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PubMed1981

Influence of age and sex on serum complement components in children.

Concentrations of eight complement components were determined on sera from 419 healthy children (198 boys and 221 girls) aged from 1 to 19 years. A significant correlation between concentration and age for all complement components (C1q, C1s, C4, C3, C5, factor B, properdin, and C1 inhibitor) was observed for girls; in the male population, a significant correlation was present only for C1q, C4, C3, C5, and properdin. The presence of a significant relationship to age suggests that this variable must be considered in establishing normal values of serum complement for children.

Adolescent↗
PubMed1985

C56 formation in the reaction mixture of isolated complement components through the classical complement pathway.

The mechanism of hemolysis of unsensitized erythrocytes by a mixture of 9 isolated, human-derived complement components, C1s, C4, C2, C3, C5, C6, C7, C8 and C9 (C1s-C9) was studied. Of the tested erythrocytes, guinea pig erythrocytes (Egp) were the most susceptible to lysis by C1s-C9, followed by human and sheep erythrocytes. Contamination of the isolated complement components by C56 was ruled out. It was determined that a factor was generated in the reaction mixture of C1s, C4, C2, C3, C5 and C6 (C1s-C6), which had lytic activity against Egp when C7, C8 and C9 were added. We found that the lytic factor was similar to C56 in the following properties: (1) the activity of the lytic factor decreased when incubated with isolated C7 prior to its reaction with Egp; (2) the lytic factor did not bind to Egp by itself but it did bind in the presence of C7; (3) EDTA did not have any inhibitory effect on the lytic factor; (4) the activity of the lytic factor decreased by treatment with anti-C5 and anti-C6 but not by treatment with anti-C3 and anti-C4, and (5) gel filtration of the reaction mixture (C1s-C6) indicated that the elution volumes of the lytic factor and of isolated C56 were similar. Thus, it is likely that C56 is generated in the reaction mixture of C1s-C6 and the lytic factor binds to unsensitized erythrocytes together with C7, to form an intermediate EC567 which is susceptible to lysis by the action of C8 and C9.

Animals↗
PubMedDate not supplied

Complement aberrations in serum from children with otitis due to S. pneumoniae or H. influenzae.

Complement components C1q, C1s, C3, C4, factor B and properdin were measured, together with C1 subcomponent complexes and Cq binding substances in acute and convalescent samples from patients with relapsing and non-relapsing otitis media due to S. pneumoniae and H. influenzae. Analysis of C1 subcomponent complexes together with the finding of low C1q levels gave evidence of a disturbed C1 function in acute OME. Furthermore, complement activation by the classical and by the alternative pathways was demonstrated. Complement aberrations were more pronounced in relapsing otitis than in non-relapsing otitis. C1q binding substances that might possibly cause the complement aberrations found were present in most of the patients.

Acute Disease↗
PubMed1993

Identity of the putative serine-proteinase fold in proteins of the complement system with nine relevant crystal structures.

The serine-proteinase domain is responsible for the proteolytic events that occur during complement activation. The sequences of nine serine proteinases of known crystal structure were compared with the serine-proteinase sequences in the six complement proteins C1r, C1s, C2, factor B, factor I and factor D to assess the degree of structural homology of the latter with the crystal structures. All sequence insertions and deletions were readily located at the protein surface. The internal location of disulphide bridges and the surface location of putative glycosylation sites are compatible with this structure. Secondary-structure predictions for the sequences were fully consistent with the crystal structures. It is concluded that the double subdomain beta-sheet motif is retained in the complement sequences, but that localized differences are observed for factor I, C2 and factor B.

Amino Acid Sequence↗
PubMed1995

Synthesis of complement proteins in amnion.

