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PubMed1987

Isolation and analysis of immune complexes from sera of patients with polymyalgia rheumatica and giant cell arteritis.

Serum samples were obtained from patients with polymyalgia rheumatica (PMR: n = 10) or giant cell arteritis (GCA; n = 7), or both. Samples were taken either before treatment or within one week of starting prednisolone. Immune complexes (IC) were concentrated by polyethylene glycol (PEG) precipitation then purified with either IgG anti-C1q-Sepharose or IgG anti-C3c-Sepharose. Complex components were separated by sodium dodecyl sulphate (SDS) gradient polyacrylamide gel electrophoresis then transferred to nitrocellulose by Western blotting. Identification of proteins was carried out using specific antisera. All the IC contained IgM (mu chain), some contained IgA (alpha chain), and IgG (gamma chain). C1r, C1s, C1q, C3, C4, and C reactive protein (CRP), where tested, were found in most but not all IC. The occurrence of properdin, factor B, alpha 2 macroglobulin (alpha 2M), factor H (beta 1H), C1 esterase inhibitor, and C4 binding protein was also investigated. Immune complexes in PMR and GCA differed from those previously characterized in rheumatoid arthritis (RA)1 purified by anti-C1q-Sepharose which contained immunoglobulins and C1q only. No properdin or factor B were detected in RA IC purified with either anti-C1q-Sepharose or anti-C3c-Sepharose.

Aged↗
PubMed2000

Acquired C1q deficiency caused by monoclonal paraproteinaemia.

Acquired C1q deficiency secondary to anti C1q auto-antibodies may result in the hypocomplementaemic urticarial vasculitis syndrome and may also be seen in active systemic lupus erythematosus. Some patients with acquired C1 inhibitor deficiency are found to have an underlying malignancy, most commonly lymphoma. We report a case of a 40-year-old man presenting with a lupus-like illness with acquired C1q deficiency secondary to a monoclonal paraprotein in the presence of splenic lymphoma with villous lymphocytes. His clinical symptoms correlated with the presence of the paraprotein. Relapse coincided with a rise in the paraprotein and fall in C1q, C3 and C4. There was no improvement in his clinical condition following combination chemotherapy. He remains on oral prednisolone.

Adult↗
PubMed1986

Interaction of C1q subcomponent with immunoglobulin M.

The affinity of human C1q subcomponent for IgM of normal human serum and Waldenström macroglobulins of patients Sew and Zuk were investigated by the polyethylene glycol 6,000 immune complexes precipitation test. This test was calibrated with heat-aggregated gamma-globulin (HAGG); maximum fixation of C1q ranged from 60 to 80% (measured as percentage of radioactivity of the immune complexes precipitate) and was observed when the C1q:HAGG concentration ratio was about 1:250. At the ratio of 1:20 the radioactivity of the precipitate was about 43% of the total. The capacity of polyclonal IgM and Waldenström macroglobulins for C1q fixation is low and variable. The percentage of C1q fixed at the C1q:IgM ratio of 1:20 for polyclonal IgM and Zuk macroglobulin was about 9%, whereas for Sew it was only about 1%.

Complement Activating Enzymes↗
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↗
PubMed1983

A comparative study of complement components in polyethylene glycol precipitated immune complexes from patients with ovarian cancer and patients with rheumatoid arthritis.

Circulating immune complexes and complement components C1q, C3 and C4 were measured following polyethylene glycol precipitation of serum from patients with ovarian cancer (OC), patients with rheumatoid arthritis (RA) and control patients (CP). The C3 and C4 content of the precipitated material was significantly greater in those patients with OC in comparison to those with RA or CP, while the C1q content did not differ significantly between the two groups of patients. A statistically significant correlation between IgG, C3 and C4 levels was found in the immune complexes of both groups of patients. C1q levels correlated significantly with IgG immune complex levels in patients with RA and CP, but did not in patients with OC. These data illustrate that immune complexes from patients with OC differ from complexes precipitated from RA sera and normal sera in their complement content. It is suggested that the largely unsuccessful attempts to detect immune complexes in sera from patients with ovarian cancer, using assays dependent on the binding of C1q may be related to differences in solubility of complexes from these patients in comparison to complexes present in non-neoplastic conditions.

Antigen-Antibody Complex↗
PubMed2000

gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.

InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimulating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidyl- inositol (PI) 3-kinase. Using affinity chromatography and enzyme-linked immunosorbent assay, we demonstrate a direct interaction between InlB and the mammalian protein gC1q-R, the receptor of the globular part of the complement component C1q. Soluble C1q or anti-gC1q-R antibodies impair InlB-mediated entry. Transient transfection of GPC16 cells, which are non-permissive to InlB-mediated entry, with a plasmid-expressing human gC1q-R promotes entry of InlB-coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB-gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q-R constitutes a cellular receptor involved in InlB-mediated activation of PI 3-kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E-cadherin, the receptor for internalin, gC1q-R is the second identified mammalian receptor promoting entry of L. monocytogenes into mammalian cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Human blood platelet gC1qR/p33.

