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PubMed1984

Association of circulating immune complexes with cytogenetic abnormalities but not with prognosis in acute nonlymphocytic leukemia.

Sera from 91 adult acute nonlymphocytic leukemia patients were tested for circulating immune complexes by the C1q binding test. In 42 patients tested prior to the initiation of therapy, C1q binding activity was inversely correlated with leukemic infiltrate of the bone marrow (rs = -0.34, p less than 0.02), but it was not related to peripheral white blood cell count or presence of infection. Patients with abnormal C1q binding activities (greater than 6%) were more likely to have cytogenetic abnormalities in their bone marrow (p = 0.02); the most frequent abnormality was an extra No. 8 chromosome. The median survival of 8 patients with abnormal values was 1.5 months as compared to 7.8 months in 34 patients with normal values. However, the C1q binding test did not identify patients likely to achieve remission; and after remission was achieved, it did not identify those likely to relapse. Differences between these findings and those recently published by other investigators are discussed.

Acute Disease↗
PubMed1989

Antibodies to the collagen-like region of C1q in sera of patients with autoimmune rheumatic diseases.

Antibodies to the collagen-like region of C1q have recently been observed in sera of patients with systemic lupus erythematosus (SLE). In this study, we documented that these antibodies were present in 47.3% of SLE patient sera, whereas they were uncommon in sera from patients with rheumatoid arthritis (2.8%) and Sjögren's syndrome (12.8%), as well as in normal sera (6.4%). Markedly elevated antibody levels (greater than 4 SD above the normal mean) were observed almost exclusively in sera of patients with SLE. Levels of antibodies to the collagen-like region correlated highly with levels of solid-phase C1q-binding IgG when analyzed by the C1q solid-phase assay for immune complexes (r = 0.87). We previously found that, after sucrose density gradient ultracentrifugation, a predominance of the solid-phase C1q-binding IgG in SLE sera sediments as monomeric IgG. These findings, together with the present data, indicate that reactivity of SLE patients' sera in the C1q solid-phase assay reflects primarily the presence of antibodies to the collagen-like region, and not the presence of immune complexes.

Arthritis, Rheumatoid↗
PubMed2006

High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis.

BACKGROUND: Anti-C1q antibodies (anti-C1q) have been shown to correlate positively with systemic lupus erythematosus (SLE) nephritis. Several clinical studies indicated a high negative predictive value, suggesting that active lupus nephritis is rarely seen in patients with no anti-C1q. However, the true prevalence of anti-C1q at the time of active lupus nephritis has not been well established. The aim of this study was to determine prospectively the prevalence of anti-C1q in proven active lupus nephritis at the time of the renal biopsy. METHODS: In this prospective multi-centre study, we investigated adult SLE patients undergoing renal biopsy for suspected active lupus nephritis. Serum samples were taken at the time of the biopsy and analysed for the presence of anti-C1q in a standardized way. The activity of lupus nephritis was classified according to the renal histology. Biopsies were also analysed for the presence of glomerular IgG, C1q and C3 deposition. RESULTS: A total of 38 patients fulfilling at least 4/11 American College of Rheumatology (ACR) criteria for the diagnosis of SLE were included. Out of this, 36 patients had proliferative (class II, III or IV) and two had class V lupus nephritis. All but one patient with proliferative lupus nephritis were positive for anti-C1q (97.2%) compared with the 35% of control SLE patients with inactive lupus nephritis and 25% of SLE patients without lupus nephritis ever. All patients were positive for glomerular C1q (36/36) and 37/38 patients had glomerular IgG deposits. Anti-C1q strongly decreased during successful treatment. CONCLUSIONS: Anti-C1q have a very high prevalence in biopsy-proven active lupus nephritis, thus a negative test result almost excludes active nephritis. The data support the hypothesis of a pathogenic role of anti-C1q in lupus nephritis.

Adult↗
PubMed1984

Association of C1q- and conglutinin-binding immune complexes with high consumption of alpha-2-macroglobulin in synovial fluids of patients with rheumatoid arthritis.

