Figure 2.
Summary of features for diseases with substantial complement involvement. (A) PNH. Acquired somatic mutations in the PIG-A gene (encoding a glycosyl transferase essential for the synthesis of GPI anchors) of hematopoietic stem cells result in a loss of or in reduced numbers of GPI anchored proteins on the surface of progenitor cells (erythrocytes, platelets, leukocytes, lymphocytes). Consequences thereof are highlighted in the figure. (B) aHUS-induced TMA. Different heterozygous mutations are linked to causing the disease. Gain-of-function mutations in complement components, loss of function mutilations in complement regulators, loss of function because of hybrid genes of the regulator factor H, or autoantibodies directed against factor H are the main contributors to aHUS inducing an imbalance in complement activation/regulation after a complement activation trigger (eg, infection, surgery; DGKE type aHUS is not covered). Key events in aHUS-induced TMA are summarized in the figure. GC, glycocalyx; EC, endothelial cells; GBM, glomerular basement membrane. (C) C3G. Like in aHUS, gain-of-function mutations of complement effector proteins or loss of function mutations in regulators are described. In addition, FH-related fusion proteins and autoantibodies either stabilizing the intrinsic short-lived convertases complexes or impairing complement regulators are reported. This leads to AP dysregulation in the fluid phase, which precipitates onto surfaces apparently without inflicting widespread cytolysis. Although TP activation products are identified in the glomeruli of patients, the C5b-9 complexes appear to be inhibited by the fluid phase inhibitors vitronectin (S protein) and/or clusterin yielding SC5b-9, which cannot insert into membrane bilayers. (D) AIHA. Cold-type autoantibodies bind to erythrocytes at temperatures lower than 37°C and induce covalent C3b deposition that is amplified via the AP amplification loop. At 37°C, the low-affinity IgM antibodies regularly dissociate. If high enough C3b densities are reached, TP-mediated cytolysis occurs via MAC. The sequence of events is similar for warm-type antibodies (usually IgG); however, these (high-affinity) antibodies bind and remain bound to red blood cells (RBCs) at 37°C. Not all IgG antibodies can activate the CP (strong enough) to lead to MAC formation and intravascular hemolysis. If not lysed, IgG and/or C3-fragment positive RBCs are recognized by phagocytes of the reticuloendothelial system (RES), resulting in extravascular removal of such RBCs without intravascular hemolysis (data not shown). Erythrocyte lysis within the vasculature is associated with thrombotic events. (E) APS/CAPS. aPL-abs are a heterogenous group of autoantibodies (mostly IgG and IgM, but IgA also occur) targeting complexes of PLs and PL-binding proteins. Occurrence of aPL-ab– and antibody binding–induced cell activation is considered first hit. Complement activation and signaling via TP activation products C5b-9 and C5a are considered second hit. The role of complement activation in augmenting thrombotic is well documented but may not explain all thrombotic events in APS.

Summary of features for diseases with substantial complement involvement. (A) PNH. Acquired somatic mutations in the PIG-A gene (encoding a glycosyl transferase essential for the synthesis of GPI anchors) of hematopoietic stem cells result in a loss of or in reduced numbers of GPI anchored proteins on the surface of progenitor cells (erythrocytes, platelets, leukocytes, lymphocytes). Consequences thereof are highlighted in the figure. (B) aHUS-induced TMA. Different heterozygous mutations are linked to causing the disease. Gain-of-function mutations in complement components, loss of function mutilations in complement regulators, loss of function because of hybrid genes of the regulator factor H, or autoantibodies directed against factor H are the main contributors to aHUS inducing an imbalance in complement activation/regulation after a complement activation trigger (eg, infection, surgery; DGKE type aHUS is not covered). Key events in aHUS-induced TMA are summarized in the figure. GC, glycocalyx; EC, endothelial cells; GBM, glomerular basement membrane. (C) C3G. Like in aHUS, gain-of-function mutations of complement effector proteins or loss of function mutations in regulators are described. In addition, FH-related fusion proteins and autoantibodies either stabilizing the intrinsic short-lived convertases complexes or impairing complement regulators are reported. This leads to AP dysregulation in the fluid phase, which precipitates onto surfaces apparently without inflicting widespread cytolysis. Although TP activation products are identified in the glomeruli of patients, the C5b-9 complexes appear to be inhibited by the fluid phase inhibitors vitronectin (S protein) and/or clusterin yielding SC5b-9, which cannot insert into membrane bilayers. (D) AIHA. Cold-type autoantibodies bind to erythrocytes at temperatures lower than 37°C and induce covalent C3b deposition that is amplified via the AP amplification loop. At 37°C, the low-affinity IgM antibodies regularly dissociate. If high enough C3b densities are reached, TP-mediated cytolysis occurs via MAC. The sequence of events is similar for warm-type antibodies (usually IgG); however, these (high-affinity) antibodies bind and remain bound to red blood cells (RBCs) at 37°C. Not all IgG antibodies can activate the CP (strong enough) to lead to MAC formation and intravascular hemolysis. If not lysed, IgG and/or C3-fragment positive RBCs are recognized by phagocytes of the reticuloendothelial system (RES), resulting in extravascular removal of such RBCs without intravascular hemolysis (data not shown). Erythrocyte lysis within the vasculature is associated with thrombotic events. (E) APS/CAPS. aPL-abs are a heterogenous group of autoantibodies (mostly IgG and IgM, but IgA also occur) targeting complexes of PLs and PL-binding proteins. Occurrence of aPL-ab– and antibody binding–induced cell activation is considered first hit. Complement activation and signaling via TP activation products C5b-9 and C5a are considered second hit. The role of complement activation in augmenting thrombotic is well documented but may not explain all thrombotic events in APS.

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