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PubMed2004

Complement determinations in human disease.

OBJECTIVE: To define techniques used for complement measurements and examine the clinical relevance of alterations of complement determinations in disease. DATA SOURCES: Data have been assembled from the authors' research, original articles, and reviews, as well as chapters and complete books on complement. STUDY SELECTION: Studies were chosen for inclusion by the opinions of the authors, relevant complement reviews, publications, and books. RESULTS: Complement has been shown to possess approximately 31 proteins, some of which are enzymes (C1r, C1s, C2, factor B, factor D), some cofactors, some inhibitors or inactivators, and others composed of membrane-integrated proteins. All of the complement proteins have been purified, and many of the respective genes have been identified. The complement cascade is a dual-edged sword, causing protection against bacterial and viral invasion by promoting phagocytosis and inflammation. Pathologically, complement can cause substantial damage to blood vessels (vasculitis), kidney basement membrane and attached endothelial and epithelial cells (nephritis), joint synovium (arthritis), and erythrocytes (hemolysis) if it is not adequately controlled. CONCLUSIONS: Definitive evidence is available that complement-mediated tissue destruction occurs after immune complex injury in the kidney and lung and may be important in lupus erythematosus and adult respiratory distress syndrome. Future studies on complement receptor structure and function may provide clues to treat effectively lupus, hemolytic anemias, and nephritis. In addition, gene therapy and antibody therapy need further refinement to treat immunodeficiency diseases.

Complement System Proteins↗
PubMed1991

Inorganic supports coated with N-substituted polyacrylamides: application to biospecific chromatography of proteins.

Wide porous glass (WPG) chemically coated with a poly-N-(2-hydroxyethyl)acrylamide layer is proposed as a carrier of biospecific ligands in affinity chromatography. The method of WPG chemical modification includes synthesis of the gamma-aminopropyl derivative followed by chemical adsorption of poly(p-nitrophenyl acrylate). Ester groups of the polyacrylate-coated WPG can be used for coupling the ligands bearing primary amino groups. Condensation of esters with ethanolamine yields a poly-N-(2-hydroxyethyl)acrylamide-coated support with non-specific adsorption properties resembling those of Sepharose 4B. Human IgG immobilized on the polyacrylate support was used for isolation of the first complement component from human serum and for its separation into subcomponents C1r, C1s and C1q by a one-step method. An unbound part of serum may be used as the R1 reagent for determining haemolytic C1 activity. The stepwise elution of C1r, C1s and C1q from the column reflects the course of C1 breakdown after its activation on immune complex formation.

Acrylic Resins↗
PubMedDate not supplied

Some aspects of the humoral and neutrophil functions in post-comatose nawareness patients.

Post-comatose unawareness (PCU) is one of the possible outcomes of severe brain injury. Patients with severe brain injury have an increased susceptibility to severe nosocomial infections for multifactorial reasons, including immune suppression at different levels. We studied different immunological aspects in 11 PCU patients. Impaired humoral immunity was found in 27% of them. Two patients had decreased haemolytic activity of the classical complement pathway, associated with decreased levels of the components C1q, C1r and C4. Another patient had very low levels of IgG2 and IgG4. The neutrophil killing activity was impaired in these three patients, but was completely restored with the addition of a heterologous serum, suggesting a humoral defect. Neutrophils showed normal chemotaxis and random migration, and the superoxide anion release by neutrophils was also found to be normal. Understanding the immunological events in PCU patients contributes to a better and more intensive therapeutic approach, which might accelerate the rehabilitation of these patients.

Adolescent↗
PubMed2000

Acute cocaine exposure up-regulates complement expression in rabbit heart.

