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PubMed1996

Characterization of the binding of serum amyloid P to type IV collagen.

Serum amyloid P (SAP), a member of the evolutionarily conserved pentraxin family, is a normal component of a number of basement membranes, including glomerular and alveolar. In vitro SAP binds to a variety of proteins including fibronectin, proteoglycans, and the collagen-like region of the complement component C1q. In these studies, binding of SAP to type IV collagen, a major component of basement membrane, was examined. Purified SAP binds to human and mouse type IV collagen but not type I, II, or III collagens. Binding of SAP to type IV collagen is dependent on the presence of Ca2+. This binding is saturable with a Kd approximately 1.2 x 10(-7) M based on solid phase binding and 4 x 10(-8) M based on the IC50 value from fluid phase binding data. Binding of SAP to type IV collagen was inhibited by both SAP and C-reactive protein (CRP). However, a 5-fold molar excess of CRP as compared with SAP was required to inhibit the SAP binding by 50%. Binding of SAP to type IV collagen was inhibited by both collagen IV and C1q but not by phosphatidylethanolamine or bovine serum albumin. The inhibition data indicate that SAP may bind to the triple helical region of type IV collagen via a site distinct from its galactan binding site. The most likely site of SAP involved in its interaction with type IV collagen may be the region spanning amino acid residues 108-120, which shows a great deal of sequence homology (60% strict identity) with the CRP region implicated in its binding to the collagen-like region of the C1q molecule.

Animals↗
PubMed2002

Surfactant protein A enhances the phagocytosis of C1q-coated particles by alveolar macrophages.

Surfactant protein-A (SP-A) plays multiple roles in pulmonary host defense, including stimulating bacterial phagocytosis by innate immune cells. Previously, SP-A was shown to interact with complement protein C1q. Our goal was to further characterize this interaction and elucidate its functional consequences. Radiolabeled SP-A bound solid-phase C1q but not other complement proteins tested. The lectin activity of SP-A was not required for binding to C1q. Because C1q is involved in bacterial clearance but alone does not efficiently enhance the phagocytosis of most bacteria, we hypothesize that SP-A enhances phagocytosis of C1q-coated antigens. SP-A enhanced by sixfold the percentage of rat alveolar macrophages in suspension that phagocytosed C1q-coated fluorescent beads. Furthermore, uptake of C1q-coated beads was enhanced when either beads or alveolar macrophages were preincubated with SP-A. In contrast, SP-A had no significant effect on the uptake of C1q-coated beads by alveolar macrophages adhered to plastic slides. We conclude that SP-A may serve a protective role in the lung by interacting with C1q to enhance the clearance of foreign particles.

Animals↗
PubMed1996

Safety and immunogenicity of a Pseudomonas aeruginosa outer membrane protein I vaccine in human volunteers.

The outer membrane protein I (OprI) of Pseudomonas aeruginosa was expressed in Escherichia coli and purified by Ni2+ chelate-affinity chromatography. After safety and pyrogenicity evaluation in animals, four groups of seven adult human volunteers were vaccinated three times at four week intervals with either 500 micrograms, 200 micrograms, 50 micrograms or 20 micrograms of OprI adsorbed onto Al(OH)3. All vaccinations were well tolerated and no systemic side effects were detected. A significant rise of antibody titers against OprI could be measured in the serum of all volunteers who had received the 500 micrograms, 200 micrograms or 50 micrograms doses. Elevated antibody titers against OprI could still be measured 30 weeks after the final vaccination. Binding of the complement component C1q to the elicited antibodies could be demonstrated, showing the ability of the latter to promote antibody-mediated complement-dependent opsonization.

Adult↗
PubMed1995

Activation of effector functions by immune complexes of mouse IgG2a with isotype-specific autoantibodies.

