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PubMed1984

Lack of activation of C1, despite circulating immune complexes detected by two C1q methods, in patients with rheumatoid arthritis.

The activation of C1 by circulating immune complexes in patients with rheumatoid arthritis was investigated. C1rC1s(C1-In)2 complexes in EDTA-plasma, reflecting C1 activation in vivo, were slightly raised in 35 of 57 patients with rheumatoid arthritis, though most patients had elevated levels of circulating immune complexes as measured with either the 125I-C1q binding test or the C1q solid phase assay. The activation of C1 by circulating immune complexes in vitro was investigated by measuring the generation of C1rC1s(C1-In)2 complexes during 60 minutes at 37 degrees C in diluted recalcified EDTA-plasma. In 16 of the 57 patients, a slightly increased C1 activation in vitro was observed. These patients tended to have high levels of circulating immune complexes. However, the majority of the patients with high levels of circulating immune complexes showed a normal C1 activation in vitro. Therefore, it was concluded that measurement of circulating immune complexes by either of the two C1q methods in patients with rheumatoid arthritis does not imply that these circulating immune complexes are able to activate C1.

Aged↗
PubMed1985

Antibody density on rat red cells determines the rate of activation of the complement component C1.

It is a common observation that there is variability in the rate of activation of C1, the first component of complement, when bound to immune complexes. The cause of this variation has been investigated with experiments designed to assess separately the effect of antibody, antigen and C1 density. Using 125I-labeled C1 and a rat monoclonal antibody specific for the class I antigen, it has been found that the rate of activation is primarily dependent on antibody density on the cell surface and not on antigen or C1 density. This finding supports the suggestion that direct contact between the C1r2C1s2 subcomponent of C1 and antibody may be required for potentiation of C1 activation.

Animals↗
PubMed1983

The first component of human complement (C1): activation and control.

The first component of human complement (C1) is a 750 000 dalton glycoprotein that requires calcium or other specific metal ions to maintain its native structure and function. Under physiologic conditions, C1 comprises two weakly interacting subunits, C1q and C1r2s2, with C1q containing the binding site(s) for activators and C1r2s2 possessing enzymatic potential. C1 circulates in a precursor state and only after "activation" does it acquire functional activity, manifested as enzymatic activity specific for its natural substrates C2 and C4. C1 activation, which is accompanied by limited proteolysis and conformational changes, can be induced by immune complexes or certain nonimmune substances. With C1 binding to an immune complex, the strength of interaction between C1q and C1r2s2 increases. C1 also spontaneously activates at 37 degrees C by an intramolecular autocatalytic mechanism although at a slower rate than that induced by activators. C1 functions are controlled by the serum glycoprotein C1-inhibitor (C1-In) which blocks the enzymatic activities of activated C1 (C1). Under physiologic conditions, C1 has a half-life of only 13 seconds in the presence of C1-In. C1 is efficiently disassembled by C1-In, thereby releasing two inactive C1rC1s(C1-In)2 complexes per C1 molecule, leaving C1q activator-bound with biologically reactive sites uncovered that are not expressed in macromolecular C1. The most recently recognized function of C1-In is that of controlling the C1 activation process itself. While having only limited effect on immune complex-induced C1 activation, C1-In effectively controls certain nonimmune-induced as well as spontaneous C1 activation. Thus C1-In plays an important role in regulating nonspecific complement activation. The latter observation is relevant for the understanding of the human disease hereditary angioedema. An overabundance of spontaneous C1 autoactivation, due to low C1-In levels, might underlie the abnormal activation of complement via the classical pathway detected in the sera of these patients. Finally, recent studies indicate that C1 may have other important biologic functions in addition to initiating the complement cascade.

Angioedema↗
PubMed1983

Hereditary angioneurotic oedema and blood-coagulation: interaction between C1-esterase-inhibitor and the activation factors of the proteolytic enzyme systems.

C-1-inactivator (C-1-INA) does not only exert its important inhibitory functions in the complement system but also in the first step in the activation of the coagulation, fibrinolytic and kallikrein system. We therefore determined in nine patients with hereditary angioneurotic oedema (HANE) with obvious quantitative or functional defects of C-1-INA, and one further patient with Quincke-type oedema of different origin, the coagulation factors of the initial phase such as Hageman factor, plasma thromboplastin antecedent (PTA) and high molecular weight kininogen (HMWK). These factors were further correlated with the concentration as well as functional activity of C-1-INA. Nine of ten patients showed a significant, sometimes even excessive, increase in the levels of factor XII (mean +/- SD = 146% +/- 63), HMWK (mean +/- SD = 126% +/- 56) and PTA (mean +/- SD = 289% +/- 294), and a decrease of C1-esterase inhibitor (C-1-inactivator), which was measured with a immunologic method (mean +/- SD = 9.6 mg/dl +/- 6.6) for its concentration as well as being measured for its activity (mean +/- SD = 30.4% +/- 24.9).

