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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↗
PubMed1984

Pharmacological studies of FUT-175, nafamstat mesilate. I. Inhibition of protease activity in in vitro and in vivo experiments.

FUT-175, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfonate (nafamstat mesilate), a novel synthetic protease-inhibiting agent, was studied to determine its in vitro effects against various proteases and other enzymes, as well as to determine its in vivo protease inhibitory effects. FUT-175 was found to inhibit, in an intense, specific and reversible way, the enzyme activities of trypsin, C1r, C1s, thrombin, kallikrein and plasmin with IC50 values of the order of 10(-6)-10(-8) M. FUT-175 also inhibited complement-mediated hemolysis, including both classical and alternative pathways, sites of inhibition being on C1r and C1s as evidenced by the intermediate-cell technique. In animal model reactions in which the complement system is known to be involved as pathogenetic factors, e.g., Forssman shock, Forssman cutaneous vasculitis, zymosan-induced paw edema, endotoxin shock and local Shwartzman reaction, FUT-175 was highly effective in that, for example, intravenous dosing at 3 mg/kg could completely protect guinea pigs from the lethal Forssman shock. FUT-175 was also found to be effective in trypsin-induced shock in mice, in lethality due to thrombin-thrombosis in mice and in kinin formation in the inflammatory process in rats.

Animals↗
PubMed2026

Complement expression profiles in human glomerular mesangial cells, endothelial cells, podocytes and proximal tubular epithelial cells.

BACKGROUND: Local expression of complement components in the kidney has been reported sporadically in both diseased and normal kidneys. This study aimed to comprehensively characterize the expression of complement components in human glomerular mesangial cells (GMCs), glomerular endothelial cells (GECs), podocytes, and proximal tubular epithelial cells (PTECs) in non-diseased renal tissue. METHODS: Complement expression in cultured human renal intrinsic cells was initially evaluated using reverse transcription polymerase chain reaction and immunofluorescence staining. These findings were further examined using publicly available single-cell RNA-sequencing datasets and 10×Genomics single-cell RNA sequencing of non-diseased human kidney tissue. The analyses focused on complement components involved in the initiation of the classical, lectin, and alternative pathways, as well as components shared among these activation pathways, terminal pathway components, complement regulators, and complement receptors. RESULTS: Complement components unique to the initial phase for classical pathway (C1S, C1R, C2, C4), lectin pathway (MBL2, FCN1, MASP1), alternative pathway (CFB, CFD), and the C3 component shared by the three activation pathways were detected in these cells. The components shared by the terminal pathways including C5, C6, C7, C8 and C9 exhibited lower expression, while complement regulators (CFH, CFI, CD55/DAF, CD46/MCP, CD59, C4BPB, PROS1/Protein S) or receptors (CD93/C1QR1, CR1), particularly membrane-bound proteins, such as DAF, MCP and CD59, which inhibit complement activation and the formation of the membrane attack complex, showed relatively high expression. CONCLUSION: These results showed that all four types of intrinsic renal cells expressed multiple complement components associated with the classical, lectin, and alternative pathways. In non-diseased kidney tissue, complement regulatory molecules involved in the control of complement activation showed relatively higher expression, whereas components of the terminal complement pathway were expressed at relatively lower levels, suggesting that renal intrinsic cells maintain a locally poised but tightly regulated complement system.

Humans↗
PubMed1989

Deposition of complement activation products on plastic-adsorbed immunoglobulins. A simple ELISA technique for the detection of defined complement deficiencies.

The activation of complement components in human serum has been studied using immunoglobulins adsorbed to microtiter plates. The sequential deposition of complement fragments was detected by a series of mono- and polyclonal antibodies in an indirect enzyme-linked immunosorbent assay (ELISA). Antibodies against C1q, C1s, C4b/d, C3b/d, factor B, C5b-9 membrane attack complex (MAC), the regulatory complement proteins C4 binding protein (C4bp) and properdin were reactive. Several lines of evidence suggest that complement activation was via the classical pathway: (1) complement activation was highly isotype-restricted with regard to the adsorbed Igs (human IgG1 and IgG3 as well as mouse IgM, IgG2a and IgG2b isotypes are strong activators in contrast to human IgG2, IgG4, IgA and mouse IgG1); (2) Ca2+ depletion, heat treatment (56 degrees C for 45 min), incubation with 0.5 M KSCN or heat-aggregated immunoglobulins (aggIgG) abrogated serum activity; (3) complement deficient sera (C1q def', C2 def', C6 def' human sera; C2 def', C4 def' guinea pig sera) showed impaired deposition of the complement components that follow the missing component in the cascade of activation. In a clinical study sera from patients with systemic lupus erythematosus (SLE) were investigated in order to measure the effect of hypocomplementemia due to complement consumption. The results obtained suggest that this new and simple assay is well suited for (1) the detection of various inherited complement deficiencies, (2) the semiquantitative evaluation of sera with decreased complement levels, (3) a more detailed study of complement components bound to a solid phase.

Adsorption↗
PubMed1994

Expression of the components and regulatory proteins of the classical pathway of complement in normal and diseased synovium.