The amnion is a metabolically active tissue that has been identified as a site of synthesis of numerous products. We report that amnion tissue explants and amnion-derived epithelial cells synthesize and secrete six proteins of the complement system, C1r, C1s, C1 inhibitor, factor B, C3, and factor H. Synthesis of C2 was minimal and variable, and C5 was not detected. The six synthesized proteins had size and subunit composition characteristic of proteins synthesized in HEp2, a long term cell line derived from malignant epithelial cells. Constitutive and regulated synthesis of five of the six proteins was similar in amnion tissue and cells. However, synthesis of factor B was different in tissue and cells; constitutive synthesis was 12-fold higher in tissue than in cells, and interleukin-1 did not alter synthesis in tissue, but increased synthesis by 11.7-fold in cells. These results indicate that amnion may be a source of complement proteins present in the amnion fluid and may contribute to local host defense along with endometrial glandular epithelial cells, which synthesize C3. Furthermore, our results suggest that amnion tissue is stimulated in vivo to synthesize factor B and cannot respond to interleukin-1 with a further increase in the synthesis rate.

Adult↗
PubMed1983

Activation of C1 by soluble IgG aggregates as detected by a novel one-step hemolytic assay that specifically measures the proenzyme form of C1s.

A new hemolytic assay is described that specifically measures the precursor form of the C1s subcomponent of the complement system. The assay employs a C1s-depleted reagent obtained by immunoadsorption of fresh human plasma on immobilized goat anti-human C1s antibodies. Linear Z plots are obtained with nanogram levels of precursor C1s, whereas C1s completely fails to induce hemolysis in the assay. Because low concentrations of C1s do not interfere with the activity of precursor C1s, the assay can be used for the stoichiometric measurement of C1 activation. The precursor C1s assay was applied to the study of C1 binding and activation by soluble aggregates of human IgG (AIgG). Incubation of purified human C1 with AIgG caused a temperature-independent consumption of whole C1 hemolytic activity, indicating binding of C1, but almost no consumption of the total (precursor + activated) C1s activity. On the other hand, activation of C1, measured as the time- and temperature-dependent consumption of precursor C1s, could greatly exceed the binding of C1. These findings can be explained by using recent findings concerning the association-dissociation equilibrium between C1q and the tetrameric complex of C1r and C1s.

Animals↗
PubMed1981

Amino acid sequence around the thiol and reactive acyl groups of human complement component C4.

Activation of the fourth component of complement (C4) by C1s results in the generation of a reactive acyl group, able to react with putrescine, and in the release of a free thiol group that cannot be detected in the native haemolytically active molecule. Both the reactive acyl group and the free thiol group have been shown to reside in C4d, a fragment of the alpha'-chain of C4b derived from digestion of the molecule with the control proteins C3b inactivator and C4-binding protein. Peptides derived from CNBr digestion of [1,4-14C]putrescine-labelled and iodo(2-14C]acetic acid-labelled C4d have been obtained and used to establish a continuous sequence of 88 residues from the N-terminus of the molecule. The thiol and reactive acyl groups are contained in an octapeptide that shows near identity with the equivalent sequences reported for alpha 2-macroglobulin and C3. Other adjacent short sections also show homology of sequence between the three proteins, and it is highly likely that they contribute to the overall structure that gives a unique reactivity to the thiol ester bond postulated to exist in the native forms of the three proteins.

Amino Acid Sequence↗
PubMed1985

Determination of C1s-C1 inhibitor complexes in plasma by means of an enzyme linked immunosorbent assay.

An enzyme linked differential antibody immunosorbent assay for the quantitation of the C1s-C1 inhibitor complex has been developed. A study of the assays' performance under various conditions has shown that before use in the assay, it is imperative to remove competing forms of C1s from the samples to be tested. This is conveniently achieved in human plasma or serum by polyethylene glycol precipitation of the C1qrs, since the C1s-C1 inhibitor complex remains soluble and can be assayed in the supernatant solution. The detection limit of the assay in the plasma milieu is 0.1 mg/l, and the concentrations of the C1s-C1 inhibitor complex were found to be 1 mg/l in citrated plasma and 2 mg/l in serum. Activation of the fibrinolytic system in vivo does not seem to result in any appreciable C1 activation, since there was no concomitant major change in the plasma concentration of the C1s-C1 inhibitor complex.

Adult↗
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↗
PubMed1984

Serum levels of C1 subunits in rheumatoid arthritis.

Modifications of radial immunodiffusion and of hemolytic assays of C1q are described, which enable the results of these assays to be in agreement with those obtained by hydroxyproline assay. Using these assays, we show that C1q serum levels are significantly increased in rheumatoid arthritis (RA) and that the excess C1q levels in this disease are not accompanied by increased levels of C1r and C1s. Active RA is therefore characterized by increased levels of hemolytically active C1q that has a physiologically active stem region unbound to C1r and C1s.

