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PubMed1992

The proteoglycan decorin binds C1q and inhibits the activity of the C1 complex.

Decorin, a small collagen-binding dermatan sulfate proteoglycan, is widely distributed as a component of extracellular matrices. Using a solid phase binding assay, we showed that decorin bound C1q at physiologic pH and ionic strength. The interaction did not require divalent cations and was time and temperature dependent reaching equilibrium in 4 h at 37 degrees C. Binding was specific and saturable with an apparent dissociation constant of 7.6 x 10(-9) M. Decorin was shown to bind pepsin-derived fragments containing the collagenous domain of C1q and collagenase-derived fragments containing the globular domain of C1q. Because these fragments share a short sequence of amino acids, this finding suggests that decorin binds to a region of C1q located near the junction of the two domains. Competition studies using purified preparations of the decorin core protein and the glycosaminoglycan chains showed that only the former inhibited binding of decorin to C1q indicating that the interaction is mediated by the decorin core protein. Decorin was shown to inhibit the hemolytic activity of purified C1 as well as C1 in normal human serum. Approximately 50% inhibition was observed at a decorin concentration of 2 micrograms/ml. Inhibition was not observed if C1 was bound to Ag-complexed antibody. Furthermore, neither the core protein nor the glycosaminoglycan chain of decorin inhibited C1, indicating that the intact proteoglycan is necessary for functional activity.

Animals↗
PubMed1986

[Immunohistochemical study of lymphoid germinal centers--synovial tissues and lymph nodes of rheumatoid arthritis patients].

Rheumatoid arthritis (RA) is recognized as one of immune complex diseases and often have the lymph follicles with the germinal center (GC) in their synovialis. The author examined the GCs of 41 RA synovialis and 7 RA lymph nodes with massive lymphadenopathy during their clinical courses using the immunohistochemical technique according to Farr and Nakane. In GCs of both RA synovialis and RA lymph nodes, the presence of immunoglobulins (IgM, IgG), early complement components (C1q, C4, C3, C3c, C3d), and monoclonal antibodies (IgM-rheumatoid factor, C3b receptor) expressed themselves in lacy network pattern light-microscopically, and were proved on the surface of follicular dendritic cells (FDCs) and lymphocytes, and in the intercellular space electron-microscopically. Furthermore, the immunostaining for dendritic reticulum cell 1 was found in lacy network pattern light-microscopically and on the cell surface of FDC electron-microscopically. It is possible that both GCs may play an important role in systemic immune response.

Adult↗
PubMed1984

Induction of various autoantibodies by mutant gene lpr in several strains of mice.

The effect of the autosomal mutant gene lpr (lymphoproliferation) on the development of various autoantibodies and immune complex (IC) glomerulonephritis was investigated in four genetically distinct strains of mice: MRL/ MpJ , C3H/HeJ, C57BL/6J, and AKR/J. The presence of the lpr gene not only enhanced the production of autoantibodies in the autoimmune MRL/ MpJ strain, but also induced the formation of various kinds of autoantibodies in the three other strains of mice without any apparent predisposition to autoimmune disease. Autoantibodies induced by the lpr gene included anti-double-stranded DNA, anti-single-stranded DNA, anti-IgG, anti-thymocyte, and anti-serum glycoprotein gp70. This indicates that the action of the lpr gene on the development of autoantibody response does not require the particular abnormalities of the MRL genome. The differences in amounts and types of autoantibodies among the lpr strains reflect the difference in the background genome of each strain, suggesting the participation of other genes or factors determining the quantity and/or specificity of autoantibodies. In addition to the development of autoantibodies, the three nonautoimmune strains of mice produced high levels of unidentified IC in the presence of the lpr gene, detectable by the C1q and the conglutinin binding tests. Their glomerular lesions, however, were relatively limited when compared with MRL/ MpJ -lpr/lpr mice, which developed severe glomerulonephritis early in their life. These results suggest that the lpr gene is able to induce the formation of various autoantibodies and IC at significant concentrations in nonautoimmune mice, but for the full manifestation of systemic lupus erythematosus there may be a requirement for supplemental genetic abnormalities or factors.

