Assignment of C1QBP encoding the C1q globular domain binding protein (gC1q-R) to human chromosome 17 band p13.3 by in situ hybridization.
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Animals↗
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Identification of a gC1q-binding protein (gC1q-R) on the surface of human neutrophils. Subcellular localization and binding properties in comparison with the cC1q-R.
Human neutrophils have multiple C1q-binding proteins. Direct ligand-binding studies with the globular domain of C1q and two-dimensional Western blot analysis revealed two gC1q-binding proteins (gC1q-R): a 33,000 M(r) protein (pI 4.5) mainly in the neutrophil plasma membrane and an 80,000-90,000 M(r) protein (pI 4.1-4.2) located mainly in the granules. Direct binding studies showed that C1q bound to this higher molecular weight protein under physiological conditions. In contrast, anti-cC1q-R antibody, which recognizes a protein binding to collagenous tails of C1q, detected only a 68,000 M(r) protein in the plasma membrane. Both the 33,000 and 68,000 M(r) receptors appear early on the surface of differentiating HL-60 cells. On mature neutrophils, surface expression of both C1q receptors was evident, but no upregulation was observed upon stimulation. Phorbol myristate acetate treatment of neutrophils downregulated both the receptors from cell surface, and significant amounts of soluble gC1q-R were in cell media supernatants, suggesting receptor shedding or secretion. gC1q-R, unlike cC1q-R, did not bind to other C1q-like ligands, namely mannose binding protein, surfactant protein-A, surfactant protein-D, or conglutinin under normal ionic conditions, suggesting a greater specificity for C1q than the "collectin" type receptor (cC1q-R). Rather, gC1q-R only bound purified C1q, and the binding was enhanced under low ionic conditions and in the absence of calcium. The role of C1q receptor shedding and its biologic consequence remain to be defined, but may contribute to the diversity of C1q-mediated responses observed in many cell types.
Blotting, Western↗
The initial reactions of graphite and gold with blood.
The initial reactions of graphite and gold with blood were investigated by short-time exposure to capillary blood and detection of surface-adsorbed plasma proteins and cells with an immunofluorescence technique. Antibodies specific to fibrinogen, complement factors C1q and C3c, prothrombin/thrombin, von Willebrand factor, and platelet- and leukocyte-membrane antigens were used. The fluorescence intensity was quantitated by computer-aided image analysis. Fibrinogen was the most abundant plasma protein immobilized on either surface, and dense populations of platelets adhered to the protein layer. Complement factors and prothrombin/thrombin were found on the graphite surface, localized in fibrin clots or related to platelets. Platelets were activated (expression of selectin CD62) on both surfaces but more extensively so on the gold surface. Activation of polymorphonuclear granulocytes (PMNGs), measured as expression of integrin CD11b, was seen on both surfaces but with different kinetics. On the graphite surface, the CD11b expression was only transient whereas on gold it increased with time. Our data indicate that graphite is more thrombogenic than gold but less inflammatory.
Adsorption↗
Cytokeratin 1 and gC1qR mediate high molecular weight kininogen binding to endothelial cells.
High molecular weight kininogen (HK) attaches to endothelial cells by separate sites on the heavy and light chains and requires 15-50 microM zinc. Previously identified binding proteins include gC1qR, cytokeratin 1, and the urokinase plasminogen activator receptor; however, their relative contributions to binding are not yet clarified. We have prepared affinity columns to which were coupled either cleaved HK or peptide LDCNAEVYVVPWEKKIYPTVNCQPLGM derived from heavy-chain domain 3. Endothelial cell membranes were solubilized and chromatographed in the presence or absence of zinc ion, the bound proteins were eluted, and active fractions were identified by dot blot using biotinylated HK, SDS/PAGE, and Western blot analysis. The peptide containing column eluate revealed but one band at 68 kDa if zinc ion was present which was identified as cytokeratin 1 by amino acid sequencing of an internal peptide. The HK affinity column revealed bands at 68 kDa (cytokeratin 1), 33 kDa (gC1qR), and 66 kDa (unidentified). HK or domain 3-derived peptide bound to the 68 kDa band; prekallikrein and Factor XII did not. HK or Factor XII bound to the 33-kDa band if zinc was present while no binding to the 66 kDa band was observed. Antibody to cytokeratin 1 inhibited HK binding to endothelial cells by 30%, antibody to gC1qR inhibited HK binding to endothelial cells by 72%, and a mixture of both inhibited binding by 86%. Our data suggest HK binding by interaction of the heavy-chain domain 3 with cytokeratin 1 and the light chain with gC1qR.
