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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↗
PubMed1989

Serum IgG antibodies to C1q in hypocomplementemic urticarial vasculitis syndrome.

Urticaria, angioedema, and arthritis are cardinal features of hypocomplementemic urticarial vasculitis syndrome (HUVS). Considered to be an immune complex-mediated disorder, HUVS has been differentiated from systemic lupus erythematosus (SLE), based on its clinical manifestations and the C1q precipitin (C1q-p) reaction, which is manifested as gel precipitation of C1q by a small percentage of HUVS IgG molecules. This phenomenon has been attributed to an Fc region abnormality, and the responsible IgG molecules are said to possess C1q-p activity. We purified IgG from 4 HUVS patients and confirmed that HUVS IgG contains C1q binding activity. F(ab')2 fragments from these patients also bound to C1q, as measured by 2 different C1q binding methods at physiologic ionic strength; HUVS IgG Fc fragments did not bind to C1q. Preincubation of HUVS F(ab')2 fragments with antibody to human F(ab')2 prevented subsequent binding to C1q. We conclude that IgG antibodies to C1q are present in HUVS serum, and it is likely that these antibodies are C1q-p. Because the clinical manifestations of HUVS and the presence of anti-C1q antibodies have been described in patients with SLE, our findings support the concept that HUVS is an autoimmune syndrome related to SLE.

Complement Activating Enzymes↗
PubMed1979

Anti-dsDNA and complement profiles as prognostic guides in systemic lupus erythematosus.

Antibodies to dsDNA, tested with circular DNA in the Farr assay, are specific for systemic lupus erythematosus. A longitudinal study showed a clear relation between the clinical state, the anti-dsDNA titer (expressed in units), and the C1q and C3 levels: when anti-dsDNA levels remained high, no exacerbations were observed. A sharp drop in anti-dsDNA, usually preceded by a rise, was related to a serious exacerbation. Only during the exacerbation when both C1q and C3 were very low was renal involvement seen.

Antibodies, Antinuclear↗
PubMed1979

Increased C1q binding immune complexes in Felty's syndrome: comparison with uncomplicated rheumatoid arthritis.

Sera from patients with Felty's syndrome (FS) and rheumatoid arthritis (RA) were examined for the presence of circulating immune complexes (IC) by using the 125I-C1q binding and monoclonal rheumatoid factor (mRF) techniques. Of 15 patients with FS, 9 (60%) had high 125I-C1q binding as compared to 3 of 26 RA patients (12%). The average C1q binding was significantly higher in the FS patients than in the RA patients without FS. C1q binding in both FS and RA patients was significantly higher than a group of 90 normal controls. In addition, serum C4 levels were significantly lower in the FS patients than in the RA patients. In contrast to these findings, IC levels in FS and RA patients were very similar when measured by the mRF technique. These studies indicate that FS patients have higher levels of complement-fixing IC in their sera than RA patients without FS. These findings raise the possibility that the complement-fixing IC found in these patients may play a role in the pathogenesis of neutropenia of FS.

Adult↗
PubMed1980

The C1q binding assay in systemic lupus erythematosus: discordance with disease activity.

To investigate the relationship of C1q binding assay (C1qBA) to disease activity in systemic lupus erythematosus (SLE), a retrospective study was carried out on 232 C1qBA performed in 33 patients with SLE. When initial values were assessed (33 tests in 33 patients), there was no relationship between positive and negative C1qBA and abnormal renal function (P = 0.482, Fisher exact test). Of 87 tests performed during active renal disease, 34 (39%) were positive; of 48 tests during active non-renal disease, 25 (52%) were positive; of 83 tests when the disease was inactive, 45 (54%) were positive; and of 14 tests during episodes of infection, 10 (71%) were positive. Corresponding means for the C1qBA were follows: renal 65.66, non-renal 78.02, inactive 56.04, infection 135.79 (no significant differences by Student's t-test). There was no significant relationship with the C1qBA when comparing active disease (renal and non-renal) with inactive disease (chi 2 Yates = 1.875, P = 0.171). When renal function abnormalities were analyzed separately, the C1qBA values were independent of azotemia or proteinuria (chi 2 Yates = 1.399, P = 0.237). Patients were seen with progressive renal disease who had consistently negative C1qBA, as well as patients with benign clinical courses despite elevated C1qBA. The discordance of the C1qBA results with disease activity in SLE highlights the limitations of immune complex (IC) determinations by a single technique, and stresses the importance of evaluating such tests in terms of both their specificity and sensitivity. These data further suggest that the relationship of IC to the disease process in SLE may be a complex one.