Animals↗
PubMed1984

Detection of circulating immune complexes by a Clq/protein A-ELISA during the preneoplastic stages of feline leukemia virus infection.

A microscale ELISA immune complex assay which utilized a solid phase C1q and a Protein A-peroxidase enzyme conjugate is described. This ELISA was used to detect and quantitate circulating immune complexes (CIC) during the initial feline leukemia virus infection. Significant increases in CIC were seen in the cats which were transiently infected at weeks three through eight after viral exposure. A persistent elevation in CIC was observed in the one cat which developed a persistent viremia. The addition of EDTA to the serum strongly interfered with this assay.

Animals↗
PubMed2004

The evaluation of recombinant, chimeric, tetravalent antihuman CD22 antibodies.

PURPOSE: The purpose of this study was to prepare chimeric antihuman CD22 tetravalent monoclonal antibodies (MAbs) with high functional affinity, long persistence in the circulation, increased antitumor activity, and conserved effector function in vitro. EXPERIMENTAL DESIGN: We investigated the association/dissociation rates of these tetravalent antibodies using CD22(+) Daudi lymphoma cells. We then tested their ability to interact with Fc receptors on a human cell line (U937), to mediate antibody-dependent cellular cytotoxicity with human natural killer cells, to bind human C1q, to inhibit the in vitro growth of CD22 Daudi cells, and to persist in the circulation. RESULTS: The rate of dissociation of the tetravalent MAbs versus the divalent antibody was considerably slower. These tetravalent MAbs inhibited the in vitro proliferation of CD22 Daudi cells at a concentration that was at least 100-fold lower than that of the divalent murine antibody. The tetravalent MAbs containing both the CH2 and CH3 domains and a chimeric recombinant divalent antibody bound similarly to Fc receptor, C1q, and mediate antibody-dependent cellular cytotoxicity equally well with human natural killer cells. The persistence in the circulation of chimeric tetravalent MAbs was considerably longer than that of chemical homodimers. CONCLUSIONS: The tetravalent anti-CD22 MAbs with intact Fc regions should make effective therapeutic agents for B-cell tumors.

Animals↗
PubMed1986

The effect of antirheumatic drugs on circulating immune complexes in rheumatoid arthritis.

The relationship between antirheumatic drug treatment and levels of circulating immune complexes (125I-C1q binding activity) has been investigated in a prospective two-year study of patients with rheumatoid arthritis using the erythrocyte sedimentation rate (ESR) and serum C-reactive protein concentration as indices of disease activity. Twenty-eight patients were treated with non-steroid anti-inflammatory drugs, 14 patients had 'second line' drugs and 13 patients were treated with adrenal corticosteroids. Serum 125I-C1q binding activity did not change during non-steroid anti-inflammatory drug treatment; however, immune complex levels did fall during treatment with new (ICI 55,897, sulphasalazine) and established (gold, penicillamine) second line drugs. Serum 125I-C1q binding activity reflected the response to treatment shown by serum C-reactive protein and ESR. Serum C-reactive protein concentration and ESR fell with all doses of adrenal corticosteroids. In contrast, immune complex levels did not fall when doses of adrenal corticosteroids were below 20 mg/day prednisolone. 125I-C1q binding activity fell during high dose adrenal corticosteroid therapy (greater than 40 mg/day prednisolone; 1 g methylprednisolone infusions). Serial measurements of 125I-C1q binding activity correspond to ESR and the serum C-reactive protein concentration in distinguishing between anti-inflammatory drugs, which provide symptomatic relief only, and second line drugs which may retard disease progression. The fall in circulating immune complex levels during 'high' dose corticosteroid treatment, but not during 'low' dose treatment, suggests that corticosteroids have a dose-dependent effect on the immune system in addition to their anti-inflammatory properties.

Adult↗
PubMed1983

Isolation and quantitation of immune complexes in diabetic syrian hamsters: a chronological study.