The consumption of alpha-2-macroglobulin (a2M) by proteinases in synovial fluids (SF) was indirectly measured by determining trypsin binding to solid-phase immunoadsorbed SF-a2M. In addition immune complexes (IC) were assessed by the solid-phase C1q-binding assay as well as the solid-phase conglutinin binding assay in rheumatoid (RA; n = 25) and osteoarthritic (OA; n = 9) SF. Elevated levels were found as follows: a2M X proteinase complexes (a2M X P) in 73.5% (RA, n = 20; OA, n = 5), solid-phase C1q-binding IC (C1q-IC) in 52% (13 out of 25 RA-SF) and bovine conglutinin binding IC (KgB-IC) in 54% (13 out of 24 RA-SF). All OA-SF were in either IC assay negative. Consumption of a2M in OA-SF and seronegative RA-SF was not more than 15% of total SF-a2M, showing a mean value of 19.5 and 13.5 micrograms a2M X P/ml SF. Seropositive RA-SF had an a2M X P mean value of 96.4 micrograms/ml SF, which differed significantly (p less than or equal to 0.05) from the former two groups. Similarly, RA-SF which were negative in either IC assay had a low a2M X P mean value (20.0 micrograms/ml SF). This contrasted sharply with the a2M X P means obtained in IC-positive RA-SF, which amounted to 131.5 micrograms a2M X P/ml SF in C1q-IC positive RA-SF and to 110.4 micrograms a2M X P/ml SF in KgB-IC positive RA-SF, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Antibody Complex↗
PubMed1984

Influence of immune-complex size and antigen-antibody ratio on immune complex detection with monoclonal rheumatoid factor and C1q.

Stabilized aggregates of human IgG were prepared over a wide range of molecular weights. These fractions with increasing molecular weight were adjusted to the same molarity or the same protein concentration and were tested in the solid phase C1q and monoclonal rheumatoid factor immune complex assays. At constant molarity results were linearly correlated with the size of the aggregates. At constant protein concentration, results were also linearly correlated with the size of the aggregates in the lower molecular weight fractions, although the number of aggregates in the fractions decreased with increasing molecular weight. It is concluded that results in these assays can only be compared with respect to concentration if the immune complexes have identical sizes. Consequently, we studied the relative affinity of C1q and monoclonal rheumatoid factor for antigen/antibody immune complexes of different sizes or different antigen/antibody ratios, using model immune complexes composed of tetanus toxoid/anti-toxoid and streptolysine O/anti-streptolysine O. Compared to C1q, monoclonal rheumatoid factor was found to have higher affinity for smaller complexes, and for complexes with higher antigen/antibody ratio. Immune complex containing sera of 5 patients with connective tissue diseases, and one normal serum, were fractionated on a Sepharose 4B column. The binding patterns of the different fractions to solid phase C1q and monoclonal rheumatoid factor were quite variable and in only one of these sera monoclonal rheumatoid factor had the expected preference for small complexes and C1q for large complexes. Moreover a remarkably high binding to C1q and/or monoclonal rheumatoid factor of the monomeric IgG fraction was found in 4 out of 5 patient sera.

Antibodies, Monoclonal↗
PubMed1983

[Interaction between fibronectin and aggregated IgG].

The present study shows that plasma fibronectin forms complexes with aggregated human IgG (a model for immune complexes) and that the resulting complexes precipitate spontaneously or after addition of PEG from buffered saline. However, no clearcut interaction was observed in serum or synovial fluid. Two currently-used immune complex assays, the C1q solid phase assay and the conglutinin binding assay in a commercial inhibition variant, were tested as to their reliability in the presence of fibronectin. While the C1q-dependent assay showed low susceptibility to fibronectin, the conglutinin binding assay gave increased immune complex values in the presence of pathological concentrations of fibronectin.

Antigen-Antibody Complex↗
PubMed1997

C1q, a subunit of the first component of complement, enhances antibody-mediated apoptosis of cultured rat glomerular mesangial cells.