We studied the synthesis of the classical pathway complement components in synovial membrane. Ribonucleic acid was extracted from the synovial membranes of patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as from normal synovial membrane. Northern blot and dot blot analysis showed that the mRNAs for all classical pathway complement components (C1qA chain, C1qB chain, C1qC chain, C1r, C1s, C4 and C2) and the fluid-phase regulatory components (C1-inhibitor, C4-bp and factor I) were present in all three types of synovial membrane. Thus, all the components of the classical pathway were expressed in normal and diseased synovium. In an attempt to determine which components were synthesised by each cell type, monocytes (mononuclear phagocytes), human umbilical vein endothelial cells (HUVEC), synovial membrane fibroblasts (from normal, OA and RA synovial membrane) and peripheral blood lymphocytes were cultured in vitro and secretion rates of individual components were measured and total cellular RNA was analysed by Northern blotting. Monocytes secreted C1q, C1r, C1s, C4, C2, C1-inhibitor and C4-bp but not factor I. Fibroblasts secreted C1r, C1s, C2, C3, C1-inhibitor and factor I but not C1q, C4 or C4-bp. HUVEC secreted C1s, C2, C1-inhibitor and factor I but not C1q, C1r, C4 or C4-bp. Lymphocytes did not secrete any of these components. In three instances mRNA was detected in the absence of secreted protein: mRNAs for the C1qA and C1qC chains were detected in HUVEC, whereas the mRNA for the C1qB chain was not, and C4 mRNA was detected in both fibroblasts and HUVEC.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis, Rheumatoid↗
PubMed2006

Existence of different but overlapping IgG- and IgM-binding sites on the globular domain of human C1q.

C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or IgM and initiates complement activation via association of serine proteases C1r and C1s. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has some structural and functional autonomy. Although a number of studies have tried to identify IgG-binding sites on the gC1q domain, no such attempt has been made to localize IgM-binding site. On the basis of the information available via the gC1q crystal structure, molecular modeling, mutational studies, and bioinformatics, we have generated a series of substitution mutants of ghA, ghB, and ghC and examined their interactions with IgM. The comparative analysis of IgM- and IgG-binding abilities of the mutants suggests that the IgG- and IgM-binding sites within the gC1q domain are different but may overlap. Whereas Arg(B108), Arg (B109), and Tyr(B175) mainly constitute the IgM-binding site, the residues Arg(B114), Arg(B129), Arg(B163), and His(B117) that have been shown to be central to IgG binding are not important for the C1q-IgM interaction. Given the location of Arg(B108), Arg (B109), and Tyr(B175) in the gC1q crystal structure, it is likely that C1q interacts with IgM via the top of the gC1q domain.

Arginine↗
PubMed1981

The intrinsic coagulation-kinin pathway, complement cascades, plasma renin-angiotensin system, and their interrelationships.

Activation of the classical complement pathway is initiated by immune complexes consisting of IgM antibody or IgG subclasses 1, 2, and 3. Binding to Clq leads to activation of C1s and digestion of C4 and C2 to yield a C3 convertase. The alternative complement pathway is initiated by complex polysaccharides as well as immune complexes of the IgA class which interact with Factors B, D, C3, and properdin to yield a stabilized C3 convertase consisting of PC3Bb. Cleavage of C3 and C5 by either pathway yields the C3a and C5a anaphylatoxins which cause histamine release from mast cells and formation of the C5b6789 attack complex causes cell lysis. Both immunologic and nonimmunologic tissue damage can initiate the surface dependent pathways of coagulation, fibrinolysis, and kinin formation. Surface bound Hageman Factor interacts with complexes of prekallikrein and HMW-kininogen as well as Factor XI and HMW-kininogen to form activated Hageman factor, kallikrein, and Factor XIa. Factor XIa continues the coagulation pathway, kallikrein and Factor XIa convert plasminogen to plasmin and kallikrein digests HMW-kininogen to yield bradykinin. The Cl inhibitor, which inactivates Cls is the major plasma inhibitor of activated Hageman factor and kallikrein. In its absence, a potentially fatal form of angioedema is seen. The inactivator of the C3a and C5a anaphylatoxins is identical to carboxypeptidase N, the major plasma inactivator of bradykinin thus demonstrating the common control mechanisms which regulate the complement and kinin-forming pathways.

Blood Coagulation↗
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↗
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↗
PubMed1985

Sequential studies of complement activation in systemic lupus erythematosus.

C1 and C3 activation, measured as C1r-C1s-C1 inactivator C1s-C1r-C1IA complexes in serum and circulating C3d were studied in serial samples from 33 patients with SLE. All patients demonstrated exacerbations during observation periods of 10-30 months and were divided into groups according to principal clincal features (mild SLE, severe extra-renal SLE, and lupus glomerulonephritis). Increased C1 activation was consistently found during exacerbation. C3d in plasma was a feature associated with severe disease flares. Activation of C1, but not of C3, was documented before flare-ups of disease activity, but such predictive information was mostly restricted to patients with extra-renal disease. C2 cleavage in plasma, studied serially in a few patients, appeared to be closely associated with C1 activation. Circulating immune complexes, measured with solid-phase C1q assay, did not always increase before development of clinical manifestations. Remission of symptoms was paralleled by decreasing concentrations of C1r-C1s-C1IA and of, when present, C3d. Similar findings were made for immune complexes but only in severe disease. Persisting C3d was observed in 3 patients, who subsequently developed renal failure. C1q levels were transiently low during flare-ups of lupus glomerulonephritis, but otherwise the concentrations of C1q, C4 and C3 did not show consistent patterns of variation in relation to disease activity.