Amino Acid Sequence↗
Altered (oxidized) C1q induces a rheumatoid arthritis-like destructive and chronic inflammation in joint structures in arthritis-susceptible rats.
Previous studies have identified an altered C1q molecule in synovial fluids from the joints of rheumatoid arthritis patients. We therefore immunized arthritis-susceptible Lewis 1A.AVN rats with either native C1q (C1q nat), altered (oxidized) C1q (C1q ox), or type II collagen (CII, induces arthritis in these animals), in order to induce arthritis. Unlike C1q nat, both CII and C1q ox were able to induce swelling and erythema of joints consistent with an arthritis-like inflammatory reaction. Histopathological evaluation of individual joint sections revealed synovitis, bursitis and tendovaginitis, massive joint destruction, and severe pannus formation. In a time-course study, no differences in onset of arthritis or pathology were observed between C1q ox-induced arthritis and that induced by CII. High titers of antibodies recognizing CII, but not C1q (native or oxidized), were detected in rats immunized with CII. In contrast C1q ox, but not C1q nat, induced antibodies reactive with both C1q and CII. Antibodies from C1q ox-immunized animals contained an antibody subset that reacted with C1q but not CII and a subset that reacted with CII but not C1q, implying that induction of an immune response to CII does not require CII. These data support the hypothesis that C1q may provide one of the early antigens involved in induction of arthritis, before CII becomes available as antigen.
Animals↗
An immunohistochemical study on cerebral vascular and senile plaque amyloid in Alzheimer's dementia.
Senile cerebral amyloidosis has been investigated using immunoperoxidase and enzyme histochemical techniques in six unfixed brains. Our findings do not support the opinion that vascular and senile plaque amyloid are immunoglobulin-derived. In contrast with recent reports we did not detect prealbumin in senile plaques and congophilic angiopathy lesions. All senile plaques contain complement factors C1q, C3 and C4. The highest peroxidase activity was found in the amyloid nucleus but the corona also showed evident peroxidase activity.
Aged↗
Free platelet count and size distribution during C1q inhibition of collagen-induced platelet aggregation.
Electronic free platelet counting was more sensitive than turbidimetry to detect collagen-induced platelet activation in human platelet-rich plasma. Purified human C1q exhibited a greater inhibitory effect on collagen-induced platelet aggregation in turbidimetry than free platelet counting. Because the change from small to large platelet aggregates is responsible for the continuing increase in light transmission, C1q was likely more capable of blocking the formation of large platelet aggregates than the formation of small aggregates from single platelets. The rate of change by collagen in light transmission and free platelet count was reduced in the presence of C1q but the timing of the peak response remained the same. Electronic platelet sizing revealed that the volume of single platelets transiently increased during the turbidimetric "lag phase". The mean, mode and median volume of the remaining free platelets then decreased, suggesting a selective loss of large, functionally more active platelets and/or platelet degranulation. C1q had no effect on the volume increment during the "lag phase", but reduced the subsequent fall in the volume of free platelets.
Adult↗
Cell-surface protein identified on phagocytic cells modulates the C1q-mediated enhancement of phagocytosis.
