A. Complement activation on diseased host surfaces involves diverse recognition molecules and initiation mechanisms that underlie three distinct activation pathways operating either in parallel or independently of each other. Briefly, binding of C1 to antigen-antibody complexes (e.g. in autoimmune pathologies) triggers the classical pathway (CP), while binding of MBL/ficolin or properdin to target surfaces, via recognition of distinct molecular patterns, initiates the lectin pathway (LP) and alternative pathway (AP), respectively. Irrespective of their initiating trigger, all pathways converge at the proteolytic activation of C3, the central component of the cascade. Assembly of C3 convertases via any of the three aforementioned activation pathways promotes surface opsonization by C3 fragment deposition mainly through an AP-mediated amplification loop, and also leads to effector generation (e.g. C3a anaphylatoxin release). C3 activation is the prerequisite for the downstream activation of the lytic pathway that begins with the cleavage of C5 and culminates in the assembly of the cell-perforating MAC. Both fluid-phase and surface-bound complement regulators (e.g. factor H, CR1, MCP) promote the factor I-mediated degradation of C3b into bioactive fragments that mediate a plethora of immunomodulatory functions in health and disease (including inflammatory signaling, phagocytic activation and modulation of adaptive immune responses). Cleavage of the central complement components C3 and C5 by their respective convertases results in the generation of the anaphylatoxins C3a and C5a that, through interaction with their cognate receptors (C3aR, C5aR1), trigger potent inflammatory signaling and chemotactic responses in a variety of myeloid and non-myeloid cell types. B. Therapeutic modulation of complement using the peptidic C3-targeted inhibitor compstatin: Compstatin acts as a highly selective protein-protein interaction inhibitor. Binding of compstatin to native C3 and also to C3b-containing convertases results in potent and broad complement inhibition through abrogation of C3 activation and AP-mediated amplification of C3 cleavage. The lack of C3b deposition also prevents C5 convertase assembly and downstream effector generation (e.g. C5a, MAC). The complement inhibitory action of compstatin is exerted regardless of the upstream trigger or complement pathway (CP, LP, AP) involved. C. Therapeutic intervention at different steps of the complement cascade affords distinct benefits and limitations to each targeting approach. Intervention at the early stages of complement initiation, such as inhibition of C1s and MASPs by C1-INH, affords effective blockade of the CP and LP, while letting the alternative pathway operate and preserve its homeostatic and immune surveillance functions. However, upstream inhibition may also still allow amplification of potentially harmful activation on diseased tissue. C3 interception using peptidic inhibitors of the compstatin family results in abrogation of C3 activation by the convertases, inhibition of AP-mediated amplification and downstream effector generation. However, compstatin does not affect initial activation of the AP through the ‘C3 tick-over’ mechanism and also allows for C4b generation through upstream activation of the CP and LP. Therefore compstatin treatment may still allow for residual opsonic activity and complement-mediated immune surveillance. Finally, C5 blockade selectively targets the lytic pathway of complement abrogating C5 activation and generation of detrimental downstream effectors (i.e. C5a, MAC), while leaving intact upstream activation pathways including C3 activation and the AP-mediated amplification loop.Abbreviations: BCR, B-cell receptor; CR1 complement receptor type 1; CR2, complement receptor type 2; CP, classical pathway, AP, alternative pathway; LP, lectin pathway; MBL, mannose-binding lectin; MASP, MBL-associated serine protease; MCP, membrane cofactor protein; DAF, decay-accelerating factor; CR’s complement receptors;
