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PubMed1995

[Inhibitory effects of sepimostat mesilate (FUT-187) on the activities of trypsin-like serine proteases in vitro].

Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 microM for trypsin, 0.029 microM for pancreatic kallikrein, 0.61 microM for plasma kallikrein, 0.57 microM for plasmin, 2.5 microM for thrombin, 20.4 microM for factor Xa and 6.4 microM for C1r. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for C1s, and Ki values for these proteases were 0.021 and 0.18 microM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 microM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 microM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 microM, while camostat revealed no inhibition by concentrations up to 1 microM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 microM, respectively, the corresponding values for camostat being 350 and 150 microM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and C1s in complement pathway.

Animals↗
PubMed1998

C1q--how many functions? How many receptors?

C1, the first component of the classical pathway of complement activation is a complex of three proteins called C1q, C1r and C1s. Normally, C1q binding to aggregated IgG molecules results in activation of the classical pathway of complement. However, C1q has a number of other observed functions, not directly related to complement, that could be mediated by recently identified binding proteins acting as cell-surface receptors or soluble modulators of C1q-mediated functions. This article discusses the various activities of C1q and the evidence that these functions might be influenced by both membrane-bound and soluble C1q-binding proteins.

Animals↗
PubMed2001

Molecular cloning of the complement (C1r/C1s/MASP2-like serine proteases from the common carp (Cyprinus carpio).

The classical pathway of complement composed of C1, C4, and C2 is an antibody-dependent activation cascade that is present in jawed vertebrates. C1 is a Ca2+-dependent complex of C1q, C1r, and C1s, and analogous to an initiation complex of the lectin pathway of complement, which consists of the mannose-binding lectin (MBL) homologous to C1q and the MBL-associated serine proteases (MASPs) homologous to C1r and C1s. Thus divergence of Clq and MBL and that of C1r, C1s and the MASPs are considered to be crucial events in the establishment and evolution of the classical complement pathway. However, molecular information on the C1 subcomponents is very limited in lower vertebrates. Here we describe two distinct C1r/C1s/MASP2-like cDNA clones (C1r/s-A, C1r/s-B) isolated from the common carp (Cyprinus carpio). They share 83% identity at the amino acid level and have a domain structure similar to that of C1r/C1s/MASPs from other species. The serine protease domain of the carp homologues lacks the histidine loop and is encoded by a single exon containing an AGY codon for the active serine residue, as in mammalian C1r, C1s, and MASP2. Southern blot and PCR analyses indicated that the carp has at least three copies of the C1r/s-A gene and a single C1r/s-B gene. Although phylogenetic tree analysis does not definitively assign carp C1r/s-A and C1r/s-B, they might represent ancestral molecules which later diverged into C1r, C1s, and MASP2 of higher vertebrates.

Alleles↗
PubMed1986

A molecular mechanism for the activation of the first component of complement by immune complexes.

The proposed activation mechanism is based upon several key concepts, including the "S"-structure for the folding of the C1r2C1s2 tetramer among the C1q arms [Poon, et al., J. molec. Biol. 168, 563-577 (1983)]; the locations of the catalytic domains on the tetramer and the resulting functional relevance of the "S"-structure [Colomb et al., Phil. Trans. R. Soc. B306, 282-292 (1984)]; the structure of C1-inhibitor [Odermatt et al., FEBS Lett. 131, 283-289 (1981)]; and the control of C1 activation by C1-inhibitor [Ziccardi, J. Immun. 128, 2505-2508 (1982)]. The proposed activation mechanism has four main features: steric exclusion of C1-inhibitor from C1 when it binds to an immune complex; signal generation through multivalent binding of the C1q heads to an irregularly-arranged cluster of antibody Fc regions, and signal transmission through the movement of the stiff C1q arms about their semi-flexible joints, causing distortion of the symmetrical cone of C1q arms; induction of rapid activation by a shift in equilibrium favoring the autocatalytic conformation of C1r2C1s2; and release of the activated C1s from the C1q arms, so that the ends of the tetramer are free for interaction with C4 and C2 and C1-inhibitor, and the C1q subcomponent becomes more flexible, allowing access of C1-inhibitor to C1r.

