Figure 1.

Overview on complement activation and cascade progression. Complement activation is mediated by the alternative pathway in the fluid phase and on surfaces, and by the lectin and the classical pathway on surfaces. Multiple regulators determine and adjust cascade progression and subsequence effector action. Thereby discriminating the action between intact self, altered self, and non-self. Three initial reactions activate the complement cascade and have different initial triggers. The alternative pathway (AP) which is initiated spontaneously and continuously in the fluid phase and in the absence of regulators is amplified on surfaces. Both the lectin (LP) and the classical pathway (CP) are initiated on surfaces. The type of surface influences activation and the regulator repertoire decides on cascade progression or inhibition. Different regulators control cascade progression in the fluid phase and on surfaces. The three pathways form surface bound convertases, the AP allows generation of the AP-C3 convertase and the LP/CP trigger CP convertase. The AP C3 convertase also triggers a potent amplification loop. The general role of both C3 convertase is to cleave the abundant plasma protein C3 (concentration 1,000–1,500 μg/ml) into the anaphylatoxin C3a and the opsonic C3b. The enzymatic response on the first enzymatic levels is frequently enhanced by the potent self-amplifying amplification loop. If activation C5 convertases are generated and again C5 convertases of the AP and of the LP/CP pathways do exist. The major role of the C5 convertase is to cleave C5 (plasma concentration 350 μg/ml) into the powerful anaphylatoxin C5a and to generate C5b. Surface bound C5b initiates terminal complement and formation of the terminal complex, C5b-9, also termed membrane attack complex which can form lytic pores. Thus, complement acts on two major enzymatic levels, each of which generates a unique set of effector components with rather diverse functions. The complexity of this cascade is mediated by regulators and inhibitors, which control activation in the fluid phase (AP) and which ensure that activation mainly occurs on non-self surfaces or modified surfaces. In the physiological setting this coordinated action allows to direct the toxic and clearance power to the foreign/modified particles. In case of any dysbalance this action can be targeted toward self-structures and this can cause pathology at specific sites.