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PubMed1977

Inhibition of the reconstitution of the haemolytic activity of the first component of human complement by a pepsin-derived fragment of subcomponent C1q.

1. A fragment of subcomponent C1q, which contained all the collagen-like features present in the intact molecule, was isolated by pepsin digestion as described by Reid [Biochem. J. (1976) 155, 5-17]. 2. The pepsin-derived fragment of subcomponent C1q did not bind to antibody-coated erythrocytes under conditions where complete binding of sub-component C1q took place. 3. The peptic fragment blocked the reconstitution of C1 haemolytic activity by competing with intact subcomponent C1q in the utilization of a mixture of the other two subcomponents, C1r and C1s. 4. Reduction and alkylation of the interchain disulphide bonds in the pepsin fragment did not markedly affect its inhibitory effect, whereas heating at 56 degrees C for 30min completely abolished the effect. 5. Lathyritic rat skin collagen and CNBr-derived peptides of pig type II collagen showed no ability to mimic the inhibitory effect of the pepsin fragment when tested over the same concentration range as used for the peptic fragment. 6. The peptic fragment was unable to block efficiently the reconstitution of C1 haemolytic activity unless it was added to the mixture of subcomponents C1r and C1s before the attempt to reconstitute C1 haemolytic activity, in solution, or on the surface of antibody-coated erythrocytes. 7. Evidence was obtained that suggested that subcomponent C1q bound the subcomponent C1r-C1s complex more efficiently when the subcomponent C1q was bound to antibody than when it was free in solution.

Binding Sites, Antibody↗
PubMed1998

Complement components and their activation products in pleural fluid.

STUDY OBJECTIVES: The aim of this study was to determine the role of complement components in pleural effusion measured with novel markers of complement activation, to assess which pathway of activation is predominant in different diseases, and to find out whether the analysis of complement components and their activation products could help in diagnostic procedure differentiating the etiologies of pleural effusion. PATIENTS: The study population consisted of 71 patients who had pleural effusion secondary to tuberculosis (n=23), rheumatic disease (n=10), or malignancy (n=38). MEASUREMENTS: Complement components and their activation products, including the soluble terminal complex SC5b-9, were measured in plasma and pleural fluid. RESULTS: In all patients with rheumatic pleurisy, pleural fluid SC5b-9 was higher than 2 AU/mL and in all patients with malignant pleural fluid it was lower than 2 AU/mL. The mean level of SC5b-9 in rheumatic pleural effusion was also significantly higher than in tuberculosis. In addition, the concentrations of pleural fluid C3 and C4 were significantly lower and the ratio C4d/C4 was significantly higher in rheumatic compared with tuberculous or malignant pleurisy. In plasma, both SC5b-9 and C1s-C1r-C1INH-complexes were significantly higher in rheumatic subjects than in other patients. In stepwise multinominal logistic regression analyses, the most significant predictors for rheumatic pleural fluid were high pleural fluid SC5b-9 and low C4. CONCLUSIONS: These observations indicate that the complement cascade is activated through both the classic and the alternative pathways in rheumatic pleurisy. Determinations of SC5b-9 and C4d/C4 in pleural fluid were the best variables differentiating rheumatic, tuberculous, and malignant effusions.

Adult↗
PubMed1976

C1q deficiency associated with urticarial-like lesions and cutaneous vasculitis.

We describe a 46 year old women with a seven year history of urticarial-like symptoms and cutaneous vasculitis with marked deficiency of C1q in the presence of normal levels of C1r and C1s and high titers of low molecular weight (7S) C1q precipitins. Hemolytic C1 activity, which was greatly reduced, was restored upon the addition of purified C1q. The other complement components were present in moderately reduced or normal levels. This patient bears resemblance to several other persons previously described with urticarial-like lesions in association with selective deficiency of C1q. The similarity of the clinical features, pathologic diagnosis, C1q levels disproportionately deficient in relation to other complement components and low molecular weight C1q precipitins support the conclusion that these are causally related in a symptom complex. The underlying basis is yet to be defined.