The exact mechanism of the cardiotoxic actions of cocaine remains unclear. The finding that the heart may be a source of injurious complement components led us to investigate whether cocaine promotes myocardial expression of complement. Rabbit isolated hearts were perfused for 70 min with either cocaine hydrochloride (1 or 10 microM), the synthetic isomer (+)-cocaine (10 microM), or procaine hydrochloride (10 or 30 microM). Compared with controls perfused with drug-free buffer, both cocaine and procaine significantly (P <. 05) increased myocardial C1q, C1r, C8, and C9 mRNA expression, whereas 10 microM (+)-cocaine had no effect on complement mRNA expression. Cocaine also significantly increased (P <.05) C3 mRNA transcription. In addition, in vivo administration of cocaine (1 mg/kg) for three consecutive days significantly increased myocardial complement mRNA expression. Cocaine and procaine also increased membrane attack complex (MAC) formation in the myocardium. The antioxidant 2-N-mercaptopropionyl glycine, attenuated the increases in complement mRNA expression induced by 1 microM cocaine and 10 microM procaine. In vivo heparin administration (300 U/kg i.v.), 2 h before removal of the heart and exposure to 1 microM cocaine, did not inhibit C1q, C1r, C3, and C8 mRNA transcription, but decreased MAC expression. It was determined previously that heparin reduces myocardial ischemia/reperfusion injury. Our results suggest that cocaine may cause myocardial injury by up-regulating local complement expression, possibly via the production of reactive oxygen species. Furthermore, the glycosaminoglycan heparin may modulate the cytotoxic effects of cocaine by impeding formation of the MAC.

Animals↗
PubMed1990

Clinical and experimental approaches to the prevention of atherosclerosis by immunological regulations.

To evaluate the involvement of the complement system in atherogenesis, we investigated the effect of camostat mesilate (CM), C1r, and C1 esterase inhibitor on cholesterol-induced atherosclerosis in rabbits. We also examined the effect of sodium dextran sulfate (DS, molecular weight: 7000), which is reported to be effective in preventing arteriosclerotic diseases and in inhibiting cholesterol-induced atherosclerosis in experimental animals, on complement activation in vitro and in vivo. The administration of CM reduced the formation of atherosclerotic lesions in cholesterol-fed rabbits. DS inhibited complement pathway in vitro, and the administration of DS reduced the C3a level in subjects. These results suggest that complement activation may possibly be involved in the atherosclerotic process.

Aged↗
PubMed2003

Importance of the prime subsites of the C1s protease of the classical complement pathway for recognition of substrates.

The classical complement pathway, which plays a vital role in preventing infection, is initiated by the action of the serine proteases C1r and C1s. We have examined the hydrolysis of substrates representing cleavage sequences in the physiological substrates for C1s, C2 and C4. These studies showed that the P(1)'-P(4)' substrate residues of C2 and C4 conferred greater affinity of substrate for enzyme and also induced a sigmoidal dependence of enzyme velocity on substrate concentration. This indicates that the substrate gave rise to homotropic positive cooperative behavior in the enzyme. When C1s was in complex with C1q and C1r, as would occur under physiological conditions, the same behavior was observed, indicating that this mechanism is relevant in the complement pathway in vivo. We further investigated the requirements of C1s for prime side amino acids by examining a substrate library in which each of the P(1)'-P(4)' positions had been substituted by different classes of amino acids. This revealed that the P(1)' position was a major determinant of the selectivity of the enzyme, while certain substitutions at the P(1)'-P(4)' positions abolished the allosteric behavior, indicating that contact residues at these positions in the C1s enzyme must mediate the cooperativity. The studies reported here highlight the importance of prime subsites in C1s for interaction with its cognate substrates in the complement pathway and therefore yield greater understanding of the mechanism of interaction between this vital protease and its physiological substrates.

Amino Acid Substitution↗
PubMed1989

Structure and function of C1 inhibitor.

