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PubMed1988

An analysis of the fluid phase C1q binding assay. The effect of endogenous C1q on the precipitation and detection of an immune complex model.

We examined the effect of endogenous C1q on the sensitivity of the fluid-phase C1q binding assay (C1qBA) in detecting an immune complex (IC) model, heat-aggregated IgG (HAIgG), at concentrations of 10-10,000 micrograms/ml sample. Results in normal human serum (NHS) or plasma (NHP) were compared with those in heat-inactivated NHS (NHS/56) in which most endogenous C1q was depleted by heat denaturation. Higher HAIgG concentrations were required in NHP and NHS to produce the same 125I-C1q precipitation seen in NHS/56. This decreased sensitivity varied from 70% at low HAIgG concentrations to 0% at high concentrations, as predicted for a large pool of endogenous C1q, in equilibrium with 125I-C1q, but in excess of that which could bind to all but the highest concentrations of IC model. In serum depleted of functional C1q on an immunoadsorbant of HAIgG, the precipitation of radiolabeled HAIgG under C1qBA conditions was concentration dependent and generated a saturation curve, showing that only a fraction of IC are usually precipitated in this assay. HAIgG precipitation was enhanced 1.4-fold in NHS/56 (8 micrograms C1q/ml) and three-fold in NHS (67 micrograms C1q/ml) suggesting that IC size is increased by endogenous C1q. In dual label experiments using 131I-HAIgG, the precipitation of 125I-C1q in NHS/56 was directly proportional to IC model precipitation, but markedly discordant in NHP, showing the measurement of IC in heat-inactivated sera superior to that in native serum. A comparison of the C1q:HAIgG ratio in PEG precipitates with that in samples, indicated that equilibrium was established between C1q and IC model. Thus the precipitation of 125I-C1q in the C1qBA represents (1) the fraction of total C1q bound to IC, and (2) the fraction of IC precipitated by PEG.

Antigen-Antibody Complex↗
PubMed1989

Family study of natural killer cell activity in C1q-deficient patients with systemic lupus erythematosus-like syndrome: association between impaired natural killer cell function and C1q deficiency.

Impaired natural killer (NK) cell activity has been found in patients with systemic lupus erythematosus (SLE)-like syndrome. The mechanism by which NK cell function is impaired in SLE patients is not quite clear. We report here a family study of NK cell activity in C1q-deficient patients with SLE-like syndrome. In both SLE-active and SLE-inactive stages of the disease, NK cell function was significantly impaired when compared with the healthy controls (10.6 +/- 2.3% and 16.9 +/- 4.8% to 34.7 +/- 9.6%, p less than 0.025). On the other hand, differences in NK cell cytotoxicity between SLE-active and SLE-inactive members of the family were not statistically relevant (p less than 0.1). Further, we found no correlation between NK cell activity and clinical or laboratory values, except for a positive correlation between function of NK cells and C1q and CH50 values, respectively (rs = 0.93, 0.01 less than p less than 0.02). To our knowledge, this is the first report on a notable association between impaired NK cell activity and C1q deficiency. The type of inheritance of C1q deficiency in this family is also discussed.

Adult↗
PubMed1994

Enhanced aggregation and beta structure of amyloid beta peptide after coincubation with C1q.

Several lines of evidence now suggest that aggregation of soluble amyloid beta peptide (A beta) into a cross beta sheet configuration may be an important factor in mediating potential neurotoxicity of A beta. Synthetic A beta has been shown to self aggregate in vitro. Here, we demonstrate that coincubation of freshly solubilized A beta with C1q, a complement component known to bind A beta in vitro and to colocalize with A beta in vivo, results in as much as a 7-fold enhancement of A beta aggregation, as well as a 2-4-fold enhancement of beta structure within aggregates. The addition of C1q to preformed A beta aggregates also results in significantly increased resistance to aggregate resolubilization.

Amyloid beta-Peptides↗
PubMed1981

The interference of fibrinogen and heparin with the determination of circulating immune complexes in the C1q-binding assay.