Complement C1↗
PubMed1982

The interaction of human plasma fibronectin with a subunit of the first component of complement, C1q.

Fibronectin is a normal plasma protein that enhances reticuloendothelial system functioning, and may participate in immune complex clearance. The interaction of 125I-fibronectin with human C1 and C1q in vitro was investigated by employing a highly reproducible solid-phase binding assay in microtiter wells. We demonstrated that although fibronectin does not bind to antigen-antibody complex (BSA-anti-BSA) or immune complexes containing C1, a 20-fold increase in binding was obtained when the complexes contained C1q alone. In the absence of antigen-antibody complexes, fibronectin binds to the C1q fixed to the wells in a dose-response fashion but not to intact C1. C1q in the fluid phase inhibits 85% of the fibronectin binding to immobilized C1q. The amount of fibronectin bound by immobilized C1q or gelatin is approximately equal. The binding of fibronectin to C1q could be inhibited by the restoration of C1r + C1s to the C1 macromolecular complex before the addition of fibronectin. The inhibition was dependent on the concentration of C1r + C1s and achieved a maximum of 70% at 100 micrograms/ml. This inhibition could be reversed by the removal of C1r and C1s subunits with EDTA or C1 inhibitor. Digestion of C1q with pepsin resulted in an 85% loss of fibronectin binding. It therefore appears that at least one site of fibronectin binding to C1q is in the globular portion of this complement component.

Animals↗
PubMed1979

Activation of human complement by liposomes: a model for membrane activation of the alternative pathway.

Liposomal model membranes were found to activate the alternative pathway of human complement. Activation was measured by C3 conversion and component consumption in serum that had been incubated with liposomes. C3 conversion did not require C1 or C2 of the classical pathway, since it was observed in serum from a C1r-deficient patient, serum from a C2-dificient patient, and normal serum in buffer containing EGTA and MgCl2. The incubation of liposomes with C2-deficient serum resulted in consumption of components C3 through C9 with no consumption of C1 or C4 in a profile typical of alternative pathwya activation. The reaction was further shown to require alternative pathway factor D, and to be independent of antibody. Activation of the alterative pathway was dependent on the membrane composition of the liposomes. A positive charge was required for liposomes to produce C3 conversion. Liposomal cholesterol concentration and phospholipid fatty acyl chain length and unsaturation all influenced activation, suggesting the importance of membrane fluidity. Positively charged liposomes containing dimyristoyl phosphatidylcholine and cholesterol required the presence of certain glycolipids for C3 conversion. The activation of the alternative complement pathway by liposomes of defined membrane composition may provide a suitable model for the study of alternative pathway activation by cellular membranes.

Agammaglobulinemia↗
PubMed1976

Evidence for immune complexes involving anti-lymphocyte antibodies associated with hypocomplementaemia in chronic lymphocytic leukaemia (CLL).

Unmeasurable total haemolytic complement (C) was observed in serum of a patient with untreated chronic lymphocytic leukaemia and recurrent non-hereditary angioedema. Analysis of C components immunochemically demonstrated a marked reduction of C1q and C1s inhibitor, undetectable C1r, C1s and an elevated B. Haemolytic C1, C4 and C2 were less than 5 percent of normal, functional C1s inhibitor was absent. Cryoglobulin and C1q precipitins were present in the serum. Of special interest was the presence of high levels of cold-reactive antilymphocyte antibody, determined by both C-dependent cytotoxicity and indirect immunofluorescence. The antibody exhibited specificities for both autologous lymphocytes and lymphocytes from normal donors; cytotoxic activity for autologous leukaemia cells was removed by absorption with normal isologous tonsil lymphocytes. Specific enrichment of this antibody relative to the serum level was demonstrated in the cryoglobulin and its isolated 19S fractions. Free lymphocyte surface antigen was also demonstrated by gel diffusion using specific rabbit antilymphocyte antiserum. These data strongly suggest the presence of pathogenetically significant circulating complexes of lymphocyte surface antigen and specific antibody in certain patients with CLL.

