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PubMed2000

Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19.

Mannan-binding lectin (MBL) and C1q activate the complement cascade via attached serine proteases. The proteases C1r and C1s were initially discovered in a complex with C1q, whereas the MBL-associated serine proteases 1 and 2 (MASP-1 and -2) were discovered in a complex with MBL. There is controversy as to whether MBL can utilize C1r and C1s or, inversely, whether C1q can utilize MASP-1 and 2. Serum deficient in C1r produced no complement activation in IgG-coated microwells, whereas activation was seen in mannan-coated microwells. In serum, C1r and C1s were found to be associated only with C1q, whereas MASP-1, MASP-2, and a third protein, MAp19 (19-kDa MBL-associated protein), were found to be associated only with MBL. The bulk of MASP-1 and MAp19 was found in association with each other and was not bound to MBL or MASP-2. The interactions of MASP-1, MASP-2, and MAp19 with MBL differ from those of C1r and C1s with C1q in that both high salt concentrations and calcium chelation (EDTA) are required to fully dissociate the MASPs or MAp19 from MBL. In the presence of calcium, most of the MASP-1, MASP-2, and MAp19 emerged on gel-permeation chromatography as large complexes that were not associated with MBL, whereas in the presence of EDTA most of these components formed smaller complexes. Over 95% of the total MASPs and MAp19 found in serum are not complexed with MBL.

Calcium↗

PubMed1996

The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives.

The present study was aimed at analyzing the existence of an impaired complement system in CLL patients. For this purpose, the serum levels of the serum complement proteins C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, C9, Factor B and properdin were repeatedly evaluated by means of radial immunodiffusion assay in 26 CLL patients over a period of 2 years. At the time of diagnosis, 18 of the 26 CLL patients showed low serum levels in at least one of these complement proteins as compared to a group of sex- and age-matched healthy subjects (P < 0.0001). Complement defects affected either the classical and/or the alternative pathway components, and in some case low levels of late components (C5-C9) were also observed. A reduced level of properdin was the most frequent abnormality (11/18). The presence of such abnormalities were correlated with the stage of the disease, and they were found in 100% of the patients (11) in advanced stages (Rai II-IV), and in 40% of patients (15) in early stages (0-1) (P < 0.004). Severe infections occurred in five patients; four of them were in advanced stages of the disease and had decreased levels of at least one complement component, whereas the remaining patient was in an early stage and had normal levels of complement components. These data support the notion that an impaired complement system might be involved in the pathophysiology of CLL and its infectious complications. Although more work is needed to sustain this hypothesis, we discuss the possibility on the basis of data obtained in the first-degree relatives of CLL patients, that in some CLL patients the complement deficit might reflect a genetic predisposition.

Adult↗

PubMed1991

Localisation of complement components in association with glomerular extracellular particles in various renal diseases.

Intraglomerular extracellular microparticles including so-called virus-like particles and striated membranous structures have been observed in various renal diseases. The presence and localisation of complement components in these extracellular bodies was studied using the protein A-gold electron microscopy method. Ultrastructurally these particles were differentiated into microspherical structures (MSS) and thread-like structures (TS). Both structures showed weak to moderate diffuse labelling with C1s, whilst the intense labelling found with C3d and C9 was confined to individual membrane-like structures of both MSS and TS. Labelling with IgA, IgG, fibrinogen and the complement components C1q, C1r, C3c C4 and C5 showed negative or trace results. There were no differences between the immunolabelling patterns of MSS and TS, nor among different renal diseases in which these structures were found. These findings raise the possibility that formation of so-called virus-like particles such as MSS and TS may be associated with complement activation.

Complement System Proteins↗

PubMed1997

Neurons express proteins of the classical complement pathway in Alzheimer disease.

Occurrence of the classical pathway complement proteins C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9 was studied in human hippocampus and temporal cortex by immunohistochemistry and Western blotting. In Alzheimer disease (AD) cases, positive staining for all of these proteins was observed in pyramidal neurons and senile plaques. In control cases, weaker pyramidal neuron staining was observed except for C1q and C1s which were not detected. On Western blots of AD hippocampal extracts, bands corresponding to those detected in normal serum were found for each of the complement proteins. Comparable bands were also detected in normal hippocampal extracts with the exception of C1s which was not observed. The intensity of the bands was generally stronger in AD than in normal extracts, but, in the latter, there was considerable variability between cases and between bands in a single case. These data suggest that pyramidal neurons may be a source of the complement components known to be associated with Alzheimer lesions.

