Iron Ions and Haeme Modulate the Binding Properties of Complement Subcomponent C1q and of Immunoglobulins

Dimitrov, Jordan D.; Roumenina, Lubka T.; Doltchinkova, Virjinia; Vassilev, Tchavdar

doi:10.1111/j.1365-3083.2006.01893.x

Cited by 34 publications

(37 citation statements)

References 74 publications

(88 reference statements)

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“…We have previously observed that exposure of C1q to hematin inhibits its binding to immunoglobulin (25), an opposite effect compared with those described for IgG. Indeed, in pathological conditions, released heme may affect both partners of the interaction, thus compensating for increased antigen binding activity of Igs.…”

Section: Mechanisms Of Heme-induced Enlargement Of the Availablementioning

confidence: 88%

“…This may influence their biological functions. Indeed, it has been observed recently that the in vitro exposure of polyclonal antibodies from healthy individuals to heme resulted in the appearance of new strong reactivities toward various autoantigens (22)(23)(24)(25). The molecular mechanisms responsible for the effects on heme on the antigen binding activity of Igs are not understood.…”

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confidence: 99%

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Antibodies Use Heme as a Cofactor to Extend Their Pathogen Elimination Activity and to Acquire New Effector Functions

Dimitrov

Roumenina

Doltchinkova

et al. 2007

Journal of Biological Chemistry

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Various pathological processes are accompanied by release of high amounts of free heme into the circulation. We demonstrated by kinetic, thermodynamic, and spectroscopic analyses that antibodies have an intrinsic ability to bind heme. This binding resulted in a decrease in the conformational freedom of the antibody paratopes and in a change in the nature of the noncovalent forces responsible for the antigen binding. The antibodies use the molecular imprint of the heme molecule to interact with an enlarged panel of structurally unrelated epitopes. Upon heme binding, monoclonal as well as pooled immunoglobulin G gained an ability to interact with previously unrecognized bacterial antigens and intact bacteria. IgG-heme complexes had an enhanced ability to trigger complement-mediated bacterial killing. It was also shown that heme, bound to immunoglobulins, acted as a cofactor in redox reactions. The potentiation of the antibacterial activity of IgG after contact with heme may represent a novel and inducible innate-type defense mechanism against invading pathogens.

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Section: Mechanisms Of Heme-induced Enlargement Of the Availablementioning

confidence: 88%

mentioning

confidence: 99%

Antibodies Use Heme as a Cofactor to Extend Their Pathogen Elimination Activity and to Acquire New Effector Functions

Dimitrov

Roumenina

Doltchinkova

et al. 2007

Journal of Biological Chemistry

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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.…”

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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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“…Heme also interacts with various plasma proteins and modulates their functions (23)(24)(25)(26). We have demonstrated previously that in vitro exposure of C1q to heme results in concentration-dependent inhibition of C1q binding to its main targets, IgG and CRP (27). The underlying mechanisms of this inhibition, however, remain poorly understood.…”

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confidence: 99%

Heme Interacts with C1q and Inhibits the Classical Complement Pathway

Roumenina

Radanova

Атанасов

et al. 2011

Journal of Biological Chemistry

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C1q is the recognition subunit of the first component of the classical complement pathway. It participates in clearance of immune complexes and apoptotic cells as well as in defense against pathogens. Inappropriate activation of the complement contributes to cellular and tissue damage in different pathologies, urging the need for the development of therapeutic agents that are able to inhibit the complement system. In this study, we report heme as an inhibitor of C1q. Exposure of C1q to heme significantly reduced the activation of the classical complement pathway, mediated by C-reactive protein (CRP) and IgG. Interaction analyses revealed that heme reduces the binding of C1q to CRP and IgG. Furthermore, we demonstrated that the inhibition of C1q interactions results from a direct binding of heme to C1q. Formation of complex of heme with C1q caused changes in the mechanism of recognition of IgG and CRP. Taken together, our data suggest that heme is a natural negative regulator of the classical complement pathway at the level of C1q. Heme may play a role at sites of excessive tissue damage and hemolysis where large amounts of free heme are released.

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Iron Ions and Haeme Modulate the Binding Properties of Complement Subcomponent C1q and of Immunoglobulins

Cited by 34 publications

References 74 publications

Antibodies Use Heme as a Cofactor to Extend Their Pathogen Elimination Activity and to Acquire New Effector Functions

Antibodies Use Heme as a Cofactor to Extend Their Pathogen Elimination Activity and to Acquire New Effector Functions

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Heme Interacts with C1q and Inhibits the Classical Complement Pathway

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