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PubMed1983

Requirements for the binding of human plasma fibronectin to the C1q subunit of the first component of complement.

We have shown previously that [125I]fibronectin (Fn) binds to solid-phase C1q in a dose-dependent manner. When C1r and C1s were added, the binding of Fn to C1q was abolished; removal of C1r and C1s restored Fn binding to C1q. In this report, we have systematically examined the optimal conditions that favor the Fn-C1q interaction. Our studies show that purified native 125I-Fn binds to C1q in a specific, saturable manner. Maximal 125I-Fn binding to C1q and gelatin occurs at low ionic strength (mu = 0.05) and drops sharply as the ionic strength is increased. At mu = 0.20, the binding to C1q is inhibited by 95%, whereas the binding to gelatin is inhibited by 50%. Optimal binding of Fn to C1q and gelatin occurs between pH 5.5 and 7.5, is decreased by 45% at 4 degrees C, and increases with incubation time; saturation of binding occurs in 60 min at 37 degrees C. Scatchard analysis of binding at mu = 0.05 indicates a single class of high affinity binding sites (Kd = 3.7 X 10(-8) M +/- 0.36 SD). The Kd of the reaction when C1q is bound to either plastic or immune complexes is essentially the same, and, in both cases, increases as the ionic strength of the medium is increased. Finally, significant binding of Fn to C1q can be demonstrated at physiologic ionic strength employing either insoluble immune complexes containing C1q or chemically cross-linked C1q.

Animals↗
PubMed1980

Effect of aspirin on the complement system in vitro.

Aspirin (acetylsalicylic acid), ASA and sodium salicylate (NaSA) activate the complement system in vitro. The activation involves the components of the classical pathway. It is, however, antibody independent. Evidence for activation are (1) consumption of C and C component activities; (2) activation of C1 evidenced by release of C1s from the macromolecular complex, and (3) C3 and C5 conversion.

Aspirin↗
PubMed1979

Complement activation by pneumococci associated with acute otitis media.

Pneumococci (types, I, III, VI, XIV, XVIII, XIX and XXIII) associated with acute otitis media were shown to activate complement in normal human serum by the classical as well as by the alternative pathway. In serum incubated with pneumococci classical pathway activation was demonstrated by decreased C4 values and the appearance of C1r-C1s-C1 IA complexes. Pneumococci caused C3 conversion in C2-deficient serum and in serum chelated with Mg++ EGTA showing activation of the alternative pathway without participation of the C42 convertase. Complement activation was more efficient when both pathways were intact. This was evident from a more pronounced C3 conversion and a greater reduction of the values for properdin and factor B in non-chelated serum as compared to Mg++ EGTA chelated serum.

Acute Disease↗
PubMed1986

Nucleotide sequence of the cDNA coding for human complement C1r.

C1r is a zymogen of a serine protease that is involved in the activation of the first component of the classical pathway of the complement system. cDNAs coding for human C1r have been isolated from libraries prepared from poly(A) RNA from human liver and Hep G2 cells. From DNA sequence analysis, the overlapping cDNA inserts were shown to span 2493 nucleotides of the C1r mRNA, not including the poly(A) tail. The cDNA sequence coding for C1r contained a 5' noncoding region, 2115 nucleotides coding for a polypeptide precursor of 705 amino acids, and a 3' noncoding region. Some variability in the length of the 3' noncoding sequence was observed with the cDNA inserts, although most contained a polyadenylation signal followed by a poly(A) tail. The A or noncatalytic chain of C-1r, which originates from the amino-terminal end of the precursor molecule, contains a potential growth factor domain and two different pairs of internal repeats. One pair of these internal repeats is closely related to the amino-terminal sequence of C1s, while the other pair of repeats is homologous to the tandem repeats present in beta 2-glycoprotein I, complement factor B, the b subunit of factor XIII, and a single region present in the alpha 1 chain of haptoglobin. The B chain of C-1r contains the catalytic portion of the enzyme and is homologous to the trypsin family of serine proteases.

Amino Acid Sequence↗
PubMed1987

The first component of complement as a constituent of human salivary sediment.

The sediment from human saliva is complement-reactive. Evidence presented shows that C1 (first component of complement) is a constituent of sediment from healthy human donors. Sediment (Sed) inactivated functionally pure C4 (fourth component of complement), and this action on C4 was inhibited by EDTA, phenylmethylsulphonylfluoride (PMSF, a serine-esterase inhibitor) and C1-inhibitor (C1-In). When Sed was incubated with 0.15 ionic strength buffer and separated by centrifugation, C1 haemolytic activity was found in the supernatant. By incubating Sed with EAC4 cells (sheep erythrocytes sensitized with rabbit antibody to which C4 has been fixed), transfer was shown of C1 from the Sed to the cells, resulting in the formation of EAC14; this transfer was inhibited by IgG directed against a subunit of C1 (anti-C1s).

