Genetic Variation in Innate Immunity Pathways and Their Potential Contribution to the SIRS/CARS Debate: Evidence from Human Studies and Animal Models

Abstract

The lack of a causal and successful treatment for sepsis has led to a re-evaluation of the condition’s pathopysiology. 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.

Lectin pathway of complement activation and relation with clinical complications in critically ill children

“…Interest in the functional consequences of genetic variation in determining susceptibility and response to disease is increasing, also in critical illness (3,4,33,34). Our study of several SNPs spread throughout the MASP1 gene encoding MASP-3 (7,35) identified two SNPs for which the variant allele was associated with higher on-admission MASP-3 levels.…”

“…The question why some patients are more susceptible to developing these complications than others is intriguing and raises the possibility of genetic predisposition. Certain genetic variants of innate immunity genes would thus orchestrate different responses to apparently similar insults (3,4).…”

Lesão pulmonar aguda induzida pela administração endovenosa de extrato da fumaça do cigarro

“…( 20 , 21 ) However, a study in mice had shown that previous induction of a low-grade systemic inflammatory response protected the animals from developing sepsis induced by Enterococcus faecalis or methicillin-resistant Staphylococcus aureus . ( 22 ) When initially a severe systemic inflammatory response was induced, severe sepsis developed after infection with microorganisms.…”

Protective effects of the active fraction from the tuber of Scirpus yagara in mouse endotoxin shock model

“…Sepsis is generally considered a systemic inflammatory disorder and is a serious clinical problem with high mortality (Hotchkiss and Karl, 2003;Kumpf and Schumann, 2010). It can be defined as a progressive failure of the circulation, characterized clinically by vascular leakage, edema, shock and organ failure (Takukyu et al, 2007).…”