C1q, a subunit of the first component of the classical C pathway, binds to specific cells of the immune system, triggering a variety of cellular responses. To identify the functional C1qR on phagocytic cells, mAbs were generated by immunization with either C1q-binding proteins isolated from U937 cells or intact U937 cells. Immunoprecipitation followed by Western blot analysis demonstrated that three mAbs, designated R139 (IgG2b), R3 (IgM), and U40.3 (IgG1), recognize the same 100,000 M(r) protein (126,000 M(r) under reducing conditions). These mAbs also co-immunoprecipitate CD43 from detergent extracts of U937, consistent with the possibility that this C1qR is a multi-subunit structure. Two Abs, R3 and R139, but not U40.3, consistently inhibited the enhancement of phagocytosis by monocytes adhered to either C1q or the collagen-like fragment of C1q (C1q-CLF). Interestingly, binding inhibition studies demonstrated that neither R139 nor U40.3 blocked the binding of [125I]C1q-CLF to U937 cells, whereas R3 did inhibit 35 to 45% of the binding of [125I]C1q-CLF to these cells. Thus, the three mAbs recognize distinct epitopes of a 100,000 M(r) polypeptide that is a component of the monocyte C1qR that modulates phagocytosis. All three mAbs recognize the extracellular domain of the molecule on neutrophils, monocytes, and U937 cells, but were not reactive with CEM or RAJI cells, T and B lymphoblastoid cell lines, respectively. Furthermore, none of these three mAbs inhibited or mimicked the C1q-mediated stimulation of superoxide production by neutrophils, suggesting that the C1qR that mediates the enhancement of phagocytosis differs in at least some critical parameter from the C1qR that mediates superoxide generation by the neutrophil.
Antibodies, Monoclonal↗
Visualization of specific antibody and C1q binding to hapten-sensitized lipid vesicles.
Specific IgG antibodies directed against the spin-label nitroxide group present as a lipid hapten in single-compartment lipid vesicles have been visualized by using freeze-etch electron microscopy. Individual "particles" with diameters of the order of 20 nm are identified as single IgG molecules bound to lipid hapten. No significant aggregation of these IgG molecules was observed over a period of 1 hr in a dipalmitoyl phosphatidylcholine vesicle at 22 degrees. Binding of the human complement component C1q results in the formation of large (approximately 50-100 nm) asymmetric particles having a partially resolved substructure that may arise from individual IgG molecules bound to the membranes as well as to C1q. The binding of C1q appears to result in a clustering of membrane-bound IgG molecules. Samples containing a serum factor (perhaps anti-IgG antibodies) exhibit some IgG clustering distinct from that produced by Clq.
Complement C1↗
Multiple sclerosis. Cerebrospinal fluid immune complexes that bind C1q.
We used a sensitive C1q-binding assay to measure levels of soluble immune complexes in 182 samples of cerebrospinal fluid (CSF) from control patients and patients with multiple sclerosis (MS). Soluble immune complexes in CSF were detected in 16% of patients with progressive MS, 38% of patients with exacerbating-remitting MS, 55% of patients with infectious or inflammatory diseases, 3% of patients with noninflammatory neurologic disorders, and in 0% of control patients with back pain. No correlations were found between the results of the C1q-binding assay and abnormalities of other CSF parameters. These included an elevated level of myelin basic protein, pleocytosis, oligoclonal bands, or an increased IgG level. Because of the lack of correlation to laboratory indexes of disease activity and the nonspecificity of a positive test, the C1q-binding assay seems to have little clinical usefulness in the diagnosis or management of patients with MS.
Antigen-Antibody Complex↗
Role of liver endothelial and Kupffer cells in clearance of human C1q in rats.