Immune complexes (IC) were isolated from the serum of streptozotocin (Sz)-induced diabetic hamsters by coprecipitation with an equine rheumatoid-C1q factor (RhC). The IC, comprised of an unknown antigen(s) and IgG, occurred at 2 distinct time intervals during the 12-week chronological study. Although all diabetic hamsters with hyperglycemia of 300 mg/dl had IC, there was no correlation between the occurrence or concentration of IC and the degree of hyperglycemia. The cycling nature of IC in the serum of diabetic hamsters suggests that the antigen component either fluctuates chronologically or that the IC contain different antigens that do not occur simultaneously.

Animals↗
PubMed1987

Measurement of immune complexes with the liquid phase C1q binding assay: ten years experience in a routine diagnostic laboratory.

We describe our 10 years experience in assaying over 15,000 clinical specimens for immune complexes (IC) using the C1q binding assay. Normal ranges were initially established using a large panel of blood donor sera and precision of the assay was optimized by inclusion of heat aggregated IgG (HAGG) as standards. Nevertheless some variability was observed due to variation in C1q binding from batch to batch and with aging of this reagent. In an empirically selected 2 year period involving over 3,000 clinical specimens, 25% had elevated concentrations of IC. Of these the majority were from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), other connective tissue disorders, infective endocarditis (IE), diffuse interstitial lung disease (DILD) and vasculitis (VASC). In RA, IE and VASC, significant correlations were observed between concentrations of IC and rheumatoid factor (RF) and the addition of a purified monoclonal RF to normal serum caused increased C1q binding. Longitudinal studies in RA and IE demonstrated a striking decline in IC in response to effective treatment. We conclude that the measurement of IC provides little additional useful diagnostic information in those diseases associated with high levels of RF but appears more useful in disorders such as SLE, IE and DILD in which RF is absent or present in low concentration. Sequential monitoring of IC in RA and IE reflects response to treatment.

Antigen-Antibody Complex↗
PubMed1987

A substrate amplification system for enzyme-linked immunoassays. Demonstration of its general applicability to ELISA systems for detecting antibodies and immune complexes.

Self recently described a substrate system for alkaline phosphatase (AP)-dependent ELISAs which markedly increased sensitivity, compared to using p-nitrophenyl phosphate. This increase is achieved by having AP, the primary enzyme, produce an activator for a secondary enzyme-substrate system, within which marked amplification occurs. We adapted this technique to study antibodies to casein, bovine serum albumin, ovalbumin, and cardiolipin in the sera of patients with systemic lupus erythematosus (SLE) and normal individuals. The new substrate system yielded titres 30-50-fold higher than those with p-nitrophenyl phosphate (Sigma 104, p-NPP). In addition, when used in a solid-phase C1q binding assay we were able to use a 1 : 100,000 dilution of AP-conjugated anti-human IgG with the amplified substrate, compared to the 1 : 1000 dilution needed with p-NPP. This system is extremely valuable because of its flexibility. It can either be very sparing of limited samples, or if the added sensitivity is not needed, 100-fold less AP conjugate may be used. Thus rare or expensive conjugates can be significantly conserved.

Animals↗
PubMed1994

Serologic markers of lupus nephritis in patients: use of a tissue-based ELISA and evidence for immunopathogenic heterogeneity.

In order to assess the ability of various serologic assays to correlate with lupus nephritis, we analysed sera obtained from 60 patients with systemic lupus erythematosus (SLE). Patients were categorized as having active nephritis (group 1), active lupus without nephritis (group 2), inactive lupus with prior nephritis (group 3), or inactive lupus without prior nephritis (group 4). Three parameters were assessed including anti-dsDNA antibodies (Farr assay), immune complexes (C1q binding), and anti-C1q antibodies (salt-stable C1q binding). Additionally, glomerular binding activity (GBA) was measured using a new solid-phase immunoassay that detects immune elements by their ability to bind glomerular tissue. We found that patients with nephritis (group 1) exhibited higher mean values for each assay than patients in each of the other three groups (P = 0.001, 0.009, 0.14, and 0.23 in the GBA, C1q, anti-dsDNA, and anti-C1q assays, respectively). The only assay which distinguished patients with nephritis (group 1) from patients having active disease without nephritis (group 2) was the GBA (mean 0.48 +/- 0.09 versus 0.15 +/- 0.04, P < 0.05). In terms of utility, all tests were specific for diagnosing nephritis among patients with lupus; however, only the GBA was reasonably sensitive. The information provided by the anti-dsDNA and C1q assays were not correlated with one another, nor additive to the GBA. Patients with false negative GBA tended to have received more intensive immunosuppression. The qualitative characteristics of GBA varied among patients with nephritis. These data suggest the pathogenesis of lupus nephritis is complex, and may be mediated by an array of immune elements. Moreover, the data indicate the potential utility for a broad tissue-based approach to detection of pathogenic immune elements over other, specific immunologic markers.