Analysis of five monoclonal autoantibodies, rheumatoid factors produced by hybridomas generated from spleen cells of BALB/c mice repeatedly infected with A/PR/8/34 human influenza A virus, revealed that they recognized distinct but spatially related epitopes. The differing isoallotypic specificity of the IgM and IgA monoclonal antibodies correlated with the presence of Ile258 and Ala305, respectively. Although these data suggest that the epitopes recognized are within the CH2 domain, all antibodies failed to inhibit IgG antigen reactivity with Staphylococcus aureus protein A (SpA), C1q, mouse C3, human Fc gamma RI or mouse Fc gamma RII, activities known to be predominantly determined by CH2 domain structures. Reactivity of the IgA antibody, Z34, with IgG2b allowed further specificity studies using a panel of 26 mutant IgG2b proteins, each having single amino acid replacements over the surface of the CH2 domain. The only substitution that affected Z34 reactivity was Asn/Ala297, which destroyed the glycosylation sequon, resulting in secretion of an aglycosylated IgG molecule. The epitope recognized by Z34 therefore seems to be located outside of the Fc gamma R and C1q binding sites, but to be dependent on the presence of carbohydrate for expression. In contrast to the binding studies, complement activation by aggregated IgG2a, through classical or alternative pathways, was inhibited by the presence of autoantibodies. The functional significance of isotype-specific autoantibody in immune regulation is discussed.

Animals↗
PubMed1996

Biosynthesis of human ficolin, an Escherichia coli-binding protein, by monocytes: comparison with the synthesis of two macrophage-specific proteins, C1q and the mannose receptor.

Ficolin is characterized by the presence of both collagen-like and fibrinogen-like sequences, and potentially has a similar overall structure as the complement protein C1q and the collectins. Previous studies have reported the presence of human ficolin mRNA predominantly in peripheral blood leucocytes. In the present study, the cellular origin of human ficolin was investigated in further detail. Preliminary studies using reverse transcriptase-polymerase chain reaction (RT-PCR) showed that ficolin mRNA was synthesized by U937 cells, a human monocyte cell line. This finding suggested that blood monocytes also normally synthesize human ficolin. Peripheral blood monocytes from adult human donors were harvested at serial time-points (0-20 hr) after adhesion to tissue culture plates, and total RNA was isolated and assayed for ficolin mRNA by RT-PCR. Ficolin mRNA was highly expressed in monocytes throughout the first 20 hr of adhesion. In contrast, C1q and mannose receptor mRNA were not detectable during the first 8 hr of adhesion, but were highly expressed by 20 hr. Cells were harvested at longer time intervals (1, 2, 4, 6 and 8 days) to determine whether ficolin expression was temporally regulated at later stages of monocyte differentiation. Ficolin mRNA levels decreased sharply from day 1 to day 6. In contrast, the levels of both C1q and mannose receptor mRNA showed no changing trend. These results are consistent with the absence of ficolin expression in many macrophage-rich tissues previously reported. The origin of ficolin from monocytes, together with its structural similarity to C1q and the collectins, raises the possibility that ficolin may be another plasma protein capable of binding to surface structures of micro-organisms. Escherichia coli was therefore incubated with human serum, and bound proteins, after elution with sugars, were analysed by Western blotting using an antiserum raised against a synthetic ficolin peptide. The antiserum identified a polypeptide of approximately 42000 MW, which is similar in size to that of ficolin as predicted from its cDNA-derived sequence.

Blotting, Western↗
PubMed1990

Significance of urinary complement components in various glomerular diseases.

The concentrations of two components of the complement system (C1q and C3) were measured in the urine and blood in 10 normal subjects and 134 patients with primary and secondary glomerulonephritis by using a highly sensitive enzyme immunoassay. The values of urinary excretion of C1q and C3 were well correlated to the ratios of fractional clearance of these complement proteins to that of neutral dextran of 55 A, which was used to minimize the influences of glomerular sieving because of their comparable molecular size to these complement components. The rate of renal tubular reabsorption of C1q and C3 were at least 89.2 and 93.4% of filtrated C1q and C3, respectively. Urinary C1q and C3 were excreted significantly in cases of membranoproliferative glomerulonephritis (MPGN), membranous glomerulonephritis, IgA nephropathy with both mesangial and capillary immune complex (IC) deposit and also in case of active lupus nephritis. On the other hand, the concentrations of these complement components were low in case of minimal lesion nephrotic syndrome, mild proliferative glomerulonephritis, inactive lupus nephritis and diabetic nephropathy without any immune staining. There was a significant correlation between the urinary excretion of C1q or C3 and intraglomerular IC deposition, especially IC deposition along the glomerular capillary wall. However, the degree of the excretion of these proteins was not correlated to the degree or permselectivity of proteinuria. The correlations between urinary C1q and C3 were observed in cases of IgA nephropathy with both mesangial and capillary deposit and MPGN, although we couldn't see the correlation in the other glomerular diseases. It is suggested that urinary excretion of such complement components represents the fixation of complement by deposited intraglomerular IC. The measurement of urinary concentration of these complement components provides a new clue to investigation or diagnosis of glomerular diseases.