Antigen-Antibody Complex↗
PubMed1979

Impairment of acute protein reactivity in chronic renal failure.

The acute phase protein response was studied after elective surgery in 13 normal subjects and 9 patients with severe chronic renal failure. Total haemolytic complement reactivity (CH50) and serum concentrations of C1q, C1s, C4, C3, factor B, properdin, C5, C9, C-reactive protein (CRP), caeruloplasmin, alpha1-acid glycoprotein and haptoglobin were measured preoperatively and on days 2, 4 and 6 after operation. Abnormalities were seen in the group with chronic renal failure. Firstly, there was no significant acute phase response of C1s, C3, C5, C9 and CH50 and a significant reduction in the response of factor B. Secondly, CRP showed prolonged elevation in the post-operative period in contrast to the transient rise seen in the control group. With the possible exception of alpha1-acid glycoprotein, the behaviour of the non-complement proteins (caeruloplasmin and haptoglobin) was comparable for the two groups. These defects could impair the physiological response to infection in patients with severe chronic renal failure.

Adult↗
PubMed1985

Lyme disease in a 12-year-old girl.

We report the case of a 12-year-old girl with erythema chronicum migrans, aseptic meningitis and knee arthralgia. Rise of specific antibody titre against an Ixodes ricinus spirochaete was demonstrated. Circulating immune complexes and high levels of C1r-C1s-C1IA complexes indicating activation of the complement system via the classical pathway were found. The clinical features and the laboratory findings warranted a diagnosis of Lyme disease.

Antigen-Antibody Complex↗
PubMed1992

Spatial and temporal expression pattern during sea urchin embryogenesis of a gene coding for a protease homologous to the human protein BMP-1 and to the product of the Drosophila dorsal-ventral patterning gene tolloid.

A cDNA clone coding for a sea urchin embryonic protein was isolated from a prehatching blastula lambda gt11 library. The predicted translation product is a secreted 64 x 10(3) Mr enzyme designated as BP10. The protein contains several domains: a signal peptide, a putative propeptide, a catalytic domain with an active center typical of a Zn(2+)-metalloprotease, an EGF-like domain and two internal repeats similar to repeated domains found in the C1s and C1r serine proteases of the complement cascade. The BP10 protease is constructed with the same domains as the human bone morphogenetic protein BMP-1, a protease described as a factor involved in bone formation, and as the recently characterized product of the tolloid gene which is required for correct dorsal-ventral patterning of the Drosophila embryo. The transcription of the BP10 gene is transiently activated around the 16- to 32-cell stage and the accumulation of BP10 transcripts is limited to a short period at the blastula stage. By in situ hybridization with digoxygenin-labelled RNA probes, the BP10 transcripts were only detected in a limited area of the blastula, showing that the transcription of the BP10 gene is also spatially controlled. Antibodies directed against a fusion protein were used to detect the BP10 protein in embryonic extracts. The protein is first detected in early blastula stages, its level peaks in late cleavage, declines abruptly before ingression of primary mesenchyme cells and remains constant in late development. The distribution of the BP10 protein during its synthesis and secretion was analysed by immunostaining blastula-stage embryos. The intracellular localization of the BP10 staining varies with time. The protein is first detected in a perinuclear region, then in an apical and submembranous position just before its secretion into the perivitelline space. The protein is synthesized in a sharply delimited continuous territory spanning about 70% of the blastula. Comparison of the size and orientation of the labelled territory in the late blastula with the fate map of the blastula stage embryo shows that the domain in which the BP10 gene is expressed corresponds to the presumptive ectoderm. Developing embryos treated with purified antibodies against the BP10 protein and with synthetic peptides derived from the EGF-like domain displayed perturbations in morphogenesis and were radialized to various degrees. These results are consistent with a role for BP10 in the differentiation of ectodermal lineages and subsequent patterning of the embryo. On the basis of these results, we speculate that the role of BP10 in the sea urchin embryo might be similar to that of tolloid in Drosophila. We discuss the idea that the processes of spatial regulation of gene expression along the animal-vegetal in sea urchin and dorsal-ventral axes in Drosophila might have some similarities and might use common elements.