When citrate plasma and serum of the same individual were tested simultaneously in the C1q-binding assay (C1qBA), binding levels in plasma were found to be 90-400% higher than in serum. The difference in 125I-Clq binding was due to the presence of fibrinogen in plasma. It was shown that complex formation between fibrinogen and 125I-Clq occurs and that this complex precipitates in the presence of polyethylene glycol, leading to the false positive results in the ClqBA. When heparin plasma was used to the assay, heparin itself also induced an increase in 125I-C1q binding that was not based on the presence of immune complexes. The effect of both fibrinogen and heparin could be inhibited by addition of protamine sulphate. Therefore, pretreatment of plasma with protamine sulphate makes it possible to use plasma samples for a reliable determination of C1q-binding levels. However, serum that is well clotted should be used preferentially.

Antigen-Antibody Complex↗
PubMed1994

Probing the C1q-binding site on human C-reactive protein by site-directed mutagenesis.

We have used oligonucleotide-directed site-specific mutagenesis to investigate structural determinants of the C1q-binding site of C-reactive protein (CRP). Eleven mutant rCRP cDNAs, D112N; D112A; D112K; D112E; K114T; K114A; K114E; K114R; R116L; D112N, K114T; and D112N, R116L were constructed and expressed in COS cells. Wild-type (wt) and all mutant rCRPs bound to phosphocholine-substituted BSA and also to pneumococcal C-polysaccharide with apparent avidities similar to native CRP, except for the R116L mutant which bound slightly less avidly. Substitution of Asn, Ala, or Lys for Asp-112 resulted in decreased avidity of ligand-bound CRP for C1q and also in decreased C-activating efficiency as estimated from a C3-fragment deposition assay. However, complexes of the D112E mutant reproducibly bound better to C1q and activated the classical pathway more efficiently than wt rCRP. Substitution of Thr, Ala, or Glu for Lys-114 increased the avidity for C1q by 2- to 3-fold and the efficiency of classical pathway activation by 20- to 30-fold compared with wt CRP. In contrast, the K114R mutant was only slightly different from wt CRP. Substitution of Leu for Arg-116 did not significantly affect C1q-binding but resulted in increased C-activating efficiency. The data indicate that the negative charge of residue Asp-112 plays a major role in the formation of the C1q-binding site of CRP and that the positively-charged residue Lys-114 and to a lesser extent also Arg-116 play important but indirect roles in C1q-binding and activation of C by CRP complexes.

Amino Acid Sequence↗
PubMed1983

C1q and C3bi binding activities of the components of a plasmin-treated human immunoglobulin preparation.

Each of the three major components isolated from a commercial plasmin-treated human immunoglobulin preparation, namely, the plasmin-resistant 7S IgG fraction (PRG), Fab fragment and Fc fragment, was tested before and after heat treatment for binding C1q and fixing C3bi. In unheated state, only PRG was found to bind C1q, whereas none bound C3bi. The binding of C1q by PRG was enhanced by heat treatment which also conferred the activity of binding C3bi to PRG and to Fc fractions, From these results, anticomplementary activity of unheated PRG fraction seems to be due mainly to the complement activation via the classical pathway, whereas the activation by the heat-treated Fc fragment might be via an alternative pathway.

Complement Activating Enzymes↗
PubMed1986

Inhibition of C1q binding to antigen-antibody complexes by a factor in rheumatoid arthritis serum.

The sera and synovial fluids of patients with rheumatoid arthritis (RA) contain a factor which decreases the binding of C1q to antigen-antibody complex (IC). Several lines of evidence suggest that this factor is distinct from the documented C1q inhibitor which is a chondroitin sulphate. It binds to IC rather than to C1q. It is resistant to digestion with chondroitinase ABC. The addition of chondroitin sulphate to serum does not inhibit the binding of IC to C1q. The observation that three purified IgM and IgG rheumatoid factors (RF) did not reduce C1q binding to IC indicates that the factor is not RF. The ability of RA sera to reduce IC binding to C1q was inversely correlated with their ability to prevent immune precipitation (PIP), and directly with levels of an inhibitor of PIP. These data suggest that the factor which binds to IC and reduces C1q binding may be responsible for the excessive immune precipitation which occurs in RA sera.

