Figure 1 Mechanisms of differential complement activation and regulation under physiological conditions Figure 1 | Mechanisms of differential complement activation and regulation under physiological conditions. When complement encounters a foreign cell, the recognition molecules C1q, mannose-binding lectin (MBL), ficolins, and collectin-11 sense antibody clusters or pathogen-associated molecular patterns (PAMPs) and activate associated serine proteases (C1r, C1s or MBL-associated serine proteases (MASPs)) that cleave C4 and C2 to form the C3 convertase (C4b2b) of the classical pathway (CP) and lectin pathway (LP) on the triggering cell. In addition, tick-over or surface interactions of C3 with certain cell surfaces leads to C3 hydrolysis and generation of initial alternative pathway (AP) C3 convertases. All C3 convertases cleave C3 into the anaphylatoxin C3a and C3b, the latter of which is deposited on activating surfaces (opsonization). Factor B (FB) binds to C3b and gets activated by Factor D (FD) to form the final AP convertases (C3bBb), which activate more C3 to C3b and fuel an amplification loop. Increasing densities of C3b deposition favour the generation of C5 convertases, which activate C5 to release the anaphylatoxin C5a and C5b, which, after tiered interactions with C6–C9 and membrane insertion, in turn forms membrane attack complexes (MACs), which leads to lysis, damage, or activation of target cells. The released anaphylatoxins act as immune mediators and, particularly in the case of C5a, attract and prime immune cells. Interaction of the C3b opsonin and its degradation products iC3b and C3dg with complement receptors (CRs) mediates cell adhesion (via CR1 (also known as CD35)) and/or phagocytic uptake (via CR3, CR4, and CRIg). Concurrently, iC3b and C3dg modulate adaptive immune responses by binding to CR2 on the B cell co-receptor, thereby lowering the threshold of B-cell stimulation. Properdin (FP) stabilizes the C3 and C5 convertases and increases complement-mediated opsonization and effector generation. On healthy cells, complement activation is tightly controlled. C1 esterase inhibitor (C1-INH), MAP1 and sMAP regulate the activity of recognition complexes, whereas soluble C4b-binding protein (C4BP) and factor H (FH) — which recognize self-surface patterns such as heparin and sialic acid, and bind to host cells — or membrane-bound regulators of complement activation (RCA) proteins (CD35, CD46 and CD55) control convertase activity by accelerating convertase decay and/or act as cofactors for the factor I (FI)-mediated degradation of C3b and C4b. Finally, CD59, clusterin (clu) and vitronectin (vtn) prevent formation of MAC. 'Silent' removal of damaged and apoptotic cells, debris, and immune complexes is achieved through the sensing of damage-associated molecular patterns (DAMPs), either directly by complement recognition complexes or mediated by modulators such as pentraxins (for example, PTX3). Controlled activation of complement occurs with limited deposition of opsonins that facilitate phagocytic clearance. In addition to C3b/iC3b/C3dg, C1q also contributes to clearance by binding to C1q receptors (gC1qR and cC1qR). CA, cofactor activity; CRIg, CR of the immunoglobulin superfamily; DAA, decay acceleration activity; FcγR, Fcγ receptor. Ricklin, D. et. al. (2016) Complement in disease: a defence system turning offensive Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.70