We have shown previously that IgG2a anti-Thy-1 MoAb (ER4G) induces apoptosis of rat mesangial cells (GMC) in vitro. Since the classical complement pathway plays an essential role in Thy-1 nephritis, we analysed whether C1q, a subunit of the first component of complement, enhances the ER4G-mediated apoptosis of rat GMC. Two different subclasses of anti-Thy-1 MoAb, ER4G (IgG2a) and ER14 (IgG1), were used. It was established that ER4G binds C1q efficiently, while ER14 reacts poorly with C1q. For the experiments of apoptosis, quiescent rat GMC were exposed for 1 h at 37 degrees C to a fixed concentration of anti-Thy-1 MoAb and incubated further for 16 h at 37 degrees C in the presence or absence of C1q. GMC exposed to medium (M-GMC) followed by incubation of the cells with medium alone was used as controls. Apoptosis was assessed by morphological studies and quantitative analysis on FACS using FITC-annexin V (the annexin V methods) or bicolour FACS analysis using FITC-annexin V and propidium iodide (the annexin V/PI method). With the annexin V method, M-GMC revealed 9.4 +/- 1.4% apoptosis. C1q had only marginal effects on apoptosis of M-GMC. GMC exposed to ER4G (ER4G-GMC) and further incubated with medium in the absence of C1q resulted in 25.7 +/- 5.7% apoptosis (P < 0.01 relative to control). Incubation of ER4G-GMC together with 100 microg/ml of C1q significantly increased GMC-apoptosis up to 39.4 +/- 4.9% (P < 0.01 relative to ER4G-GMC incubated in the absence of C1q). This enhancing effect of C1q on apoptosis of ER4G-GMC was time- and dose-dependent. In contrast, C1q did not significantly alter the apoptosis of either GMC exposed to ER14 (ER14-GMC) or to F(ab')2-ER4G (F(ab')2-ER4G-GMC), while ER14-GMC or F(ab')2-ER4G-GMC incubated with medium resulted in significant apoptosis compared with control. These results were supported by morphological studies and bicolour FACS analyses in time course experiments using the annexin V/PI method. The effect of C1q is dependent on the presence of intact C1q-containing globular heads and does not occur with collagen-like fragments of C1q. Furthermore, incubation of ER4G-GMC with anti-mouse K-chain antibodies also increased ER4G-mediated GMC-apoptosis. These results indicate for the first time that C1q enhances antibody-mediated apoptosis of rat GMC in vitro, presumably by its binding to ER4G and probably by additional cross-linking of Thy-1 on the surface of GMC.

Animals↗
PubMed1981

Polyethylene glycol enhances the binding of C1q to circulating immune complexes.

By radioimmunoassay we measured the amount of endogenous C1q that was precipitated by polyethylene glycol (PEG) under the conditions of the 125I-C1q-binding test (C1q-BT). We found a linear correlation between the percentage endogenous C1q that was precipitated and the 125I-C1q-binding activity (C1q-BA). We concluded that the 125I-C1q behaves like the endogenous C1q. To detect circulating immune complexes (CIC) which had already bound C1q, human sera were added to tubes coated with anti-C1q. Under the conditions used, no C1q-bearing CIC were detected. In addition, 7 sera from patients with high C1q-BA were analyzed by sucrose-gradient ultracentrifugation. No C1q was found in the fast sedimenting fractions, although C1q-BA was detected in these fractions. With IgG-coated tubes we observed that PEG enhanced the binding of 125I-C1q as well as endogenous C1q to aggregated and monomeric IgG. PEG also enhanced the binding of CIC to C1q-coated tubes. The results suggest that CIC detected by the C1q-BT do not bear C1q in significant amounts in the circulation and that these CIC become detectable only in the presence of PEG.

Animals↗
PubMed1989

Role of C1q in phagocytosis of Salmonella minnesota by pulmonary endothelial cells.

