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PubMed1995

Antibody-independent binding of complement component C1q by Legionella pneumophila.

Incubation of Legionella pneumophila Philadelphia 1 in normal human serum depleted of either classical-pathway component C1q or alternative-pathway component factor B resulted in activation of the complement system. Experiments focused on the role of the classical pathway in complement activation revealed that legionellae bound C1q independently of antibody. Purified preparations of L. pneumophila major outer membrane protein but not serogroup 1 lipopolysaccharide bound C1q independently of antibody. This suggests that antibody-independent binding of C1q by L. pneumophila can result in activation of the classical pathway in normal human serum and that major outer membrane protein may be a C1q acceptor on the L. pneumophila cell surface.

Antibodies, Bacterial↗

PubMed1996

Autocrine induction of macrophage synthesis of complement subcomponent C1q by endogenous interferon-alpha/beta.

Peritoneal macrophages (M phi) constitutively synthesize and secrete interferon-alpha (IFN-alpha) and IFN-beta, as well as complement subcomponent C1q. Because exogenous interferon-gamma (IFN-gamma) stimulates Mø synthesis of C1q, our purpose was to determine if endogenous secretion of IFN-alpha/beta regulated the constitutive level of endogenous C1q mRNA synthesis in an autocrine fashion. Both exogenous IFN-alpha and IFN-beta effectively substituted for IFN-gamma in stimulating M phi C1q mRNA expression in a dose-dependent fashion by northern blot analysis. Neutralizing anti-INF-alpha/beta antibodies inhibited M phi constitutive C1q mRNA synthesis by approximately twofold and abrogated the feedback stimulatory effects of exogenous C1q on C1q mRNA expression. Paraffin oil-elicited inflammatory M phi displayed distinctively different constitutive levels of C1q mRNA expression from thioglycollate brothelicited M phi, which was correlated with their relative levels of secretory IFN-alpha/beta by ELISA. Exogenous IFN-alpha/beta also restored C1q mRNA synthesis of AKR mouse M phi with low constitutive C1q mRNA expression. The cumulative results support the concept that constitutive synthesis of C1q by M phi is regulated by the endogenous synthesis and secretion of IFN-alpha/beta, which appears to act in an autocrine fashion.

Animals↗

PubMed1987

Regulation of the alternative pathway of human complement by C1q.

The interaction of C1q with C3b and its effect on C3b activities in the alternative pathway of complement (APC) have been studied. Purified C1q markedly inhibited C3b deposition on and lysis of rabbit erythrocytes by the isolated cytolytic APC. It also blocked formation of the C3 convertase, C3b, Bb as well as binding of Factors B and H to sheep erythrocytes (E) bearing C3b. The direct and specific binding of C1q to C3b was clearly demonstrated using the hemagglutination technique at low ionic strength (0.1 M NaCl). C1q concns of 2 micrograms/ml and higher agglutinated, in a dose-dependent fashion, EC3b but not E, EC3bi or EC3d. Addition of C1r and C1s to C1q and formation of C1 did not affect its capacity to agglutinate EC3b. The C1q-mediated agglutination of EC3b was inhibited by EDTA, MgEGTA, C3b and Factor B but not by native C3 or collagen. Heating C1q (56 degrees C) markedly potentiated its agglutinating activity whereas collagenase-treated C1q lost most of its activity. Taken together, these results suggest that C1q binds through its "heads" and in the presence of calcium ions to a site on C3b that is adjacent to the Factor B and Factor H binding sites. This interaction may down-regulate the activity of the alternative pathway of complement on surfaces which activate both the classical and alternative pathways of complement.

Animals↗

PubMed1987

The effect of vitamin C nutriture on complement component C1q concentrations in guinea pig plasma.

This study shows that guinea pigs fed 100 times the amount of vitamin C needed for growth and for prevention of scurvy have elevated levels of complement component C1q. C1q is a plasma protein rich in hydroxyproline, an amino acid whose biosynthesis requires ascorbate. C1q is essential for host defense against pathogens, both as a component of the classical complement pathway and as an opsonin in the phagocytosis process. We measured C1q in vitamin C-depleted guinea pigs that had been repleted for 4 wks with the following daily doses of ascorbate (mg/100 g body wt): 0.50 (suboptimal), 2.0 (adequate), 10 (ample) and 50 (tissue saturating). We measured C1q in three ways: indirectly by quantifying protein-bound hydroxyproline and directly by hemolytic assay and by immunodiffusion against anti-C1q. Regardless of the method, plasma C1q was 30-50% higher in animals fed tissue-saturating ascorbate than in those fed adequate or suboptimal amounts of the vitamin (p less than 0.05, one-way analysis of variance, least significant difference test). These data confirm and significantly extend earlier work that provided indirect evidence for a relationship between C1q and ascorbate nutriture in the guinea pig. They are consistent with a possible relationship between ascorbate nutriture and host defense.

