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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↗
PubMed1997

A second serine protease associated with mannan-binding lectin that activates complement.

The complement system comprises a complex array of enzymes and non-enzymatic proteins that is essential for the operation of the innate as well as the adaptive immune defence. The complement system can be activated in three ways: by the classical pathway which is initiated by antibody-antigen complexes, by the alternative pathway initiated by certain structures on microbial surfaces, and by an antibody-independent pathway that is initiated by the binding of mannan-binding lectin (MBL; first described as mannan-binding protein) to carbohydrates. MBL is structurally related to the complement C1 subcomponent, C1q, and seems to activate the complement system through an associated serine protease known as MASP (ref. 4) or p100 (ref. 5), which is similar to C1r and C1s of the classical pathway. MBL binds to specific carbohydrate structures found on the surface of a range of microorganisms, including bacteria, yeasts, parasitic protozoa and viruses, and exhibits antibacterial activity through killing mediated by the terminal, lytic complement components or by promoting phagocytosis. The level of MBL in plasma is genetically determined, and deficiency is associated with frequent infections in childhood, and possibly also in adults (for review, see ref. 6). We have now identified a new MBL-associated serine protease (MASP-2) which shows a striking homology with the previously reported MASP (MASP-1) and the two C1q-associated serine proteases C1r and C1s. Thus complement activation through MBL, like the classical pathway, involves two serine proteases and may antedate the development of the specific immune system of vertebrates.

Amino Acid Sequence↗
PubMed2005

Immune function of C1q and its modulators CD91 and CD93.

C1q is a subcomponent of the first component of complement C1, which is a multimolecular complex comprising one molecule of C1q and two molecules each of the autoreactive proteases, C1r and C1s. This multimolecular complex triggers the classical pathway of complement. Advances in the past several years have provided a partial crystal structure of the C1q subunit. This, together with gene deletion of C1q, has allowed further insight into the multifunctional immune aspects of this molecule. Two C1q-mediated functions that have received intense scrutiny recently are C1q-mediated apoptotic clearance of cell debris and phagocytosis. This has led to a heightened search for specific receptors for the collagen-like region (CLR) as well as the globular heads. Two transmembrane proteins, CD91 and CD93, have been proposed to interact indirectly with the CLR of C1q, promoting apoptotic clearance and phagocytosis, respectively. The aim of this article is to provide an overview of the structural and functional information that implicates CD91 and CD93 in C1q-mediated functional effects.

Animals↗
PubMed1982

Requirement for an additional serum factor essential for the antibody-independent activation of the classical complement sequence by Gram-negative bacteria.

Killing of Salmonella minnesota and Salmonella typhimurium S and R strains in serum of nonimmune humans and guinea pigs was drastically reduced in the selective absence of C1q, C1r, Ca2+, C4, or C2, the components of the classical complement pathway. Binding of C1 and C1q to the S form and six different core-deficient R mutant strains became stronger the shorter the lipopolysaccharide molecule. C1 and C1q had, under physiological conditions, no affinity to the serum-resistant S forms, whereas these components were bound by the serum-sensitive R forms with high affinity. However, a mixture of the individual complement components C1-C9, which rapidly lysed sensitized erythrocytes, did not kill the serum-sensitive bacteria. Isolated C1 bound to these bacteria cleaved fluid-phase C4 but did not convert C2. C2 turnover could be detected only when serum was used as a source of C1 or C4, indicating that an additional serum component is necessary for the antibody-independent bactericidal effect. Functional tests indicated that this factor is a euglobulin which mediates binding of C4 to the bacteria even in the absence of C1 or after treatment with EDTA. Binding of C4 followed by the generation of C4b sites as acceptors for C2 was a prerequisite for the killing of the bacteria. The factor could not be replaced by immunoglobulin G or immunoglobulin M, nor was it blocked by preincubation with anti-immunoglobulin G or anti-immunoglobulin M.

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↗
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↗
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↗
PubMed2000

Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2.

Mannan-binding lectin (MBL) plays a pivotal role in innate immunity by activating complement after binding carbohydrate moieties on pathogenic bacteria and viruses. Structural similarities shared by MBL and C1 complexes and by the MBL- and C1q-associated serine proteases, MBL-associated serine protease (MASP)-1 and MASP-2, and C1r and C1s, respectively, have led to the expectation that the pathways of complement activation by MBL and C1 complexes are likely to be very similar. We have expressed rMASP-2 and show that, whereas C1 complex autoactivation proceeds via a two-step mechanism requiring proteolytic activation of both C1r and C1s, reconstitution with MASP-2 alone is sufficient for complement activation by MBL. The results suggest that the catalytic activities of MASP-2 split between the two proteases of the C1 complex during the course of vertebrate complement evolution.

Carrier Proteins↗
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↗
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↗
PubMed1976

Humoral immunostimulation. VI. Increased calcium uptake by cells treated with antibody and complement.

When L cells were treated with anti-L cell antibody in medium depleted of complement, rapid increases in calcium uptake were obtained over a wide range of antiserum concentrations. Concomitant cell growth and viability studies demonstrated that stimulation of cell growth occurred at higher dilutions of antiserum whereas cytotoxicity occurred at lower dilutions. The stimulatory and toxic effects of antibody on cell growth were potentiated by complement as was the enhancement in calcium uptake. Sera deficient in C1R, C2,4D, C4, C3-C9 did not increase the calcium uptake response to antibody whereas augmentation did occur with C6-deficient serum. A specific role for complement was further indicated by the ability of purified complement components to restore the response to complement in complement-deficient sera. C3 with C3-C9 deficient serum, but not C2, C5, and C6 with C3-C9 deficient serum restored augmentation effects. Taken together with the results of previous studies it is apparent that complement augments both calcium and nucleoside uptake and that the effect is primarily via the classical complement pathway through C3. Substrate saturation studies demonstrated that antibody activated the facilitated diffusion of calcium altering the Vmax but not the Km of transport whereas addition of complement altered both the Vmax and Km. These findings suggest that one of the early effects of enhancing antibody upon tumor cell metabolism in vitro is to stimulate uptake of calcium. In view of the suspected role of Ca++ in cell proliferation the increase in cell-associated calcium may be important in the subsequent proliferative response.

Antigen-Antibody Reactions↗
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↗
PubMed1993

Synthesis and structure-activity study of protease inhibitors. V. Chemical modification of 6-amidino-2-naphthyl 4-guanidinobenzoate.

By developing 6-amidino-2-naphthyl 4-guanidinobenzoate (I, FUT-175) as a basic structure, its various derivatives were synthesized and their inhibitory activities on trypsin, plasmin, kallikrein, thrombin, C1r and C1s as well as on complement-mediated hemolysis were examined. The protective effect of these compounds on complement-mediated Forssman shock was also examined in guinea pigs. 6-Amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-benzoate (41, FUT-187) was found to be a suitable compound for oral administration with anti-complement activity superior to that of compound I.

Animals↗
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↗
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↗
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↗
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↗