Angioedema↗
PubMed1989

Structural analysis of the uEGF gene in the sea urchin strongylocentrotus purpuratus reveals more similarity to vertebrate than to invertebrate genes with EGF-like repeats.

The gene uEGF, a member of the epidermal growth factor family in the sea urchin Stronglyocentrotus purpuratus, is known to express two transcripts that are regulated developmentally in the embryo. We have partially sequenced several uEGF genomic and cDNA clones. We suggest that the smaller transcript is the result of splicing out an internal region present in the larger mRNA, probably with eight EGF-like repeats. The predicted two uEGF products have a signal peptide followed by an EGF-like repeat and a region with approximately 120 amino acids homologous to domain III in complement component C1s. Following these domains, the short product has 12 tandem EGF-like repeats, whereas the long product has approximately 20 tandem repeats. At the carboxy terminus both products have a region homologous to avidin. Unlike Notch and lin-12, no transmembrane domain was found in uEGF. We also show here that uEGF shares two characteristics with vertebrate members of the EGF family, but not with invertebrate members of the same family. (1) All the EGF-like domains sequenced are represented by single exons. (2) All the introns sequenced follow the first nucleotide of a codon. This supports the hypothesis that the organization of the EGF-like domains in vertebrates and in uEGF derived from a common ancestor. Thus, an alternative molecular datum is provided to support the hypothesis of echinoderm-chordate relationships.

Amino Acid Sequence↗
PubMed2000

In vivo microscopy reveals that complement inhibition by C1-esterase inhibitor reduces ischemia/reperfusion injury in the liver.

Complement plays a decisive role in postischemic tissue injury, a process responsible for severe damage after organ ischemia. Several pathophysiologic mechanisms initiated upon reperfusion are mediated by complement inducing microcirculatory disturbances. Here, we demonstrate the effects of complement inhibition using C1-esterase inhibitor (C1-INH) on microcirculation after liver ischemia by in vivo microscopy (IVM). In rats, the left liver lobe was clamped for 70 min. C1-INH was given 1 min prior to reperfusion. Controls received Ringer's solution. IVM was performed 30-100 min after reperfusion. Non-perfused acini decreased and sinusoidal perfusion increased substantially after treatment. Leukocyte adherence to sinusoidal and venular endothelium was markedly reduced by C1-INH. Transaminases were significantly decreased by C1-INH. Our data obtained by IVM suggest that complement activation is an early key event of ischemia/reperfusion injury. These observations demonstrate for the first time that reperfusion related microcirculatory disorders can be minimized by C1-INH. This compound should be evaluated in clinical application.

Animals↗
PubMed1997

Complement Cls, a classical enzyme with novel functions at the endochondral ossification center: immunohistochemical staining of activated Cls with a neoantigen-specific antibody.

The secondary ossification center of 14- to 16-day-old hamster tibiae was examined immunohistochemically with active and inactive Cls-specific antibodies, RK5 and RK4, respectively. At the ossification center, chondrocytes differentiate from proliferating and hypertrophic to degenerating stages, and their site is occupied by the bone marrow. Cls was strongly immunostained in hypertrophic chondrocytes. In order to discover whether Cls is activated at a particular site, the cartilage was immunostained with RK5 and RK4. RK5 mainly reacted with degrading matrix around invading vessels. In contrast, RK4 strongly stained hypertrophic chondrocytes. Immunoelectron microscopy revealed Cls on degrading fragments of chondrocytes and fibers of cartilage matrix. Decorin, one of the major matrix proteoglycans, was dose and time dependently degraded by Cls. Type II collagen and type I gelatin were also degraded. Articular cartilage from patients with rheumatoid arthritis was positively immunostained (11/12 cases) with an anti-Cls monoclonal antibody (mAb) PG11, whereas normal articular cartilage (5/5 cases) was negative, suggesting Cls participation in the etiology of rheumatoid arthritis.

Amino Acid Sequence↗
PubMed1990

Hereditary angioedema: its diagnostic and management perspectives.

Although hereditary angioedema accounts for only a small fraction of all cases of angioedema, it is the most common genetically linked clinical disorder caused by the deficiency of a protein associated with complement activation. Attacks may be complicated by incapacitating cutaneous swelling, life-threatening upper airway impediment, and severe gastrointestinal colic. Recent physicochemical and genetic studies have contributed significantly to our understanding of the structure of the inhibitor protein. Measurement of serum C4 titer is an efficacious screening test. Normal levels during symptomatic periods rule out the diagnosis, whereas decreased levels warrant determination of C1 esterase inhibitor titer by immunoassay or functional assay. The functional assay is necessary to ascertain the genetic variant form. The importance of making the correct diagnosis cannot be overemphasized. It can avert potentially fatal consequences, such as upper airway obstruction and unnecessary abdominal surgery. The application of short-term preventive measures can avoid complications associated with trauma. Finally, abatement or elimination of symptoms in patients with incessant and disabling attacks can be attained by long-term therapy with currently available attenuated androgens.

