Selective inhibition of the interaction of C1q with immunoglobulins and the classical pathway of complement activation by steroids and triterpenoids sulfates

Bureeva, Svetlana; Andia-Pravdivy, Julian; Symon, Andrey; Бичучер, А. М.; Moskaleva, Vera; Попенко, В. И.; Shpak, Alexey V.; Швец, В. И.; Козлов, Л. В.; Kaplun, Alexander

doi:10.1016/j.bmc.2007.03.002

Cited by 31 publications

(26 citation statements)

References 31 publications

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“…Thus, unconjugated bilirubin, which is a product of heme catabolism, found at high concentrations in the case of liver diseases or of hemolytic anemia, binds to C1q and inhibits the classical complement pathway (45,46). Moreover, synthetic heterocyclic compounds such as bisphenol disulfates, sulfated steroids, and triterpenoids also inhibit the classical complement pathway at the level of C1q (47,48). Two of these compounds, betulin disulfate and 9,9-bis(4Ј-hydroxyphenyl) fluorene disulfate, were studied in detail (43).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Uncontrolled activation of the classical C pathway is involved in many inflammatory pathologies, such as ischemia/reperfusion injury, and selective inhibitors for this pathway are needed (1,21). In contrast, C1q deficiency is directly correlated with autoimmune diseases, such as systemic lupus erythematosus and glomerulonephritis, associated with accumulation of apoptotic cells (34,35).…”

Section: C1q-gr Binds the Polyanionic Hp And Dna Molecules Through Nementioning

confidence: 99%

“…To decipher the structural determinants for the specific C1q binding to deoxy-D-ribose compared with ribose, x-ray analyses of C1q-GR crystals were performed in the presence of these two molecules. In contrast, sulfated molecules, such as triterpenoid sulfates, heparin (Hp) sulfates, or chondroitin sulfates, have been shown to interact with C1q and inhibit activation of the classical C pathway (19)(20)(21). This prompted us to investigate C1q binding to heparan sulfates through the combined use of surface plasmon resonance (SPR) and x-ray analyses.…”

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confidence: 99%

Cutting Edge: C1q Binds Deoxyribose and Heparan Sulfate through Neighboring Sites of Its Recognition Domain

Garlatti

Chouquet

Lunardi

et al. 2010

The Journal of Immunology

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C1q, the recognition subunit of the C1 complex of complement, is an archetypal pattern recognition molecule with the striking ability to sense a wide variety of targets, including a number of altered self-motifs. The recognition properties of its globular domain were further deciphered by means of x-ray crystallography using deoxy-d-ribose and heparan sulfate as ligands. Highly specific recognition of deoxy-d-ribose, involving interactions with Arg C98, Arg C111, and Asn C113, was observed at 1.2 Å resolution. Heparin-derived tetrasaccharide interacted more loosely through Lys C129, Tyr C155, and Trp C190. These data together with previous findings define a unique binding area exhibiting both polyanion and deoxy-d-ribose recognition properties, located on the inner face of C1q. DNA and heparin compete for C1q binding but are poor C1 activators compared with immune complexes. How the location of this binding area in C1q may regulate the level of C1 activation is discussed.

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“…Thus, the development of substances to control the interaction of C1q with immune complexes are of interest (Bureeva et al, 2007). In particular, highly specific approaches that will block particular regions on C1q such as the C1q globular heads would be highly desirable and is the subject of the present study.…”

Section: Introductionmentioning

confidence: 99%

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Duvall

Tomlinson

Boackle

2008

Molecular Immunology

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We sought to specifically regulate the binding of human C1q, and thus the activation of the first complement component, via the construction of a single chain antibody variable binding region fragment (scFv) targeting the C1q globular heads. Here we describe details of the construction, expression and evaluation of this scFv, which was derived from a high affinity hybridoma (Qu) specific for the C1q globular heads. The scFv was comprised of the Qu variable-heavy chain domain (VH) linked to the Qu variable-light chain domain (VL) and was termed scFv-QuVHVL. When mixed with either purified C1q or with human serum as a source of C1, scFv-QuVHVL bound to C1q and competitively restricted the interaction of C1q or C1 with immobilized IgG or with IgG1 antibody-coated cells, and prevented the activation of native C1 in human serum as determined by analyses of C1-mediated C4 deposition and fluid phase C4 conversion. However scFv-QuVHVL could be manipulated to become a C1 activator when it was irreversibly immobilized onto microtiter ELISA plates, prior to contact with human serum complement. This functional dichotomy can be a useful tool in selectively elucidating, differentiating, inducing or inhibiting specific roles of human C1q and the classical complement pathway in complement-mediated physiological processes. We project that once fully humanized, fluid phase scFv-QuVHVL could become a useful therapeutic in limiting inadvertent host tissue damage elicited by the classical complement pathway.

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Selective inhibition of the interaction of C1q with immunoglobulins and the classical pathway of complement activation by steroids and triterpenoids sulfates

Cited by 31 publications

References 31 publications

Heme Interacts with C1q and Inhibits the Classical Complement Pathway

Heme Interacts with C1q and Inhibits the Classical Complement Pathway

Cutting Edge: C1q Binds Deoxyribose and Heparan Sulfate through Neighboring Sites of Its Recognition Domain

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

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