Adult↗
PubMed1991

Localisation of complement components in association with glomerular extracellular particles in various renal diseases.

Intraglomerular extracellular microparticles including so-called virus-like particles and striated membranous structures have been observed in various renal diseases. The presence and localisation of complement components in these extracellular bodies was studied using the protein A-gold electron microscopy method. Ultrastructurally these particles were differentiated into microspherical structures (MSS) and thread-like structures (TS). Both structures showed weak to moderate diffuse labelling with C1s, whilst the intense labelling found with C3d and C9 was confined to individual membrane-like structures of both MSS and TS. Labelling with IgA, IgG, fibrinogen and the complement components C1q, C1r, C3c C4 and C5 showed negative or trace results. There were no differences between the immunolabelling patterns of MSS and TS, nor among different renal diseases in which these structures were found. These findings raise the possibility that formation of so-called virus-like particles such as MSS and TS may be associated with complement activation.

Complement System Proteins↗
PubMed1976

Physicochemical and functional characterization of the C1r subunit of the first complement component.

C1r was isolated from serum by an improved method and found to be a glycoprotein with a sedimentation coefficient of 7.0S. Under conditions of physiologic ionic strength and pH, C1r consist of two apparently identical noncovalently linked 95,000 dalton polypeptide chains. Antisera to C1r detected a protein of gamma-mobility on electrophoresis of serum in agarose in the presence of calcium, and a Beta-mobility protein when the electrophoretic separation was carried out in EDTA. On sucrose gradient ultracentrifugation of normal human serum in the presence of calcium, C1r antigenicity was found in the 19 S region of the gradient. On the other hand, when the gradient contained EDTA, C1r antigenicity was found in the 7 S region. No reaction of anti-C1r with C1r-deficient sera was observed. C1r had a high affinity for active C1s or proenzyme C1s in the presence of calcium and was able to activate C1s and to form C1 in conjunction with C1q and C1s. Activation of C1s by C1r was inhibited by calcium, C1 inactivator, polyanethol sulfonate, and DFP. Activation of C1s by C1r occurred only after a preliminary incubation of C1r for a brief time at 37 degrees C before addition of C1s. The ability of C1r to form C1 in conjunction with C1q and C1s was, however, progressively lost on incubation at 37 degrees C. Trypsin, although potentiating the activity of crude C1r, did not modify the activity of purified C1r. Its action was on a trypsin-sensitive inhibitor separated from C1r in the final step of the isolation procedure. The binding of 125I-C1r to sensitized sheep erythrocytes required the presence of C1q and calcium but not C1s, whereas the binding of 125I-C1s required C1q, C1r and calcium. Thus, C1r functions as not only the activator of C1s, but also serves as the physical link between C1q and C1s in macromolecular C1.

Animals↗
PubMed1997

Role of the P2 residue of complement 1 inhibitor (Ala443) in determination of target protease specificity: inhibition of complement and contact system proteases.

A dysfunctional C1 inhibitor (C1 INH) from a family in whom the propositus presented with systemic lupus erythematosus but without angioedema previously was shown to have diminished inhibitory activity toward isolated C1r and C1s, and intact C1. The mutation was identified as replacement of Ala443 (P2) with Val. This study further analyzed the reactivity of this mutant and characterized two mutants with Ser or Asp at this position. Ser at P2 does not interfere with binding of target proteases. However, the mutant with Asp at this position is unable to bind C1r and beta factor XIIa, and also has a decreased rate of reaction with C1s and kallikrein. Therefore, alteration of polarity alone had no effect on binding, while a bulky and/or charged side chain was not tolerated. Although defective in inhibition of C1r and C1s, the P2 A-->V mutant had acquired the ability to complex with trypsin. It also completely retained the ability to complex with kallikrein and factor XIIa. None of the 10 individuals expressing this mutant protein has ever had angioedema. This observation, combined with normal inhibition of contact system proteases and defective inhibition of complement proteases, suggests that angioedema is caused by bradykinin generated from contact system activation.

Alanine↗
PubMed1977

[Anticomplement activity of a polyanion: pentosan sulfuric polyester. III. Mechanism of functional inactivation of the different properdin and complement system fractions].