C1 inhibitor (C1 INH) is a plasma protease inhibitor that is essential for regulation of activation of the complement and kinin generating systems. It is the only inhibitor of C1r and C1s in plasma, and is responsible for about half of the kallikrein and the majority of plasma factor XII inactivating activity. Based on sequence homology, C1 INH is a member of the serpin family of protease inhibitors and related proteins, and its mechanism of action is identical to those of the other protease inhibitor members of the family. Susceptible proteases cleave C1 INH at an Arg-Thr peptide bond (the P1 and P1'residues) that is 34 amino acid residues from the carboxy terminus of the protein. A stable bimolecular complex then is formed between the larger amino terminal portion of the C1 INH molecule and the protease. C1 INH inactivation of C1r and C1s within activated macromolecular C1 results in dissociation of C1 with release of complexes consisting of two molecules of C1 INH and one molecule each of C1r and C1s. C1q is thus allowed to interact with zymogen C1r and C1s or with C1q receptors. Autoactivation of intact macromolecular C1 is also prevented by C1 INH. The structure of C1 INH is quite similar to other serpin plasma protease inhibitors, and C1 INH appears to retain all the major structural features required for maintaining tertiary structure and inhibitory function.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

The complement system in HIV disease.

Different aspects of the relationship between the HIV infection and the complement system were studied. 1. No significant differences were found between seronegative controls, asymptomatic, and symptomatic (ARC, AIDS) HIV-seropositive patients in the plasma levels of complement components C4, Bf, and C3. 2. Using sensitive ELISA assays, a significant increase was observed in the levels of protein-protein complexes which are formed at the activation of the classical (C1r-C1s-C1-INH) and alternative (C3b-Bb-P) pathways, indicating that both complement pathways are activated in the HIV disease. No significant differences were found, however, in the levels of these complexes between the groups of asymptomatic and symptomatic HIV-infected patients. 3. Artificial immune complexes of synthetic peptides representing some immunodominant epitopes of HIV envelope (gp120, and gp41) proteins, and human polyclonal anti-HIV IgG were found to weakly activate both the classical and alternative complement pathways. 4. An elevated percentage of the lymphocytes carrying a complement activation fragment, C3d, was detected in the blood of HIV seropositive patients as compared to the seronegative controls. No significant positive correlation was found between the percentage of these cells and that of any T cell subsets tested.

Complement Activation↗
PubMedDate not supplied

Complement and C1q binding substances in otitis media.

Complement activation, as shown by increased amounts of complexes composed of C1r-C1s-C1 IA, and abnormal complexes of C1r-C1s were demonstrated in serum from patients with acute pneumococcal and chronic otitis media, serous or mucoid respectively. C1q binding substances were shown in middle ear effusions and in sera from patients with chronic serous otitis media. Presence of immune complexes and/or bacterial products capable of binding c1q results in formation of C1r-C1s-C1 IA complexes and may also cause the generation of C1r-C1s complexes. Such a dissociation of the C1 component will compromise the important opsonic function of the classical pathway.

Acute Disease↗
PubMed1989

Hereditary and acquired deficiencies of C1 inhibitor.

Angioneurotic edema results from acquired or genetic deficiency of C1 inhibitor (C1 INH), a member of the serpin family of protease inhibitors. C1 INH is the only plasma protease inhibitor of activated C1r and C1s, the serine protease subcomponents of the first complement component. It is also the major inhibitor of plasma kallikrein and of coagulation factor XIIa. C1 INH consists of a single polypeptide chain of 478 amino acid residues. It is the most heavily glycosylated plasma protein; a large portion of the carbohydrate is O-linked to serine and threonine residues. Hereditary angioneurotic edema (HANE) occurs in individuals heterozygous for deficiency of C1 INH. Most patients have absolute deficiency of C1 INH (type 1 HANE), while others (15% of kindred) synthesize a dysfunctional C1 INH protein. The molecular genetic defects in the C1 INH gene in both type 1 and type 2 HANE currently are being defined. Acquired angioneurotic edema (AANE) also is of two types. One of these occurs in individuals with B-cell lymphoproliferative disorders (type 1) and the other is characterized by the presence of autoantibodies directed toward the C1 INH molecule.

Angioedema↗
PubMed1998

Complement-related serine proteases in tunicates and vertebrates.

Serum mannose-binding lectin binds to pathogens in association with a serine protease termed MASP, and in this form, plays a crucial role in innate immunity by activating complement in a manner similar to activation via the classical pathway. MASP, C1r and C1s belong to the same family of serine proteases. In addition to its presence in advanced species, MASP also exists in primitive life forms such as tunicates and may be an evolutionary prototype of this family.