Arginine↗
PubMed1996

Evidence for endogenous C1q modulates TNF-alpha receptor synthesis and autocrine binding of TNF-alpha associated with lipid A activation of murine macrophages for nitric oxide production.

The role of endogenously synthesized complement subcomponent C1q on autocrine binding of tumor necrosis factors (TNF-alpha) and on TNF-alpha receptor (TNF-R) mRNA synthesis by mouse macrophages was investigated. Activation of C3H mouse peritoneal macrophages (C3H-PM phi) by Lipid A induced TNF-alpha and nitric oxide (NO) to kill tumor targets. Such activation also increased macrophage-endogenous C1q synthesis and secretion in a dose-dependent fashion. Antibody for C1q markedly inhibited C3H-PM phi NO production in response to Lipid A, but had no effect on TNF-alpha production. C3H-PM phi treated with C1q or Lipid A displayed increased TNF-R mRNA synthesis and in combination with Lipid A and anti-C1q antibody inhibited TNF-R and nitric oxide synthase (NOS) mRNA synthesis compared with Lipid A only, but had no effect on TNF mRNA synthesis. In vitro treatment of C3H-PM phi with C1q also increased TNF-alpha binding to their surfaces. Taken together, the data indicate that endogenously synthesized C1q is operative in promoting TNF-R mRNA synthesis and resultant autocrine binding of TNF-alpha for induction of NOS in the process of NO-mediated tumor cytotoxicity by Lipid A-activated macrophages.

Adjuvants, Immunologic↗
PubMed1985

Immunohistochemical findings in acute atherosis associated with intrauterine growth retardation.

Lesions of acute atherosis in 23 placentas from pregnancies complicated by fetal growth retardation (less than tenth percentile) were studied by an immunoperoxidase staining. Twelve of them were from normotensive pregnancies, ten complicated by pregnancy induced hypertension, and the remaining associated with systemic lupus erythematosus. Twenty-three placentas with physiological changes of the spiral arteries corresponding to normal pregnancies served as controls. Six of the cases complicated by fetal growth retardation showed absence of physiological changes in basal decidua. Massive intramural granular deposits of IgM, a smaller amount of C3 and C1q, and slight deposits of IgA and IgG were found in vessels with acute atherosis. No intramural deposition of immunoglobulins or complement was observed in vessels with or without physiological changes. The presence of granular deposits of immunoglobulins and complement within the vessel walls with acute atherosis may be related to an immunological disorder, probably mediated by immune complexes.

Acute Disease↗
PubMed1982

Structural and functional studies in C1q deficiency.

The sera of two brothers were found totally lacking hemolytic C activity. One of them, a 16-yr-old male, presented a severe lupus-like syndrome, whereas the other was apparently healthy. Immunochemical quantitation of C components in both sera showed depressed levels of C1q, whereas the levels of C1r, C1s, and C1 inhibitor were elevated. C4, C3, C5, factor B, and beta 1H levels were in the normal range. Hemolytic C1 activity was totally lacking. C4 titers were elevated (150% of normal). C2 hemolytic activity was about one-third of normal, and the titers of the terminal components C3-C9 were also reduced in the two siblings. Double immunodiffusion against anti-C1q antiserum showed a partial loss of C1q antigenic determinants in the two siblings. Furthermore, the C1q of both siblings was unable to interact with immunoglobulins or to associate with C1r and C1s. Addition of purified human C1q to the sera restored their total C and C1 hemolytic activity. The dose response to the C1q addition was linear, indicating that the functional deficiency was not due to the presence of a serum inhibitor. Although antigenically deficient in comparison with normal C1q, the abnormal C1q appeared to have a larger m.w., as determined by gel chromatography. Investigation of other members of this family suggests a genetically linked disorder, because four out of six siblings had the same dysfunctional C1q in their serum.

