Schematic representation of the complement cascade in normal individuals, in patients with paroxysmal nocturnal hemoglobinuria (PNH), and in patients with PNH receiving the C5 inhibiting antibody eculizumab (modified from Bessler 2005).49 In humans the complement system consists of more than 30 plasma and cell-surface proteins and may be activated by three different pathways: the classical, lectin, and alternative pathway. The classical pathway is activated by antibody–antigen complexes, the lectin pathway involves carbohydrate recognition by pattern-recognition receptors, such as mannose-binding lectin (MBL) and the subsequent activation of MBL-associated serine proteases. The alternative pathway does not involve specific recognition molecules. It is initiated by the covalent binding of a small amount of C3 to hydroxyl or amine groups on the cell-surface molecules of microorganisms. This pathway also functions to amplify the activation of C3. The primary goal of the activation pathway is C3b deposition on the target cell. The activation pathway is followed by the formation of the membrane attack complex (MAC) in the lytic pathway of complement activation, which is necessary for the lysis of the target: C3b, once deposited on the target cells, becomes part of a C5 convertase. After C5b is formed by the C5 convertase, no further proteolytic reaction occurs in the complement cascade. The assembly of the MAC is formed by protein-protein interaction. The deficiency of the surface proteins CD55 and CD59 leads to the uncontrolled lysis of PNH red cells by complement. The C5 binding antibody blocks the lytic pathway of complement activation. Reproduced with permission from Bessler M. Inside blood.
