Fig. 1

The complement cascade pathways. The classical pathway is initiated by binding of C1q to antibody chains triggering the activation of C1s and C1r. The activated C1 complex cleaves circulating C2 and C4 molecules into active C2a, C2b and C4a, C4b molecules leading to the formation of the C3 convertase following binding of the active C2b to C4b (C4b2b). The lectin pathway is triggered by recognition of microbial carbohydrates by ficolins, mannan binding lectin (MBL), or collectins which bind to mannan binding lectin serine peptidases (MASPs) forming a complex. The activated MASPs also lead to cleavage of C2 and C4 into active C2a, C2b and C4a, C4b fragments and thus the formation of the C3 convertase (C4b2b). The alternative pathway is triggered by spontaneous C3 activation by C3 hydrolysis which in the presence of Factor B and Factor D leads to the formation of a fluid phase C3 convertase through binding of the hydrolysed C3 to an active Bb fragment (C3(H2O)Bb. C3(H2O)Bb has the ability to cleave C3 into active C3a and C3b fragments. Binding of C3b to Bb results in the formation of the C3 convertase of the alternative pathway (C3bBb). All three pathways converge at the C3 step in order for the cascade to proceed further to the formation of the C5 convertase by binding of an active C3b molecule to the existing C3 convertases which results in their conversion into active C5 convertases (C4b2bC3b, C3bBbC3b). The C5 convertases cleave circulating C5 molecules into active C5a and C5b molecules allowing binding of C5b to the cell membrane and its assembly with C6, C7 and C8 molecules in order to polymerize C9 molecules  and eventually form C5b-9, also known as the membrane attack complex (MAC). Formation of sufficient MAC molecules on the cell membrane ultimately leads to lysis while simultaneous release of C3a and C5a anaphylatoxins and their binding to respective cellular receptors C3aR and C5aR1, will allow for initiation of cellular activation and chemotaxis promoting a strong inflammatory state. The presence of complement regulatory proteins (CRPs), cell bound (CD55, CD46, CD59, CR1) or circulating (C4b binding protein, Factor H, vitronectin, clusterin) prevent overactivation of the complement cascade pathways and dysregulation of the complement system