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PubMed1992

Circulating immune complex levels measured by new ELISA kits utilizing monoclonal anti-C1q and anti-C3d antibodies correlate with clinical activities of SLE but not with those of RA.

The authors studied sera from both patients with SLE and from those with RA to evaluate clinical usefulness and significance of circulating immune complexes (CIC) detected with new ELISA kits utilizing monoclonal anti-C1q and anti-C3d antibodies. CIC values of patients with SLE significantly correlated to severity of disease activities evaluated by clinical symptoms and laboratory tests, especially for serum complement levels. Since substances detected with the ELISA kits were closely related to serum complement components, it was determined that a direct relationship exists between clinical activities and CIC values appearing in SLE patients with hypocomplementemia. In RA patients, CIC values did not correlate to clinical activities evaluated by Lansbury's index, anatomical bone damage with X-ray or functional assessment of activities of daily living, but did significantly correlate to levels of IgM-RF, serum IgG concentrations and some markers of systemic inflammation. Detection of IC after fractionation of RA sera revealed a broad range of molecular sizes detectable with the ELISA kits, which indicated that CIC in vivo were heterogenic and complicated in formation, degradation and interaction with serum complements.

Adult↗
PubMed2000

Structural and functional evidence for microglial expression of C1qR(P), the C1q receptor that enhances phagocytosis.

Microglial activation has been associated with several degenerative diseases of the central nervous system (CNS). One consequence of activation is the induction of a more efficient phagocytic response, and it is therefore important to determine what factors regulate microglial phagocytosis and whether this capacity influences the progression of neurodegenerative changes. Previous studies have demonstrated that complement component C1q enhances Fc receptor- and CR1-mediated phagocytosis in cells of the myeloid lineage via a cell surface receptor, C1qRp. Because C1q has been found in the area of lesions in several degenerative CNS diseases, the current investigations were carried out to characterize the effects of C1q on microglial phagocytosis. Neonatal rat microglia were shown to express C1qRp, as assessed by flow cytometry and immunocytochemistry. Interaction of these cells with substrate-bound C1q was shown to enhance both FcR-and CR1-mediated phagocytosis two- to fourfold. In addition, introduction of an antibody raised against the carboxy-terminal, cytoplasmic domain of C1qRp into microglia by electroporation markedly diminished the ability of C1q to enhance uptake of IgG-coated targets, whereas nonspecific IgG had no such effect. These results suggest that C1q in areas of active degeneration may promote the phagocytic capacity of microglia via interaction with microglial C1qRp.

Animals↗
PubMed1991

Antilymphocytic antibodies and marrow transplantation. XIV. Antibody-induced suppression of graft-versus-host disease in C3-decomplemented mice differentiates two T-cell-depletion pathways.

Remarkable differences in the suppression of graft-versus-host disease (GVHD) have been found for anti-Thy-1 antibodies to relate to (1) antigen density and antibody coating on the target cells, (2) antibody isotype, and (3) uptake of complement subcomponent C1q. Regarding (2) and (3) we now demonstrate that depletion of the third complement component C3 by cobra venom factor (CVF) differentiates two T-cell elimination pathways in mice: four rat IgG2c anti-Thy-1 monoclonal antibodies (MoAbs) with low uptake of mouse C1q lost most of their T-cell-depleting and consequently GVHD-preventing effect in C3-depleted H2 IA incompatible semiallogeneic (C57BL/6xCBA)F1 mice. In contrast, eight rat IgG2b, mouse IgG2a, and 2b anti-Thy-1 MoAbs with high affinity for C1q still remained strongly T-cell-depleting and prevented GVHD even in fully mismatched CBA mice depleted of C3. In conjunction with our observation that anti-Thy-1 MoAbs also suppress GVHD in C5-deficient AKR mice, we conclude that complete complement activation until T-cell lysis is not required for our antibodies to be effective in vivo. Activation, but only until deposition of C3b on target-cells for opsonisation via C3b receptors, is necessary with the less immunosuppressive anti-Thy-1 IgG2c isotype with low affinity for C1q. Mouse C1q uptake and C3/C4 deposition on target cells were measured with labeled antibodies and localized in T-cell areas. Interestingly, not even activation until C3b is necessary with the most immunosuppressive C1q-high-affine isotypes. As far as the latter is concerned, we discuss whether elimination of antibody-coated cells via Fc receptors is enhanced by binding to C1q-receptors and/or by intercalating C1q expressed on macrophages.

Animals↗
PubMed1996

Relative efficacies of amyloid beta peptide (A beta) binding proteins in A beta aggregation.

