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PubMed1983

Activation of the first component of complement, C1: comparison of the effect of sixteen different enzymes on serum C1.

In this study, the effect of sixteen different enzymes on serum C1 and its subcomponents was investigated. The sixteen enzymes could be divided into three groups. First, enzymes which activate native C1: trypsin (optimal concentration 2.4 x 10(-4) mM); alpha-chymotrypsin (2.3 x 10(3) mM); thrombin (1.0 x 10(-5) mM); plasmin (1.9 x 10(-5) mM); elastase (5.8 x 10(-5) mM); pronase (3.0 x 10(-6) mM). All these enzymes are serine esterase and activate native serum C1 bound to EAC4 at the given concentration within 10 min at 30 degrees C. Furthermore, native C1 inhibited by a pentosanpolysulfoester, Sp54, is unable to undergo the internal activation but can be externally activated by the serine esterases. Second, enzymes which do not activate native C1 but result in a dose and time-dependent loss of C1 activity: collagenase; pepsin; carboxypeptidase B. Third, enzymes which have no effect on C1 and C1: Lysozyme; neuraminidase; beta-galactosidase; L-amino acid oxidase; arginase; streptokinase, and acetylcholinesterase.

Animals↗
PubMed1986

A simple one-step hemolytic assay of the first component of human complement (C1) with polyethylene glycol treated human serum: details of the assay procedures and its application to the C1 activation study.

C1 was removed from human serum by polyethylene glycol (PEG) precipitation and the supernatant (C1 deficient serum, C1D) was used for assay of C1 hemolytic activity (C1D method). Serum concentration of PEG 6,000 ranging from 3.5-4% was determined to be suitable for preparation of C1D, but C1D prepared by PEG 4,000 were proved unsatisfactory for use. Oxidation of C1D by iodine treatment increased C1 activity by two-fold. The C1D method was comparable in sensitivity to the conventional method, and the correlation between the 2 methods was good (r = 0.94). The C1D method was shown to be a useful tool for the study of C1 activation, since the method specifically measured C1, but not C1 activity. A half-life (T1/2) of C1 activity in fluid phase at 37 degrees C was 20 min under physiologic conditions.

Complement Activation↗
PubMed1995

Complement C1 inhibitor is produced by brain tissue and is cleaved in Alzheimer disease.

C1 inhibitor was identified in human brain tissue by Western blotting and by immunohistochemistry using multiple antibodies to the native protein. The presence of C1 inhibitor mRNA was identified by reverse transcriptase-polymerase chain reaction analysis of brain mRNA extracts. The mRNA was also detected in cultured postmortem human microglia and in the IMR-32 human neuroblastoma cell line. Immunohistochemically, the native protein was detected in residual serum of capillaries and pyramidal neurons of both control and Alzheimer disease cases, as well as in occasional senile plaques of Alzheimer tissue. The reacted protein was detected on dystrophic neurites and neuropil threads in Alzheimer tissue by 4C3 monoclonal antibody, which recognizes a neoepitope following suicide inhibition. These data indicate that C1 inhibitor, a regulatory molecule controlling multiple inflammatory proteolytic cascades, is produced in normal brain. In Alzheimer disease, C1 inhibitor undergoes a prominent reaction in abnormal neuronal processes, such as dystrophic neurites and neuropil threads.

Alzheimer Disease↗
PubMed1991

[Angioedema due to acquired complement-C1-inhibitor deficiency in a female patient with non-Hodgkin lymphoma and autoimmune hemolytic anemia].

A case of angioedema due to acquired deficiency of the regulatory protein C1-esterase-inhibitor (C1-INH) is reported. The edematous attack occurred 3 1/2 weeks after initiation of successful therapy for autoimmune-hemolytic anemia in the course of long-standing non-Hodgkin's lymphoma. At the time of acute edema the complement profile was typical: virtual absence of C1-INH function was associated with diminished concentrations of the components of the classical pathway of complement (C1q, C1r, C1s, C2, C4) and reduced complement hemolytic activity (CH50). Anti-C1-INH-autoantibodies were not detected. The angioedema lasted for about one week, and no further attacks occurred during the five-months follow-up period. Although there was only a minor adjustment to the therapy, the C1q, C2, C4 and CH50 values gradually increased to levels close to the lower limit of the normal range, while C1r and C1s showed normal values. In contrast to most other reports, this case was characterized by angioedema which was precipitated only after initiation of appropriate treatment for the underlying disease rather than before therapy or even diagnosis of the underlying disease.