Adolescent↗
PubMed2005

Complexes between C1q and C3 or C4: novel and specific markers for classical complement pathway activation.

Classical pathway activation is often assessed by measuring circulating levels of activated C4. However, this parameter does not discriminate between activation through the classical or the lectin pathway. We hypothesized that during classical pathway activation, complexes are formed between C1q and activated C4 or C3. Using ELISA, we investigated whether such complexes constitute specific markers for classical pathway activation. In vitro, C1q-C3d/C4d complexes were generated upon incubation of normal recalcified plasma with aggregated IgG or an anti-C1q mAb that activates C1 (mAb anti-C1q-130). In contrast, during incubation with C1s or trypsin, C1q-C3d/C4d complexes were not generated, which excludes an innocent bystander effect. Additionally, C1q-C3d/C4d complexes were not generated during activation of the alternative or the lectin pathway. Repeated freezing and thawing did not influence levels of C1q-C3d/C4d complexes in recalcified plasma. To measure C1q-complement complexes in plasma samples, we separated unbound complement proteins from C1q-C3d/C4d complexes in the samples prior to testing with ELISA. In samples from patients undergoing cardiopulmonary bypass surgery or suffering from rheumatoid arthritis, we found higher levels of C1q-C4 complexes than in samples from healthy individuals. We conclude that complexes between C1q and C4 or C3 are specific markers of classical complement pathway activation.

Arthritis, Rheumatoid↗
PubMed1987

[Complement activation after the intravascular administration of contrast media: a comparison between ionic and nonionic x-ray contrast media].

The effects of intravascular radiographic contrast media on the complement system were investigated in 46 patients. An ionic (sodium-/meglumine amidotrizoate, n = 22) or a non-ionic (iohexol, n = 24) contrast agent was applied for an i.v. urography. The levels of the complement-compounds C1q, C3, C5 and of the C1 inhibitor were determined at the end of the infusion and 20 minutes later. In both groups we obtained a significant (p less than 0.01) decrease of C3 during infusion for 10 to 15%. 20 minutes later these values were almost normalized again. Infusion of iohexol additionally caused a marked consumption of C5 and C1q (reduction to 85%), while the ionic contrast agent had no significant effect on these components. Both contrast media caused a decrease of the C1-inhibitor levels. Our results demonstrate an activation of the complement system by i.v. application of radiographic contrast media. The decrease of the C1q-level due to infusion of iohexol indicates an additional involvement of the classical activation pathway of the complement cascade.

Complement Activating Enzymes↗
PubMed2005

Immunoperoxidase versus immunofluorescence in the assessment of human renal biopsies.