Angioedema↗
PubMed1990

Hormonal regulation of complement biosynthesis in human cell lines--I. Androgens and gamma-interferon stimulate the biosynthesis and gene expression of C1 inhibitor in human cell lines U937 and HepG2.

C1 inhibitor (C1inh), a member of the serine protease inhibitor gene superfamily, is a glycosylated plasma protein inhibiting the proteolytic activities of C1r and C1s and involved in the regulation of coagulation, fibrinolysis and kinin-releasing systems. In this study, the in vitro effect of androgen hormones, dehydroepiandrosterone (DHEA), testosterone (TEST) and recombinant human gamma-interferon (gamma-IFN), has been determined on the production of C1inh in human cell lines. In both human monocytoid/histiocytoid cell line U937 and in hepatoma derived cell line HepG2, DHEA and TEST upregulated the gene expression and secretion of C1inh. The most pronounced effect was detected in the concn range 10(-7)-10(-9) M of the hormones. Under the same conditions DHEA and TEST had no detectable effect on the biosynthesis of C3, C2 and factor B by these cells, but DHEA at higher concn (10(-4) M) slightly increased that of C4 in HepG2 cells. Both in U937 and in HepG2 cells recombinant gamma-IFN markedly increased the gene expression and secretion of C1inh. This effect of gamma-IFN was abolished by histamine.

Carcinoma, Hepatocellular↗
PubMed1977

Proenzymic C1s associated with catalytic amounts of C1r. Study of the activation process.

1. Proenzymic C1s isolated from human plasma by euglobulin precipitation and DEAE-cellulose chromatography is associated with trace amounts of C1r (0.5--1% on a molar basis). Incubation for 2 h at 37 degrees C leads to the proteolytic activation of C1s. The proteolysis is characterized by the sigmoidal appearance of C1s esterase activity and of the typical heavy (57 000-dalton) and light (28 000-dalton) fragments of C1s on sodium dodecyl sulphate-polyacrylamide gel electrophoresis. 2. The C1s activation process observed is markedly temperature and concentration dependent, and the rate of activation is decreased by calcium and high ionic strength (I = 0.9). Diisopropyl phosphorofluoridate, benzamidine, polyanethol sulfonate and pentosane polysulphate inhibit the activation, which is also sensitive to C1-inactivator and anti-C1r IgC. From the kinetic experiments and from the inhibition characteristics, the activation of C1s can be attributed to the presence of C1r, which appears to undergo activation and then to activate secondarily C1s.

Calcium↗
PubMed1981

Activation of the classical pathway of complement by Hageman factor fragment.

A fragment of activated Hageman factor (HFf) has been demonstrated to activate the classical pathway of complement in a manner that is analogous to complement activation by antigen-antibody complexes or aggregated IgG. Thus C1, C4, C2, C3, and C5 were found to be depleted on addition of HFf to serum. The reduction of serum hemolytic activity was maximal upon addition of 5 micrograms HFf and an incubation time of 60 min at 37 degrees C. Consumption of the total complement activity and of the individual components proceeded in a dose-dependent fashion. No comparable activity was observed when equimolar concentrations of either the native Hageman factor (HF) or two-chain activated form of Hageman factor (HFa) were incubated with serum. Further, the ability of HFf to convert serum C3 and C4 was similar to that of aggregated IgG as assessed by immunoelectrophoresis. This function of HFf appeared to be independent of plasminogen (or plasmin) since plasminogen-free serum was indistinguishable from normal serum. Radial double immunodiffusion experiments using antiserum to C1q, C1r, and C1s on HFf-treated serum demonstrated the dissociation of the C1 trimolecular complex, with concomitant reduction of C1r antigenicity that is indicative of C1 activation. Thus, HFf appears to lead to C1 activation upon incubation with serum or when incubated with partially purified C1. This may represent a control link between activation of the intrinsic coagulation-kinin pathway and the initiation of the classical complement cascade.

Animals↗
PubMed2002

Structural biology of the C1 complex of complement unveils the mechanisms of its activation and proteolytic activity.