Platelets are involved in the development of many types of vascular lesions. In addition to their role in primary hemostasis, they participate in inflammatory processes that may contribute to the development of thrombosis, atherosclerosis and vasculitis. In this regard, we have been interested in platelet interactions with the complement subcomponent C1q. C1q has been shown to modulate platelet interactions with collagen and immune complexes, and has been identified at sites of vascular injury and inflammation, as well as in atherosclerotic lesions. Platelets express a variety of C1q binding sites, including gC1qR/p33 (gC1qR), a multifunctional, multicompartment cellular protein. Here we focus on the structure and function of platelet gC1qR and its emerging role in modulating platelet function at sites of vascular injury and inflammation.

Bacterial Adhesion↗
PubMed1976

Subunit composition and structure of subcomponent C1q of the first component of human complement.

1. Unreduced human subcomponent C1q was shown by electrophoresis on polyacrylamide gels run in the presence of sodium dodecyl sulphate to be composed of two types of non-covalently linked subunits of apparent mol.wts. 69 000 and 54 000. The ratio of the two subunits was markedly affected by the ionic strength of the applied sample. At a low ionic strength of applied sample, which gave the optimum value for the 54 000-apparent mol.wt. subunit, a ratio of 1.99:1.00 was obtained for the ratio of the 69 000-apparent mol.wt. subunit to the 5400-apparent-mol.wt. subunit. The amount of the 54 000-apparent-mol.wt. subunit detected in the expected position on the gel was found to be inversely proportional to increases in the ionic strength of the applled sample. 2. Human subcomponent C1q on reduction and alkylation, or oxidation, yields equimolar amounts of three chains designated A, B and C [Reid et al. (1972) Biochem. J. 130, 749-763]. The results obtained by Yonemasu & Stroud [(1972) Immunochemistry 9, 545-554], which showed that the 69 000-apparent-mol.wt. subunit was a disulphide-linked dimer of the A and B chains and that the 54 000-apparent-mol.wt. subunit was a disulphide-linked dimer of the C chain, were confirmed. 3. Gel filtration on Sephadex G-200 in 6.0M-guanidinium chloride showed that both types of unreduced subunit were eluted together as a single symmetrical peak of apparent mol.wt. 49 000-50 000 when globular proteins were used as markers. The molecular weights of the oxidized or reduced A, B and C chains have been shown previously to be very similar all being in the range 23 000-24 000 [Reid et al. (1972) Biochem. J. 130, 749-763; Reid (1974) Biochem. J. 141, 189-203]. 4. It is proposed that subcomponent C1q (mol.wt. 410000) is composed of nine non-covalently linked subunits, i.e. six A-B dimers and three C-C dimers. 5. A structure for subcomponent C1q is proposed and is based on the assumption that the collagen-like regions of 78 residues in each of the A, B and C chains are combined to form a triple-helical structure of the same type as is found in collagens.

Chromatography, Gel↗
PubMed2000

Lupus susceptibility genes on human chromosome 1.

During the past five years, there has been an intense interest in studying candidate susceptibility genes for systemic lupus erythematosus (SLE). Many such studies have been focused on candidates located on chromosome 1, demonstrating association of certain genetic variants with SLE. Some of the tested candidate genes were chosen because they encode molecules with relevant immunological functions that may play a role in the pathogenesis of SLE. More recently, the identification of genomic segments linked to SLE has suggested novel positional candidate genes. Thus far, there is considerable evidence supporting that multiple genes on this chromosome contribute to the development and expression of SLE. This review highlights the genetic loci located on chromosome 1 that have recently been associated with SLE. These include loci encoding the tumor necrosis factor receptor 2 (TNFR2), complement component C1q, Fcgamma receptors, T cell receptor zeta chain, interleukin-10 (IL-10), poly (ADP-ribose) polymerase (PARP), and HRES-1.

Antigens, CD↗
PubMed1998

A newly discovered function for C1 inhibitor, removal of the entire C1qr2s2 complex from immobilized human IgG subclasses.