Adolescent↗
PubMed2001

Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.

Animals↗
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↗
PubMed1977

Conversion of C5 precipitin line in the serum treated with activating substances of complement system.

The hemolytic activity of C5 in the serum treated with zymosan, immune precipitate, or C1s was measured, and the C5 precipitin line on immunoelectrophoresis and the protein concentration of C5 in these serum specimens were also analyzed. A marked decrease in the hemolytic activity of C5 and a complete conversion of C5 precipitin line from beta- to alpha-globulin region were observed in teh serum treated with more than 1 mg/ml of zymosan. The elongation of C5 precipitin line from beta- to alpha-globulin region and the decrease in C5 hemolytic activity were observed in the serum treated with the immune precipitate. But neither change in C5 precipitin line, nor a decrease in hemolytic activity of C5 was observed in C1s treated serum. C5 protein concentrations in these serum preparations were essentially the same as those of control. From these results, it was concluded that the immunoelectrophoretic change of C5 precipitin line might express the grade of the decrease in C5 hemolytic activity in the serum treated with the activating substances of the complement system.

Antigen-Antibody Complex↗
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↗
PubMed2001

Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation.

The complement system is an important inflammatory mediator during procedures such as cardiopulmonary bypass and hemodialysis when blood is exposed to large areas of biomaterial surface. This contact between blood and the biomaterials of implants and extracorporeal circuits leads to an inflammatory response mediated by the complement system. The aim of this study was to assess the ability of a complement regulator (factor H) immobilised on a biomaterial surface to inhibit complement cascade mediated inflammatory responses. The cross-linker N-succinimidyl 3-(2-pyridyldithio) propionate was used to immobilise factor H on a model biomaterial surface without affecting the biological activity of the inhibitor. Binding of factor H was then characterised using quartz crystal microbalance-dissipation (QCM-D) and enzyme immunoassays for products of complement activation: bound C3 fragments and soluble C3a, sC5b-9, and C1s-C1INA. Immobilised factor H reduced the amount C3 fragments deposited on the biomaterial surface after incubation with serum, plasma. or whole blood. In addition, lower levels of soluble C3a and sC5b-9 were generated after incubation with whole blood. In summary, we have demonstrated that complement activation on a highly activating model surface can be inhibited by immobilised factor H and have defined prerequisites for the preparation of future biomaterial surfaces with immobilised regulators of complement activation.

Biocompatible Materials↗
PubMed1981

Complement in pneumococcal infections with varying degrees of severity.

Complement component levels (Clq, Cls, C4, C3, factor B and properdin) and C1 subcomponent complexes (C1r-C1s, C1-r-C1-, C1-r-C1-s-C1 inactivator, 1A) were studied in 16 adults with pneumococcal infections varying severity. Patients with fulminant disease and signs of septic shock showed pronounced hypocomplementemia. In patients with pneumococcal pneumonia or meningitis elevated levels of C1-r-C1-s-C1- IA complexes indicated activation of C1, despite normal levels of C1q, C1s, C4 and C3. Moderately decreased properdin values suggested involvement of the alternative pathway. In adults with pneumococcal otitis no changes in the complement profile was found. In contrast, pronounced aberrations of the C1 subcomponents were earlier demonstrated in children with otitis.

Adolescent↗
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↗
PubMed1986

Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11.

C1 inhibitor is a heavily glycosylated plasma protein that regulates the activity of the first component of complement (C1) by inactivation of the serine protease subcomponents, C1r and C1s. C1 inhibitor cDNA clones have been isolated, and one of these (pC1INH1, 950 base pairs) has been partially sequenced. Sequence analysis demonstrates that the C1 inhibitor is a member of the serpin "superfamily" of protease inhibitors. In the region sequenced, C1 inhibitor has 22% identity with antithrombin III, 26% with alpha 1-antitrypsin and alpha 1-antichymotrypsin, and 18% with human angiotensinogen. C1 inhibitor has a larger amino-terminal extension than do the other plasma protease inhibitors. In addition, inspection of residues that are invariant among the other protease inhibitors shows that C1 inhibitor differs at 14 of 41 of these positions. Thus, it appears that C1 inhibitor diverged from the group relatively early in evolution, although probably after the divergence of angiotensinogen. Southern blot analysis of BamHI-digested DNA from normal individuals and from rodent-human somatic cell hybrid cell lines (that contain a limited but varied human chromosome complement) was used to localize the human C1 inhibitor gene to chromosome 11.

Amino Acid Sequence↗