Genetic variation in innate immunity pathways and their potential contribution to the SIRS/CARS debate: evidence from human studies and animal models.

The lack of a causal and successful treatment for sepsis has led to a re-evaluation of the condition's pathophysiology. The failure of anti-inflammatory strategies has implied compensatory immunosuppression to play a central part in fatal clinical cases. While searching for novel therapeutic strategies, the question arose whether pro-inflammation (systemic inflammatory response syndrome, SIRS) or anti-inflammation (compensatory anti-inflammatory response syndrome, CARS) are dominant in sepsis, and may be counteracted by therapeutic measures. Here we ask whether in a given organism--man or mouse--the lack of any functional protein involved in this cascade may help in understanding the events. In humans, genetic variations exist, and some of them have functional consequences altering the inflammatory response to pathogens. In mice, knockout animals were created, which may assist us in understanding the SIRS/CARS cascade. Here we summarize data on genetic variations in the TLR- and cytokine system and their influence on course of infectious diseases and sepsis. In addition, we summarize animal experiments and conclude that both cascades may be needed for containing infection. Imbalances in both the pro- and anti-inflammatory system may be harmful. Thus, interventional strategies have to be introduced carefully, and in the future genetic profiling may be needed in order to tailor therapies in the best way.