Animals↗

PubMed1991

Complement component C1q and its receptor are involved in the interaction of human sperm with zona-free hamster eggs.

C1q is a component of the classical complement pathway that can react with the Fc-fragment of immunoglobulins and with other proteins, such as fibronectin, laminin, and a specific C1q receptor present on several cell types. Given its role in many adhesion systems, mainly related to phagocytosis, we tested the effects of C1q on the interaction between human spermatozoa and zona-free hamster eggs. The presence of C1q in the medium used for gamete coincubation resulted in promotion of sperm-oolemma adhesion and an inhibition of penetration. The number of adherent sperm per egg at 5 micrograms/ml concentration was 90 +/- 35 vs. 29 +/- 7 for the control (P less than 0.001). At 1 microgram/ml, the lower concentration at which C1q had an effect, the number of penetrating sperm/egg was 0.6 vs. 1.7 for the control without C1q (P less than 0.01), and the percent of penetrated eggs was 28% vs. 85%. At 50 micrograms/ml, the percent of penetrated eggs was 7%, with a penetration index of 0.07. The addition of C1q to the medium resulted in sperm agglutination, which varied between sperm donors. The presence of C1q receptors, as detected by anti-C1qR monoclonal antibodies (Mabs), was demonstrated both on zona-free hamster eggs by immunobead rosetting and on human spermatozoa by immunobead binding and indirect immunofluorescence. Mabs directed against different epitopes of C1qR had different effects on gamete interaction, with a partial inhibition of penetration mediated by some of them. The binding of C1q to antibody-free human spermatozoa was also demonstrated both by means of indirect immunofluorescence and utilizing 125I-C1q.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Elevation by muroctasin of the serum level of the complement subcomponent C1q in mice and of its biosynthesis by cultured mouse peritoneal macrophages.

Augmentative effects of muroctasin (N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine, (MDP-Lys(L18] on the production of a subcomponent of the first complement component, C1q, in mice were examined. The serum level of C1q in mice treated subcutaneously with muroctasin was found to be elevated significantly at 24 h (p less than 0.1) and 48 h (p less than 0.01). At 24 h, samples of peritoneal macrophages were derived from mice, and incubated with Dulbecco's Modified Eagle Medium (MEM) at 37 degrees C for 24 h. At 19 h of incubation, the C1q concentration in the supernatant of the culture also increased significantly (p less than 0.05). Moreover, when the peritoneal macrophages from non-treated mice were cultured in MEM containing muroctasin (0.001 microgram/ml), the amount of C1q in the culture supernatants also increased significantly 3 h (p less than 0.01) after cultivation. These results indicate that muroctasin activated C1q generation by macrophages in mice through direct and/or indirect mechanisms.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

Localization of the site on the complement component C1q required for the stimulation of neutrophil superoxide production.

C1q, the recognition subunit of the classical complement pathway, interacts with specific cell surface molecules via its collagen-like region (C1q-CLR). This binding of C1q to neutrophils triggers the generation of toxic oxygen species. To identify the site on C1q that interacts with the neutrophil C1q receptor, C1q was isolated, digested with pepsin to produce C1q-CLR, and further cleaved with either trypsin or endoproteinase Lys-C. The resulting fragments were separated by gel filtration chromatography and analyzed functionally (activation of the respiratory burst in neutrophils) and structurally. Cleavage of C1q-CLR with endoproteinase Lys-C did not alter its ability to trigger neutrophil superoxide production. However, when C1q-CLR was incubated with trypsin under conditions permitting optimal cleavage, the ability of C1q-CLR to stimulate superoxide production in neutrophils was completely abrogated. Fractionation of the digests obtained with the two enzymes and identification by amino acid sequencing permitted localization of the receptor interaction site to a specific region of the C1q-CLR. Circular dichroism analyses demonstrated that cleavage by trypsin does not denature the remaining uncleaved collagen-like structure, suggesting that after trypsin treatment, the loss of activity was not due to a loss of secondary structure of the molecule. However, irreversible heat denaturation of C1q-CLR also abrogated all activity. Thus, a specific conformation conferred by the collagen triple helix constitutes the functional receptor interaction site. These data should direct the design of future specific therapeutic reagents to selectively modulate this response.