In vitro, the drug pentosan-poly-sulfoester (PPS) changes the electrophoretic migration of different proteins from the complement and properdin systems, such as native C3 (beta 1C globulin), C3c (beta-1A globulin), C3d (alpha-2D globulin), C1s inactivator (ClsINA), Clq and properdin factor B (B). Their more anodal migration is the consequence of a molecular alteration and persists after prolonged dialysis. These structural changes, yet undefined, explain the loss of functional activity of these proteins, and the anticomplementary activity of this drug. Moreover, PPS is able to block the alternate pathway activation by its action on properdin factor B (C3 proactivator). In fact, in presence of PPS, the activators of the properdin systems such as C3 nephritic factor are inactive. These altered mobilities are also responsible for the overestimation in the antigenic concentration of B (+ 45%), C4 (+27%) and C3/C3c (+ 14%), found in human serum containing 50 mg/ml of PPS. PPS has an original action upon the complement and properdin systems, which allows its clinical use as a potent inhibitor of the humoral mediators of inflammation.

Binding Sites↗
PubMed1999

Up-regulated production and activation of the complement system in Alzheimer's disease brain.

We used reverse transcriptase-polymerase chain reaction and Western blotting techniques to measure the levels of complement mRNAs and their protein products in Alzheimer's disease (AD) brain compared with non-AD brain. mRNAs for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 were detected in the 11 regions of brain that were investigated. The mRNA levels were markedly up-regulated in affected areas of AD brain. In the entorhinal cortex, hippocampus, and midtemporal gyrus, which had dense accumulations of plaques and tangles, C1q mRNA was increased 11- to 80-fold over control levels, and C9 mRNA 10- to 27-fold. These levels were substantially higher than in the livers of the same cases. Western blot analysis of AD hippocampus established the presence of all of the native complement proteins as well as their activation products C4d, C3d, and the membrane attack complex. These data indicate that high levels of complement are being produced in affected areas of AD brain, that full activation of the classical complement pathway is continuously taking place, and that this activation may be contributing significantly to AD pathology.

Adult↗
PubMed1979

Studies on the nature of heat-labile anti-complementary activity in normal human serum.

Heat-labile anti-complementary activity (ACA) appears in normal human serum during storage or heating as endogenous haemolytic activity disappears. Following gel filtration of unheated serum, two peaks of heat-labile ACA are present. The ACA of both whole and fractionated serum has previously been attributed to the presence of heat-labile immunoglobulin aggregates or immune complexes. Our data demonstrate that the heavy peak of ACA obtained by gel filtration does not bind to 125I-C1q or to Raji cells, and that its effect is abolished to C1INH, suggesting that it represents C1 rather than immunoglobulin aggregates or immune complexes. The lighter peak of ACA in fractionated serum has the functional characteristics of C1s and free C1s is demonstrable in fractions containing this activity. The ACA of whole serum likewise has functional characteristics of C1. The anti-complementary effect of C1 on guinea-pig complement would not be evident in the complement fixation assay until most endogenous haemolytic activity in human serum has been inactivated, either by heat or by storage. C1INH only partially inhibits this ACA in serum or in solutions containing isolated C1 in high concentrations. These observations indicate that heat-labile ACA in whole or fractionated sera is due to the presence of C1 and C1s and that this activity cannot be taken as evidence for the presence of immune complexes.

Agammaglobulinemia↗
PubMed1995

Synergistic inhibition of human cell-mediated cytotoxicity by complement component antisera indicates that target cell lysis may result from an enzymatic cascade involving granzymes and perforin.

A widely accepted theory of lymphocyte-mediated cytotoxicity (CMC) proposes that upon effector cell (EC) and target cell (TC) interaction, release of perforin, serine proteases and other lytic moieties contained within cytoplasmic granules results in TC lysis. Complement activation and the activation of the various enzymatic activities associated with cytotoxic granules have strikingly similar modes of action and both lead to pore formation in their respective targets. We report here that by using antisera to early and late complement components we were able to inhibit CTL, NK and ADCC cytotoxicity up to 100%, even though binding of EC to TC was unaffected. Furthermore, we showed that addition of C1q or C1s (two serine proteases) antisera to C9 antisera, at titers too low to inhibit separately, resulted in synergistic inhibition of CMC. Anti-C1s together with anti-C1q (or anti-C8 with anti-C9) did not result in synergy. This finding supports a cascade model of activation for lytic molecules released from EC. In addition, we demonstrated that anti-C1q and anti-C1s bind to proteins in the 30-kD region and anti-C9 binds to proteins in the 70-kD region, coinciding with published molecular weights of granzymes and perforin, respectively. Finally, lytic ability of purified granules was also inhibited by complement antisera, further suggesting that activation occurs outside of TC. Taken as a whole, these data indicate that TC lysis may be the result of a cascade of events involving granzymes and perforin, analogous to that seen with the complement system.

Antibodies, Monoclonal↗
PubMed1985

Purification and characterization of the C3 convertase of the classical pathway of human complement system by size exclusion high-performance liquid chromatography.

