Fig. 1

Key Components of the Complement System: C1q is the initiating molecule of the classical pathway. Binding to any of a number of substrates triggers its activation, leading to an enzymatic cascade with cleavage of the core solution-phase components C4, C2, C3, and C5 to generate activated fragments. The lectin pathway is initiated by MBL or related ficolin or collectin family members [22]. They activate the same cascade (C4, C3, and C5) as C1q by binding to a different but overlapping set of substrates, including carbohydrate and acetylated structures [21]. The alternative pathway is initiated by spontaneous solution-phase hydrolysis of C3 to generate C3b-H₂O, which then becomes associated with the activated protease Bb to cleave other C3 molecules, generating C3b [23]. If close enough to a surface, C3b can covalently attach to initiate the surface amplification loop described above. It is important to note the distinction between the alternative complement pathway and the complement amplification loop. The alternative pathway is defined by its initiating mechanism—the spontaneous activation of C3 via non-enzymatic hydrolysis. This event leads to production of C3b, which then engages factor B and the amplification loop. However, since all three complement pathways lead to production of C3b and engage the amplification loop, this loop functions as a general “complement amplification loop” or “C3b amplification loop.” Hence, unless specifically affecting the spontaneous hydrolysis rate of C3, genetic polymorphisms or mutations that affect amplification impact the activity of all three pathways (e.g., FH, FI, FB, FD, C3, and FHR1/3). Also of note, the classical and lectin pathways will remain active as long as their substrates are present