Contributions of animal models to mechanistic understandings of antibody‐dependent disease and roles of the amplification loop

Summary The complement system plays an important pathophysiologic role in human diseases associated with immune or ischemic insults. In addition to understanding the effector mechanisms that are important for the biological effects of the system, substantial efforts have gone into understanding which specific complement activation pathways generate these potent effects. These approaches include the use of gene‐targeted mice and specific pathway inhibitors, as well as the integration of human disease genetic and biomarker studies. In some disease states, it is quite clear that the alternate pathway plays a unique role in the initiation of the complement system. However, although initially a widely unexpected finding, it has now been shown in many tissue‐based disease models and in initial human studies that engagement of the amplification loop is also essential for tissue injury when the classical and/or lectin pathways initiate pathway activation through pathogenic autoantibodies. This review provides evidence for such a conclusion through animal models, focusing on pathogenic antibody passive transfer models but also other relevant experimental systems. These data, along with initial biomarkers and clinical trial outcomes in human diseases that are associated with pathogenic autoantibodies, suggest that targeting the alternative pathway amplification loop may have near‐universal therapeutic utility for tissue‐based diseases.