Antigen-Antibody Complex↗
PubMed1985

Mutual inhibition of the binding of Clq and protein A to rabbit IgG immune complexes.

A complex of rabbit IgG antibody with horseradish peroxidase covalently linked to Sepharose 4B was used as an insoluble immune complex for studying the binding of complement factor C1q protein A from Staphylococcus aureus, and its IgG-binding fragments AB and B, to rabbit IgG. It was shown that protein A (mol. wt approx. 42,000) and fragments AB and B (mol. wts approx. 14,000 and 7000, respectively) inhibited the binding of C1q to insoluble immune complex at 4 degrees C. However, at 37 degrees C fragment B did not inhibit this binding. On the other hand, C1q, when bound to an insoluble immune complex, almost completely blocked the binding of protein A and fragment B at both temps. The higher affinity of C1q for its CH2-binding site than of fragment B for its CH2-binding site may explain the displacement of the latter from the CH2 domain. The mutual inhibition of the binding of C1q and protein A (and its smaller fragments) indicates that the binding sites for C1q and protein A are closely located in the CH2 domain.

Animals↗
PubMed1982

The relationship between collagen and C1q biosynthesis in cultured human fibroblasts.

The relationship between collagen and C1q biosynthesis has been investigated in cultured human fibroblasts. This was done by measuring the effects of variation in cell density, inhibition of prolyl hydroxylase and complexing of C1q on synthesis and/or secretion of both proteins. It was found that synthesis and secretion of both proteins were not co-ordinate, and that therefore regulation of expression of both proteins is probably not linked. However complexing of C1q did result in marked stimulation in collagen synthesis, suggesting that the fibrosis which follows inflammation may result from binding of C1q to the immune complexes formed in the inflammatory process.

2,2'-Dipyridyl↗
PubMed1982

Conformational changes in C1q after binding to immune complexes: detection of neoantigens with monoclonal antibodies.

The formation of neoantigens within the C1q molecule after the binding of C1r and C1s to C1q and the binding of C1q to immune complexes is described. The neoantigens were detected by different monoclonal anti-C1q antibodies. This immunochemical study supports the hypothesis drawn from functional studies that the activation of the classical C pathway results from conformational changes within the C1q molecule leading to the activation of C1r and subsequently C1s.

Animals↗
PubMed1992

DNA binds and activates complement via residues 14-26 of the human C1q A chain.

The mechanism by which DNA activates the classical complement pathway was investigated, with emphasis upon the C1q binding sites involved. DNA bound to both the collagen-like and globular regions of C1q. Binding reactivity with DNA was retained after reduction/alkylation and sodium dodecyl sulfate treatment of C1q. DNA bound preferentially to the A chain of C1q. Binding sites for DNA were localized by using synthetic C1q A chain peptides to two cationic regions within residues 14-26 and 76-92, respectively. Peptides 14-26 and 76-92 avidly bound DNA in enzyme-linked immunosorbent and gel shift assays. Peptide 14-26 also precipitated with DNA and blocked its ability to bind C1q and activate C. Replacement of the two prolines with alanines or scrambling the order of the amino acids resulted in loss of ability of peptide 14-26 to inhibit C1q binding and complement activation by DNA; similar investigations showed a sequence specificity for peptide 76-92 as well. These experiments identify C1q A chain residues 14-26 as the major site, and residues 76-92 as a secondary site, through which DNA binds C1q and activates the classical complement pathway, and demonstrate that a peptide identical to residues 14-26 can modulate C1q binding and complement activation by DNA.

Amino Acid Sequence↗
PubMed1998

The multiligand-binding protein gC1qR, putative C1q receptor, is a mitochondrial protein.