Complement C1↗
PubMed1988

Natural course of joint destruction and fluctuation of serum C1q levels in patients with rheumatoid arthritis.

Using the number of joints with erosion in a total of 68 joints throughout the body, we studied a population of patients with rheumatoid arthritis whose disease duration was 10-15 years. Three groups, each showing a Poisson distribution, were found: the subset with least erosive disease (LES), the subset with more erosive disease (MES), and the subset with mutilating disease (MUD). The mean number of joints with erosion was 10.9 in LES, 32.2 in MES, and 53.5 in MUD. In LES, erosive articular changes were primarily limited to the peripheral smaller joints. In MES, the larger axial joints were also involved. Almost all joints were extensively damaged in MUD. During the early period of disease, differences between the 3 groups were highly significant in the rapidity of carpal bone destruction, as assessed by the yearly reduction of carpal height ratio (P less than 0.001), and in the serum C1q level (P less than 0.001).

Adult↗
PubMed1988

Evidence for the presence of autoantibodies to the collagen-like portion of C1q in systemic lupus erythematosus.

We investigated the connection between the C1q solid-phase binding assay (C1q SPBA) and double-stranded DNA antibodies, and analyzed the immune complex material in systemic lupus erythematosus (SLE) sera. Comparison with a new monoclonal assay for C1q-bearing immune complexes (the 242G3 assay) revealed that the immune complexes in SLE bind specifically to solid-phase C1q, and not to fluid-phase C1q. The C1q solid-phase binding activity sedimented as 7S IgG, was insensitive to DNase treatment, and could be selectively absorbed by C1q-coupled beads and by bovine serum albumin-anti-bovine serum albumin C1q beads, but not by DNA. Thus, antibodies to double-stranded DNA do not interfere in the C1q SPBA. Isolated IgG from SLE serum precipitated the collagen-like portions, and not the globular, Fc-recognizing portions, of C1q. F(ab')2 fragments of IgG from SLE patient serum were able to bind C1q. These data show that in SLE sera, especially in those with low levels of CH50 and C1q, autoantibodies that react with the collagen-like part of C1q are detectable. Since in the C1q SPBA, the C1q molecule is randomly fixed to the solid phase, we can detect not only immune complexes, but also antibodies that react with the collagen part of C1q; this may explain the high percentage of positive results for SLE sera in the C1q SPBA, in contrast to results of other immune complex assays.

Antigen-Antibody Complex↗
PubMed1981

Circulating immune complexes in patients with benign and malignant colorectal tumours.

Circulating immune complexes were measured using a modified Clq binding assay in 100 preoperative patients with colorectal cancer and in 52 patients with benign polyps. Sixty-one per cent of the patients with cancer and 49 per cent of the patients with benign polyps had elevated levels, as did 92 per cent of those with malignant polyps. There was no relation to a, the stage of the disease, with 10 out of 13 Dukes' A tumours (77 per cent) having increased levels; b, the degree of differentiation of the cancers; c, the tumour mass. However, cancers on the right side of the colon had significantly higher levels than rectal cancers.

Adult↗
PubMed1975

Chemical analysis and electron microscopy studies of human C1q prepared by different methods.