BACKGROUND: For half a century, immunofluorescence (IF) on frozen sections has been the gold standard for immunohistochemical evaluation of renal biopsy specimens. In routine diagnostic immunohistopathologic evaluation, traditional IF has been replaced to a large extent by immunoperoxidase (IP) methods applied to paraffin sections of formaldehyde-fixed tissue. This is caused in part by the practical disadvantages inherent in the IF method, eg, separate tissue specimen and handling, UV microscopy, fading and impermanence of the label-making archiving, and difficult later investigation. Our aim for the present study is to evaluate IP as an alternative to IF in the diagnostic assessment of renal biopsy specimens. METHODS: Proteolytic antigen retrieval, antibodies effective on deparaffinized sections, a sensitive detection system (Dako EnVision HRP; Dako, Copenhagen, Denmark), and a standardized and rigorously controlled procedure were applied to a series of renal biopsy specimens (n = 81) previously classified by means of light microscopy (LM) and IF. Staining for immunoglobulin G (IgG), IgA, IgM, C1q, and C3c were recorded as positive or negative for IF and IP in paired proportions, presuming that IF was the test standard. RESULTS: Concordant observations were 71% for all (282 of 398 observations), 82% for IgG (65 of 79 observations), and 89% for IgA (72 of 81 observations). The majority of discordant observations (74 of 116 observations) were positive by means of IP, with mesangial deposits of IgM and C1q that were not found by IF. Statistically, there was no significant difference in outcomes between IF and IP for IgG, IgA, and C3c ( P > 0.2). In addition, IP staining allowed simultaneous evaluation of tissue by LM and therefore correlation between tissue structure and immune deposits not readily attained by IF. CONCLUSION: In the present study, it is documented that for the detection of IgG, IgA, and C3c, IP applied to protease-digested deparaffinized sections of formaldehyde-fixed renal tissue is, with few exceptions, equal to IF on frozen sections. The EnVision HRP method used here is several times more effective in terms of primary antibody dilution than earlier existing IP methods, and because the avidin-biotin system is not involved, very little nonspecific background staining will occur. Discordant observations (116 of 398 observations; 29%) were in the majority (91 of 116 observations) due to positive IP findings of IgM and C1q, which deserve additional investigation.

Biopsy, Needle↗
PubMed2003

Cutting edge: proliferating fibroblasts respond to collagenous C1q with phosphorylation of p38 mitogen-activated protein kinase and apoptotic features.

Interactions of C1q collagen tails with human fibroblasts induce G(1) mitotic arrest. The hypothesis tested in this study is that the antiproliferative effect of C1q tails is mediated through activation of stress responsive pathway(s). Upon C1q treatment, proliferating fibroblasts were examined by immunoblotting with a panel of Abs to the mitogen-activated protein kinase (MAPK) superfamily. The cells selectively increased phosphorylation of p38 MAPK, upstream dual activator MAPK kinase 3/6, and downstream transcription factors activating transcription factor 2, ETS domain transcription factor 1, and C/EBP homologous protein in a time-dependent manner. Phosphorylations were mediated, in part, by ligation of surface C1q tail-binding calreticulin. These events correlated with the appearance of apoptotic nuclei and DNA fragmentation in the cultures, which increased with a time response curve. The apoptotic features were linked to p38 activities because the selective inhibitor SB203580 prevented both phosphorylation of the pathway and DNA fragmentation. Hence, p38 activation might provide a molecular basis for linking mitotic arrest and apoptosis of fibroblasts by C1q tails.

Adult↗
PubMed1995

Local versus systemic immunoreactivity to collagen and the collage-like region of C1q in rheumatoid arthritis and SLE.

In this paper we discuss recent data concerning immunoreactivity on the one hand to the cartilage derived molecule type II collagen (CII) and on the other hand to the complement factor C1q, in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). By using the ELISPOT method we have been able to show that production of antibodies to CII and to C1q is common in inflamed joints but not in the periphery of RA-patients, whereas production to C1q is commonly seen in the circulation of active SLE patients. Previously an immunological cross-reactivity has been described between these two proteins. The possibility of in vivo cross-reactivity between these two molecules might have consequences for the different disease manifestations in RA and SLE. This paper also stresses the importance of single cell analysis of antibody production when evaluating local antibody production in different body compartments and also when the aim is to assay changes in antibody production over time.

Animals↗
PubMed1994

Collectins, collectin receptors and the lectin pathway of complement activation.

The collectins are a group of soluble multimeric lectins, which contain collagenous segments, and resemble the complement protein C1q in aspects of their structures and functions. This group of proteins, which includes MBP, SP-A, SP-D, conglutinin and CL-43, are known to act as opsonins in various circumstances, and are likely to have roles in innate immunity. The focus of current research is to pursue the hypothesis that the collectins recognize and bind to non-host carbohydrate structures on microorganisms and particles, and participate in the processing or elimination of such material, either by direct interaction with phagocytic cell receptors, or by indirect routes such as complement activation .

Animals↗