C1 is the multimolecular protease that triggers activation of the classical pathway of complement, a major element of antimicrobial host defense also involved in immune tolerance and various pathologies. This 790,000 Da complex is formed from the association of a recognition protein, C1q, and a catalytic subunit, the Ca2+-dependent tetramer C1s-C1r-C1r-C1s comprising two copies of each of the modular proteases C1r and C1s. Early studies mainly based on biochemical analysis and electron microscopy of C1 and its isolated components have allowed for characterization of their domain structure and led to a low-resolution model of the C1 complex in which the elongated C1s-C1r-C1r-C1s tetramer folds into a more compact, "8-shaped" conformation upon interaction with C1q. A major strategy used over the past years has been to dissect the C1 proteins into modular segments to characterize their function and solve their structure by either X-ray crystallography or nuclear magnetic resonance spectroscopy (NMR). The purpose of this review is to focus on this information, with particular emphasis on the architecture of the C1 complex and the mechanisms underlying its activation and proteolytic activity.

Animals↗
PubMed1982

Complement: activation, consequences, and control.

The activation of complement provides the humoral (fluid-phase) effector mechanism most responsible for immune-mediated injury. The classical pathway is activated by an antigen-antibody reaction. The binding of C1q initiates the sequential activation of the eleven proteins. The classical pathway has a calcium-dependent step (C1q, C1r, C1s) and a magnesium-dependent reaction (the enzymatic action of C1s on C4 and C2). The alternative pathway appears to be spontaneously activated, but the perpetuation of that activation is dependent upon the availability of an activating (or protective) surface which interferes with the inactivation of C3b by control proteins. The alternative pathway has a magnesium-dependent step, the binding of B to C3b to form the C3 convertase. Once initiated, the alternative pathway activation results in the sequential activation of nine proteins, six of which are common to both pathways. The activation of complement results in a variety of biologic consequences which can result in injury to the host. The potential destructiveness of the effects of complement activation is modulated by a series of control proteins.

Carrier Proteins↗
PubMedDate not supplied

Purification and characterization of RHP (factor H) and study of its interactions with the first component of complement.

RHP has been purified from the plasma of both normal individuals and patients with rheumatoid arthritis (RA). RHP from both these sources was shown to be identical with Factor H by reaction with antisera and N-terminal amino acid sequence analysis. Factor H, from both normal and RA sera, inhibited the solubilization of immune precipitates but did not affect prevention of immune precipitation. Factor H was shown to inhibit the haemolytic activity of fluid-phase C1, but unlike C1-inhibitor, it had little effect on C1 bound to EA (EAC1). Factor H was shown to complex with intact C1, to isolated C1q and to the C1r:C1s tetramer. However, binding of factor H to C1 did not dissociate the C1 macromolecule. A C1-Factor H complex was detected in the serum and plasma from normal individuals and patients with systemic lupus erythematosus and RA. Serum levels of this complex were reduced, by EDTA-treatment of serum and by activation of complement by the classical pathway.

Arthritis, Rheumatoid↗
PubMed1975

The identification of a previously unrecognized subcomponent of the first component of complement.

The use of an affinity chromatography method designed to isolate C1 from serum has led to the discovery of a novel plasma protein, II-P2, associated with C1. The persistent Ca++-dependent association of II-P2 with C1 subcomponents following euglobulin precipitation, affinity chromatography on Sepharose-IgG, and density gradient ultracentrifugation indicates that II-P2 might be a C1 subcomponent. Using purified preparations of II-P2 it was found that a) II-P2 was retained on Sepharose-IgG through a Ca++-dependent link with C1q,b) II-P2 enhanced the C1 activity of mixtures of C1s and C1q in a dose-dependent fashion, c) II-P2 bound firmly to EAC1q4 cells and enhanced their C1s-binding ability. Fractionation of C1 by DEAE-Cellulose chromatography under the conditions that led to the original identification of C1q, C1r, and C1s resulted in recovery of II-P2 in the fractions containing C1r. The evidence presented confirms that II-P2 is a C1 subcomponent (C1t).