Amino Acid Sequence↗
PubMed1995

Complement components C1q, C1r/C1s, and C1INH in rheumatoid arthritis. Correlation of in situ hybridization and northern blot results with function and protein concentration in synovium and primary cell cultures.

OBJECTIVE: To analyze the synovial site and the cell types expressing C1q, C1r/C1s, and C1-esterase inhibitor (C1INH) and to characterize newly synthesized C1q in patients with rheumatoid arthritis (RA). METHODS: Tissue and primary cell cultures of synovium from RA patients were analyzed for C1q, C1r/C1s, and C1INH by Northern blotting, in situ hybridization, and pulse-chase experiments for C1q. RESULTS: The de novo synthesis of C1q, C1r/C1s, and C1INH in synovium and primary cell cultures was proven by Northern blot and by antigenic and functional analysis. In in situ hybridization experiments, the synovial lining cell layer was identified as the site of C1q, C1r, and C1INH expression. In contrast, immunohistologic analysis showed that C1q, C1s, and C1INH proteins were present in a thin film covering the synovial lining cells. In situ hybridization performed on primary cell cultures provided evidence that only macrophages were able to express C1q, whereas fibroblasts and stellate cells synthesized C1r. CONCLUSION: The synovium is important for the synthesis and secretion of C1q and C1r/C1s, as well as the control protein C1INH, which supports the idea of a locally occurring inflammatory process in RA patients.

Arthritis, Rheumatoid↗
PubMed1997

Secreted chondroitin sulfate proteoglycan of human B cell lines binds to the complement protein C1q and inhibits complex formation of C1.

We recently characterized a species of proteochondroitin sulfate (CSPG) secreted by human B cell lines that closely resembles in its structure the serum-derived C1q inhibitor (C1qI). These proteoglycans have in common a molecular mass of approximately 130 to 150 kDa with a core protein of 30 kDa to which up to four chondroitin sulfate chains each of approximately 26 kDa are attached. Since this B cell-derived CSPG is a potential source for serum C1qI, we measured its capacity to interact with C1q in solid-phase binding and complex electrophoresis assays. B cell CSPG purified from culture supernatants of the two human B cell lines JOK-1 and U266 strongly bound to C1q. In contrast to the secreted form, cellular proteoglycan of the myeloma cell line U266 did not interact with C1q. Binding of C1q to CSPG was competitively inhibited by free glycosaminoglycans (GAG) in the order dextran sulfate > heparin > heparan sulfate > chondroitin-6-sulfate (CS-C) > dermatan sulfate (CS-B) > chondroitin-4-sulfate (CS-A). B cell CSPG inhibited the hemolytic activity of C1q and C1. In addition, B cell CSPG blocked C1q receptor binding in a dose-dependent manner. The proteoglycans did not influence the activity of C1 complex already bound to EAC4 target cells. By interaction of CSPG with solid-phase-bound C1q, formation of the C1 complex upon the addition of C1r and C1s was impaired. Strong binding of B cell CSPG to C1q, its inhibition of C1q activity, and its structural similarities to the previously described human serum C1qI indicate that B cells produce a soluble CSPG, which may act as C1qI under physiologic conditions.

B-Lymphocytes↗
PubMed1978

Demonstration and quantitation of activation of the first component of complement in human serum.

Activation of the first component of human complement (C1) in human sera can be readily detected in double immunodiffusion studies with anti-C1q, anti- C1r, and anti-C1s as it produces a characteristic pattern quite different from that of precursor C1. Native macromolecular C1 gives a continuous line of precipitation with antisera to C1q, C1r, and C1s in double diffusion studies. After activation of C1 by incubation of serum with complement activators, three major changes occurred in the Ouchterlony pattern. First, spurring of the C1s precipitin line over that of macromolecular C1, indicating release of C1s from C1, was observed with low doses of activator. Release of C1s was quantitated by single radial diffusion and shown to be complete with the highest activator dose examined. Second, C1q was released with larger activator doses as shown also by spurring of the precipitin line due to this component over the remaining macromolecular C1. Third, and most surprising, C1r antigenicity was progressively lost as the activator dose was increased and no C1r line remained with the highest dose of activator tested. This was not true with C1s as there was no change in the total C1s concentration in serum incubated with various activator doses. These observations provide two approaches to the quantitation of C1 activation in human serum. First, C1r and C1s can be quantitated by single radial diffusion. A decrease in the C1r:C1s ratio correlates with activation. Second, C1s released by the activation can be quantitated by single radial diffusion if the agarose contains high concentrations of anti-C1q to confine C1, also containing C1s, to the area near the application well, and lesser concentrations of anti-C1s to permit free C1s to produce a measurable ring. The extent of release of C1s also correlates with activation. These immunochemical techniques to quantitate C1 activation directly inserum do not require specialized reagents. It is hoped that they will be useful in screening pathological sera and in monitoring the status of the complement system in patients.