The Re mutant of Salmonella minnesota adheres in much greater numbers than the wild type to endothelial cells derived from the bovine pulmonary artery. Since the Re mutant is distinguished from wild-type S. minnesota by its ability to bind C1q and since endothelial cells possess receptors for C1q, we examined the role of C1q in the phagocytosis of the S. minnesota Re mutant. First, preincubating endothelial cells with C1q-enriched medium resulted in increased adherence of the Re mutant (17.9 x 10(4) versus 6.6 x 10(4]. Second, preincubating the Re mutant with C1q-enriched medium resulted in increased numbers of adherent bacteria (62.1 x 10(4) versus 6.6 x 10(4]. Preincubation of both endothelial cells and bacteria with C1q-enriched medium resulted in increased adherence above control levels but less adherence than when either cells or bacteria were preincubated separately in C1q-enriched medium. If serum depleted of C1q was used for preincubation of endothelial cells or bacteria, adherence was reduced below control levels. Thus, C1q plays an important role in the initial steps (recognition, binding, and ingestion) of phagocytosis. Next, the role of C1q was investigated in the respiratory burst response. Levels of superoxide anion released from endothelial cells 15 min after phagocytosis of the Re mutant (100 bacteria per endothelial cell) were assayed by measurement of the superoxide dismutase-inhibitable reduction of ferricytochrome c. Superoxide anion release was increased during phagocytosis of the Re mutant (35 nmol of O2- per 3 x 10(6) endothelial cells) and was also elevated above control values by incubation with soluble C1q (10 nmol of O2- per 3 x 10(6) endothelial cells). These results indicate a role for C1q in both the ingestion and the response of endothelial cells to the S. minnesota Re mutant.

Animals↗
PubMed1986

The effect of fibronectin on the processing of C1q- and C3b/bi-coated immune complexes by peripheral blood monocytes.

In the past several years, it has been demonstrated that plasma fibronectin (Fn) binds to the C1q subunit of the complement system. The effect of Fn on the processing of immune complexes containing C1q and C3b by human peripheral blood monocytes was investigated. Preincubation of monocytes with Fn causes a significant increase in attachment of sheep erythrocytes coated with IgM and C1q (EIg-MC1q), but does not mediate their ingestion. EIg-MC1q attach to the Fn-treated monocytes via the C1q receptor because Fab anti-Fn antibodies do not inhibit their attachment to the monocytes. In addition, Fn-treated monocytes exhibit no change in C1q receptor number or affinity compared with monocytes treated with buffer. Fn mediates the phagocytosis of C3b/bi-coated particles, and C1q can enhance this process in two ways. First, phagocytosis of particles bearing C3b/bi and Fn is enhanced by the presence of C1q on the immune complex. Second, monocytes on Fn-coated surfaces ingest more particles if they are coated with both C3b/bi and C1q, compared with particles coated with either C3b/bi or C1q alone.

Animals↗
PubMed1990

The spleen is not a major synthetic site of alternative pathway components.

The serum concentrations of the complement proteins C1q, C1s, C4, C3, factor D, factor B, properdin, C1 inactivator, factor I and factor H were determined in 7 patients before and after splenectomy. The concentrations of C1q, factor D and properdin were moderately decreased 1-2 days after surgery, while the other components were virtually unchanged. During the course of 4 weeks the values either returned to normal, or were slightly increased. In general, the findings could be ascribed to the inflammatory plasma protein response and were similar in cholecystectomized patients. The results provided no evidence of significant complement protein synthesis in the human spleen.

Adult↗
PubMed1993

C1Q, a subunit of the first component of complement, enhances the binding of aggregated IgG to rat renal mesangial cells.