The aggregation of amyloid beta peptide (A beta) into its fibrillar, cross beta-pleated configuration is generally viewed as a critical event in the pathophysiology of Alzheimer's disease (AD). A diverse group of molecules, the A beta binding proteins, has been evaluated for their effects on this process. However, most of these studies have used micromolar or greater reagent concentrations, and their different methods have not permitted quantitative comparisons of the efficacy of different A beta binding proteins in augmenting or inhibiting aggregation. In the present work we have undertaken a coherent analysis using fluorimetry of thioflavin T-stained experimental solutions. The complement protein C1q, serum amyloid P, and transthyretin significantly enhanced the formation of precipitable, cross beta-pleated aggregates in solutions of 800 nM A beta 1-42. Under these same experimental conditions, alpha 1-antichymotrypsin had no significant effect on the aggregation process, and both the E3 and E4 isoforms of apolipoprotein E were significant inhibitors. There was a non-significant trend toward the E3 isoform exhibiting greater inhibition than the E4 isoform. Of the aggregation-facilitating molecules, C1q was substantially and significantly the most potent.

Alzheimer Disease↗
PubMed1998

Participation of factor B in residual immune complex red cell binding activity observed in serum from a C2-deficient systemic lupus erythematosus patient may delay the appearance of clinical symptoms.

OBJECTIVE: To investigate whether participation of factor B (FB) in immune complex transport might explain long periods of clinical remissions in a homozygous C2-deficient patient with systemic lupus erythematosus (SLE) treated regularly with plasma infusions. METHODS: Immune complex red cell binding (ICRB) was assayed as enzyme activity, C3d by enzyme-linked immunosorbent assay, and FB by immunoelectrophoresis. RESULTS: C2-deficient sera showed low-grade ICRB, which correlated with levels of FB. This activity could be blocked with antibodies to C1q, C4, or FB, but not by antibodies to C2. C3d levels in the patient's plasma changed during infusion, followed by a gradient increase during remission. Comparison of ICRB, C3d, and FB suggested an inverse relationship between FB levels and clinical symptoms. CONCLUSION: In C2 deficiency, FB may interact with C4 to provide a low-grade ICRB. This activity could be clinically significant in patients with C2 deficiency and explain why they are less prone to SLE than patients with C1q or C4 deficiency.

Antibodies↗
PubMed1983

Determination in the nanogram range of C1q in serum and unconcentrated CSF by electro-immunodiffusion.

A new method for the determination of C1q in serum and cerebral spinal fluid (CSF) is described. The method has a sensitivity of 6 ng per assay or 1.2 mg/l. With this technique the mean value for C1q in normal human serum was 276 +/- 25 mg/l. The ratio of C1q in the blood compared with that in the CSF of normal individuals was more than 400: 1, since essentially no C1q could be detected in normal CSF. This ratio dropped considerably in some patients with neurological disorders, due to an increase in C1q levels in the CSF. Evidence is presented that these increased levels of CSF C1q are largely due to local synthesis of C1q rather than transudation of plasma C1q. This suggests that C1q in the CSF may serve as a marker of macrophage activity inside the central nervous system.

Complement Activating Enzymes↗
PubMed1991

Gene expression of the A- and B-chain of mouse C1q in different tissues and the characterization of the recombinant A-chain.

Immunoscreening of a mouse macrophage cDNA library with an anti-mouse C1q-antibody resulted in the isolation of cDNA clones. The deduced amino acid sequence was homologous to the A-chain of human C1q. Homology on the DNA level was found to be 76% and on the protein level 72% thus it appeared the clones coded for the mouse C1q A-chain. An immunoblot of murine serum C1q separated by SDS-PAGE was detected with an A-chain specific antibody that had been affinity purified on recombinant mouse C1q A-chain expressed in Escherichia coli. The antibody preparation reacted exclusively with the mouse C-chain (as defined by SDS-PAGE). Northern blot analysis with strand-specific cDNA probes coding for the A- and B-chain of murine C1q showed that mouse peritoneal macrophages produced the highest concentration of C1q gene transcripts. RNA from mouse spleen, thymus, heart, and brain gave substantial hybridization signals, whereas RNA preparations from liver, kidney, lung, and small intestine appeared to contain only trace amounts of C1q mRNA. In a Northern blot analysis of different guinea pig cells and tissues, only RNA preparations from peritoneal macrophages hybridized with the mouse C1q probes. These results indicate that macrophages are a major site of C1q biosynthesis.