Complement C1↗
PubMed1975

Effects of anesthesia, surgery and inflammation upon host defense mechanisms. I. Effects upon the complement system.

Complement protein levels and C7 hemolytic activity were measured in four individuals following anesthesia and surgery, and in a group of 20 patients with inflammatory diseases. Seven of the eight complement components studied characteristically were elevated, most dramatically C1s and C3PA. Elevation of C1s often was greater than elevation of C1q, displaying an independent variation of C1s and C1q in both postoperative and inflammatory disease patient groupds. The major increases of C components were seen subsequent to the peak C-reactive protein response, as was the occurrence of the 'reactor state', a propensity to formation of C56 which surprisingly was associated with increased levels of C7. Levels of properdin frequently were reduced postoperatively. It is concluded that multiple complement components, with the notable exception of properdin, respond as acute phase reactants which are elevated and changed in proportion postoperatively and during inflammatory disease.

Anesthesia, General↗
PubMed1989

Role for the third constant domain of the IgG H chain in activation of complement in the presence of C1 inhibitor.

The multidomain architecture of Ig H chains was initially implicated in the variety of functions imposed on each species of Ig. However, the activation of C by IgG is the only function that has been attributed to a single domain of C gamma 2, whereas most of other functions of IgG require both C gamma 2 and C gamma 3 domains. This one domain-one function relationship in the C activation by IgG, too, was questioned recently by the fact that a C gamma 3-less fragment of rabbit IgG, F(acb)2, is definitely less capable of activating C than intact IgG. Here we reexamined capacities of F(acb)2 to bind and activate C1 in the presence and absence of C1 inhibitor (C1-In) in comparison with intact IgG, by using SRBC sensitized with these proteins (EFacb, EIgG). At an ionic strength of 0.065 and 37 degrees C, where C1q was bound equally well by these cells and the dissociation was limited, C1s, presumably in the form of C1r2C1s2, dissociated from EFacb at a rate 7-fold greater than that from EIgG, irrespective of the presence or absence of C1-In. A physiologic concentration of C1-In reduced the rate of C1 activation by EFacb to 5% that by EIgG. The results present evidence that the C gamma 3 domain, too, plays a crucial part in the C1 activation process by stabilizing the zymogenic conformation of C1 and protecting it from the attack by C1 inhibitor.

Animals↗
PubMed1989

[Stepwise dissociation of subcomponents of C1, the first component of human complement, upon activation on an affinity sorbent].

An affinity sorbent comprising macroporous glass coated with the polymer with the polymer with immobilized immunoglobulin IgG was used for the isolation from human serum of the first component of the complement and for its separation into subcomponents C1r, C1s and C1q by the one-step procedure. Serum C1 was quantitatively bound to the sorbent at 0 degrees C. The unbound part of the serum can be used as a R1 reagent for determining the hemolytic activity of C1. After activation of bound C1 by heating (30 degrees C, 40 min) the activated subcomponent C1r is eluted from the sorbent. Stepwise elution with EDTA at pH 7.4 or with EDTA + 1 M NaCl at pH 8.5 results in a selective and quantitative elution of the activated subcomponent C1s and subcomponent C1q. Stepwise elution of C1 subcomponents from the affinity sorbent after activation reflects the process of C1 breakdown following its activation on immune complexes.

Animals↗
PubMed1983

Complement components in 100 newborns and their mothers determined by electroimmunoassay.