Five differently isolated and purified human C1q preparations were examined by electron microscopy and analyzed by polyacrylamide gel electrophoresis in 0.1% sodium dodecyl sulfate and 0.5 M urea. The amino acid and carbohydrate composition of C1q purified by the DNA method are reported and compared with results obtained on C1q isolated by other procedures. Electron microscopy showed that all C1q preparations had six peripheral subunits connected by fibrillar strands to a central subunit. The presence of small amounts of dimers was also observed. The physico-chemical properties of the molecule are independent of the purification method used. The five C1q preparations labeled with 125I in presence of lactoperoxidase formed two types of noncovalently linked subunits. In each case the smaller (central) subunit contained over thirty times as much radioactivity as the larger (peripheral) subunit supposed to interact with immune complexes. Reduction and alkylation confirmed for each preparation the presence of three polypeptide chains, the smaller of which contained essentially all radioactivity.

Amino Acids↗
PubMed1988

The complement subcomponent C1q mediates binding of immune complexes and aggregates to endothelial cells in vitro.

The present studies were initiated to investigate whether soluble immune complexes, upon interaction with complement, can bind to endothelial cells. Human umbilical vein endothelial cells (HUVE) were incubated with purified human 125I-labeled C1q at 4 degrees C in RPMI-0.5% bovine serum albumin and assayed for binding. Optimal binding of 125I-labeled C1q to HUVE was reached within 2 h, and saturation of binding was found at concentrations of 5 micrograms/well input. The binding of 125I-labeled C1q was inhibitable with unlabeled C1q and by the collagenous region of pepsin-cleaved C1q. No inhibition was observed with the globular heads of C1q, suggesting that C1q binds to HUVE via the collagenous region of C1q. When HUVE were first reacted with various concentrations of C1q, washed and subsequently incubated with 125I-labeled aggregated human IgM (AIgM), binding of 125I-labeled AIgM to HUVE occurred depending on the dose of C1q. Only those aggregates of IgM which react with C1q in a solid-phase C1q binding assay were able to bind to HUVE presensitized with C1q. In addition it was shown that C1q mediated binding of aggregated IgG to HUVE. Furthermore, immune complexes (IC), that were prepared with bovine thyroglobulin (BTg) and rabbit anti-BTg, bound to C1q-preincubated HUVE. These studies suggest that localization of IC on endothelium can be enhanced following interaction of the IC with complement.

Antigen-Antibody Complex↗
PubMed1988

C1q acts synergistically with phorbol dibutyrate to activate CR1-mediated phagocytosis by human mononuclear phagocytes.

The adherence of human monocytes and culture-derived macrophages to surfaces coated with complement subcomponent C1q has been previously shown to enhance Fc receptor (FcR)-mediated phagocytosis by these cells. We examined the effects of C1q on C3b/C4b receptor (CR1)-mediated phagocytosis by mononuclear phagocytes. A small percentage of human monocytes cultured in the presence of serum became competent to ingest sheep erythrocytes bearing IgM and C4b (EAC4b). This phagocytic activity was enhanced when these cultured-derived macrophages were adhered to C1q-coated surfaces. However, when cultured in a defined serum-free medium, these cells did not ingest EAC4b, even in the presence of C1q. To investigate this differential responsiveness, we studied the effects of C1q in conjunction with cell-activating agents on CR1 activation. Treatment of serum-free cultured monocytes with phorbol dibutyrate (PDBu), prior to addition of the targets, induced these cells to ingest EAC4b. In addition, when exposed to C1q, both the percentage of these PDBu mononuclear phagocytes ingesting EAC4b and the number of targets ingested increased threefold over the level achieved by macrophages treated with PDBu alone. The chemoattractant N-formyl-methionyl-leucyl-phenylalanine did not activate CR1-mediated phagocytosis and did not substitute for PDBu in causing synergy with C1q. Freshly isolated monocytes adhered to human serum albumin-coated glass slides in the absence or presence of PDBu did not phagocytose EAC4b. Also C1q did not stimulate monocyte CR1-mediated phagocytosis. However, addition of PDBu to cells adherent to the C1q surface triggered phagocytosis of EAC4b. The concentration of PDBu and the time of addition of PDBu relative to addition of the EAC4b targets were found to be important parameters for the achievement of maximal synergy in both the freshly isolated and cultured cell systems. This enhanced phagocytic activity was also seen with cells adhered to the purified collagen-like, pepsin-resistant, fragment of C1q. Since this region was previously shown to interact with C1q surface receptors, it appears that occupancy of this receptor is triggering events contributing to the enhanced cellular function. These experiments suggest that C1q and PDBu promote ingestion via CR1 by different but synergistic mechanisms. These data also demonstrate that the CR1-mediated enhancement of phagocytosis is not specific for FcR-mediated ingestion, but also applies to phagocytosis via CR1.