A protein of 33 kDa (p33) that tightly binds to the globular domains of the first complement component, C1q, is thought to serve as the major C1q receptor (gC1qR) on B cells, neutrophils, and mast cells. However, the cellular routing and the subcellular localization of p33/gC1qR are unknown. We have performed confocal laser-scanning microscopy and found that p33/gC1qR is present in intracellular compartments, where it colocalizes with the mitochondrial marker protein, pyruvate dehydrogenase. No surface staining for p33/gC1qR on endothelial EA.hy926 cells was observed. A fusion protein of the p33/gC1qR presequence with green fluorescent protein translocated to the mitochondria of transfected COS-7 cells. Concomitantly, a 6-kDa portion of the fusion protein was proteolytically removed. The 33 amino-terminal residues of the presequence proved sufficient to direct reporter constructs to mitochondria. Association of p33/gC1qR with mitoplasts indicated that the mature protein of 209 residues resides in the matrix and/or the inner membrane of mitochondria. Immunocytochemistry of fetal mice tissues revealed a ubiquitous expression of p33/gC1qR, most prominently in tissues that are rich in mitochondria. Thus, the candidate complement receptor p33/gC1qR of intact cells cannot interact with plasma C1q due to mutually exclusive localizations of the components. The functional role of p33/gC1qR needs to be reconsidered.

Animals↗
PubMed1992

RHP is antigenically related to factor H and binds to the globular heads of C1q.

RHP was purified from normal serum by sequential euglobin precipitation, ion exchange chromatography on DEAE-Sephacel and gel filtration using Sephacryl S-300. RHP reacted with anti-Factor H antibodies in ELISA assays and in Western blots, suggesting that it is antigenically related to Factor H. It bound to intact C1q but not to the collagen-like N-terminal half of the molecule. C1q-specific monoclonal antibody BUS-1, which blocks the binding of C1q to immune complexes, did not block the binding of RHP to C1q. This implies that the binding sites on C1q for IgG and RHP do not overlap.

Binding Sites↗
PubMed1990

Bell's palsy: an immune complex disease.

Serum levels of C4-containing circulating immune complexes in 48 patients with Bell's palsy were studied by an enzyme-linked immunosorbent assay (ELISA) using chicken antibodies. We have previously reported elevated levels of C1q- and C3-containing immune complexes when compared to the serum of 42 healthy persons. We now found the levels of C4-containing immune complexes in these sera to be slightly decreased, but these patients' sera had a slightly increased ability to activate and bind C4 to a model immune complex. The results indicate that the fairly low levels of C4-containing immune complexes were not due to a defect in C4 activation but point to a rapid modification of C4 in the immune complex in vivo or low binding of C4 to the immune complexes. This study also shows that it is preferable to use assays that detect C1q- and C3-containing immune complexes when analyzing sera from patients with Bell's palsy.

Adult↗
PubMed2006

Clinical value of autoantibodies against C1q in children with glomerulonephritis.

OBJECTIVE: Autoantibodies against C1q (anti-C1q) have been found in a number of autoimmune and renal diseases. They are best described in adult patients with systemic lupus erythematosus, where a strong correlation between the occurrence of anti-C1q and severe lupus nephritis (LN) has been observed. However, the role of anti-C1q in children with systemic lupus erythematosus has not yet been determined. Furthermore, the clinical importance of anti-C1q in other forms of glomerulonephritis remains to be elucidated. The aim of this study was to investigate anti-C1q in children with different forms of glomerulonephritis including LN. METHODS: We prospectively investigated 112 children with different forms of newly diagnosed glomerulonephritis for the presence of anti-C1q by an enzyme-linked immunosorbent assay and compared them with healthy controls. Associations between anti-C1q and disease manifestations at the time of the measurements and during follow-up were investigated. RESULTS: Twenty-one of 112 patients were positive for anti-C1q compared with 0 of 40 healthy controls. Anti-C1q was associated with activity in LN and with disease severity in patients with acute poststreptococcal glomerulonephritis (APSGN). In LN, 7 of 12 patients were found to be anti-C1q positive. Six of these 7 had active disease at the time of the serum sampling compared with 1 of 5 of the anti-C1q-negative children. In children with APSGN, 8 of 24 were positive for anti-C1q. Anti-C1q-positive APSGN patients had significantly higher proteinuria and more often hypertension than those without anti-C1q. All 4 patients in which APSGN did not resolve spontaneously were anti-C1q positive. CONCLUSIONS: Anti-C1q is associated with active LN in children. In addition, children with anti-C1q-positive APSGN have more severe disease than those who are anti-C1q negative. These data suggest APSGN is another disease in which anti-C1q has a pathogenic role.