Aged↗

PubMed1982

Spontaneous activation of the first component of human complement (C1) by an intramolecular autocatalytic mechanism.

For biochemical characterization, the first component of human complement (C1) was reconstituted from physiologic concentrations of purified C1q, 125I C1r, and 131I C1s. Upon incubation at 37 degrees C, C1 spontaneously activated, as evidenced by the characteristic proteolysis of the C1r and C1s polypeptide chains as detected by SDS-PAGE analysis. This spontaneous C1 activation followed first-order kinetics (t 1/2 = 4 min and k = 0.173 min-1) with an activation energy of 19.1 kcal/mol. Spontaneous C1 activation was unaffected by the general protease inhibitor phenylmethylsulfonylfluoride (PMSF) but reversibly blocked by a known inhibitor of C1 activation, nitrophenylguanidinobenzoate (NPGB). Spontaneous C1 activation was measured at C1 concentrations ranging from 9 to 160 nM (i.e., 0.05 to 1.0 times physiologic concentrations). The data indicate that C1 spontaneously activates by an intramolecular autocatalytic mechanism, for first-order kinetics were observed over the entire concentration range with t 1/2 = 4 min at each concentration. However, the percentage of activable C1 decreased with dilution due to C1 dissociation (i.e., C1qr2s2 leads to C1q + C1r2s2). The observed concentration of C1 that spontaneously activated at each dilution equalled the concentration of C1 present as macromolecular C1. When reconstituted C1 was mixed with normal human serum (NHS) and then incubated at 37 degrees C, spontaneous C1 activation was completely inhibited. Pretreating NHS at 56 degrees C for 30 min destroyed its inhibitory activity. In conclusion, C1 spontaneously autoactivates at 37 degrees C by an intramolecular mechanism. This activation is suppressed in NHS.

Benzoates↗

PubMed1997

A neoepitope-based enzyme immunoassay for quantification of C1-inhibitor in complex with C1r and C1s.

Monoclonal antibodies (MoAb) recognizing neoepitopes exposed on activation products of complement proteins but hidden in the native components have been used for quantification of activated complement. A previously produced and characterized mouse MoAb, recognizing a neoepitope on the human plasma protein C1-inhibitor complexed with its substrates, was used to design an enzyme immunoassay for detection of C1-inhibitor complexed with C1r and C1s. These complexes are indicators of early classical complement pathway activation. The standard was serum activated with heat aggregated IgG defined to contain 1000 arbitrary units (AU)/ml. The lower detection limit was approximately 0.05 AU/ml corresponding to 0.005% of fully activated serum. The reliability of the assay, including day-to-day variation, was tested. Intra-assay variation coefficients were 12% for low plasma control and 13% for high plasma control (n = 12 for both). Inter-assay variation coefficients were 12% for low control (n = 6), 19% for high control (n = 6) and 15% for the normal plasma control (n = 9). A 2.5-97.5 percentile reference range (normal blood donors) was 16-33 AU/ml. Two patients with systemic lupus erythematosus had considerably elevated plasma levels of the activation product (56 and 62 AU/ml), and six patients with hereditary angioedema had normal plasma levels despite considerably reduced C1-inhibitor concentration. We conclude that the present method is sensitive and reliable for detection of early classical pathway activation and superior to previously published methods by utilizing neoepitope specificity and non-radiolabelled reagents.

Animals↗

PubMed1984

Complement components, complement activation, and acute phase response in systemic lupus erythematosus.