Samples of blood were obtained from 100 healthy full-term women in labour and, after delivery, from the umbilical cord of their infants. By electroimmunoassay, complement components were quantitated in serum (C1q, C1r, C1s, C1 IA, C2, P, D. I, H, C6 and C7) or in EDTA-plasma (C4, C3, B, C5. and C). The concentrations of C7 in cord serum was twice that found by others using a functional assay. Concentrations of C1r, I and C6 in the cord sample were 50-60 per cent of those in healthy blood donors used as reference, and that of D was about 130 per cent. The cord serum and plasma concentrations of the remaining components agreed with previously reported values. The maternal levels of C2, C4, C3, B, H, C5 were 40-60 per cent higher than those of the reference.

Complement C4↗
PubMed1985

Effect of EDTA and citrate on the functional activity of the first component of complement, C1, and the C1q subcomponent.

The first component of complement, C1, is a calcium-dependent complex of the three distinct subcomponents, C1q, C1r, and C1s. Earlier observations revealed that treatment of C1 with EDTA led to a loss of hemolytic C1 activity even after recalcification. Therefore, it was of interest to study whether EDTA has an additional effect on C1 and its subcomponents, beside its chelating capacity. The chelating effect of EDTA was compared to that of citrate. It was found that treatment of C1 or C1 with EDTA followed by addition of Ca++ led to a loss of hemolytic activity up to 90%, depending on EDTA concentration. Even pretreatment of EDTA with varying amounts of Ca++ did not prevent the inactivation of C1 or C1. In contrast, after dissociation of C1 or C1 by citrate, 100% of the original C1q activity is recoverable on addition of C1q deficient serum as source of C1r and C1s. EDTA-treated serum, however, showed a concentration-dependent loss of hemolytic C1q activity, indicating an inhibitory effect of EDTA on C1q. EDTA-treated C1q, fluid phase or bound to EA, was no longer able to form an hemolytically active C1 complex by interaction with C1r and C1s.

Calcium↗
PubMed1985

In vivo degradation of rat C1q induced by intravenous injection of soluble IgG aggregates.

Immune complexes are able to bind and activate the first component of complement, C1. Upon activation of C1, C1r and C1s are rapidly inactivated by C1-In which also forms a complex with these two subcomponents, resulting in their release from C1-immune aggregate complexes. The fate of C1q after the binding C1 to immune complexes in vivo is not clear and, therefore the clearance of radiolabelled rat C1q was investigated in normal rats and in rats receiving soluble aggregated human IgG. 125I-labelled rat C1q was cleared with a half-life (T 1/2) of 12.4 hr in normal rats. Injection of AIgG into rats that had previously received 125I-C1q accelerated the clearance of 125I-C1q, resulting, finally, in a T 1/2 of 53 min. The levels of circulating endogenous C1q were also followed using haemolytic titrations and immunochemical measurements. Directly after injection of AIgG into rats, there was a rapid decrease in C1q haemolytic activity to less than 25% of the initial value after 10 min. The rate of disappearance of C1q antigen, was, however, much slower, the lowest concentration being 30% at 2 hr. C1q haemolytic activity and the C1q antigen level returned to virtually normal values after 24 hr. Plasma samples were taken at different time intervals after the injection of AIgG and subjected to gel filtration on Sephacryl S-400 columns. It was found that, in the 10 min samples, C1q antigen and C1q haemolytic activity, each with an estimated molecular weight (MW) of 400,000, were detected together. In addition, there was C1q antigen with a MW of less than 69,000 without C1q haemolytic activity. SDS-PAGE analysis of the various serum samples indicated that the low MW C1q antigen had an apparent MW of 25,000. Measurement of uptake of 125I-C1q in various organs indicated that the main site of clearance of 125I-C1q is the liver.

Animals↗
PubMed2000

Expression of complement messenger RNAs by human endothelial cells.

This study evaluated complement mRNA expression in human brain microvessel endothelial cells (HBMEC), human umbilical vein endothelial cells (HUVEC), and cells of the human derived ECV304 line. Cerebral endothelial cells and HUVEC expressed detectable levels of complement gene mRNAs for the C1q B-chain, C1r, C1s, C2, C3, C4, C5, C7, C8 gamma-subunit and C9. In addition to C6 mRNA, C1q and C9 were not detected in ECV304 cells. These results indicate that endothelial cells may be a source of complement proteins in brain and other organs of the body.

Cell Line↗