Physiology and pathology of the C3 amplification cycle: A retrospective

The C3 “Tickover” hypothesis, a mechanism whereby the host maintains constant surveillance of potential invading pathogens, targeting them for elimination through amplified C3b generation and C3-dependent effector mechanisms, was proposed by the late Professor Peter Lachmann in 1973. This unique insight came from a combined understanding of the complement system as it was then defined and the nature of the disease process in rare complement deficiencies and complement-driven diseases. In this review, I give a personal perspective of how understanding of “Tickover” has developed in the subsequent 50 years, culminating in the introduction into the clinic of therapeutic agents designed to combat amplification-driven disease.