Animals↗
PubMed1979

Kinetics of the agglutination of IgG-coated latex particles by C1q: the influence of heat-labile serum components.

Interaction between human C1q and IgG coated latex particles has been studied by means of a standard aggregometer equipment. A dose-dependent agglutination was observed and 100 ng of C1q were readily detected. The kinetics of the agglutination was also monitored. Serum, partially purified C1, and high molecular weight fractions from Sephadex G-200 fractionated serum produced agglutination only in the presence of EDTA. In the absence of this chelator these products disintegrated preformed C1q-IgG-latex particle agglutinates. This disagglutinating principle is heat-sensitive and tentatively macromolecular C1 dependent. The most probable basis of the activity is the competition between C1, with a high affinity for IgG particles, and C1q. The inability of C1 to induce particle agglutination might be caused by the C1 subunits C1r and C1s sterically inhibiting the subunit C1q to bridge between the particles.

Agglutination↗
PubMed1991

Human immunodeficiency virus type 1 activates the classical pathway of complement by direct C1 binding through specific sites in the transmembrane glycoprotein gp41.

Human immunodeficiency virus type 1 (HIV-1), in contrast to animal retroviruses such as murine leukemia virus, is not lysed by human complement. Nevertheless, HIV-1 activates complement via the classical pathway independent of antibody, and C3b deposition facilitates infection of complement receptor-bearing cells. Using gel exclusion chromatography on Sephacryl S-1000, purified virions were found to bind 125I-labeled C1q, but not 125I-labeled dimeric proenzyme C1s. Virions activated the C1 complex, reconstituted from C1q, proenzyme C1r, and 125I-labeled proenzyme C1s, to an extent comparable with that obtained with immunoglobulin G-ovalbumin immune complexes. To determine the activating viral component, recombinant viral proteins were used: in the solid phase, soluble gp41 (sgp41) (the outer membrane part of gp41, residues 539-684 of gp160) bound C1q, but not dimeric proenzyme C1s, while gp120 was ineffective. In the fluid phase, sgp41 activated the C1 complex in a dose- and time-dependent manner, more efficiently than aggregated Ig, but less efficiently than immune complexes. To localize the C1 activating site(s) in gp41, synthetic peptides (15-residue oligomers spanning amino acids 531-695 of gp160) were used. Peptides covering positions 591-605 and 601-620 and, to a lesser extent, positions 561-575, had both the ability to bind C1q and to induce C3 deposition. These data provide the first experimental evidence of a direct interaction between the C1 complex and HIV-1, and indicate that C1 binding and activation are mediated by specific sites in gp41.

Binding Sites↗
PubMedDate not supplied

[The mechanism of inhibition of the activation of the complement first component by polyanions and polycations ].

Polyethyleneimine (PEI, 50 kDa) and polymethacrylic acid (PMA, 200 kDa) were shown to inhibit the lysis of sheep erythrocytes induced by the guinea pig complement. They twofold suppress the hemolysis at the concentrations of 0.47 and 0.89 microgram/ml, respectively. The inhibitory effect on the binding of the C1q subunit of human complement to the sensitized sheep erythrocytes (EA) was found to depend on the component of the reaction with which the inhibitors were preliminarily incubated. When an inhibitor, C1q, and EA were simultaneously incubated, the inhibition constants for PEI and PMA were 17 +/- 6 and 8.1 +/- 0.1 micrograms/ml, respectively. The preincubation of EA with PEI and the subsequent washing out of the inhibitor resulted in the inhibition constant of 22 +/- 3 micrograms/ml. No inhibitory effect was observed after a similar preincubation of EA with PMA. No inhibition was also detected when the inhibitors were added after the formation of the C1q complex with antibodies. These observations suggest that the binding of antibodies to cationic PEI prevents the C1q-antibody complex formation, while the binding of anionic PMA to the active site of C1q impedes the interaction of this subunit with immunoglobulins. Moreover, within the range of concentrations studied, the studied inhibitors did not affect the subsequent C1q binding to the C1r and C1s enzymes.

Animals↗