Fig. 1. An overview of the complement system with focus on most relevant targets for therapeutic inhibition. The complement system acts as a recognition system and can recognized danger and be activated through three initial pathways (upper part of figure), all converging to the cleavage of C3 to generate C3a and C3b (middle part of figure). The classical pathway (CP) is typically activated by antibodies, but amyloid β fibrils and pentraxins, including CRP, serum amyloid P component (SAP), and PTX3, can activate C1. The lectin pathway (LP) is activated through recognition of carbohydrates by MBL, ficolins, and collectins. Furthermore, LP activation may be mediated through IgM antibodies (e.g., directed against damaged self antigens). Both the CP and the LP activate C4 to C4a, and C4b and C2 subsequently bind to C4b and make the C4bC2b convertase after C2 is cleaved to C2a and C2b. The alternative pathway (AP) is activated by foreign or damaged cells, as facilitated by the continuous spontaneous hydrolysis of C3. AP also has an important function in the complement system providing an amplification loop enhancing C3 activation independent of which pathway that is initially activated. This effect is enhanced due to properdin (FP), the only positive regulator in the complement system, which stabilizes the C3 convertase. Cleavage of C3 leads to formation of a C5 convertase, cleaving C5 into C5a and C5b. The anaphylatoxins C3a and C5a bind to the receptors C3aR, C5aR1, and C5aR2, leading to downstream production of proinflammatory and/or anti-inflammatory mediators (lower left part of figure). C5b initiates the formation of the TCC, which forms the membrane attack complex (MAC) if inserted into a membrane (bottom part of figure). This may lead to lysis of bacteria and cells or in sublytic doses to activation of cells. The cleavage and inactivation of C3b generate iC3b, binding to complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) and facilitating phagocytosis, oxidative burst, and downstream inflammation (right part of figure). The complement system is tightly regulated by soluble inhibitors (marked in yellow), including C1-inhibitor (C1-INH), factor H (FH), factor I (FI), C4BP, carboxidase inactivation of the anaphylotoxins (AI), vitronectin (Vn), and clusterin (CLU), keeping the continuous low-grade activation in the fluid phase in check. Host cell membranes are equipped with a number of inhibitors to protect them against attack by complement (right part of figure), including MCP (CD46), CR1 (CD35), DAF (CD55) controlling C4 and C3 activation, and CD59 protecting against final assembly of the C5b-9 complex. Some selected attractive targets for therapeutic inhibition are indicated by red asterisks. Although many more could have been included, we selected C1s as a specific target from the CP, MBL, and MASP-2 from the LP, factor B, factor D, and properdin as specific for the AP and then C3 as the major component at which all three pathways converge and would be a very efficient blocker of the system. C5 is the next main candidate to block completely, as it will block the inflammatory potent C5a fragment and formation of the inflammatory and lytic C5b-9 complex or the solueble form sC5b-9. In addition, C5a can be inhibited, preserving the C5b-9 pathway, or the C5b7 can be blocked to prevent C5b-9 formation, leaving C5a open. Finally, the anaphylatoxin receptor’s axes can be blocked to prevent signaling. In particular, blocking of C5aR1 will attenuate the proinflammatory inflammation, whereas the effects of blocking C3aR and C5aR2 receptors are to be studied in more detail since they might have more anti-inflammatory effects. FB, factor B. (The figure is a modified version of one published in J Leukoc Biol (2014) 101:193–204. Barratt-Due A, Pischke SE, Nilsson PH, Espevik T, Mollnes TE. Copyright by Mollnes TE.)