Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Abstract

© F e r r a t a S t o r t i F o u n d a t i o n Complement systemThe complement system is an evolutionary highly conserved cascade system that makes up part of the innate immune system. [7][8][9] Complement activation can occur via three distinct pathways (classical pathway (CP), lectin pathway (LP) and alternative pathway (AP) that converge at the level of C3 cleavage and eventually lead to a common terminal pathway (TP) ( Figure 1A).The AP can be initiated by spontaneous hydrolysis of the central complement component into C3b(H 2 O). C3b(H 2 O) is an acceptor for the next AP protein Factor B (FB) which is then cleaved by the serine protease factor D (FD), resulting Complement inhibition in AIHA haematologica | 2015; 100 (11) 1389 The lectin pathway is initiated by binding of MBL (or ficolins) to sugar structures followed by activation of C2 and C4 by MASP1/MASP2, leading to the formation of lectin C3 convertase (C2aC4b). (E) C3-activation by the classical, lectin or alternative C3 convertase results in the formation of the C5 convertase. C5 convertase subsequently activates C5 resulting in the formation of the membrane attack complex (MAC). C: complement factor; MAC: membrane attack complex; MBL: mannan binding lectin; MASP: MBL-associated serine protease; P: properdin; C1-inh: C1-inhibitor; FI: factor I; CR1: complement receptor 1; MCP: membrane co-factor protein; DAF: decay accelerating factor; C4BP: C4-binding protein; FH: factor H. A B C D E © F e r r a t a S t o r t i F o u n d a t i o nin the fluid phase C3 convertase (C3b(H 2 O)Bb), that can cleave multiple C3 molecules into C3b and C3a. C3b binds to nucleophilic targets on cell membranes 10 and C3a acts as a pro-inflammatory anaphylatoxin ( Figure 1B). Low-level activation of C3 can significantly be accelerated through a positive feedback loop resulting in the formation of additional alternative C3 convertases on the surface (C3bBb) that are stabilized by properdin (P) and eventually give rise to the formation of a C5 convertase (C3bBbC3b), which subsequently cleaves C5 into C5b and C5a.10 C5b attaches to the surface and subsequently binds to C6, C7 and C8 to form the C5bC8 complex allowing polymerization of C9 to form the membrane attack complex (MAC), which inserts into target membranes and induces cell lysis ( Figure 1A and E). 11,12 Next to lysis by the MAC, cleavage of both C3 and C5 results in the generation of pro-inflammatory anaphylatoxins (C3a, C5a) that attract and activate leukocytes 13 and C3b opsonization of the target surface facilitates uptake by phagocytic cells in the liver and spleen.During evolution complement activation became more specific by the development of recognition molecules. The CP is initiated by binding of C1q to the Fc-part of IgM or IgG complexed with their target antigens. IgM is most efficient in complement activation, due to its polymeric nature. Human IgG activates complement in the order IgG3>IgG1>IgG2, whereas IgG4 does not activate complement at all.14 As the affinity of C1q for a single IgG Fc tail is...

<p>Cold agglutinin disease: current challenges and future prospects</p>

“…Although approved only for hereditary angioedema, which is not a complement-mediated disorder, pharmacological doses of C1-INH were shown to stop complement activation and hemolysis and efficiently improve anemia when used as rescue therapy in a patient with a severe, IgM-mediated warm-AIHA. 77,78 Recently, a similar effect was observed in a patient with acute, severe CAS. 21 However, levels of endogenous C1-INH are normal in CAD and CAS; frequently repeated high doses are likely to be required to maintain the effect, and, therefore, C1-INH is probably not attractive as a long-term therapy.…”

Reduction of Isoagglutinin in Intravenous Immunoglobulin (IVIG) Using Blood Group A- and B-Specific Immunoaffinity Chromatography: Industry-Scale Assessment

“…It is generally accepted that IgM and IgG antibodies to A and B blood group antigens are present in human serum [ 24 ]. IgM isoagglutinins are considered to have a higher hemolytic potential as IgM is a strong activator of complement [ 15 , 25 ]. Current IVIG products contain only traces of IgM (e.g., ≤10 mg/l for Privigen); however, their IgM isoagglutinin content has generally not been investigated.…”

Eryptosis in autoimmune haemolytic anaemia

“…IgG aab may lead to RBC destruction via Fc‐mediated phagocytosis and, if complement is activated, via C3b‐mediated phagocytosis. IgM aab usually activate complement and may lead to RBC destruction via C3b‐mediated phagocytosis or C5b‐9 membrane attack complex . The mechanism of how IgA aab lead to RBC destruction has not been fully elucidated .…”