Heme interacts with C1Q and inhibits the classical complement pathway

Roumenina, Lubka; Radanova, Maria; Атанасов, Б.; Popov, Krastio T.; Kaveri, Srini V.; Lacroix‐Desmazes, Sébastien; Frémeaux‐Bacchi, Véronique; Dimitrov, Jordan D.

doi:10.1016/j.molimm.2011.06.347

Cited by 7 publications

(9 citation statements)

References 38 publications

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“…13,30 Heme has a dual role in complement, activating AP but inhibiting the binding of C1q to its ligands. 23 We investigated the mechanism of AP complement activation and showed that it results from the interaction of heme with the C3 molecule, which favors C3 homophilic interactions and leads to the formation of an active AP C3/C5 convertase.…”

Section: Discussionmentioning

confidence: 99%

“…Absorbance spectra of hemin were recorded by using a Unicam Helios b UV-vis spectrophotometer, as described previously. 23 Human C3, C3b, or C3a (Calbiochem; CompTech) was diluted to 500 nM in PBS. Aliquots of heme resulting in final concentrations of 0.01 to 20 mM were added to the optical cell-containing proteins and to a reference optical cell containing PBS only.…”

Section: Endothelial Cell Assaysmentioning

confidence: 99%

“…HexServer (http://hexserver.loria.fr/) was used to accommodate the heme molecule to C3, as described previously for C1q. 23 Criteria for final C3-heme complex selection were based on the total energy of binding. Visualization was done by PyMol (www.pymol.org).…”

Section: Endothelial Cell Assaysmentioning

confidence: 99%

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Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Frimat

Tabarin

Dimitrov

et al. 2013

Blood

213

248

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Key Points• Heme activates complement alternative pathway in serum and on endothelial cell surfaces.• Heme-induced complement activation in the presence of complement mutations contributes as a secondary hit to the development of aHUS.Atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormalities of the complement system leading to alternative pathway (AP) overactivation and by glomerular endothelial damage, thrombosis, and mechanical hemolysis. Mutations per se are not sufficient to induce aHUS, and nonspecific primary triggers are required for disease manifestation. We investigated whether hemolysis-derived heme contributes to aHUS pathogenesis. We confirmed that heme activates complement AP in normal human serum, releasing C3a, C5a, and sC5b9. We demonstrated that hemeexposed endothelial cells also activate the AP, resulting in cell-bound C3 and C5b9. This was exacerbated in aHUS by genetic abnormalities associated with AP overactivation. Heme interacted with C3 close to the thioester bond, induced homophilic C3 complexes, and promoted formation of an overactive C3/C5 convertase. Heme induced decreased membrane cofactor protein (MCP) and decay-accelerating factor (DAF) expression on endothelial cells, giving Factor H (FH) a major role in complement regulation. Finally, heme promoted a rapid exocytosis of Weibel-Palade bodies, with membrane expression of P-selectin known to bind C3b and trigger the AP, and the release of the prothrombotic von Willebrand factor. These results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS. (Blood. 2013;122(2):282-292) IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare kidneypredominant thrombotic microangiopathy (TMA) associated with formation of fibrin-platelet clots in the glomerular microvasculature leading to mechanical hemolysis. 1 This disease is related to a dysregulation of the complement alternative pathway (AP), as shown by the identification of genetic or acquired abnormalities in AP regulators or activators in more than 60% of patients. 2 aHUS has an incomplete penetrance among mutation carriers, and a triggering event is presumably required for the disease manifestation. This primary hit can be an infection, pregnancy, drug, or other cell-activating event. Sera from aHUS patients carrying mutations deposit complement on endothelial cells activated by inflammatory cytokines, 3 suggesting continuous aggression on the endothelium. However, not all infections trigger aHUS in patients. It is frequently the second pregnancy postpartum period that is associated with the disease.4 Therefore, other factors appear to be necessary to exceed the threshold of tolerable endothelial stress leading to severe TMA lesions.In acute phase TMA, mechanical hemolysis induces the release of hemoglobin into the bloodstream. 5 This hemoglobin is readily oxidized to ferric hemoglobin (methemoglobin) which, in turn, liberates heme. In physiological conditions...

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Section: Discussionmentioning

confidence: 99%

Section: Endothelial Cell Assaysmentioning

confidence: 99%

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Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Frimat

Tabarin

Dimitrov

et al. 2013

Blood

213

248

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“…38,39 In contrast, a negative effect of free heme on C1q binding to IgG and IgM has been described. 40,41 It was mentioned that classical pathway activation can be modulated by released heme by inhibiting the binding of C1q to its ligands. However, it still remains to be investigated whether the amount of released heme in AIHA patients with extravascular hemolysis is sufficient to exert the reported effects on the complement system in vivo.…”

Section: (See Above)mentioning

confidence: 99%

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Wouters

2015

Haematologica

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© 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...

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“…The exact ligands of C1q on dying cells are not well studied, but include cell-derived molecules, like phosphatidyl serine and DNA (20)(21)(22), or blood-borne factors, such as CRP, serum amyloid P, pentraxin 3, and natural IgM (23)(24)(25)(26)(27). All of these molecules are recognized by the globular domain of C1q (3,19,(28)(29)(30). Failure of C1q to opsonize apoptotic cells results in defective phagocytosis by monocytes (12), decreased threshold of dendritic cell activation (31), and, hence active immune response, generating autoantibodies, such as in lupus (11).…”

Section: Discussionmentioning

confidence: 99%

Functional Complement C1q Abnormality Leads to Impaired Immune Complexes and Apoptotic Cell Clearance

Roumenina

Sène

Radanova

et al. 2011

The Journal of Immunology

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C1q plays a key role in apoptotic cell and immune complex removal. Its absence contributes to the loss of tolerance toward self structures and development of autoimmunity. C1q deficiencies are extremely rare and are associated with complete lack of C1q or with secretion of surrogate C1q fragments. To our knowledge, we report the first case of a functional C1q abnormality, associated with the presence of a normal C1q molecule. Homozygous GlyB63Ser mutation was found in a patient suffering from lupus with neurologic manifestations and multiple infections. The GlyB63Ser C1q bound to Igs, pentraxins, LPSs, and apoptotic cells, similarly to C1q from healthy donors. However, the interaction of C1r2C1s2 and C1 complex formation was abolished, preventing further complement activation and opsonization by C3. The mutation is located between LysB61 and LysB65 of C1q, suggested to form the C1r binding site. Our data infer that the binding of C1q to apoptotic cells in humans is insufficient to assure self-tolerance. The opsonization capacity of C4 and C3 fragments has to be intact to fight infections and to prevent autoimmunity.

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Heme interacts with C1Q and inhibits the classical complement pathway

Cited by 7 publications

References 38 publications

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Functional Complement C1q Abnormality Leads to Impaired Immune Complexes and Apoptotic Cell Clearance

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