Adolescent↗
PubMed1986

Altered erythrocyte C3b receptor expression, immune complexes, and complement activation in homosexual men in varying risk groups for acquired immune deficiency syndrome.

We studied levels of erythrocyte C3b receptors (E-CR1) and correlated them to the level of circulating immune complexes (CIC) and complement activation in patients with or at risk for acquired immunodeficiency syndrome (AIDS). A significant reduction was found in patients with AIDS (185 +/- 93 CR1/cell), AIDS-related complex, and generalized lymphadenopathy, whereas healthy male homosexuals or normal controls had 434 +/- 193 and 509 +/- 140 CR1/cell, respectively (P less than 0.001). Family studies indicate that this defect is acquired. Reduction in E-CR1 was associated with increased levels of CIC when assayed by binding to Raji cells, but not when tested by C1q binding. Complement activation was assessed by levels of C3bi/C3d-g in plasma, measured with a monoclonal antibody specific for a neoantigen in C3d. AIDS patients had increased C3 activation (2.68 +/- 1.67%) when compared with normal controls (0.9 +/- 0.22%) (P less than 0.01). The decreased E-CR1, the presence of CIC, and C3 activation suggest that complement activation by immune complexes may play a role in the clinical expression of the disease.

AIDS-Related Complex↗
PubMed1985

Humoral immunity in normal and complicated pregnancy.

To evaluate the role of some immunological phenomena involved in the pathogenesis of preeclamptic toxaemia, we studied the humoral immune reactivity in patients with preeclamptic toxaemia during the third trimester of pregnancy, and three days and six weeks after delivery. The results were compared with those of patients with intrauterine growth retardation and with uneventful pregnancy. During the third trimester, patients with complicated preeclamptic toxaemia had significantly lower IgG, CH50, C4 and C3 levels than normal pregnants. Post-partum levels of IgM were significantly higher than in all other groups of patients. Circulating immune complexes were not detectable by a C1q binding assay in patients and controls. However, with a conglutinin binding assay and a granulocyte phagocytosis test complexes were demonstrable in patients with complicated preeclampsia (incidence 44% and 33%, respectively). In addition, 66% of these patients showed deposits of immunoglobulins and complement components in superficial blood vessels of the skin biopsy, suggestive of the presence of tissue deposits of immune complexes. This was found in about 30% of the other patient groups and in none of control pregnants. Allo-antibodies to lymphocytes were present in 63% of complicated preeclamptic toxaemia patients and 22% of normal pregnants. Our data show several changes in humoral immune reactivity in preeclamptic toxaemia which may contribute to the pathogenesis of this disorder.

Adult↗
PubMed1982

Semiologic value of C1q and C4 cutaneous deposits. An immunofluorescent study.

One hundred twenty skin biopsies from patients with different skin diseases were found to be positive for C3 cutaneous staining by immunofluorescence study. By the direct immunofluorescence method, we looked for C1q and C4 and immunoglobulin deposits in all those biopsies. C1q and/or C4 were only found in dermatoses with a recognised humoral immunologic mechanism; in some cases C1q and/or C4 deposits were found in the absence of immunoglobulins. The results showed that identification of C1q and C4 is important in routine immunopathologic studies, and provide interesting data of diagnostic value.

Biopsy↗