Animals↗
PubMed2006

Isolation and characterization of an anti-complementary polysaccharide D3-S1 from the roots of Bupleurum smithii.

The preliminary data from hemolytic assays indicated that the hot-water extract of the roots of Bupleurum smithii had anti-complementary activity. Further bioactivity-guided fractionation led to the isolation of D3-S1, a homogeneous form of acidic polysaccharide. D3-S1 was a branched polysaccharide with average molecular weight about 2,000,000 Da, composed of Ara, Gal and GalA in the ratio of 2.6:1.0:1.2, along with trace of Rha, Glc, Xyl and Man. Methylation analysis and NMR identified the linkages of the residues of D3-S1. Functional analysis showed that D3-S1 inhibited complement activation on both the classic and alternative pathways with CH(50) value of 0.34+/-0.02 mg/ml and AP(50) value of 0.081+/-0.003 mg/ml, respectively. Preliminary mechanism studies by using complement component depleted-sera indicated that D3-S1 selectively interacts with C1s, C3 and C4, but not C1q, C1r, C2, C5 and C9. The results suggested that D3-S1 could be of potential benefits in treatment of the complement-associated diseases.

Animals↗
PubMed1989

Effect of lipopolysaccharide on C3 and C5 production by human lung cells.

Although studies to date have demonstrated the ability of the monocyte/macrophage to produce C components in vitro, very few studies on C production by nonhepatic tissue cells have been reported. Recently, using 35S-methionine incorporation and immunoprecipitation techniques our laboratory has demonstrated the ability of tissue cells, i.e., the human lung type II pneumocyte (A549) and human lung fibroblast (WI-38), to synthesize and secrete a variety of early and terminal complement components, as well as several regulatory proteins in vitro, i.e., C1r, C1s, C4, C3, C5, C6, C7, C8, C9, factor B, factor H, factor I, and C1s inactivator. In our studies, we extended these observations by demonstrating the capability of LPS to modulate C3 production by A549 pneumocytes. Specifically, using a sensitive ELISA we demonstrated that A549 pneumocytes exposed to LPS induced an 80 to 180% increase in C3 levels when compared to untreated A549 cells. Interestingly, LPS had no effect on C5 production or total protein synthesis by A549 pneumocytes. In the case of the WI-38 fibroblast, LPS had no effect on 1) C3 production, 2) C5 production, or 3) total protein synthesis in vitro. These studies demonstrate that agents such as LPS have the potential to selectively regulate C production (i.e., C3) in individual lung cells in vitro, and suggests that in vivo LPS may alter the local tissue reservoir of C components during infection and lung injury, thus impacting on pulmonary inflammation and host defense.

Animals↗
PubMed1983

Electron microscopy of the complement protein C1q from the bullfrog, Rana catesbeiana.

The complement protein C1q, isolated from bullfrog (Rana catesbeiana) serum, was found by electron microscopy to resemble human C1q; peripheral globular units, probably six in number, are connected by thin strands to a hollow stem-like central structure. The dimensions of frog and human C1q were also found to be very similar. These results are consistent with earlier observations that frog and human C1q are similar, although not identical, in overall size, subunit structure, amino acid composition, and functional properties. Evidently this protein, which binds to antigen-antibody complexes and to C1r and C1s, thereby forming a physical link between the immune and complement systems, has been highly conserved in evolution.

Animals↗
PubMed2001

Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2.

Mannan-binding lectin (MBL)-associated serine proteases-1 and 2 (MASP-1 and MASP-2) are homologous modular proteases that each interact with MBL, an oligomeric serum lectin involved in innate immunity. To precisely determine their substrate specificity, human MASP-1 and MASP-2, and fragments from their catalytic regions were expressed using a baculovirus/insect cells system. Recombinant MASP-2 displayed a rather wide, C1s-like esterolytic activity, and specifically cleaved complement proteins C2 and C4, with relative efficiencies 3- and 23-fold higher, respectively, than human C1s. MASP-2 also showed very weak C3 cleaving activity. Recombinant MASP-1 had a lower and more restricted esterolytic activity. It showed marginal activity toward C2 and C3, and no activity on C4. The enzymic activity of both MASP-1 and MASP-2 was specifically titrated by C1 inhibitor, and abolished at a 1:1 C1 inhibitor:protease ratio. Taken together with previous findings, these and other data strongly support the hypothesis that MASP-2 is the protease that, in association with MBL, triggers complement activation via the MBL pathway, through combined self-activation and proteolytic properties devoted to C1r and C1s in the C1 complex. In view of the very low activity of MASP-1 on C3 and C2, our data raise questions about the implication of this protease in complement activation.