Angioedema↗
PubMed1988

A sensitive method to assay blood complement C1- inhibitor activity.

Hereditary angioneurotic edema results from deficiency of complement protein C1- inhibitor. Using a new spectrophotometric assay for C1-s esterase activity on the N-alpha-benzoyl-L-arginine ethyl ester, we describe a routinely available method for quantifying low C1- Inhibitor functional activities in EDTA-treated plasma of hereditary angioneurotic edema patients. C1- Inhibitor activity is deduced from the residual esterase activity of C1-s incubated with 20-80 microliters plasma samples. Arbitrary units (volume of sample inhibiting 50% of C1-s activity) were used to express C1- Inhibitor normal activity which was estimated as 22,500 +/- 5,000 (SD) U/l in 45 healthy individuals. The correlation with C1- Inhibitor antigen in these healthy individuals and 89 patients with varying concentrations of C1 Inhibitor ranging from 0.05-1.05 g/l was r = 0.91. Levels down to 2,000 U/l could be estimated. Specific inhibitory activity is an absolute requirement to distinguish between type I and type II hereditary angioneurotic edema.

Complement C1 Inactivator Proteins↗
PubMed1990

Degradation of type I and II collagen by human activated C1-s.

The activated first component of human complement, C1-s, was shown to cleave type I and II collagen and gelatin. The proteolytic activity was heat labile and was inhibited by a monoclonal antibody (M241) which recognized light chain of active human C1-s or by a serine protease inhibitor, DFP, but not by a chelating agent.

Amino Acid Sequence↗
PubMed1984

Neutron scattering studies of subcomponent C1q of first component C1 of human complement and its association with subunit C1r2C1s2 within C1.

Neutron scattering studies are reported on subcomponent C1q of component C1 of human complement, and on C1, the complex of C1q with subunit C1r2C1s2. For C1q, the molecular weight was determined as 460,000. The radius of gyration at infinite contrast RC is 12.8 nm. The RC values for the proteolytically cleaved forms of C1q, namely the heads and the stalks, are 1.5 to 2 nm and 11 nm, respectively, and thus the axis-to-arm angle of C1q is estimated at 45 degrees. Neutron data for subunit C1r2C1s2 are published elsewhere. The neutron data on C1 lead to an RC value of 12.6 nm for proenzymic C1 and a molecular weight of 820,000. The wide-angle scattering curve of C1q exhibits a minimum at Q = 0.28 nm-1 and a maximum at 0.39 nm-1; on the addition of C1r2C1s2, this minimum disappears. The neutron data on C1 indicate that C1q and C1r2C1s2 have complexed with a large conformational change in one or both parts. No conformational changes can be detected on the activation of C1 by this method.

Complement Activating Enzymes↗
PubMed1982

Characterization of the activation of the human C1r complement molecule.

The proenzyme form of C1r was isolated by sequential chromatography from the euglobulin fraction of human serum on DEAE-Sepharose 6B-CL, CM-Sepharose 6B-CL and Sepharose S-300-CL. This C1r had the tendency to spontaneously activate within 60-90 min of incubation at 37 degrees C in presence of EDTA and more slowly in the presence of Ca2+. The spontaneous activation of C1r was found to be a bimolecular process and could be completely inhibited by DFP in the pH range 6-9 and in the presence of Ca2+ without affecting the hemolytic C1r activity. [14C]DFP bound to trace proteins in the 60-90 kD range, but not to C1r proenzyme. The spontaneous activation of C1r was diminished in the presence of EDTA by DFP, but could not be completely suppressed. EDTA acts by removing Ca2+ from C1r, thereby changing the conformation of the protein and causing an increased digestibility of the C1r H-chain. At temperatures above 0-4 degrees C this influence destroyed the ability of C1r proenzyme and enzyme to form macromolecular C1 and thereby abolished its hemolytic activity. We conclude from these results that the spontaneous C1r activation in the pH range 6-9 and in the presence of Ca2+ is due to contaminant proteases. C1r activated also spontaneously at higher pH values between pH 9 and 13.2, but the spontaneous activation ceased abruptly at pH 13.4. An intramolecular process of activation cannot be excluded at these high pH values. It is, however, not clear, whether this activation is a suitable model for the C1r activation in the C1 molecule, because the hemolytic activity of C1r was substantially diminished under the high pH conditions.

Complement Activating Enzymes↗