Antigen-Antibody Complex↗
PubMed1978

Relevance of circulating immune complexes in childhood acute lymphoblastic leukaemia.

Circulating immune complexes have been measured using the (125I)C1q binding test in 216 sera from 135 children with acute lymphoblastic leukaemia. Increased circulating immune complexes were detectable in 10.7% of the sera and 10.4% of the children. There was no correlation between the presence of circulating immune complexes and prognosis, but a strong correlation with a history of recent infection.

Adolescent↗
PubMed1978

Circulating immune complexes in rats bearing chemically induced tumours. II. Characterization of sera from different stages of tumour growth.

Sera from rats bearing intraperitoneal implants of an aminoazo dye-induced hepatoma were fractionated by Sephadex G200 and DEAE-cellulose ion exchange column chromatography. Isolated fractions were examined for their capacity to bind [125I]C1q as a measure of immune complex levels, and for their ability to bind soluble tumour-specific antigen as well as to react with antigens expressed at the surface of viable hepatoma cells. Elevated levels of circulating immune complexes in unfractionated serum were directly detectable during early tumour development although, following serum fractionation, immune complexes were identified at both early and late stages of tumour growth. The present findings suggest that the detection of immune complexes in unfractionated samples of late tumour-bearer serum using a C1q-binding assay is masked by the increasing production of tumour-specific antibodies and by a shift from complement fixing to non-complement-fixing tumour-specific antibodies.

Animals↗
PubMed1981

Report on international comparative evaluation of possible value of assays for immune complexes for diagnosis of human breast cancer.

There have been several reports on the possible value of measurements of circulating immune complexes for the diagnosis of human breast cancer. To begin to evaluate this possibility and the comparability of results among laboratories, a cooperative study was organized under the auspices of the International Agency for Research on Cancer and the National Cancer Institute (NCI) of the United States. Investigators from four laboratories performing assays for immune complexes were sent coded aliquots of serum specimens from the NCI-Mayo Clinic Serum Bank. The serum panel consisted of specimens from 30 patients with breast cancer (including 20 from untreated patients with resectable tumors), 30 preoperative patients with benign breast disease, and 30 normal women. Although some significant differences in levels of immune complexes between cancer patients and controls were seen, none of the assays had sufficient discriminatory capacity to support optimism about the diagnostic value of this approach. To relate the results with immune complexes to those with a widely used cancer marker, the same sera were also tested for levels of carcinoembryonic antigen (CEA). The CEA assay provided significant discrimination between cancer patients and normal donors but did not significantly discriminate between malignant and benign breast diseases.

Antigen-Antibody Complex↗
PubMed1984

A comparison of the properties of two classes, C4A and C4B, of the human complement component C4.

A remarkable difference has been observed between the reactivity of the two forms of human complement component C4. C4B binds twice as effectively as C4A to antibody-coated red cells, but the reverse occurs with protein-antigen complexes. C4B reacts much more effectively with hydroxyl groups than C4A and this is reversed for reaction with amino groups in spite of the very small difference in amino acid sequence between the two forms of C4. No other differences in stability, activation or inactivation were observed. These findings emphasise the biological advantage of the duplication of the C4 gene in its reaction with a wide range of antigenic structures. The correlation of the presence of different forms of C4 with susceptibility to autoimmune diseases may be explicable by these big differences in binding reactivity.

Amino Acid Sequence↗