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PubMed1991

Kinetics of the biosynthesis of complement subcomponent C1q by murine macrophages: effects of stimulation by interferon-gamma.

The effects of interferon-gamma (IFN-gamma) on the kinetics of biosynthesis of complement subcomponent C1q by mouse inflammatory peritoneal macrophages were determined. Stimulation of macrophages with various concentrations of IFN-gamma produced a dose-dependent increase in C1q mRNA accumulation which was detected as early as 3 h and sustained through 24 h, as determined by Northern blot analysis. A corresponding early increase in the extracellular accumulation of functional C1q was detected in culture supernatants after 3-9 h stimulation of macrophages with IFN-gamma that was sustained for 24-48 h as determined by a complement hemolytic assay. Autoradiographic analysis of [35S]methionine-labeled secretory C1q confirmed the protracted dose-dependent secretion of C1q by IFN-gamma stimulated macrophages during 24-48 h of culture. Western blot analysis of macrophage lysates indicated no significant changes in endogenous C1q levels following stimulation with IFN-gamma either after 3-9 h or 24-48 h when both C1q mRNA and extracellular accumulation were at their peak. Our results indicate that IFN-gamma promotes early and protracted mRNA accumulation and secretion of C1q by macrophages without intracellular accumulation, presumably due to the rapid rate of secretion of newly synthesized C1q. It is apparent that priming of macrophages with IFN-gamma provides a rapid and abundant source of secretory C1q for potential interaction with various macrophage triggering agents which also bind C1q.

Animals↗

PubMed1997

Secreted chondroitin sulfate proteoglycan of human B cell lines binds to the complement protein C1q and inhibits complex formation of C1.

We recently characterized a species of proteochondroitin sulfate (CSPG) secreted by human B cell lines that closely resembles in its structure the serum-derived C1q inhibitor (C1qI). These proteoglycans have in common a molecular mass of approximately 130 to 150 kDa with a core protein of 30 kDa to which up to four chondroitin sulfate chains each of approximately 26 kDa are attached. Since this B cell-derived CSPG is a potential source for serum C1qI, we measured its capacity to interact with C1q in solid-phase binding and complex electrophoresis assays. B cell CSPG purified from culture supernatants of the two human B cell lines JOK-1 and U266 strongly bound to C1q. In contrast to the secreted form, cellular proteoglycan of the myeloma cell line U266 did not interact with C1q. Binding of C1q to CSPG was competitively inhibited by free glycosaminoglycans (GAG) in the order dextran sulfate > heparin > heparan sulfate > chondroitin-6-sulfate (CS-C) > dermatan sulfate (CS-B) > chondroitin-4-sulfate (CS-A). B cell CSPG inhibited the hemolytic activity of C1q and C1. In addition, B cell CSPG blocked C1q receptor binding in a dose-dependent manner. The proteoglycans did not influence the activity of C1 complex already bound to EAC4 target cells. By interaction of CSPG with solid-phase-bound C1q, formation of the C1 complex upon the addition of C1r and C1s was impaired. Strong binding of B cell CSPG to C1q, its inhibition of C1q activity, and its structural similarities to the previously described human serum C1qI indicate that B cells produce a soluble CSPG, which may act as C1qI under physiologic conditions.

B-Lymphocytes↗

PubMed1991

Binding of the human complement subcomponent C1q to hybrid mouse monoclonal antibodies.