A new function for C1 inhibitor (C1 INH) is reported. C1 inhibitor dislodged the entire activated C1 complex (C1qr2s2) from immobilized human IgG. C1 binding to doses of immobilized human IgG3, IgG1, or IgG2 was quantified as a function of time. When human serum, as a source of C1qr2s2, was added to relatively low doses of immobilized IgG, C1q binding peaked at 1.0 min then gradually decreased. However when purified C1q was applied to immobilized IgG, C1q binding did not diminish with time. The removal of C1q was duplicated by adding purified C1 INH to C1qr2s2 which had been bound to immobilized IgG. The dislodgement of C1q from immobilized IgG required the presence of intact C1qr2s2 and of C1 INH. This removal of C1q by purified C1 INH was prevented when activated C1s was used to neutralize C1 INH function or when relatively high levels of IgG were immobilized.

Binding, Competitive↗
PubMed1984

Assay, purification and further characterization of 7S C1q-precipitins (C1q-p) in hypocomplementemic vasculitis urticaria syndrome and systemic lupus erythematosus.

C1q-precipitins (C1q-p) are comprised of 7S IgG with C1q-binding activity found in sera of patients with hypocomplementemic vasculitis urticaria syndrome ( HVUS ) and systemic lupus erythematosis (SLE). We have utilized C1q-coated polystyrene beads to selectively isolate C1q-p and to establish a sensitive and quantitative assay of C1q-p and immune complex activity. Purified C1q-p was comprised of polyclonal IgG which retained 7S sedimentation and solid phase C1q-binding activity at physiological ionic strength both in the presence and absence of normal human sera. No precipitation interaction was observed between C1q-p and fluid-phase C1q or C1 under the conditions tested. Purified C1q-p had no activity in the Raji cell immune complex activity. C1q-p activity also was observed in and purified from SLE serum; this activity was distinguishable from 7S immune complex activity detected by Raji cells which was also present in SLE serum. These studies indicate that C1q-p is a 7S IgG molecule found in HVUS as well as some SLE sera and has activity in C1q-binding but not in Raji cell-binding immune complex assays. These data also suggest that C1q-p is a monomeric, polyclonal IgG with preferential affinity for bound C1q. In addition to its potential role in immune complex disease, C1q-p may also provide an important tool for studying the interaction of immunoglobulin and C1q, and should contribute important information to understanding the pathobiology of immune complex disease.

Antigen-Antibody Complex↗
PubMed1981

[Immunological implications in the pathogenesis of Horton arteritis].

Fragments of temporal artery obtained by surgical biopsy from 3 patients suffering from Horton arteritis were employed for immunopathologic studies by direct immunofluorescence. In 2 of the cases, granular deposition of IgM, C1q and C3 but not of albumin were observed in the wall of vasa vasorum of the temporal artery. Elution techniques determined the disappearance of the immunoreactants. In one case in which biopsy fragments of temporal artery were obtained prior to and after steroid treatment it was observed that IgM and complement, previously present, disappeared after such treatment. The data reported indicate that indeed immunologic factors play a role in the pathogenesis of the disease and that the immunoreagents present on the wall of vasa vasorum are not evidence of increased vascular permeability but indicate an active immunologic process which takes place in them.

Albumins↗
PubMed1985

Structural model of the collagen-like region of C1q comprising the kink region and the fibre-like packing of the six triple helices.

A detailed three-dimensional model of the collagenous part of C1q was derived by model building and computer-aided energy refinement calculations. The proposed structure is based on the collagen-like (-Gly-Xaa-Yaa-) repeating sequence of 78 to 81 residues in the N-terminal regions of the constituent A, B and C chains, on the mode of disulphide linkage between the 18 chains of C1q, and on its electron microscopically derived gross structure. It is demonstrated that the interruptions of the repeating sequence about half-way along the length of the collagenous regions (Gly36-Ile37-Arg38-Thr39 in the A chain and Ala36-Ile37-Hy138 in the C chain) do not lead to a disruption of the triple helical conformation but rather to a bend of about 60 degrees in an otherwise continuous triple helix. These features are consistent with a flexibility comparable with that of regular triple helices and with the observed low proteolytic susceptibility of the kink region. The azimuthal orientation of the kink is defined approximately by ArgA38 being located in the cap of the knee. Because of this extra residue between two glycine residues, a bad contact that would arise between the methyl group of AlaC36 and the peptide carbonyl of IleA37 in a straight triple helix is relaxed. The model features also a cluster of hydrophobic contacts between large hydrophobic side-chains in the interaction edges between the six collagen triple helices aligned with their about 10 nm long N-terminal regions in the fibril-like endpiece of C1q. The azimuthal orientations of the triple helices were derived by energy calculations of side-chain interactions previously applied to fibre-forming collagens. Independently, the same orientations and interaction edges were derived from the azimuthal orientation of the kink and the electron microscopically observed orientations of the triple helical arms that emerge from the endpiece, and which carry the C-terminal globular binding domains. The structural model has a number of implications for the assembly of the first component of complement from C1q and the zymogen complex C1r2C1s2 and possible mechanisms of its activation.

