[Angioneurotic edema acquired during chronic lymphoid leukemia. A case].
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Angioedema↗
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Results for “Complement C1s”
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Measurement of complement activation products in patients with chronic rheumatic diseases.
Measurement of the complement activation products C1s:C1-inh, C3bP and C5b-9 by ELISA in plasma samples from normals, rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE) patients showed significantly elevated levels in the two patient groups (P less than 0.0001 for C1s:C1-inh, C3bP and C5b-9) compared to normals. In seropositive RA patients there were significant correlations between the levels of the three complement activation complexes and IgM-RF, IgG-RF and IgA-RF. However, IgM-RF did not interfere with any of the ELISA systems. Mean levels of C1s:C1-inh, C3bP and C5b-9 were the same in paired plasma and synovial fluids; however, C3bP levels in the paired samples did not correlate with one another by rank. Our conclusions are that: (a) elevated plasma levels of these complement activation products are detectable in rheumatic diseases; (b) plasma levels of these complement activation products are related to Rheumatoid factor (RF) levels in seropositive RA patients; and (c) IgM-RF does not influence these solid-phase ELISA procedures.
Antibodies↗
C1s, the protease messenger of C1. Structure, function and physiological significance.
C1s is the modular serine protease, which executes the catalytic function of the C1 complex: the cleavage of C4 and C2. Like other complement serine proteases C1s has restricted substrate specificity and it is engaged into specific interactions with other subcomponents of the complement system. There has been a rapid progress in determining the 3D structure of complement serine proteases and in revealing the role of the individual domains in the protein-protein interaction properties. In this review we summarize recent findings on the structure of C1s, and on the mechanism of action of this protease. The results obtained by genetic engineering, physico-chemical and functional studies are reviewed. The physiological relevance of the proteolytic action of C1s and its possible implications in health and disease will also be discussed.
Animals↗
A novel PCR-based technique using expressed sequence tags and gene homology for murine genetic mapping: localization of the complement genes.
The complement system is a cascade of serum proteins and receptors which forms a vital arm of innate immunity and enhances the adaptive immune response. This work establishes the chromosomal localization of four key genes of the murine complement system. Mapping was performed using a novel and rapid PCR restriction length polymorphism method which was developed to exploit the murine expressed sequence tag (EST) database. This technique circumvents the laborious cDNA or genomic cloning steps of other mapping methods by relying on EST data and the prediction of exon-intron boundaries. This method can be easily applied to the genes of other systems, ranging from the interests of the individual researcher to large-scale gene localization projects. Here the complement system, probably one of the most well-characterized areas of immunology, was used as a model system. It was shown that the C3a receptor C1r and C1s genes form an unexpected complement gene cluster towards the telomeric end of chromosome 6. The second mannose binding lectin-associated serine protease gene was mapped to the telomeric end of chromosome 4, which is distinct from other complement-activating serine proteases. These results provide new insights into the evolution of this group of proteins.
Animals↗
Cell surface and serum protein phosphorylation by U-937 cell ectoprotein kinases.
Incubation of intact U-937 cells with 0.1 microM [gamma-32P]ATP for 10 min resulted in Mg(2+)-independent radiolabelling of about 40 cell surface proteins, some of which became more intensely labelled when cells were differentiated. Presence of 2% newborn calf serum revealed major labelling of three serum proteins with molecular weights of 170, 85 and 61 kDa. Out of several tested purified human serum proteins, complement factor 1s (C1s) exhibited specific labelling of the 28 kDa subunit. This capacity of monocytic cell ectokinases to phosphorylate cell surface and serum proteins may have significance for the regulation of interactions between these cells and their environment. In addition, phosphorylation of components of the complement system suggest a possible new means of regulating the immune response through the action of extracellular kinases.
Blood Proteins↗
C1. The first component of complement: the subcomponents of C1q, C1r, C1s, C1-inhibitor, C1q-receptors. Dedicated to Prof. Paul G. Klein.
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Complement C1↗
Interaction of mannose-binding protein with associated serine proteases: effects of naturally occurring mutations.