Activation of the classical pathway of the complement system is initiated by the binding of C1q to antibody complexes. Here we evaluated the C1q binding capacity of series of monospecific and bispecific hybrid mouse monoclonal antibodies (mAb) and compared them with parental (conventional) mAb. The hierarchy in C1q binding capacity of the bispecific anti-HuIgA1/HRP mAb with homologous H-H chain combinations (IgG2a-2a, IgG2b-2b and IgG1-1) and the parental anti-HuIgA1 or anti-HRP mAb was identical; IgG2a greater than IgG2b much greater than IgG1. Hybrid IgG1-2a mAb bind intermediate amounts of C1q when compared with the IgG1 and IgG2a parental antibodies. IgG1-2b and IgG1-1 hybrid mAb did not bind any C1q, like the IgG1 mAb. We could not observe any difference in C1q binding efficiency between monovalently bound IgG1-2a, IgG2a-2a and IgG2b-2b anti-HuIgA1 HRP mAb and the bivalently bound IgG1-2a, IgG2a-2a and IgG2b-2b anti-HuIgA1 mAb, respectively. Furthermore, these hybrid ms anti-HuIgA1 and bs anti-HRP/HuIgA1 mAb were able to lyse HuIgA1-coated erythrocytes, in the presence of 50% human serum, as efficiently as their parental counterparts. These data indicate that a simultaneous binding of both F(ab') fragment to antigen is not a necessary prerequisite for binding and activation of C1q.

Antibodies, Monoclonal↗

PubMed1983

Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes.

The capacity of cultured human monocytes to synthesize and to secrete the subcomponents of C1 and C1 inhibitor was examined. Non-stimulated monocytes secreted C1q and C1s from day 5 of culture. C1s reached a plateau immediately at its maximum level, whereas C1q secretion increased progressively until the end of the second week. Between day 12 and day 25, C1q secretion remained nearly constant (1-15 fmol/day per microgram of DNA, depending on the donor), whereas C1s secretion decreased and even in some cases stopped. C1r and C1 inhibitor were not secreted in detectable amounts by these resting cells. Stimulation of monocytes by yeasts, immunoglobulin G-opsonized sheep red blood cells or latex beads did not modify consistently C1q and C1s secretion. Activation by conditioned media from mitogen-, antigen- or allogeneic-stimulated lymphocyte cultures increased C1q production from 2 to 7 times and re-activated C1s secretion. Under the same conditions of activation, C1 inhibitor was secreted (up to 300 fmol/day per microgram of DNA) and C1r became detectable in culture supernatants. Isolated human monocytes are thus able to synthesize the whole C1 subcomponents; C1, if assembled, could be protected from non-immunological activation by locally produced C1 inhibitor. Activated monocytes appear to be a good tool for studying the assembly of C1 subcomponents and the role of C1 inhibitor in this process.

Cells, Cultured↗

PubMed1987

Modulation of FcR function by complement: subcomponent C1q enhances the phagocytosis of IgG-opsonized targets by human monocytes and culture-derived macrophages.

We have investigated the interaction of C1q, a subunit of the first component of complement, with human monocytes and culture-derived macrophages. Adherence of these mononuclear phagocytes to surfaces coated with C1q induced a marked enhancement of the phagocytosis of sheep erythrocytes opsonized with IgG anti-Forssman antibody (EA-IgG). This C1q-mediated enhancement of phagocytosis was dose dependent, and was specifically blocked by pretreatment of the C1q-coated surfaces with F(ab')2 anti-C1q. The augmentation of FcR-mediated phagocytosis by C1q was determined to be a result of the interaction between the C1q and the phagocytic effector cell, and was not due to interaction between the surface-bound C1q and the EA-IgG. Neither resting nor N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes were induced by C1q to increase FcR-mediated phagocytosis. Experiments conducted with purified fragments of C1q suggest that the C1q phagocytosis enhancement signal resides in the collagen-like tail domain of the molecule. This region is the same portion of the molecule previously shown to interact with the cell surface C1q receptor. Native type I collagen was unable to enhance FcR-mediated phagocytosis by mononuclear phagocytes. It has been demonstrated that C1q can be localized to areas of inflammation, and additionally C1q can be secreted by macrophages in culture. In view of these findings and the results of our present study, we hypothesize that C1q could provide local, direct, and non-opsonic enhancement of phagocytosis by mononuclear phagocytes in areas of infection and inflammation.

Cell Adhesion↗

PubMed2026

Proteomic profiling of cephalic vein reveals potential biomarkers for arteriovenous fistula neointimal hyperplasia in ESRD patients.