Previous reports have shown the presence of C1Q-R on monocytes, macrophages, polymorphonuclear cells, fibroblasts, platelets, lymphocytes, and endothelial cells. The present study demonstrates a functional C1Q-R on rat renal mesangial cells (MC). Incubation of MC with increasing concentrations of [125I]C1Q resulted in a dose-dependent binding of [125I]C1Q to MC; the binding of [125I]C1Q was inhibitable by excess unlabeled C1Q or C1Q stalks whereas BSA and C1Q globular heads had no effect. Scatchard analysis of the data revealed the presence of 6.2 x 10(7) binding sites/cell with an affinity of 4.9 x 10(6) M-1 for C1Q. Immunoprecipitation of 125I-labeled MC membrane proteins with C1Q or mAb directed against human C1Q-R revealed a single 66- to 68-kDa band under reducing conditions. We have shown previously that soluble stable aggregates of IgG bind to rat MC in a dose-dependent fashion. In addition the presence of a receptor for IgG has been described on rat MC. In order to find out whether there is a cooperative effect between C1Q and AlgG in binding of [125I]AlgG to MC, we incubated [125I]AlgG in the presence of increasing concentrations of C1Q, and showed a 5- to 15-fold enhancement of binding of [125I]AlgG to MC. Neither heat-inactivated C1Q nor C1Q stalks were able to enhance the binding of [125I]AlgG to MC. Enhanced binding by C1Q was only observed when aggregated IgG was used; the binding of monomeric IgG to MC was not affected by C1Q. These studies indicate that there is a cooperative effect between Fc gamma R and C1Q-R on MC in the recognition of immune complexes.

Animals↗
PubMed1998

Mam33p, an oligomeric, acidic protein in the mitochondrial matrix of Saccharomyces cerevisiae is related to the human complement receptor gC1q-R.

Mam33p (mitochondrial acidic matrix protein) is a soluble protein, located in mitochondria of Saccharomyces cerevisiae. It is synthesized as a precursor with an N-terminal mitochondrial targeting sequence that is processed on import. Mam33p assembles to a homo-oligomeric complex in the mitochondrial matrix. It can bind to the sorting signal of cytochrome b2 that directs this protein into the intermembrane space. Mam33p is encoded by an 801 bp open reading frame. Gene disruption did not result in a significant growth defect. Mam33p exhibits sequence similarity to gC1q-R, a human protein that has been implicated in the binding of complement factor C1q and kininogen.

Amino Acid Sequence↗
PubMed1999

Overrepresentation of the Fcgamma receptor type IIA R131/R131 genotype in caucasoid systemic lupus erythematosus patients with autoantibodies to C1q and glomerulonephritis.

OBJECTIVE: To test the hypothesis that there is an association between the Fcgamma receptor type IIA (FcgammaRIIA)-H/R131 polymorphism and autoantibodies to the collagenous region (CLR) of C1q in patients with systemic lupus erythematosus (SLE). METHODS: One hundred ninety-five Caucasoid lupus patients were studied. Anti-C1q(CLR) antibodies in serum were measured by enzyme-linked immunosorbent assay (ELISA) and FcgammaRIIA genotype analysis was performed by polymerase chain reaction. Immunoglobulin subclass of the autoantibodies was measured by ELISA. RESULTS: Fifty-six patients were anti-C1q antibody positive, and Ig subclass analysis indicated a predominance of IgG2 anti-C1q antibodies. Analysis of the SLE population as a whole revealed no significant difference in the allele frequencies of R131 and H131 compared with controls. There was, however, a significantly increased frequency of the R131 allele both in the anti-C1q-positive subgroup of patients (chi2 = 7.66, P<0.01) and in the 71 patients with nephritis (chi2 = 7.76, P< 0.01), compared with controls. CONCLUSION: FcgammaRIIA-R131 constitutes a heritable susceptibility factor for the development of SLE with manifestations in the kidney in Caucasoid patients. The close associations demonstrated between this FcgammaRII variant, antibodies to C1q(CLR), and glomerulonephritis may be due to a failure of clearance of the potentially pathogenic IgG2 autoantibody.

Alleles↗
PubMed1984

Serum C1q levels as a prognostic guide to articular erosions in patients with rheumatoid arthritis.