In the present study the contribution of rat liver endothelial cells (EC) and Kupffer cells (KC) in the clearance of human (hu) C1q in rats was investigated. In untreated rats and rats depleted from KC the clearance kinetics and the tissue distribution of hu C1q were measured. In untreated rats, the clearance of hu C1q occurred in a monophasic manner with a half-life of 66 +/- 26.7 min. The clearance of hu C1q in KC-depleted rats was delayed significantly (p < 0.001) and occurred with a half-life of 217 +/- 78.8 min. Fifteen min after injection, 11 +/- 3.5% of hu C1q was found in the liver of untreated rats and 8 +/- 1.4% was found in the liver of KC-depleted rats. The percentage non-trichloroacetic acid precipitable activity in the circulation, as a measure for degradation of C1q, reached a level of 11.6 +/- 5.6% at 240 min in untreated rats compared with 4.6 +/- 5.8% in KC-depleted rats. Double immunofluorescence staining 5 min after administration of C1q in untreated rats, revealed that C1q was associated with KC and EC in the liver. Fifteen minutes after i.v. injection of hu C1q, there was an uptake of C1q in the hepatocytes. In KC-depleted rats, 5 min after administration of hu C1q, C1q was bound to the EC. Fifteen minutes after injection, C1q was also found in the hepatocytes. Electron microscopical studies revealed that C1q binds to EC, and that it is internalized in the hepatocytes and KC. The clearance of hu C1q in untreated rats was inhibited by preadministration of high concentrations of bovine C1q. These data show that rats depleted from KC are able to bind, internalize and degrade C1q, and that EC may play a role in the handling of C1q and C1q bound to immune complexes.
Animals↗
C1 dissociation in serum: estimation of free C1q by electroimmunoassay.
A two-stage electroimmunoassay was developed for measuring macromolecular C1 (C1qrs) and free C1q. The method was based on Ca2+ dependent fixation of C1qrs to agarose, followed by immune precipitation of dissociated C1s in the presence of EDTA. Free C1q was estimated from the increase in C1qrs resulting from saturation of C1q in the samples with purified C1r-C1s. The assay system was studied under various experimental conditions. Combined analysis by electroimmunoassay and crossed immunoelectrophoresis indicated that part of the free C1q in undiluted normal serum could be attributed to physiological C1 activation. Owing to concentration dependent C1qrs dissociation the proportion of free C1q increased with the dilution of serum. Results obtained with serum and with purified C1qrs were consistent with the formation of an equimolar C1q:C1r-C1s complex. However, the capacity for C1r-C1s binding appeared to be higher in the purified system than in serum. Serum concentrations of free C1q were high in some of the patients with disease conditions characterized by increased C1 activation, such as systemic lupus erythematosus or primary biliary cirrhosis.
Complement Activating Enzymes↗
Experimental transmission of Neisseria gonorrhoeae from pregnant rat to fetus.
Sprague-Dawley rats were infected on day 20 of pregnancy by intraperitoneal inoculation with Neisseria gonorrhoeae. Disseminated gonococcal infection (DGI) and pelvic inflammatory disease (PID) strains in the presence of C1q but not in the presence of bovine serum albumin (BSA) were able to spread from the pregnant rat to the fetus and resulted in fetal mortality. Transmission of DGI and PID strains that are serum resistant (ser(r)) and sac-4 positive but not of a local infection strain that is ser(s) and sac-4 negative was facilitated by the C1q-dependent mechanism. This study provides the first experimental model that may mimic the transmission of gonococcal infection from mother to the fetus during pregnancy.
Animals↗
Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie.
Following peripheral exposure to transmissible spongiform encephalopathies (TSEs), infectivity usually accumulates in lymphoid tissues before neuroinvasion. The host prion protein (PrPc) is critical for TSE agent replication and accumulates as an abnormal, detergent insoluble, relatively proteinase-resistant isoform (PrPSc) in diseased tissues. Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie. In mouse scrapie models, the absence of FDCs blocks scrapie replication and PrPSc accumulation in the spleen, and neuroinvasion is significantly impaired. The mechanisms by which the TSE agent initially localizes to lymphoid follicles and interacts with FDCs are unknown. Antigens are trapped and retained on the surface of FDCs through interactions between complement and cellular complement receptors. Here we show that in mice, both temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays the onset of disease following peripheral infection, and reduces the early accumulation of PrPSc in the spleen. Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets.
Animals↗
Association between ongoing anti-C1q antibody production in peripheral blood and proliferative nephritis in patients with active systemic lupus erythematosus.