Arteriovenous fistula (AVF) is the preferred vascular access for patients with end-stage renal disease; however, its failure is primarily due to neointimal hyperplasia. Five patients who underwent initial AVF surgery served as the control group, and another five patients with failed AVF surgery served as the experimental group. Herein, we employed mass spectrometry (MS)-based quantitative proteomics coupled with tandem mass tag labeling to screen differentially expressed proteins (DEPs) in the anastomotic cephalic vein, followed by bioinformatics analyses and verification experiments. A total of 121 DEPs were identified in the failed AVF group. GO analysis was primarily enriched in protein binding, nucleic acid binding, enzyme binding, mRNA binding, cadherin binding, catalytic activity, and cell adhesion molecule binding. KEGG pathways were mainly enriched in cell aggregation and adhesion, actin cytoskeleton, extracellular matrix-receptor interaction, PI3K-Akt signaling pathway, complement and coagulation cascades, and cholesterol metabolism. Protein-protein interaction network consisted of 86 (71.07%) DEPs, including complement VII (C7), factor IX (F9), SERPINC1, microfibril-associated glycoprotein 4 (MFAP4), complement C1s subcomponent, complement C1q subcomponent subunit A, complement C1q subcomponent subunit B, tissue factor, and von Willebrand factor, which interacting with numerous other proteins. In the expanded validation for different patients, C7, F9, SERPINC1, and MFAP4, were verified by immunohistochemical staining and Western blotting, which were consistent with the proteomics results. Collectively, this study identifies a series of potential diagnostic biomarkers, and explores the underlying mechanisms associated with AVF dysfunction.

Humans↗

PubMed2005

Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype.

Mannose-binding lectin (MBL) is a circulating serum protein that is sequestered to sites of inflammation and infection. MBL is a member of the collectin family with structural similarities to the lung collectins and functional similarities to C1q. Both MBL and C1q activate complement; C1q activates the classical pathway and MBL the lectin pathway. Here we demonstrate that MBL binds apoptotic cells in vitro and confirm a role for MBL in clearance of apoptotic cells in vivo. Despite MBL null mice demonstrating defective apoptotic cell clearance they did not develop spontaneous autoimmunity, lymphoproliferation, or germinal center expansion although increased numbers of peritoneal B1 cells were detected. These data demonstrate an important in vivo role for MBL in clearance of dying cells and adds the MBL null animals to the few animals with demonstrable in vivo apoptotic cell clearance defects. Moreover, it demonstrates that failure of apoptotic cell clearance can be dissociated from autoimmunity.

Animals↗

PubMedDate not supplied

Contribution to the mode of action of univalent gold.

Au+ binds to the collagen structure and, therefore, the authors studied the kinetics of the interaction between sodium gold thiosulphate (SGTS) and C1q complement subcomponent, the structure of is partially collagenous. The kinetics was evaluated densitometrically and compared with that of collagen and SGTS. On the basis of those results, the effect of SGTS upon collagen type-II-induced arthritis (CIA) was investigated in Wistar rats. SGTS (20 mg per kg of body weight weekly) was administered i.m. starting i) with the first immunization dose, ii) with the second immunization dose, and iii) after the onset of arthritis. Regardless of the timing of drug administration the manifestation of arthritis was decreased, but the decrease was more expressed in the first two groups. It was concluded that SGTS administration is capable of inhibiting CIA, provided that the drug is applied sufficiently early. Since formation of antibodies to type-II collagen remained unaffected, it is feasible that the mode of action of gold complexes is based mainly on blocking the activation of complement system.

Animals↗

PubMed1987

In vivo immunosuppression by pan-T cell antibodies relates to their isotype and to their C1q uptake.