C1q was measured serially by single radial immunodiffusion in 54 rheumatoid arthritis (RA) patients over a period of more than 5 years, and values were correlated with laboratory, radiographic, and clinical findings. The number of joints with erosion (NJE) was determined retrospectively from radiographs of patients who had RA of greater than 7 years duration. In patients with clinically "burned out" RA, C1q levels were not statistically different from those of healthy adults. During the period of active disease, each patient's C1q level remained very constant, irrespective of erythrocyte sedimentation rate, C-reactive protein (CRP) level, or whether the RA was active or in remission. No sustained correlation was found between the C1q level and the other 2 acute phase reactants, but patients with C1q levels of at least 250 micrograms/ml showed a positive CRP over a period of years, in contrast to those with C1q levels below 250 micrograms/ml. Patients with an initial C1q above 250 micrograms/ml had more erosive RA when compared with those having C1q levels below 250 micrograms/ml. These data suggest that active RA can be classified into two subsets by C1q levels, one with persistent inflammation and a high NJE and another without persistent inflammation and with a low NJE.

Adolescent↗
PubMed1983

An enzymatically active antigen-antibody probe to measure circulating immune complexes. II. E. coli beta-galactosidase in the probe and C1q as the recognition unit.

An enzymatically active probe (beta-galactosidase-anti-beta-galactosidase complex) is used to measure circulating immune complexes (CIC), in a competition assay where probe and CIC are confronted with a 'recognition unit'. The latter is bovine conglutinin in the original description of this method. Here we describe a version utilizing human or bovine C1q. The two techniques are compared for their sensitivity and specificity, on both in vitro formed tetanus toxoid-anti-toxoid complexes and on sera from patients with selected diseases. The results confirm that the two recognition units are sensitive to families of CIC that only partially overlap. The parallel use of conglutinin and C1q yields both quantitative and qualitative information on the nature of CIC in individual sera.

Animals↗
PubMed1990

Quantitative determination of retrovirus-specific immune complexes.

ELISA methodology was adapted to measure antigen-specific immune complexes (ASIC) containing retroviral antigens. Using ICs artificially generated from MuLV gp70 and monoclonal antibodies against gp70 we showed that ICs can be quantified by measuring the levels of antibody and antigen and comparing these to the total content of ICs. Furthermore, this method permits determination of the composition of ICs containing an excess of antigen or antibody (i.e., small or large complexes). The levels of the ASIC were correlated with the levels of ICs containing undefined antigen components as determined by the C1q ELISA. Using this method it was possible to determine levels of MuLV gp70 specific ICs in various mouse sera.

Aging↗
PubMed1992

Determination of monoclonal antibody specificity by immunoadsorption and western blotting.

A rapid and simple method has been developed for identifying the specificity of monoclonal antibodies at an early stage in the production of hybridomas. The technique is a micro-method utilizing biotinylated crude antigen and the surface of microtiter plates as an immunoaffinity matrix. The monoclonal antibodies to be tested are adsorbed to the microtiter wells and incubated with the labeled antigen preparation. Non-specific binding can be reduced by blocking and repeated washing steps. The specific antigen is then eluted by SDS-containing buffers, subjected to SDS-PAGE, blotted onto nitrocellulose and detected by enzyme-labeled avidin in a Western blot assay. The amount of bound and removed antigen can be quantitated by developing eluted and non-eluted control wells by ELISA techniques. Since this ELISA can be performed rapidly, only samples which contain sufficient specific material can be selected for electrophoresis and blotting. The major advantages of the technique are (i) the use of a non-radioactive label resulting in an easy and time-saving procedure, (ii) the possibility of quantitating the amount of captured and detached antigen by ELISA, (iii) the need for only a minimal amount of antigen, (iv) the use of unpurified antibodies of all isotypes, (v) a high signal-to-noise ratio, and (vi) as with all immunoprecipitation techniques, the possibility of detecting SDS-sensitive epitopes and of using crude antigen preparations. Using this method we were able to characterize monoclonal antibodies against both soluble proteins (mouse and human C1q) and membrane determinants (human pan T cell CD5 and CD7).

Animals↗