Amino Acid Sequence↗

PubMed1998

Platelet receptors for the complement component C1q: implications for hemostasis and thrombosis.

Platelets participate in a variety of responses of the blood to injury (1). In addition to their well known role in hemostasis and thrombosis, platelets play a role in inflammation and react with components of the immune system. Immune complexes and aggregated IgG, for example, are known to activate platelets via ligation of Fc gamma RII receptors and induce the release of platelet granule contents, including biogenic amines and adenine nucleotides (2). Platelets also interact with the complement subcomponent C1q utilizing binding sites that are unrelated to C1s, a complement subcomponent which was originally suggested to support C1q binding to thrombocytes (3). The physiologic and pathologic consequences of platelet C1q receptor occupancy are incompletely understood. Platelet C1q receptors may contribute to immune complex localization and clearance, as has been suggested for C1q receptors on phagocytic cells (4), but considerable evidence is emerging to suggest that the interaction between C1q and platelets may influence hemostasis and perhaps, more profoundly, thrombotic complications resulting from immune injury. This review will summarize current concepts in C1q receptor biology as it relates to human platelet function and blood coagulation.

Animals↗

PubMed2005

Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR.

Dendritic cells (DCs) are recruited to inflammatory sites where they phagocytose and process antigens for subsequent presentation to the T lymphocytes in the lymphoid tissue. Several leukocyte chemoattractants and their specific receptors have been shown to induce the migration of DC. The complement protein C1q has multiple immune functions including acting as a chemoattractant for neutrophils, eosinophils and mast cells. Therefore, the objective of this study was to determine if soluble C1q can induce chemotaxis of DC. Culturing cells in GM-CSF and IL-4 for 5 to 7 days generated human monocyte-derived DCs. In addition, LPS was added from day 5 to 7 to induce DC maturation. Cells were classified as either immature or mature DC by assessing the cell surface markers by flow cytometry, phagocytosis of dextran-FITC and T cell proliferation in an allogenic MLR. Immature DCs express the C1q receptors (C1qR), gC1qR and cC1qR/CR and, accordingly, display a vigorous migratory response to soluble C1q with maximal cell movement observed at 10-50nM. In contrast, mature DCs neither express C1qR nor do move to a gradient of soluble C1q. Varying the concentration gradient of C1q (checkerboard assay) showed that the protein largely induces a chemotactic response. Finally, blocking gC1qR and cC1qR/CR by using specific antibodies abolished the chemotactic response to C1q but had no effect on a different chemoattractant C5a. These results clearly demonstrate that C1q functions as a chemotactic factor for immature DC, and migration is mediated through ligation of both gC1qR and cC1qR/CR.

Animals↗

PubMed1988

C1q component of complement binds to fibrinogen and fibrin.

The interaction of complement component C1q with fibrinogen and fibrin was studied by using a solid-phase direct binding assay. Scatchard analysis of radioiodinated fibrinogen binding to C1q indicated at least two high-affinity binding constants (Kd) calculated as 8.5 and 120 nM. In contrast, binding of radioiodinated fibrin to C1q showed only a single class of binding sites with a calculated Kd of 600 nM. Fibrinogen-C1q binding was shown to decrease as a function of increasing salt concentrations, indicating either the presence of charged amino acids in the binding sites or an ionic strength induced conformational dependency of the binding. In direct binding studies using isolated fragments of C1q, both the collagen-like domain of C1q and the globular domains of C1q were shown to bind fibrinogen, indicating at least one binding site for fibrinogen is located in each of the major domains of C1q. Addition of the thrombin-generated peptides of fibrinogen, fibrinopeptides A and B, enhanced C1q-fibrinogen binding, again indicating a complex binding interaction. These results indicate that C1q and fibrinogen are capable of high-affinity interactions that may serve to sequester these complexes in areas of tumors, immune complex deposition, or wounds.

Binding Sites↗

PubMed1995

Collagen-like complement component C1q is a membrane protein of human monocyte-derived macrophages that mediates endocytosis.