Aged↗
PubMed1986

Biosynthesis of the subcomponents C1q, C1r and C1s of the first component of complement (C1) by guinea pig hepatocyte primary cultures.

Thus far, the synthesis of C1q by liver cells has not been demonstrated. To investigate this possibility, viable hepatocytes were isolated from the liver of guinea pigs and primary cultures were established. The cells (10(6) cells/ml) were cultured under serum-free conditions for 8 days and the culture medium was changed every 24 h. The few contaminating Kupffer cells were lysed by preincubating the cell cultures with a monoclonal (22C4-8) antibody directed against a nonpolymorphic Ia determinant and preabsorbed rabbit serum. The hemolytic activity of C1 and its subcomponents C1q and C1r/C1s was tested in the supernatants. Guinea pig hepatocyte primary cultures synthesize and secrete up to 3 X 10(3) effective C1q molecules/cell/24 h and 34 X 10(3) effective C1r/C1s molecules/cell/24 h. The synthesis of C1q and C1r/C1s could be reversibly inhibited by cycloheximide (50 micrograms/ml). Furthermore, to demonstrate de novo synthesis of the C1q subcomponent, endogeneous labeling with 3H-proline (or 14C-proline) was performed. The immunoprecipitated C1q from cellular lysates and culture medium was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Compared to biosynthetically labeled guinea pig C1q from peritoneal macrophages, three corresponding bands (30, 28 and 24 kDa, respectively) were detectable in the fluorograph. The data show that guinea pig hepatocytes are able to synthesize C1 subcomponents, whereby the synthesis of C1q and C1r/C1s occurs independently.

Animals↗
PubMed2003

X-ray structure of the Ca2+-binding interaction domain of C1s. Insights into the assembly of the C1 complex of complement.

C1, the complex that triggers the classical pathway of complement, is assembled from two modular proteases C1r and C1s and a recognition protein C1q. The N-terminal CUB1-EGF segments of C1r and C1s are key elements of the C1 architecture, because they mediate both Ca2+-dependent C1r-C1s association and interaction with C1q. The crystal structure of the interaction domain of C1s has been solved and refined to 1.5 A resolution. The structure reveals a head-to-tail homodimer involving interactions between the CUB1 module of one monomer and the epidermal growth factor (EGF) module of its counterpart. A Ca2+ ion is bound to each EGF module and stabilizes both the intra- and inter-monomer interfaces. Unexpectedly, a second Ca2+ ion is bound to the distal end of each CUB1 module, through six ligands contributed by Glu45, Asp53, Asp98, and two water molecules. These acidic residues and Tyr17 are conserved in approximately two-thirds of the CUB repertoire and define a novel, Ca2+-binding CUB module subset. The C1s structure was used to build a model of the C1r-C1s CUB1-EGF heterodimer, which in C1 connects C1r to C1s and mediates interaction with C1q. A structural model of the C1q/C1r/C1s interface is proposed, where the rod-like collagen triple helix of C1q is accommodated into a groove along the transversal axis of the C1r-C1s heterodimer.

Amino Acid Sequence↗
PubMed2000

The complement regulators C1 inhibitor and soluble complement receptor 1 attenuate acute lung injury in rabbits.