The aim of this study was to compare ongoing production of anti-C1q antibodies (anti-C1q) in peripheral blood with serum anti-C1q levels in patients with systemic lupus erythematosus (SLE), especially in patients with nephritis. Using the ELISPOT technique for the detection of IgG and IgA anti-C1q production, 21 patients with active SLE were investigated. ELISAs for IgG and IgA anti-C1q were compared with the ELISPOT results. Six of the patients were found to have proliferative nephritis (WHO grade III/IV) confirmed by renal biopsy. High numbers of IgG anti-C1q spot-forming cells (SFC), defined as > 20/10(5) plated peripheral blood mononuclear cells (PBMC), were exclusively observed in patients with proliferative nephritis (P < 0.0001). Serum levels of IgG anti-C1q were significantly increased in patients with proliferative nephritis (P = 0.039). High ongoing IgG anti-C1q production was observed in all patients with proliferative nephritis, which may be a contributory factor in the pathogenesis of this disorder. The detection of IgG anti-C1q production may be valuable in the clinical investigation of patients with suspected SLE nephritis.
Adolescent↗
Contributions of C1q, bacterial lipopolysaccharide, and porins during attachment and ingestion phases of phagocytosis by murine macrophages.
In contrast to the S-form of Salmonella minnesota, its Re mutant binds to mouse peritoneal macrophages. The binding reaction triggers an oxidative burst, measured by a chemiluminescent reaction. The oxidative burst was abolished in the presence of either purified lipopolysaccharide or porins (outer membrane proteins) extracted from the Re mutant, suggesting that both components are involved in binding of the Re mutant to macrophages. In addition, Fc-recognizing membrane structures on the macrophage surface bind the Re mutant. Preincubation of macrophages with the Re mutant abolishes immunoglobulin G-sensitized erythrocyte-induced chemiluminescence. Macrophages preincubated with immunoglobulin G-sensitized erythrocytes had a low chemiluminescent signal, and after treatment of the cells with the Re mutant, there was an additional, higher signal. Binding of purified C1q to the Re mutant decreased the adherence of the Re mutant to macrophages, resulting in a diminished chemiluminescent signal. Blocking of endogenous macrophage membrane-associated C1q with a monoclonal antibody [F(ab')2 fragment] directed against mouse macrophages (recognizes the A and B chains of C1q) diminished the oxidative burst. Therefore, the endogenous C1q of macrophages also appears to be involved in attachment of the S. minnesota Re mutant.
Adhesiveness↗
Fibronectin binds to C1q: possible mechanisms for their co-precipitation in cryoglobulins from patients with systemic lupus erythematosus.
Fibronectin and C1q frequently co-precipitated in cryoglobulins from patients with SLE. As a portion of the C1q molecule is similar to collagen to which fibronectin has a high affinity, we studied whether fibronectin specifically bound to C1q. Fibronectin was found to bind to both native and heat-inactivated C1q. The binding was enhanced by Ca++ and low ionic strength. We have also demonstrated that fibronectin is capable of binding to C1q fixed to immune complexes. The interaction between fibronectin and C1q may play a role in cryoglobulin formation and in clearance of immune complexes by reticuloendothelial system.
Antigen-Antibody Complex↗
The first component of complement. A quantitative comparison of its biosynthesis in culture by human epithelial and mesenchymal cells.
Epithelial and mesenchymal cells synthesized and secreted all three subcomponents of the first component of complement (C1): C1q, C1r, and C1s. Quantitatively, however, columnar and transitional epithelial cells secreted 400--3,700 times more hemolytically active C1 than monocytes or fibroblasts. Only columnar epithelial cells synthesized C1 subcomponents with subunit structures similar to their serum counterparts. Transitional epithelial cells, fibroblasts, and monocytes produced C1q and C1s with subunits of apparent molecular weights larger than reported values. C1r from all cell lines was physiochemically similar to serum C1r.
Cells, Cultured↗