There is considerable interest in the use of monoclonal anti-T cell antibodies for immunosuppression during organ transplantation. However, the in vitro cytotoxic titers of these monoclonal reagents do not correlate with their immunosuppressive potency when injected in vivo. A relationship nevertheless seems to exist between immunosuppression and the isotype of anti-mouse Thy-1 antibodies, because among several anti-Thy-1 antibodies of mouse and rat origin, the only two found to cause immunosuppression in vivo belonged to the rat IgG2b and mouse IgG2a isotype. We show here that a quantitative positive correlation exists between an antibody-induced humoral effector mechanism and immunosuppression. We measured the uptake of the C1q complement subunit by polyclonal rabbit and rat anti-thymocyte globulin and also seven monoclonal anti-Thy-1 antibodies in an immunohistochemical assay or a radioimmunoassay. Immunosuppression was studied in a murine graft-vs-host and skin allograft model. Our results suggest strongly that a stable association between the C1 protein and a potential binding antibody is an essential prerequisite of antibody-dependent cell inhibition in vivo that suppresses the immunoresponse against strongly incompatible transplantation antigens.

Animals↗

PubMed1994

[Conformational analysis and hemolytic activity of immunoglobulin G fragment 285-292 and its analogs].

Theoretical conformational analysis was carried out for the 285-292 fragment of human immunoglobulin G (His-Asn-Ala-Lys-Thr-Lys-Pro-Arg) and its analogues containing Arg, Glu, Gly, Lys, or Trp residue instead of the His residue in position 1. Spectropolarimetic investigation of these peptides showed the analogues to have different activities in the C1q-mediated erythrocytes hemolysis assay. Comparison of the low-energy structures sets of the compounds tested allowed to suggest a model of the "biological active" conformation for the peptide molecule in the course of the C1q complement component binding.

Complement C1q↗

PubMed1990

[Autoantibodies against the complement component C1q in systemic lupus erythematosus].

Autoantibodies against C1q, a subcomponent of the first complement component C1, could be detected in 49.4% of sera from patients with systemic lupus erythematosus (SLE). They are directed against the collagen-like portion of the C1q molecule and recognize only bound, but not fluid-phase C1q. The appearance of these autoantibodies in the course of SLE correlates with the detection of IgG in the C1q-Solid-Phase-Binding-assay, with high titres of dsDNA-antibodies and with depressed total complement activity (CH50) and C1q-values. Our investigations show that autoantibodies against the collagen-like portion of bound C1q but not immune complexes are the main constituent of C1q-binding IgG in SLE.

Autoantibodies↗

PubMed1988

Complement subcomponent C1q in various strains of mice. Its serum content correlates with that of immunoglobulin G.

The protein amount and the hemolytic activity of the initiating complement component (C1q) in the classical pathway, and the level of immunoglobulin G (IgG) in sera of various inbred mouse strains were measured in parallel with those in sera of closed colony mice. C1q levels were significantly high in male A/He and C57BL/10Sn mice, and conspicuously high in female C57BL/10Sn mice. In these strains and C57BL/6J mice of both sexes, IgG levels were also significantly high. IgG levels were strikingly high in female NZB mice and NZW mice of both sexes. On the other hand, both C1q and IgG levels were conspicuously low in BALB/c mice of both sexes and in male CBA mice, and surprisingly low in BALB/c-nu (nude) mice of both sexes. A significant correlation was observed between serum levels of C1q and IgG. The C1q specific activity, however, was equivalent in all serum samples with approximately 2 x 10(13) effective molecules/mg. The subunit composition of C1q analyzed by polyacrylamide gel electrophoresis was well comparable within all strains of mice tested. These results may suggest that mouse serum C1q does not have any phenotypic polymorphism.

Animals↗

PubMed1996

Transfection of L929 cells with complement subcomponent C1q B-chain antisense cDNA inhibits tumor necrosis factor-alpha binding to mediate cytotoxicity and nitric oxide generation.

