1. Figure 3 Pathological activation of complement
Figure 3 | Pathological activation of complement. Various events contribute to the development and progression of complement-related diseases. Excessive generation of triggers, such as the massive influx of pathogen-associated molecular patterns during sepsis or release of damage-associated molecular patterns (DAMPs) during trauma or tissue injury, leads to binding of recognition molecules and induces a complement response. These pronounced complement responses can lead to bystander activation of healthy host tissues in proximity to the initial trigger (for example, a pathogen). Moreover, the recognition of inappropriate targets, such as biomaterials (for example, implants or haemodialysis filters) or accumulating debris resulting from ageing or oxidative stress can induce misguided complement activation that contributes to inflammatory complications. Complement deficiencies can contribute to the generation of autoantibodies owing to impaired removal of immune complexes and other mechanisms, and the resulting antibodies can activate complement by binding to neoantigens on damaged cells or to self-antigens on healthy cells, with subsequent sensing by C1 complexes. Autoantibodies can also influence the activity of the complement system by interfering with the surface- recognition capacity of regulators of complement activation (RCA) proteins such as factor H (FH), or by stabilizing convertase complexes, thereby exacerbating complement activation. Gain-of-function mutations in complement components or loss-of-function mutations and deficiencies in complement regulators largely define the systemic activation profile of complement (marked by thick and thin arrows to indicate the level of activity), and can lead to attack of susceptible organs such as the kidney. In addition to circulating systemic complement, local secretion of complement components by tissue cells and infiltrating or tissue-resident immune cells contributes to activation events. The generation of complement effectors leads to the attraction and activation of immune cells, with release of proinflammatory mediators such as cytokines, reactive oxygen species (ROS) or reactive nitrogen species. The resulting cell damage further stimulates complement activation and fuels a vicious cycle of complement activation, inflammation, and tissue damage. Finally, strong crosstalk between complement and the coagulation system contributes to thrombotic events.
Ricklin, D. et. al. (2016) Complement in disease: a defence system turning offensive
Nat. Rev. Nephrol. doi: /nrneph