Mannose-binding protein (MBP; mannose-binding lectin) forms part of the innate immune system. By binding directly to carbohydrates on the surfaces of potential microbial pathogens, MBP and MBP-associated serine proteases (MASPs) can replace antibodies and complement components C1q, C1r, and C1s of the classical complement pathway. In order to investigate the mechanisms of MASP activation by MBP, the cDNAs of rat MASP-1 and -2 have been isolated, and portions encompassing the N-terminal CUB and epidermal growth factor-like domains have been expressed and purified. Biophysical characterization of the purified proteins indicates that each truncated MASP is a Ca(2+)-independent homodimer in solution, in which the interacting modules include the N-terminal two domains. Binding studies reveal that both MASPs associate independently with rat MBP in a Ca(2+)-dependent manner through interactions involving the N-terminal three domains. The biophysical properties of the truncated MASPs indicate that the interactions with MBP leading to complement activation differ significantly from those between components C1q, C1r, and C1s of the classical pathway. Analysis of MASP binding by rat MBP containing naturally occurring mutations equivalent to those associated with human immunodeficiency indicates that binding to both truncated MASP-1 and MASP-2 proteins is defective in such mutants.
Amino Acid Sequence↗
Trimer and tetramer complexes containing C1 esterase inhibitor, C1r and C1s, in serum and synovial fluid of patients with rheumatic disease.
During activation, the first component of complement C1q (C1r-C1s)2 is dissociated in conjunction with the formation of complexes containing C1 esterase inhibitor (C1-INH). Trimer complexes, with zymogen C1s associated with a firm C1-INH-C1r complex (C1-INH-C1r-C1s) can be distinguished from tetramer complexes C1-INH-C1r-C1s-C1-INH) in which C1-INH is firmly bound to both proteases. In the present study a two-stage electroimmunoassay was developed for the specific measurement of C1-INH-C1r-C1s. In the first step, C1-INH and its complexes were immunoprecipitated with anti-C1-INH during electrophoresis in the presence of Ca2+. In the second step, C1s contained in C1-INH-C1r-C1s was dissociated in the presence of EDTA and was measured by immunoprecipitation with anti-C1s. C1-INH-C1r-C1s were consistently found in normal sera. Normal sera did not contain C1-INH-C1r-C1s-C1-INH as assessed with a previously described ELISA procedure. Sera and synovial fluids from two groups of patients with inflammatory arthritis were investigated. In rheumatoid arthritis patients (n = 15) C1-INH-C1r-C1s complexes were usually found at high concentration both in serum and synovial fluid. C1-INH-C1r-C1s-C1-INH complexes were also present with values that were higher in synovial fluid than in serum, in accord with previous findings of classical pathway activation in the inflamed joints of the patients. Patients with spondylarthritic syndromes (n = 7) had serum and synovial fluid C1-INH-C1r-C1s concentrations that were comparable to those of the rheumatoid arthritis patients. If at all present, C1-INH-C1r-C1s-C1-INH were detected in trace amounts. Thus, C1 activation in patients with spondylarthritic syndromes appeared to be efficiently controlled at the C1r level. Distinguishing between C1-INH-C1r-C1s and C1-INH-C1r-C1s-C1-INH may prove of value in further studies of the activation and control of C1 in disease.
Animals↗
Synthesis of classical pathway complement components by chondrocytes.
Using immunohistochemical studies, C1q, C1s, C4 and C2 were detected in chondrocytes in normal human articular cartilage and macroscopically normal articular cartilage from the inferior surfaces of hip joints of patients with osteoarthritis. Using reverse-transcribed polymerase chain reaction (RT-PCR), mRNA for C1q, C1s, C4 and C2 was also detected in RNA extracted from articular cartilage. C1r, C3, C1-inhibitor, C4-binding protein and factor I were not detected by either technique. Articular chondrocytes cultured in vitro synthesized C1r, C1s, C4, C2, C3 and C1-inhibitor but not C1q, C4-binding protein or factor I, as assessed by enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis. Thus cultured articular chondrocytes have a complement profile that is similar to that of cultured human fibroblasts rather than that of articular chondrocytes in vivo. Complement synthesis in cultured chondrocytes was modulated by the cytokines interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), showing that cytokines can probably regulate complement synthesis in intact cartilage. The possible roles of local synthesis of complement components by chondrocytes in matrix turnover and the regulation chondrocyte function are discussed.
Base Sequence↗
Purification of human complement subcomponent C4. C4 cleavage by C1s.