The role of complement subcomponent C1q in the modulation of TNF-alpha binding to L929 cells to mediate cytotoxicity and nitric oxide (NO) generation was investigated. Transfection of L929 with murine C1q B-chain antisense plasmid cDNA rendered them markedly less susceptible to TNF-mediated cytotoxicity coincident with a decreased capacity for TNF-alpha binding and expression of cell surface C1q protein. The inhibitory effects of L929 transfection with C1q B-chain antisense were transiently expressed at 24 hr post-transfection with full recovery of cellular functions by 72 hr. Transfected L929 cells were fully reconstituted in their TNF-alpha binding and in their cytotoxic response following exposure to soluble C1q which was bound to their cell surface. Transfection with C1q B-chain antisense also significantly inhibited NO generation by L929 cells in response to stimulation by TNF-alpha, IFN-alpha/beta, and LPS. Taken together, these results indicate that endogenously synthesized C1q is prerequisite for binding of TNF-alpha to L929 cells to mediate cytotoxicity and NO generation.

Animals↗

PubMedDate not supplied

Complement and C1q binding substances in otitis media.

Complement activation, as shown by increased amounts of complexes composed of C1r-C1s-C1 IA, and abnormal complexes of C1r-C1s were demonstrated in serum from patients with acute pneumococcal and chronic otitis media, serous or mucoid respectively. C1q binding substances were shown in middle ear effusions and in sera from patients with chronic serous otitis media. Presence of immune complexes and/or bacterial products capable of binding c1q results in formation of C1r-C1s-C1 IA complexes and may also cause the generation of C1r-C1s complexes. Such a dissociation of the C1 component will compromise the important opsonic function of the classical pathway.

Acute Disease↗

PubMed1998

Binding of complement subcomponent C1q to Streptococcus pyogenes: evidence for interactions with the M5 and FcRA76 proteins.

Binding of C1q, the first component of the complement system, to some human pathogens has been earlier reported. In the present study, direct binding of C1q to group A streptococci (GAS) of various serotypes as well as some other Gram-positive and Gram-negative species was demonstrated. The interaction between C1q and GAS was investigated more in detail. In hot neutral extracts of a number of GAS strains two components of 64 and 52 kDa, respectively, bound C1q; alkaline and SDS extracts yielded the 52 kDa component as the main C1q-binding substance. Trypsin treatment of the SDS extracts of two GAS strains suggested the C1q-binding component(s) to be of protein nature. C1q-binding material purified from the SDS extract of an avirulent strain, type T27, was separated in 12% SDS-PAGE and probed in Western blot with human C1q and fibrinogen, conjugated to horse radish peroxidase (HRP) as well as rabbit IgG antibodies complexed to HRP (PAP system). The 52 kDa component was non-reactive with fibrinogen or rabbit IgG. However, C1q-binding components purified from the alkaline extracts of two M-positive strains revealed strong binding of either fibrinogen (type M5) or both fibrinogen and rabbit IgG (type M76); the molecular mass of these components. 55 kDa and 43-40 kDa, respectively, was in agreement with the reported molecular mass of the M5 and FcRA76 proteins. Our findings suggest that C1q may interact with GAS through certain M-family proteins as well as by a so far unidentified surface factor of protein nature occurring in most GAS strains. The involvement of M-family proteins, regarded as virulence factors of these organisms, may suggest the interaction of GAS with C1q as biologically important.

Antigens, Bacterial↗

PubMed2006

Interactions between mouse IgG2 antibodies are common and mediated by plasma C1q.

BACKGROUND: The simultaneous use of multiple antibodies for multicolor flow cytometry is increasingly common and presents the opportunity for antibody interactions. METHODS: Antibodies of differing isotypes were evaluated in pair-wise combinations for the presence of antibody interactions, using a standard whole blood lysing method or variations thereof. RESULTS: Artifactual interactions were identified and preferentially involved IgG2a (58%) or IgG2b (33%) antibodies and a single IgG1 antibody (3%). The interactions were present in all 10 random peripheral blood samples evaluated and required only whole blood and the two antibodies. Plasma removal prior to antibody incubation eliminated the interaction, as did switching any single IgG2 antibody to an IgG1 clone. Heat-inactivated plasma eliminated the interactions, and the addition of purified C1q to washed cells was capable of recreating the interaction in its entirety, confirming the mediation by complement C1q. CONCLUSIONS: Complement C1q mediates significant interactions between mouse IgG2 class antibodies; these interactions are very common and may be prevented by either complete serum removal or use of alternate IgG1 clones. Such interactions represent a significant potential source of artifact in the use of whole blood lysis methods for specimen preparation for multicolor flow cytometry.

