Halting targeted and collateral damage to red blood cells by the complement system

Abstract

The complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

Keywords: Autoimmune hemolytic anemia; Complement; Complement inhibitors; Complement therapeutics; Paroxysmal nocturnal hemoglobinuria.

Fig. 1

Mechanisms of extravascular and intravascular hemolysis. (A) Complement activation on RBCs can occur via the CP (in AIHA) or via the AP (in PNH). Extravascular hemolysis via the CP is the consequence of opsonization of the RBC with antibodies, fragments of C4 (C4b or C4d), and/or fragments of C3 (C3b, iC3b, or C3d). Extravascular hemolysis via the AP (tick-over) depends on opsonization with C3 fragments only. Phagocytes express Fc and complement receptors, which bind to antibodies or the complement components on the target cell, respectively. The synergy between both receptors results in highly effective phagocytosis. Upon phagocytosis, the whole RBC is internalized into the phagocyte within the phagosome. (B) Intravascular hemolysis can be initiated by both the AP and CP. C1q can bind to antibodies on an RBC, which induces the cleavage of C2 and C4, forming the CP convertase C4b2a. Both the CP convertase and spontaneous background hydrolysis (tick-over) of C3 in the AP result in C3b cleavage. C3b can then deposit on the cell, or bind to C4bC2a, forming the C5 convertase. Upon cleavage of C5, C5b is formed, which associates with C6, C7, C8, and multiple C9 molecules to form the membrane attack complex (MAC), which inserts itself into the cell membrane, resulting in lysis. Figure created using Servier Medical Art

Fig 2.

Mechanism behind complement-mediated destruction of RBCs in PNH and AIHA. (A) Healthy RBCs express the GPI-anchored complement regulator CD55, which induces decay of C3 convertases, and CD59, which prevents MAC formation. PNH RBCs, however, do not express these regulators, meaning that C3b arising from tick-over can result in opsonization of the RBC. On PNH RBCs, further complement activation is not prevented and can result in MAC formation and intravascular hemolysis or in extravascular hemolysis by phagocytosis of C3 fragment-opsonized RBCs in the liver or spleen, which are often iC3b or C3b opsonized in PNH patients. (B) RBC autoantibodies in AIHA patients of either IgG or IgM class bind to RBCs and can induce CP activation, which leads to further opsonization of the RBC with complement and in some cases to MAC formation and direct lysis. The opsonized RBC can be phagocytosed via the IgG-Fc receptors and complement receptors. Figure created using Servier Medical Art

Fig 3

The complement system and targets of novel complement therapeutics. This overview shows the current drug developing landscape for AIHA and PNH. Scissors indicate the cleavage of a protein by a protease. Dotted lines indicate the breakdown of proteins. Figure adapted from [135]. *These drugs do not directly target C5a but rather the C5a receptor C5aR