Amino Acid Sequence↗
PubMed1983

Isolation and characterization of circulating immune complexes in patients with rheumatoid arthritis.

We studied soluble immune complexes in sera and synovial fluids of ten patients suffering from Rheumatoid Arthritis (RA), six seropositive and four seronegative. Isolation of the immune complexes was obtained by a combination of gel filtration and affinity chromatography from biological fluids. The first step involved preparation of a globulin-enriched fraction by precipitation of either serum or synovial fluid with 5% polyethylene glycol 6000. The precipitate was solubilized in Borate NaCl buffer and fractioned by gel filtration in Ultrogel AcA 34. Eluted peaks were submitted to affinity chromatography on a Protein A-Sepharose CL 4B column. The recovered material was analyzed by double immunodiffusion and electrophoresis in 6-20% polyacrylamide gel containing sodium dodecylsulphate (SDS-PAGE) and was shown to contain IgG, IgM, IgA with small amounts of C1q, C3 and C4. Observation occurred that there is a different distribution of macromolecular and intermediate complexes in seropositive and seronegative samples respectively, total C1q binding activity being equal.

Antigen-Antibody Complex↗
PubMed1988

Purification and characterization of the 1q subcomponent of canine complement and its use in the 125I-C1q binding assay for detection of immune complexes.

The complement subcomponent, C1q, was isolated from serum obtained from clinically normal dogs, using a rapid 2-step process involving affinity chromatography. Yield of C1q ranged from 8 to 10 mg/L of serum. Hemolytically active C1q had 3 protein bands after sodium dodecyl sulfate polyacrylamide gel electrophoresis under reducing conditions and formed a single line of identity with rabbit anti-canine C1q. The amino acid composition of canine C1q was similar to that of human C1q and contained a high percentage of glycine. Isolated canine C1q was iodinated, and the fluid-phase binding assay was used to detect circulating immune complexes in dogs with systemic lupus erythematosus and rheumatoid arthritis.

Amino Acids↗
PubMed1988

A monoclonal antibody to C1q which appears to interact with C1r2C1s2-binding site.

A monoclonal antibody (SB-4) to human C1q was prepared. The equilibrium constant of the antibody for C1q was found to be greater than 10(10) M-1. It has been shown that the antibody binds to the A-B chain dimer, probably via the B chain of C1q. Pepsin digestion of C1q at pH 4.5, which fragments the globular regions but leaves the collagenous region intact, allowed the demonstration that the antigenic site is located in the collagenous region of the molecule. The effect of the antibody on haemolytic activity has shown that it is capable of inhibiting the formation of EAC1 cells from EAC1q cells plus C1r and C1s but is incapable of inhibiting the C1 activity of performed EAC1 cells. This indicates that the binding of the antibody to the collagenous portion of the B chain of C1q probably prevents interaction between C1q and the C1r2-C1s2 complex.

Antibodies, Monoclonal↗
PubMed1984

Serum levels of C1 subunits in rheumatoid arthritis.

Modifications of radial immunodiffusion and of hemolytic assays of C1q are described, which enable the results of these assays to be in agreement with those obtained by hydroxyproline assay. Using these assays, we show that C1q serum levels are significantly increased in rheumatoid arthritis (RA) and that the excess C1q levels in this disease are not accompanied by increased levels of C1r and C1s. Active RA is therefore characterized by increased levels of hemolytically active C1q that has a physiologically active stem region unbound to C1r and C1s.

Arthritis, Rheumatoid↗
PubMed1988

Guinea pig macrophages synthesize a low molecular weight form of C1q with affinity for the C1r2C1s2-complex but which does not bind to Fc in immunoglobulin aggregates.

Biosynthetically labelled C1q secreted by guinea pig peritoneal macrophages was analysed by sedimentation through sucrose gradients followed by SDS-PAGE. In addition to the haemolytically active C1q of mol. wt 460,000 Da a low mol. wt (LMW) form of C1q was identified which had no detectable affinity for Fc of aggregated immunoglobulin, but which retained the ability to associate with the C1r2s2-complex. This LMW-C1q was covalently associated with two additional polypeptides of mol. wt 46 and 50 kDa.

Animals↗
PubMed1985

Immunohistopathologic evaluation of C1q in 800 renal biopsy specimens.