The collagen-like C1q molecule, a subcomponent of the first component of complement, C1, is synthesized by macrophages (M phi). Previously, we have demonstrated that C1q is a membrane protein of guinea pig peritoneal macrophages (M phi). To extend this observation as a general biologic characteristic of M phi, we investigated human (hu) monocyte-derived M phi. Interestingly, surface labeling with the biotin derivative sulfosuccinimidyl-6-(biotinamido)-hexanoate of M phi, freshly isolated monocytes, lymphocytes, granulocytes, and myelomonocytic U937 cells revealed that C1q occurs only on the surface of M phi and not on the surface of the other cells types. Therefore, C1q appears to be a marker for differentiation into M phi. FITC-labeled, fixed Staphylococcus aureus coupled to membrane C1q via a monoclonal alpha-hu-C1q Ab were used to demonstrate that membrane C1q is capable of mediating phagocytosis. Various detergents (Nonidet P-40, digitonin, lubrol, and Triton X-114) were used to solubilize membrane C1q. Membrane C1q of hu M phi is tightly bound to or located in the intact membrane, since treatment of cells with acidic buffers ("acid strip") failed to remove C1q from the cell surface. However, repeated freezing and thawing of cells and washing of segregated membranes with buffer containing 1 M KCl and 3 M urea brought about a marked release of membrane C1q.

Amino Acid Sequence↗

PubMed1991

Complement component C1q activity and ascorbic acid nutriture in guinea pigs.

When guinea pigs are fed tissue-saturating amounts of ascorbate, C1q concentrations are significantly higher than in those animals fed only enough ascorbate for adequate growth and for the prevention of scurvy. C1q is the recognition protein of the classical complement pathway, a system of blood proteins that constitutes an important part of host defense against pathogens. The observed effect of ascorbate nutriture on C1q concentrations is consistent with the known role of ascorbic acid in hydroxyproline biosynthesis. C1q is a hydroxyproline-containing protein with structural similarities to collagen.

Analysis of Variance↗

PubMed1991

Collagenase of Clostridium perfringens type A: degradation of human complement component C1q.

The semipurified collagenases from Clostridium perfringens type A strains 2-Cli and ATCC 13124, both characterized by molecular weights of 79.4 kilodaltons, partially degraded purified human complement (C) component C1q. The following purified human serum proteins were refractory: C components C3, C4, C5, C6, C7, C8, and C9; immunoglobulin (Ig)A (from colostrum), IgG, and IgM; alpha 2-macroglobulin, haptoglobin, and C-reactive protein.

Blotting, Western↗

PubMed1993

Interactions of complement fraction C1q, fibronectin, and immunoglobulin G with polyacrylic microparticles used as solid-phase in immunoassay.

A microparticle-enhanced nephelometric immunoassay was recently described, where polyacrylic, hydrophilic, and polyfunctional microparticles are used as the solid phase. It is a one-step immunoassay based on the nephelometric quantification of microparticle agglutination. In such assays, the measurement of analytes at low concentration may be impaired by the need of using undiluted biological samples. This leads to work with high concentrations of several proteins liable to interfere with the agglutination process. In this paper, we report on a study performed with human serum and purified proteins, which were assayed by classical analytical methods. This work identified three major components of human serum specifically involved in yielding polyacrylic microparticle instability: complement fraction C1q, fibronectin, and immunoglobulins G. In this order of importance, they all showed a marked ability to be adsorbed on the microparticle's surface. Pretreatment of human serum with microparticles decreased the concentrations in C1q (82%), fibronectin (16%), and immunoglobulin G (4%) very unequally. However, it allowed the elimination of microparticle instability, consequently providing the possible use of such polyacrylic microparticles in a one-step nephelometric immunoassay of analytes at low concentration in biological samples, without washes or phase separation.

Acrylates↗

PubMed2006

Structure and function of the long pentraxin PTX3 glycosidic moiety: fine-tuning of the interaction with C1q and complement activation.