Arthritis, Rheumatoid↗
PubMed1982

Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1.

Interactions between proenzymic or activated complement subcomponents of C1 and C1 Inh (C1 inhibitor) were analysed by sucrose-density-gradient ultracentrifugation and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The interaction of C1 Inh with dimeric C1r in the presence of EDTA resulted into two bimolecular complexes accounting for a disruption of C1r. The interaction of C1 Inh with the Ca2+-dependent C1r2-C1s2 complex (8.8 S) led to an 8.5 S inhibited C1r-C1s-C1 Inh complex (1:1:2), indicating a disruption of C1r2 and of C1s2 on C1 Inh binding. The 8.5 S inhibited complex was stable in the presence of EDTA; it was also formed from a mixture of C1r, C1s and C1 Inh in the presence of EDTA or from bimolecular complexes of C1r-C1 Inh and C1s-C1 Inh. C1r II, a modified C1r molecule, deprived of a Ca2+-binding site after autoproteolysis, did not lead to an inhibited tetrameric complex on incubation with C1s and C1 Inh. These findings suggest that, when C1 Inh binds to C1r2-C1s2 complex, the intermonomer links inside C1r2 or C1s2 are weakened, whereas the non-covalent Ca2+-independent interaction between C1r2 and C1s2 is strengthened. The nature of the proteinase-C1 Inh link was investigated. Hydroxylamine (1M) was able to dissociate the complexes partially (pH 7.5) or totally (pH 9.0) when the incubation was performed in denaturing conditions. An ester link between a serine residue at the active site of C1r or C1s and C1 Inh is postulated.

Binding Sites↗
PubMed1986

Functional analysis of activated C1s, a subcomponent of the first component of human complement, by monoclonal antibodies.

Three mouse monoclonal antibodies (M365, M81, and M241) directed against human C1s were used to analyze the structure of C1s related to the enzymatic activity. M365 and M81 recognized different epitopes on the heavy chain of C1s and could bind to C1s, as well as to C1s. The C4 cleaving activity of C1s was completely blocked by M81 and was partially blocked by M365. Although the C2 cleaving activity of C1s was partially inhibited by M81, no blocking was observed with M365. Both antibodies had no effect on the esterolytic activity of C1s. These results indicate that the C4 and C2 binding sites on C1s reside in the heavy chain, and they are distinct from each other. M241 could bind only to C1s, an active form of C1s. After reduction of C1s, M241 could not react with either heavy or light chain of C1s. The esterolytic activity of C1s was markedly reduced by M241. Furthermore, M241 blocked not only the cleavage of C4 and C2 by C1s but also the complex formation of C1s and C1 inactivator. From these observations, we suggest that M241 reacts with the active site of C1s, and both heavy and light chains of C1s participate in the composition of the active site.

Antibodies, Monoclonal↗
PubMed1983

Measurement of antibody-dependent binding, proteolysis, and turnover of C1s on liposomal antigens localizes the fluidity-dependent step in C1 activation.

The antibody-dependent binding and activation of the first component of human complement (C1) by liposomes containing nitroxide spin-label lipid haptens have been simultaneously measured. The liposomes were either fluid (dimyristoylphosphatidylcholine) or solid (dipalmitoylphosphatidylcholine) at the temperature of the experiments (32 degrees C). In 10 minutes fluid liposomes activate 40% of the C1 whereas solid liposomes only activate 10% of the C1. The fraction of C1 bound at the end of the activation incubation is approx. 2% for fluid liposomes and approx. 4% for solid liposomes. This binding is consistent with the relative amounts of antibody which bind to these two types of liposomes. These results demonstrate turnover of C1 or C1r2s2 on the liposome surface. It is concluded that the differential activation of C1 is due to a difference in the rate of activation of C1 after it is bound to the liposome surface. Lower limits for the activation rate constant for C1 bound to fluid and solid liposomes are estimated to be 8 X 10(-2) s-1 and 1 X 10(-2) s-1, respectively.

Animals↗