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Centrifugation, Density Gradient↗
Complement components C1r/C1s, bone morphogenic protein 1 and Xenopus laevis developmentally regulated protein UVS.2 share common repeats.
Property patterns were constructed, based on an alignment of related domains in human complement subcomponents C1r and C1s as well as in the sea urchin protein uEGF. This kind of consensus pattern was able to identify similar domains in a human bone morphogenic protein, in a Xenopus laevis embryonal protein involved in dorsoanterior development and in a calcium-dependent serine protease secreted from malignant hamster embryo fibroblast cells. Because of the high level of overall sequence homology this protease may be the hamsters' equivalent of the human complement subcomponent C1s. The resulting multiple alignment of all studied domains suggests functionally and structurally important regions.
Amino Acid Sequence↗
The role of C1s, C1r and properdin in the initiation of the C3b-dependent feedback mechanism of the complement system.
The influence of activated C1s, C1r and properdin in the fluid phase initiation of the C3b-dependent feedback mechanism of the human complement was studied. It was found that C1s caused conversion of C3 and factor B in a normal serum, but not in a serum genetically deficient in C4 or in a serum to which Na2EDTA had been added. When a normal serum was incubated with C1r before incubation with C1s, only C3 was converted, whereas factor B remained in the unaltered native state. Properdin did not influence the C1s mediated conversion of C3 and factor B. When activated properdin was added to a properdin-depleted serum, both C3 and factor B were converted. Activated properdin was also incubated with purified C3 and purified C3b. It was shown that C3 was converted to C3b, but C3b was not degraded despite prolonged incubation.
Chromatography, Affinity↗
Immune complexes and complement profile in essential mixed cryoglobulinemia before and after plasma exchange.
Five patients affected by essential mixed cryoglobulinemia (EMC) with renal involvement unresponsive to high doses of corticosteroids, have been treated with 16 plasma exchanges (PE). The plasma removed at each apheresis was 1652 +/- 416 ml. The following data were evaluated before and after PE: levels of immune complexes as detected by cryocrit and C1q binding assay; total complement activity (CH50) and alternative pathway complement activity (APCH 50); concentrations of 9 complement components (C1q, C1s, C4, C3, C5, C6, B, I and H) and of the C3 split product C3d. By definition all serum samples had detectable cryoprecipitates and 4 out 5 had C1q binding activity higher than the upper limit of 2 SD. The effect of the PE was the decrease of cryocrit and of C1q binding activity approximately to one half their initial values. The basal complement profile suggested and excessive activation of complement through the classical pathway. Indeed we found low levels of the early complement components (C1q, C1s and C4), reduced CH50, normal levels of C3 and an increase of C3 split product C3d concentrations. APCH50 as well as C5, C6, B, I and H concentrations were found within the normal range. After each PE a significant decrease of the previously normal components was observed. The decrease was independent of the replacement fluid used (5% albumin solution or fresh plasma or cryoglobulin-depleted autologous plasma) and had a short duration. Indeed all these components after the drop following the PE increased rapidly reaching the basal level over a period of 24-48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Antigen-Antibody Complex↗
Effect of thiol compounds on human complement component C4.
Thiol compounds have been investigated as inhibitors of the covalent binding reaction of human complement protein C4 using Sepharose-C1s as a combined activating and binding surface. o- and p-substituted aminothiophenols are equally effective inhibitors, whereas the m-substituted compound is a less potent inhibitor. The anti-hypertensive drug captopril is also shown to inhibit the covalent binding reaction. A comparison of the effects of these compounds on the covalent binding reaction of isolated C4A and C4B has been made. Results suggest that a Pro-to-Leu substitution in C4B is likely to account for the differences in inhibitory potency of C4B compared with C4A observed with the aromatic inhibitors.
Aminophenols↗
Complement component C5: engineering of a mutant that is specifically cleaved by the C4-specific C1s protease.