Antibodies, Antinuclear↗
PubMed1985

Interaction of fibronectin with C1q and collagen. Effects of ionic strength and denaturation of the collagenous component.

By attaching native collagen and C1q to Sepharose, it was possible to test the binding of fibronectin (Fn) to the native and heat-denatured forms of these proteins without complications due to aggregation, precipitation, or fibril formation. Binding to the native proteins occurred only at low (sub-physiological) ionic strength whereas binding to the denatured proteins occurred even in 1 M NaCl. Thus both of these proteins possess one or more strong sites which are masked in the native state and become exposed during thermal denaturation. Fn did not bind to albumin-Sepharose or IgG-Sepharose either before or after heat-denaturation. C1q bound readily to native IgG-Sepharose but did not mediate the binding of Fn. Nor did Fn inhibit the reconstitution of C1 on antibody-coated erythrocytes. The fluorescence polarization of fluorescein-labeled collagen in 1 M NaCl displayed a downward transition at 38-40 degrees C consistent with unfolding of the triple helix. In the presence of Fn, the same material displayed an upward transition at slightly lower temperature suggesting that gross unfolding is not required to expose the strong binding site(s).

Affinity Labels↗
PubMed1998

Characterization of the murine gene of gC1qBP, a novel cell protein that binds the globular heads of C1q, vitronectin, high molecular weight kininogen and factor XII.

gC1qBP is a novel cell protein which was found to interact with the globular heads of C1q, high mol. wt kininogen, factor XII and the heparin-binding, multimeric form of vitronectin. The protein sequence shows no homology to any protein family. This paper describes the genomic organization of mouse gC1qBP and the characterization of its 5' flanking region. The mouse gene consists of six exons separated by five introns, and its total length is approximately 6kb. Exon 1 encodes the putative signal peptide, a long stretch of 70 amino acid residues, and the first four amino acid residues found in the mature gC1qBP. Exons 2-5 encode four very hydrophilic domains, whereas exon 6 encodes a neutral domain. The amino acid sequence responsible for binding to the heparin-binding, multimeric form of vitronectin is located in exon 2. A 1kb DNA fragment upstream of the first initiation codon was sequenced, which contained four potential TATA boxes, seven CAAT boxes, six SP1 sites and various putative transcription factor-binding elements, indicating that the promoter region is in close proximity to the first exon. The mouseC1qbp gene was mapped to chromosome 11, closely linked to D11Mit4 using genomic DNAs from a (C57BL/6J x Mus spretus)F1 x Mus spretus backcross.

Amino Acid Sequence↗
PubMed1988

Circulating immune complexes in systemic lupus erythematosus: a reappraisal of the solid phase C1q radioimmunoassay.

Data from a pool of 150 patients with systemic lupus erythematosus (SLE) were used to evaluate the clinical usefulness and specificity of the solid phase C1q radioimmunoassay (SPC1q RIA) for circulating immune complexes (CIC). We found that the assay results correlated with the severity of lupus nephritis but that they did not adequately reflect or predict disease activity so as to directly influence decisions regarding treatment. In addition, the contribution of non-IC reactants to the assay results was found to be of some concern. Finally, we could not demonstrate the presence of anti-DNA antibodies in CIC from patients with SLE.

Antigen-Antibody Complex↗
PubMed1984

Intravenous gammaglobulin treatment in patients with hypogammaglobulinaemia.