Amino Acid Sequence↗
PubMed1987

Concentrations of C1q, factor B, factor D and properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes.

The concentrations of C1q, factor B, factor D and properdin were determined in healthy children belonging to various age groups of one through five years of age. All concentrations were found to be age-dependent, though they varied from one component to another with regard to ontogenetic pattern. Thus, the concentrations of factor B were high, and those of factor D low throughout the age range studied. C1q and properdin levels were lowest in the younger children, who also showed a fairly high incidence of C1r-C1s complexes in excess of C1q. Since the concentrations of C1q are influenced by those of IgG, the presence of C1r-C1s complexes might partly have reflected maturation of immunoglobulin synthesis during ontogeny.

Age Factors↗
PubMed1990

Significance of low molecular weight C1q in systemic lupus erythematosus.

The significance of high serum concentrations of low molecular weight C1q (LMW-C1q) in patients with systemic lupus erythematosus (SLE) was studied. Concentrations of LMW-C1q were increased in SLE, but not in rheumatoid arthritis or acute poststreptococcal glomerulonephritis. Concentrations of LMW-C1q in SLE serum samples correlated with titres of anti-dsDNA and were inversely related to concentrations of normal C1q and C3. Serial studies in six patients, who had rising anti-dsDNA titres and who developed a major exacerbation requiring admission to hospital, showed that LMW-C1q increased in parallel with anti-dsDNA, reaching peak values of more than 2000% of normal just before or at the time of clinical relapse and decreasing during convalescence. Most marked increases in LMW-C1q were noted in the three patients in whom C1q concentrations remained normal, whereas increases were less in the three patients who had strongly depressed concentrations of normal C1q. A study of C1q biosynthesis by macrophages cultured from patients with SLE and high serum concentrations of LMW-C1q did not show impaired secretion of normal C1q in favour of LMW-C1q, but indicated that serum concentrations of LMW-C1q may reflect the synthetic rate of C1q in vivo. The results show that increased serum concentrations of LMW-C1q may be helpful in diagnosing SLE and suggest that serial determination of LMW-C1q in serum may have predictive value in monitoring patients with SLE.

Antibodies, Antinuclear↗
PubMed2001

Antibody-mediated phagocytosis of the amyloid beta-peptide in microglia is differentially modulated by C1q.

Microglial ingestion of the amyloid beta-peptide (Abeta) has been viewed as a therapeutic target in Alzheimer's disease, in that approaches that enhance clearance of Abeta relative to its production are predicted to result in decreased senile plaque formation, a proposed contributor to neuropathology. In vitro, scavenger receptors mediate ingestion of fibrillar Abeta (fAbeta) by microglia. However, the finding that cerebral amyloid deposition in a transgenic mouse model of Alzheimer's disease was diminished by inoculation with synthetic Abeta has suggested a possible therapeutic role for anti-Abeta Ab-mediated phagocytosis. Microglia also express C1qR(P), a receptor for complement protein C1q, ligation of which in vitro enhances phagocytosis of immune complexes formed with IgG levels below that required for optimal FcR-mediated phagocytosis. The data presented here demonstrate FcR-dependent ingestion of Abeta-anti-Abeta complexes (IgG-fAbeta) by microglia that is a function of the amount of Ab used to form immune complexes. In addition, C1q incorporated into IgG-fAbeta enhanced microglial uptake of these complexes when they contained suboptimal levels of anti-Abeta Ab. Mannose binding lectin and lung surfactant protein A, other ligands of C1qR(P), also enhanced ingestion of suboptimally opsonized IgG-fAbeta, whereas control proteins did not. Our data suggest that C1qR(P)-mediated events may promote efficient ingestion of Abeta at low Ab titers, and this may be beneficial in paradigms that seek to clear amyloid via FcR-mediated mechanisms by minimizing the potential for destructive Ab-induced complement-mediated processes.

Amyloid beta-Peptides↗
PubMed1991

Evaluation of protective mAbs against Pseudomonas aeruginosa outer membrane protein I by C1q binding assay.

Seven monoclonal antibodies (mAbs) against the outer membrane proteins (OPRs) F, H and I of Pseudomonas aeruginosa were prepared. Western blot analysis has shown the mAbs to cross-react with all 17 serotypes of P. aeruginosa according to the International Antigenic Typing Scheme. Two of the mAbs (2A1, 6A4) protected mice against fatal P. aeruginosa pneumonia. The protective potential of the mAbs did not correlate with the immunoglobulin isotype nor with the fine antigen specificity and the in vitro bactericidal activity of the mAbs. Only the binding of the first complement component C1q of the mAbs as estimated in vitro by an ELISA was significantly correlated with their protective potential.

Animals↗