Base Sequence↗
PubMed1981

Immunofluorescence studies on the subcomponents of the first component of complement (C1): detection of C1q and C1s in different cells of biopsy material and on human as well as on guinea pig peritoneal macrophages.

The first component of complement (C1) is a macromolecule consisting of three distinct subcomponents, C1q, C1r, and C1s. In regard to its production site and its role in phagocytic processes it was of interest to find out whether these different subcomponents could be detected in human biopsy material only as a complex in individual cells or whether C1 subcomponents could be found on different cells. To study this question, monospecific fluorescein-labelled anti-human-C1q IgG and monospecific rhodamine-labelled anti-human C1q IgG were used. Biopsy material from human rectum was stained with fluoresceinated antisera, either by use of one antiserum or by double staining. Using this technique, these observations were made: C1q as well as C1s were detectable in individual cells in the subepithelial area of the gut. Furthermore, C1q and C1s could be found together in the same cell or separately in different cells. These findings were supported by experiments with cultured peritoneal macrophages either from human or from guinea pig. The examination of the cultured cells with the two antisera revealed that individual cells were stained either by anti-C1q or by anti-C1s antibodies. The specificity of the detection of the individual subcomponents was also proven by the peroxidase technique and by using fluoresceinated anti-human C1q F(ab')2. The membrane immunofluorescent staining revealed the presence of C1q on the membrane of the macrophage.

Animals↗
PubMed1986

C1 activation, with C1q in excess of functional C1 in synovial fluid from patients with rheumatoid arthritis.

Free Clq, in functionally active form was present in increased amounts in the synovial fluid of patients with rheumatoid arthritis. The presence of free Clq was associated with low concentrations of hemolytic C1, low C4 and raised amounts of C3dg/d fragments in the synovial fluid. The findings suggested intra-articular C1 activation with dissociation of C1 into free C1q and complexes containing C1r, C1s, and C1 inactivator. However, the immunochemical properties of synovial fluid C1r-C1s-C1 inactivator complexes appeared to differ from those of the complexes formed in serum, which hampered quantification with the assay used. Control patients with osteoarthritis or spondylarthritic syndromes did not show evidence of intra-articular complement activation, even though 1 patient with Reiter's disease had unexplained low concentrations of synovial fluid C4 and C3. The concentrations of circulating complement components were largely normal in the patients. Slightly increased concentrations of free C1q and C1r-C1s-C1 inactivator complexes in serum and C3dg/d fragments in EDTA plasma were observed, particularly in the patients with rheumatoid arthritis.

Adult↗
PubMed1970

Deficiency of C1r in human serum. Effects on the structure and function of macromolecular C1.

THE EXPERIMENTS PRESENTED HERE UTILIZE A HUMAN SERUM MARKEDLY DEFICIENT IN HEMOLYTIC COMPLEMENT ACTIVITY TO SHOW THAT: (a) The hemolytic deficiency is the result of a selective deficiency in hemolytic C1. (b) The relative absence of hemolytic C1 is due to a profound deficit in C1r function associated with less than normal C1s protein and hemolytic function and normal C1q protein concentration and function. This deficit in C1r in the face of normal C1q suggests that different cell types are responsible for the synthesis of each of these components. (c) Whatever the basis for the deficiency of C1r function, this defect results in an inadequate association of the remaining C1 subcomponents, C1q and C1s, even in the presence of calcium ions, thus suggesting that C1r has an important role in the assembly and/or maintenance of macromolecular C1.

Adolescent↗