Intravenous gammaglobulin was compared with the standard British intramuscular preparation in patients with hypogammaglobulinaemia and chronic bronchitis. Five patients were given six months' treatment with the weekly intramuscular preparation and six months' treatment with intravenous gammaglobulin given once every 18 days. During the trial they recorded symptoms of infection, absence from work, and sputum volume; lung function tests were performed during the intravenous treatment. The half life of the intravenous IgG and changes in serum IgG and C1q concentrations were also measured in seven other patients who received intravenous gammaglobulin every two weeks for 12 weeks. IgG concentrations, sputum volume, and infection scores were significantly better during intravenous treatment and there were no adverse effects from the intravenous gammaglobulin. These five patients were significantly more healthy when they received an intravenous gammaglobulin preparation, probably because the intravenous preparation increased serum IgG concentrations. Although longer studies are needed, intravenous gammaglobulin should be considered for patients with severe chest disease and those who cannot tolerate intramuscular injections.

Agammaglobulinemia↗
PubMed1994

Comparative immunohistochemical characteristics of human choroid plexus in vascular and Alzheimer's dementia.

Autoimmune alterations are indirectly supported in Alzheimer's disease by the demonstration of circulating antibodies directed to the epithelial basement membrane (BM) of the choroid plexus. We used immunohistochemical methods to compare the characteristics of choroid plexuses obtained postmortem from 15 patients. Six had a diagnosis of Alzheimer's disease, five had multi-infarct dementia (MID), and one suffered from mixed dementia. Similar tissue from three age-matched, non-demented controls was studied as well. Age-related psammoma bodies, lipofucsin, and flattened epithelial cells were present in all cases. Specific alterations were evident in Alzheimer's disease patients only. These were comprised of pseudolinear deposits of immunoglobulin (Ig)G and coarse deposits of C1q along the thickened and segmented epithelial BM, and were associated with IgM in five cases. Although no lymphoid infiltration was demonstrated, MHC Class II+ macrophages were observed in the plexus stroma, and numerous epithelial cells were class II+. These observations suggest that immune alterations, possibly of autoimmune origin, may be involved in Alzheimer's disease, leading to severe lesions of the choroid plexus. Such anomalies could be responsible for some of the alterations of cerebrospinal fluid (CSF) production or composition noted in this disease.

Aged↗
PubMed1986

Flow cytometric detection and quantitation of immune complexes using human C1q-coated microspheres.

A solid phase human C1q-binding fluorescent immunoassay for the measurement of immune complexes in human serum was developed. The solid phase used was 5 micron diameter polystyrene microspheres. Serum immune complexes bound to the C1q-coated microspheres were measured by flow cytometry using fluoresceinated anti-human IgG, and heat-aggregated human IgG as a standard. Patient samples were assayed and results compared to a standard fluoroimmunometric C1q-binding immune complex assay. Greater differences in circulating immune complexes were observed between the healthy control group mean and the mean of the patient values in the microsphere-flow cytometric method than were seen in the standard assay. In the microsphere-flow cytometric assay, the mean patient value was 7.5 times greater than the control mean, whereas in the standard assay the mean patient value was 2.8 times the control mean. Preliminary results suggest greater sensitivity of the microsphere-flow cytometric method over the other method.

Antigen-Antibody Complex↗
PubMed2001

Hereditary angioedema: a broad review for clinicians.

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

Acute Disease↗
PubMed1986

Anti-C1q affinity isolated circulating immune complexes correlate with extra-articular rheumatoid disease.

Circulating immune complexes (CIC) were isolated from sera of 35 patients with rheumatoid arthritis (RA) by a two-step method using 2% polyethylene glycol precipitation and anti-C1q affinity chromatography. By this method CIC were exclusive to 19 patients with vasculitis, nodules, or Sjögren's syndrome. Levels of CIC did not correlate with the severity of synovitis but reflected the extent of extra-articular disease. Furthermore, in four patients with persistent severe synovitis observed over a period of 4 to 16 months, the levels of CIC paralleled changes in extra-articular disease. Despite such additional evidence, whether the relationship between CIC and tissue injury is causative or consequential remains unresolved.

Aged↗