Figure 2.

Complement and PNH. The hemolysis of PNH is due to aberrant regulation of the APC. The APC is a component of the innate immune system. Unlike the classical pathway of complement that requires a recognition factor such as antibody to activate the pathway, the APC is continuously active. Therefore safeguards have evolved to protect host cells against APC-mediated injury. In the case of erythrocytes, 2 GPI-APs, CD55 and CD59, serve this function. Two enzymatic convertases amplify the activity of the APC (top). The C3 convertase consists of activated C3 (C3b), activated factor B (Bb, the enzymatic subunit of the complexes that is proteolytically activated by factor D, a trace plasma protein that may be activated by 1 of the mannose-binding lectin-associated serine proteases), and factor P (formerly called properdin). Factor P stabilizes the C3 convertase, allowing each convertase to activate many molecules of C3, and in the process, generate the weak anaphylatoxin, C3a. The C5 convertase is similar in structure to the C3 convertase except that 2 molecules of C3b are required to position C5 for cleavage by activated factor B (Bb). Many molecules of C5 are cleaved by the C5 convertase, and this process generates many molecules of the potent anaphylatoxin and neutrophil chemo-attractant, C5a. Activated C5 (C5b) is the nidus for formation of the MAC of complement consisting of C5b, C6, C7, C8, and multiple molecules of C9. The MAC inserts into the lipid bilayer of the cell, forming a transmembrane torus that results in osmotic lysis. CD55 (DAF) blocks the formation and stability of both the C3 and C5 convertases, whereas CD59 (MIRL) blocks formation of the cytolytic MAC, primarily by inhibiting binding and multiplicity of C9. Eculizumab is a humanized monoclonal anti-C5 antibody that prevents activation of C5 by the C5 convertase. Consequently, the MAC cannot form (and C5a is not generated), accounting for the inhibition of the intravascular hemolysis of PNH. However, eculizumab does not inhibit formation of the C3 convertase, accounting for the opsonization by activation and degradation products of C3 observed in patients with PNH treated with eculizumab. Normal RBCs are protected against APC-mediated injury (black crosses represent APC C3 and C5 convertase formation; yellow stars represent MAC formation) by CD55 (blue ovals) and CD59 (green ovals) (bottom). PNH cells lacking the complement inhibitory proteins CD55 and CD59 undergo complement-mediated lysis, releasing cellular contends including hemoglobin (red circles) and LDH into the plasma.