Fig. 2.

Principal mechanisms of complement involvement in disease. A The reaction of complement toward different surfaces is largely driven by the sum of stimulatory (orange circles) and regulatory entities (green circles). Under physiological conditions, this enables immune surveillance by forcefully removing microbial intruders and silently clearing endogenous threats while sparing healthy host cells. However, hyperactivation of the system by massive influx of bacteria (sepsis) may lead to strong bystander attack of host cells that overpower the regulatory capacity, while the inflicted cell damage may exacerbate the response. Biomaterials (e.g., liposomes), auto-antibodies (e.g., in AIHA), cell debris (e.g., atherosclerotic plaque), or hypoxia-induced damage patterns may trigger a misguided complement response that induces cell damage (e.g., reperfusion injury), inflammation, and/or adverse crosstalk reactions. Finally, insufficient regulation on host cells may increase their vulnerability to complement attack (e.g., by bystander activation). B Most complement-related conditions are driven by excessive activation and/or insufficient regulation of the complement response. However, exploitation of complement regulation is also observed as part of the immune invasion strategy of many pathogens and cancer cells