Because activation of the complement system plays a major role in the pathogenesis of acute lung injury, the availability of new specific complement inhibitors represents a promising therapeutic approach. In the present study we investigated pulmonary edema formation and pulmonary artery pressure (PAP) in acute complement-induced lung injury for possible therapeutic impact of the complement regulators C1 inhibitor and soluble complement receptor 1. Eighteen isolated and ventilated rabbit lungs were perfused with pooled normal human serum (NHS, final concentration 35%) in Krebs-Henseleit buffer in a recirculating system. Lung weight gain and PAP were continuously recorded. Complement activation was blocked by the addition of C1 inhibitor (1.0 U/mL, n = 6) or sCR 1 (2.0 microg/mL, n = 6). Lungs that received NHS without inhibitors served as controls (n = 6). This study was performed according to the Helsinki Declaration and approved by the local government. Application of NHS resulted in an increase of PAP within 20 min from 8+/-2 to 42+/-6 mmHg, which was significantly (P < 0.05) decreased by C1-Inh (25+/-5 mmHg) and sCRI (20 +/-3 mmHg). Moreover, pulmonary edema formation after NHS, as assessed by overall weight gain, was reduced by both C1-Inh and sCR1, compared with controls. These findings were paralleled with significantly decreased thromboxane release rates and reduced tissue deposition of C3c and C5b-9. C1 inhibitor and sCR1 attenuate the complement-induced pulmonary capillary leakage and PAP increase, indicating the protective effect of complement inhibition in isolated perfused rabbit lungs.

Animals↗
PubMed1976

Role of C1 in the complement activating effect of Pseudomonas aeruginosa lipopolysaccharide preparations.

The complement consumption of endotoxin preparations extracted by the trichloroacetic acid or phenol-water method from different Pseudomonas aeruginosa strains was measured in normal human and guinea pig serum and in serum chelated with Mg2+-EGTA. In the chelated serum, which was essentially Ca2+-free, the first component of complement (C1) could not exert its function. All preparations tested consumed considerably less complement activity in chelated than in normal serum. The proportion of CH50 units fixed in Mg2+-EGTA and in normal serum was always higher in the tricholoracetic acid extract than in the phenol-water extract of the same strain. The part of LPS molecule that was able to activate the complement system in Ca2+-free serum was partially separated from the C1-requiring part by the combination of different extraction methods. The results suggest that on the LPS molecules two different sites are responsible for the complement activating effect through the classic and the alternative pathways.

Animals↗
PubMed1979

C1 inhibitor-dependent dissociation of human complement component C1 bound to immune complexes.

The interaction of C1 inhibitor with complement component C1 bound to immune complexes was examined by using 125I-labelled C1 subcomponents. The inhibitor binds rapidly to subcomponent C1s, and more slowly to subcomponent C1r. Formation of the C1r-C1 inhibitor complex causes rapid dissociation of subcomponents C1r and C1s from the antibody-antigen-component C1 aggregate. The rate and extent of this release are proportional to C1 Inhibitor concentration and are also dependent on ionic strength. Results obtained with purified C1 Inhibitor, plasma or serum as source of C1 Inhibitor are all closely comparable. Only slight dissociation of subcomponent C1q is observed under the same range of conditions. The implications of the release phenomenon are discussed in relation to the structure of component C1 and the possibility of differential turnover of C1 subcomponents.

Antibody Affinity↗
PubMed1991

C1 inhibitor: different mechanisms of reaction with complement component C1 and C1s.

Inactivation of human complement subcomponent C1-s by its regulator C1 inhibitor at physiological ionic strength proceeded at a 3-fold higher rate when C1-s was in the physiological C1- complex with subcomponents C1q and C1-r rather than as purified subunit. When the C1- complex was disassembled by chelation of calcium, the C1-s subcomponent was inactivated by C1 inhibitor at rates similar to those for the purified proteinase. Increasing ionic strength had little effect on the reaction of purified C1-s with C1 inhibitor but greatly diminished the rate of reaction of intact C1-. Addition of heparin accelerated the inactivation of purified C1-s by C1 inhibitor up to 25-fold but increased the inactivation of intact C1- only about 5-fold. These differences in the inactivation of C1-s by C1 inhibitor, depending on whether the proteinase is free or complexed with other subcomponents of C1-, suggest different mechanisms of reaction. Occurrence of subcomponent C1-s in a macromolecular complex with C1q and C1-r, thus, appears to be critical not only for directing its physiological activation but also its inactivation.

Complement C1↗