The prototypic long pentraxin PTX3 is a unique fluid-phase pattern recognition receptor that plays a nonredundant role in innate immunity and female fertility. The PTX3 C-terminal domain is required for C1q recognition and complement activation and contains a single N-glycosylation site on Asn 220. In the present study, we characterized the structure of the human PTX3 glycosidic moiety and investigated its relevance in C1q interaction and activation of the complement classical pathway. By specific endo and exoglycosidases digestion and direct mass spectrometric analysis, we found that both recombinant and naturally occurring PTX3 were N-linked to fucosylated and sialylated complex-type sugars. Interestingly, glycans showed heterogeneity mainly in the relative amount of bi, tri, and tetrantennary structures depending on the cell type and inflammatory stimulus. Enzymatic removal of sialic acid or the entire glycosidic moiety equally enhanced PTX3 binding to C1q compared to that in the native protein, thus indicating that glycosylation substantially contributes to modulate PTX3/C1q interaction and that sialic acid is the main determinant of this contribution. BIAcore kinetic measurements returned decreasing K(off) values as sugars were removed, pointing to a stabilization of the PTX3/C1q complex. No major rearrangement of PTX3 quaternary structure was observed after desialylation or deglycosylation as established by size exclusion chromatography. Consistent with C1q binding, PTX3 desialylation enhanced the activation of the classical complement pathway, as assessed by C4 and C3 deposition. In conclusion, our results provided evidence of an involvement of the PTX3 sugar moiety in C1q recognition and complement activation.

Animals↗

PubMed1975

In vitro synthesis of some complement components (C1q, C3 and C4) by lymphoid tissues and circulating leucocytes in man.

Human lymphoid tissues and peripheral blood leucocytes and monocytes were studies with respect to the synthesis of complement components (C1q, C3 and C4) using an in vitro culture technique. All of the lymphoid tissues investigated (bone marrow, thymus, lymph node, spleen, tonsil, adenoid) synthesize complement components in different patterns. C3 was produced by all lymphoid tissues except the spleen, which was the only lymphoid tissue in which C4 production was regularly found. C1q synthesis was demonstrated in the spleen and adenoid cultures, and occasionally also in those of lymph node tissue. Lymphocytes in peripheral blood from normal individuals and in thoracic duct lymph, and also from patients suffering from chronic lymphatic leukaemia, do not synthesize any of these complement components. Peripheral blood leucocyte samples from normal individuals, containing 60 per cent lymphocytes and 40 per cent monocytes, do synthesize C3, however. Separation of the monocytes from these samples showed that it was in these cells that the synthesis of C3 occurred. Production of C3 by mononuclear phagocytes is also supported by the finding that peripheral blood leucocytes from patients suffering from acute monocytic leukaemia synthesize C3. C1q and C4 synthesis could not be demonstrated in any of the cultures of circulating leucocytes.

Adenoids↗

PubMed1989

Binding of complement components C1q, C3, C4 and C5 to a model immune complex in ELISA.

When normal human serum is added to microELISA plates coated with monomeric or aggregated IgG various complement components become bound and can be detected with specific chicken anti-C1q, anti-C3, anti-C4 and anti-C5 antibodies. Using such assays we found increased C1q- and decreased C3- and C4-binding in sera from patients with SLE. In contrast, sera from patients with rheumatoid arthritis showed decreased C3 binding but normal C1q binding. The decreases in C3 and C4 binding observed in the sera from patients with SLE were larger than the corresponding decreases determined by radial immunodiffusion. Comparing these results with those of the CH50 assay, the correlation coefficient between CH50 and the C3-binding assay was 0.48. There was no correlation between the results of the CH50 and those of the C1q-, C4- or C5-binding assays.

Antigen-Antibody Complex↗

PubMed2004

Non-proteolytic, receptor/ligand interactions associate cellular membrane type-1 matrix metalloproteinase with the complement component C1q.

Membrane type-1 matrix metalloproteinase (MT1-MMP), a prototypic member of the membrane-tethered MMP family, is an essential component of a cellular proteolysis apparatus. Recognition of protein cleavage targets followed by proteolysis is a main function of MT1-MMP. For the first time, however, we present evidence that MT1-MMP and other structurally related membrane MMPs bind C1q, the recognition unit of the first component of complement C1 that initiates activation of the classical pathway of complement. These interactions involve the catalytic domain of MT1-MMP and the C1q globular domain. In silico modeling followed by mutagenesis and the in vitro and cell-based binding studies showed that the His(171)-Glu-Lys-Gln-Ala-Asp(176) and Val(223)-Arg-Asn(224) peptide sequences of MT1-MMP are directly involved in the binding with C1q. These sequence regions are spatially distant from the active site of the protease. As a result, the catalytically active and the catalytically latent forms of cellular MT1-MMP are both efficient in binding with C1q. In agreement, despite the MT1-MMP/C1q interactions, C1q is totally resistant to MT1-MMP proteolysis. The discovery of the unconventional, receptor/ligand-like interactions of MT1-MMP with C1q, an essential component of immunity, is a significant step toward a more complete understanding of the role of this membrane-tethered protease in cancer.

Amino Acid Sequence↗