The frequency, distribution, and intensity of C1q localization were evaluated in 800 renal biopsy specimens, and these observations were correlated with light, immunofluorescence, and electron microscopy findings. Intense C1q immunostaining was most frequent in proliferative and membranous lupus glomerulonephritis and in a recently described form of proliferative glomerulonephritis designated "C1q nephropathy." Moderate intensity C1q immunostaining was observed in most cases of type I but not type II, membranoproliferative glomerulonephritis. Unlike lupus membranous glomerulopathy, non-lupus membranous glomerulopathy usually did not have extensive C1q localization. C1q was scanty or absent in IgA nephropathy and antiglomerular basement membrane antibody mediated glomerulonephritis. C1q, along with IgM and C3, was often present at sites of glomerular sclerosis, especially in focal segmental glomerulosclerosis. Extraglomerular C1q was most frequent and most intense in cases of lupus nephritis having extraglomerular immune deposits. The presence or absence and intensity of C1q immunostaining were shown to be useful in the differential diagnosis of some glomerulopathies.

Autoantibodies↗
PubMed1983

An extended C1q-binding assay using lactoperoxidase- and chloramine-T-iodinated C1q. Immediate distinction between immune-aggregate-mediated and non-immune-aggregate-mediated C1q binding.

An extension of the C1q-binding assay for the detection of immune-aggregate-mediated and non-immune-aggregate-mediated C1q binding is reported. The assay involves the use of two different C1q preparations, one radioiodinated by means of lactoperoxidase (LPO-125I-C1q) and the other by means of chloramine-T (CT-125I-C1q). The treatment with CT for 20 min at room temperature before iodination for 1 min led to abolishment of the C1q-binding capacities to complexed IgG: approximately 50% of LPO-125I-C1q but only 2% of CT-125I-C1q bound to 80 micrograms/ml of IgG forming part of tetanus toxoid/anti-tetanus toxoid complexes or to 200 micrograms/ml of heat-aggregated human gamma globulin. Similar results were obtained with staphylococcal protein-A-aggregated IgG. CT-treated C1q was haemolytically inactive. In contrast to the results with complexed IgG, CT treatment did not markedly reduce binding capacities of C1q to heparin: approximately 55% of LPO- and CT-125I-C1q were bound by 127 U/ml of commercial heparin in normal human serum. Both C1q preparations bound to a comparable extent to fibronectin, fibrinogen, and various bacterial endotoxins. When the LPO- and CT-125I-C1q-binding patterns obtained on serum samples from patients with systemic lupus erythematosus, rheumatoid arthritis, or essential mixed cryoglobulinaemia were compared with binding patterns observed using laboratory reactants, an immediate detection of non-immune-aggregate-mediated C1q binding became possible.

Antigen-Antibody Complex↗
PubMed2000

Generation of complement C3 and expression of cell membrane complement inhibitory proteins by human bronchial epithelium cell line.

BACKGROUND: The interrelationship between human airway epithelium and complement proteins may affect airway defence, airway function, and airway epithelial integrity. A study was undertaken to determine (1) whether unstimulated human bronchial epithelium generates complement proteins and expresses cell membrane complement inhibitory proteins (CIP) and (2) whether stimulation by proinflammatory cytokines affects the generation of complement and expression of cell membrane CIP by these cells. METHODS: Human bronchial epithelium cell line BEAS-2B was cultured in a serum-free medium. Cells were incubated with and without proinflammatory cytokines to assess unstimulated and stimulated generation of complement C3, C1q and C5 (by ELISA), and to examine the expression of cell membrane CIP decay accelerating factor (DAF; CD55), membrane cofactor protein (MCP; CD46), and CD59 (protectin) by flow cytometry analysis. RESULTS: Unstimulated human bronchial epithelial cell line BEAS-2B in serum-free medium generates complement C3 (mean 32 ng/10(6) cells/72 h, range 18-52) but not C1q and C5, and expresses cell membrane DAF, MCP, and CD59. Interleukin (IL)-1alpha (100 U/ml/72 h) and tumour necrosis factor (TNF-alpha; 1000 U/ml/72 h) increased generation of C3 up to a mean of 78% and 138%, respectively, above C3 generation by unstimulated cells. DAF was the only cell membrane CIP affected by cytokine stimulation. Interferon (IFN)-gamma (10 U/ml/72 h) and TNF-alpha (1000 U/ml/72 h) increased DAF expression up to a mean of 116% and 45%, respectively, above that in unstimulated cells. MCP and CD59 expression was not consistently affected by IL-1alpha, TNF-alpha, or IFN-gamma. CONCLUSIONS: Local generation of complement C3 and expression of cell membrane CIP by human bronchial epithelium and its modulation by proinflammatory cytokines might be an additional regulatory mechanism of local airway defence and may affect airway function and epithelial integrity in health and disease.

Bronchi↗