The C3 convertase of the classical pathway of the complement system is a liable complex, C4b,2a, and is activated by limited proteolysis of two components, C4 and C2, by C1s. By utilizing iodine-treated C2 and size exclusion high-performance liquid chromatography (HPLC), we have succeeded in isolating for the first time the classical pathway C3 convertase. Size exclusion HPLC demonstrated that the apparent molecular mass of the C3 convertase was 280K daltons. The C3 convertase decay-dissociates spontaneously into C4b and C2a. The decay-dissociation is a temperature-dependent reaction and the half-lives of the C3 convertase at 24, 30, and 37 degrees C were estimated to be 400, 180, and 60 min, respectively. The decay-dissociation was also dependent on pH and was accelerated by increasing pH. In addition, the decay-dissociation of the C3 convertase was accelerated by C2b. This result suggests that C2b acts as a feedback inhibitor on the activation of the classical pathway of complement system.

Chemical Phenomena↗
PubMedDate not supplied

Complement components and activation in primary biliary cirrhosis.

Total complement activity was normal in 18 patients with primary biliary cirrhosis using two hemolytic assays capable of distinguishing between defects in classical and alternative pathways. Activation of the classical pathway was demonstrated in all patients by formation of complexes between C1r, C1s, and C1 inactivator. Large amounts of free C1q, not in complex with C1r and C1s, were demonstrated in the majority of patient sera. Furthermore, C4 levels were within the normal range or slightly subnormal. No evidence for alternative pathway activation was found. Increased mean levels of several complement components, in particular C1 inactivator, C2, C3, factor B, factor H, were noted. A significant correlation between these complement factors, derived mainly from the liver, and ceruloplasmin suggests that this elevation might be secondary to cholestasis. In contrast, no significant correlation with levels of early reacting acute phase reactants, immunoglobulins, or circulating immune complex-like material were observed. It is concluded that activation of the complement system by the classical pathway is common in patients with primary biliary cirrhosis.

Antigen-Antibody Complex↗
PubMed2004

cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection.

The first component of complement, C1, is a multi-molecular complex comprising of C1q and the Ca(2+)-dependent tetramer C1r(2)-C1s(2). The traditional role of C1q within the complex is that of recognition signal-a signal, which is instantly converted into a highly specific intramolecular proteolytic activation of the C1r(2)-C1s(2) tetramer thereby triggering activation of the classical pathway. Another important function of C1q is its ability to bind to a wide range of cell types resulting in the induction of cell-specific biological responses. These cells include polymorphonuclear leukocytes, monocytes, lymphocytes, dendritic cells, endothelial cells and platelets. Interaction of C1q with endothelial cells and platelets, for example, leads to cellular activation followed by release of biological mediators and/or expression of adhesion molecules, all of which contribute, directly or indirectly to the inflammatory process. These specific responses are mediated by the interaction of C1q with C1q binding proteins or receptors on the cell surface. To date, four types of putative C1q binding cell surface expressed proteins/receptors have been described. These include cC1q-R/CR, or calreticulin (CR), a 60 kDa protein, which is also known as collectin receptor; gC1q-R/p33, a 33 kDa homotrimeric protein; C1q-Rp (CD93), a 120 kDa, O-sialoglycoprotein; and CR1 (CD35), the receptor for C3b. Although the specific role of each of these molecules in a given C1q-mediated cellular response is yet to be worked out, all of them may, in one form or another, participate in the inflammatory processes associated with vascular or atherosclerotic lesions, autoimmune diseases, or infections. The main focus of our laboratory for the past 20 years has been to elucidate the structure and function of cC1q-R/CR and gC1q-R/p33, both of which have been isolated and characterized on the basis of their ability to bind C1q. The purpose of this article is therefore to provide an up to date overview of these two proteins with particular emphasis on their unique structural and functional features, their multi-faceted nature and most importantly their role in infection and inflammation.

Animals↗
PubMed1987

[A case report of hereditary angioedema and studies on the serum components of complement, C1-inactivator and proteinase inhibitors during edema attack].

Sixteen years old girl was admitted because of for the past ten years' frequent edema attack and abdominal pain. Laboratory examination revealed hypocomplementemia, marked depletion of the fourth component of complement and low level of C1-inactivator. Familial studies revealed that her mother was also hypocomplementemic and in low level of C1-inactivator. Serial studies performed on the alterlation of components of complement, C1-inactivator, alpha 1-antitrypsin, antithrombin III, and alpha 2-macroglobulin during edema attack. The fourth component of complement and C1-inactivator were markedly depleted in remission and attack. Remarkable depletion was found in antithrombin III and esterase inhibition activity of C1-inactivator during attack. In contrast, alpha 1-antitrypsin and alpha 2-macroglobulin did not change. The present study may explain that Hageman factor fragments, activated by C1s, promotes kinin generation via kalikrein activation. And the condition that complete functional deficiency of C1-inactivator was main role in this circuit. Fibrynolysis and late components of complement was less influence on edema attack.

Adolescent↗