Animals↗

PubMed2004

Microglial activation and increased synthesis of complement component C1q precedes blood-brain barrier dysfunction in rats.

A reliable way to visualise the state of microglial activation is to monitor the microglial gene expression profile. Microglia are the only CNS resident cells that synthesise C1q, the recognition sub-component of the classical complement pathway, in vivo. C1q biosynthesis in resting ramified microglia is often low, but it increases dramatically in activated microglia. In this study, the expression of C1q was used to monitor microglial activation at all stages of 3-chloropropanediol-induced neurotoxicity, a new model of blood-brain barrier (BBB) breakdown. In rats, 3-chloropropanediol produces very focused lesions in the brain, characterised by early astrocyte swelling and loss, followed by neuronal death and barrier dysfunction. Using in situ hybridisation, immunohistochemistry, and real-time RT-PCR, we found that increased C1q biosynthesis and microglial activation precede BBB dysfunction by at least 18 and peak 48 h after injection of 3-chloropropanediol, which coincides with the onset of active haemorrhage. Microglial activation is biphasic; an early phase of global activation is followed by a later phase in which microglial activation becomes increasingly focused in the lesions. During the early phase, expression of the pro-inflammatory mediators interleukin-1beta (IL1beta), tumour necrosis factor alpha (TNFalpha) and early growth response-1 (Egr-1) increased in parallel with C1q, but was restricted to the lesions. Expression of C1q (but not IL1beta, TNFalpha or Egr-1) remains high after BBB function is restored, and is accompanied by late up-regulation of the C1q-associated serine proteases, C1r and C1s, suggesting that microglial biosynthesis of the activation complex of the classical pathway may support the removal of cell debris by activation of complement.

Animals↗

PubMed1999

Up-regulation of endothelial cell binding proteins/receptors for complement component C1q by inflammatory cytokines.

Endothelial cells express a variety of receptor systems involved in humoral defense, including receptors for the collagen-like and globular domains of the complement component C1q, designated cC1qR and gC1qR, respectively. In the present study a microvascular endothelial cell line was used to test the hypothesis that expression of these C1q-binding proteins may be affected by vascular inflammatory reactions. The results demonstrate that the expression of both cC1qR and gC1qR by bone marrow vascular endothelial cells is up-regulated by inflammatory mediators, interferon-gamma, tumor necrosis factor-alpha, and lipopolysaccharide (Escherichia coli, 055:B5) in a dose- and time-dependent manner, as detected by enzyme-linked immunosorbent assay. cC1qR and gC1qR expression increased significantly (P < .05) within 4 to 7 hours and doubled after 22 hours of stimulation. 3H-thymidine incorporation studies and direct cell counts confirmed that increased C1qR expression was not due to increased cell proliferation. Northern blot analysis revealed that the up-regulation of cC1qR and gC1qR protein expression was preceded by increases in corresponding mRNA levels, suggesting increased gene transcription. Indeed C1qR mRNA up-regulation was prevented by actinomycin D, and C1qR protein synthesis was inhibited by cycloheximide. Bone marrow vascular endothelial cell exposure to C1q, however, did not alter cC1qR or gC1qR expression, but up-regulation of the leukocyte adhesion molecule ICAM-1 was noted in the presence of aggregated C1q. The up-regulation of C1qR by inflammatory mediators and the ability of C1q itself to increase ICAM-1 expression suggest a potential role for these binding sites in vascular inflammation and immune injury.

Blotting, Northern↗