Previous studies showed that simply inserting or substituting a few amino acid residues immediately downstream of the proteolytic activation site in C component C3 renders that site susceptible to the C4-specific C1s protease. This report describes the results of extending those studies to the closely related component C5. We found that small changes, similar to those that made C3 susceptible to C1s, were insufficient to render C5 C1s-sensitive; and neither more extensive substitution downstream of the cleavage site with a 14 residue long segment from C4, nor upstream substitution with an 8 residue long C4 segment gave C1s cleavage. However, substitution of both the upstream and downstream segments gave a hybrid C5 protein, designated ASC4, which was cleaved by C1s. The protease sensitivity of ASC4 was curious, however, in that C1s was more active against the secreted extracellular biosynthetic precursor, pro-ASC4(E) than mature ASC4, whereas a C5-specific convertase cleaved the mature protein but not the precursor. In contrast, both mature and precursor forms of wild-type C5 were cleaved by the C5 convertase, but neither of course is recognized by C1s. These results demonstrate that a mutant C5 molecule can be constructed that is cleaved at the activation site by both C1s and C5 convertase. This suggests that the structures necessary for specific recognition by the two proteases have little or no overlap and that recognition by C5 convertase involves residues that are distant from the activation site itself.
Amino Acid Sequence↗
Functional characterization of complement proteases C1s/mannan-binding lectin-associated serine protease-2 (MASP-2) chimeras reveals the higher C4 recognition efficacy of the MASP-2 complement control protein modules.
C1s and mannan-binding lectin-associated serine protease-2 (MASP-2) are the proteases that trigger the classical and lectin pathways of complement, respectively. They have identical modular architectures and cleave the same substrates, C2 and C4, but show markedly different efficiencies toward C4. Multisite-directed mutagenesis was used to engineer hybrid C1s/MASP-2 molecules where either the complement control protein (CCP) modules or the serine protease (SP) domain of C1s were swapped for their MASP-2 counterparts. The resulting chimeras (C1s(MASP-2 CCP1/2) and C1s(MASP-2 SP), respectively) were expressed and characterized chemically and functionally. Whereas C1s(MASP-2 SP) was recovered as an active enzyme, C1s(MASP-2 CCP1/2) was produced in a proenzyme form and was susceptible to activation by C1r, indicating that the activation properties of the chimeras were dictated by the nature of their SP domain. Similarly, each activated chimera had an esterolytic activity characteristic of its own SP domain and cleaved C2 with an efficiency comparable with that of their parent C1s and MASP-2 proteases. Both chimeras cleaved C4, but whereas C1s(MASP-2 SP) and C1s had Km values in the micromolar range, C1s(MASP-2 CCP1/2) and MASP-2 had Km values in the nanomolar range, resulting in 21-27-fold higher kcat/Km ratios. Thus, the higher C4 cleavage efficiency of MASP-2 arises from a higher substrate recognition efficacy of its CCP modules. Remarkably, C1s(MASP-2 CCP1/2) retained C1s ability to associate with C1r and C1q to form a pseudo-C1 complex and to undergo activation within this complex, indicating that the C1s-CCP modules have no direct implication in either function.
Amino Acid Sequence↗
C1, the first component of complement: structure-function-relationship of C1q and collectins (MBP, SP-A, SP-D, conglutinin), C1-esterases (C1r and C1s), and C1-inhibitor in health and disease.
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Amino Acid Sequence↗
Structure and activity of C1r and C1s.
During activation of the first component of the classical complement pathway the two zymogen subcomponents, C1r and C1s are converted to active proteolytic enzymes. Activated C1r cleaves C1s which then becomes the activator of C4 and C2. Amino acid sequence studies of the proteolytic chains of C1r and C1s, carried out in Oxford and Aberdeen respectively, have shown that they belong to the serine proteinase family. Modelling of these sequences to the three-dimensional coordinates of chymotrypsin (Birktoft & Blow 1972) reveals that both molecules have a conserved structural core, and that most of the differences lie in the external loops. Catalytically functional residues (Ile-16, His-57, Asp-102, Ser-195) are conserved, and residue 189 is aspartic acid, consistent with the known trypsin-like specificity of cleavage. Examination of the amino acid sequences of C4a, and comparison with those of the homologous molecules C3a and C5a, shows that there is a marked difference in the distribution of basic residues near the C-terminal arginine residue which is the site of action of C1s. When these amino acid sequences are modelled to the coordinates of C3a (Huber et al. 1980) and docked to the active site of C1s, the basic residues of C4a appear to interact with two glutamate residues peculiar to C1s, suggesting that this interaction may contribute to the ability of C1s to discriminate C4 from C3 and C5.
Amino Acid Sequence↗