Complement alternative pathway (AP)

Left. Three phases of complement activity are illustrated:

Phase 1. Initiation of a "tick-over," or the spontaneous activation of the AP, occurs through the hydrolysis of C3 to C3(H₂O), which associates with factor B (fB). Cleavage by factor D (fD) results in the generation of a pro-C3 convertase, C3(H2O)Bb. This proconvertase cleaves C3 into C3a and C3b, setting the stage for the amplification phase of the complement cascade.

Phase 2. Amplification of cleavage of C3 into C3a and C3b provides a source of C3b, from which additional C3 convertase is generated in a robust amplification process. Complement factor H (fH) and complement factor I (fI) are important regulators of complement activity, while properdin (fP) potentiates complement activity. Persistent amplification ultimately leads to generation of C5 convertase and triggering of the terminal pathway of complement.

Phase 3. Effector in further pathway continues unchecked; C5 convertase is formed. This serine protease cleaves C5 into C5a and C5b. C5b associates with C6, C7, C8, and C9 to generate the membrane attack complex (MAC). Multiple different levels of investigation are required to evaluate the complement system. Simply measuring C3 and C4 serum levels is not adequate. Obtaining detailed data on complement is comparable to adding pieces to a puzzle, and allows for a more complete picture of complement activity in the individual with C3G.

Right. A comprehensive analysis includes the following:

A. Genetic testing

B. Screening for autoantibodies (acquired drivers of disease)

C. Measuring complement biomarkers (complement proteins and their breakdown products)

D. Quantitating complement pathway activity