interventions. The relevance of early identification of ancestral biomarkers that predict a shift from protective to deleterious immune outcomes is emphasized.