The investigation concerned 33 systemic lupus erythematosus (SLE) patients assigned to three groups representing mild SLE, more severe extra renal SLE, and SLE with significant renal involvement. In patients with extrarenal disease, the inflammatory plasma protein response was often pronounced during exacerbation, as evidenced by markedly increased concentrations of C-reactive protein (CRP), alpha 1-antichymotrypsin, alpha 1-antitrypsin, and orosomucoid. CRP responses were rare in patients with renal involvement, despite the increased concentrations of other acute-phase reactants in some of these patients. Superimposed bacterial infections were not clearly distinguished by raised CRP concentrations. The classical pathway of complement was activated in all patients during exacerbation, as indicated by increased concentrations of C1r-C1s-C1 inactivator complexes and C2a fragments. C1, C2, and probably also C3 activation varied according to the amounts of circulating C1q-binding immune complexes, as measured by solid-phase assay. Manifest hypocomplementemia was usually associated with glomerulonephritis. Participation of complement components in the inflammatory plasma protein response apparently counteracted the development of hypocomplementemia in many patients with extrarenal SLE. Circulating C3d was detected in all patients during exacerbation of renal disease and in most patients with severe extrarenal manifestations. Inverse relationships were found between immunochemical C2 concentrations and the percentage of cleaved C2 and between C3 and C3d. There was no appreciable consumption of factors B and D and properdin of the alternative pathway in the patients. High concentrations of factor D, a low molecular weight protein, were exclusively found in patients with renal involvement and could be ascribed to retention due to reduced glomerular filtration.

Antigen-Antibody Complex↗

PubMed1993

Chemical characterization and location of ionic interactions involved in the assembly of the C1 complex of human complement.

The C1 complex of human complement comprises two loosely interacting subunits, C1q and the Ca(2+)-dependent C1s-C1r-C1r-C1s tetramer. With a view to gain information on the nature of the ionic interactions involved in C1 assembly, we have studied the effects of the chemical modifications of charged residues of C1q or the tetramer on their ability to reconstitute the C1 complex. Treatment of C1q with pyridoxal-5'-phosphate, acetic anhydride, and citraconic anhydride, as well as with cyclohexanedione and diethylpyrocarbonate, inhibited its ability to associate with C1s-C1r-C1r-C1s. Treatment of the collagen-like fragments of C1q with the same reagents yielded the same effects. Treatment of C1s-C1r-C1r-C1s with 1-ethyl-3-[-3-(dimethylamino) propyl] carbodiimide also prevented C1 assembly, through modification of acidic amino acids which were shown to be located in C1r. Further studies on the location of the interaction sites within C1q, using ligand-blotting and competition experiments with synthetic peptides, were unsuccessful, suggesting that these sites are contributed to by two or three of the C1q chains. It is concluded that C1 assembly involves interactions between acidic amino acids of C1r and lysine (hydroxylysine) and arginine residues located within the collagen-like region of C1q. Sequence comparison with mannan binding protein, another collagen-like molecule which binds the C1s-C1r-C1r-C1s tetramer, suggests Arg A38, and HyL B32, B65, and C29 of C1q as possible interaction sites.

Acetic Anhydrides↗

PubMed1976

The role of C1 esterase inhibitor in the activation of C1r, a subcomponent of the first component of complement from human plasma.

Clr was isolated from human serum by DEAE-cellulose column chromatography in the presence of EDTA. The isolated Clr did not hydrolyze N(alpha)-acetyl-L-arginine methyl ester, unless activated by brief treatment with trypsin [EC 3.4.21.4]. On thecolumn, the C1 esterase inhibitor activity was found to coincide with Clr but not C1s (another subcomponent of the first component) C1r was isolated from the euglobulin fraction of human serum by DEAE-cellulose column chromatograph. On Sephadex G-200 column chromatography, Clr was eluted in the void volume, whereas Clr was eluted in a position corresponding to a molecular weight of 140,000-160,000. The results indicated that, on activation, Clr was converted to an enzyme of lower molecular weight...

Chromatography, Ion Exchange↗

PubMed1983

Nature of the metal ion requirement for assembly and function of the first component of human complement.

The first component of human complement (C1) was reconstituted from equimolar concentrations of its purified subunits C1q, C1r, and C1s, in the presence of each of nine different metal ions for the purpose of studying the qualitative and quantitative nature of the metal ion requirement for C1 assembly and function. For C1 reconstituted with each metal ion, three assays characteristic of C1 were performed as follows: (1) spontaneous C1 activation in the absence of the regulatory protein C1-inhibitor was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis by simultaneously quantifying the specific proteolysis of the C1r and C1s subunits; (2) C1 activation induced by aggregated IgG in the presence of C1 inhibitor was similarly analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis; and (3) formation of 16 S macromolecular C1 was determined in the analytical ultracentrifuge. For all experiments, trace metal contaminants were removed from buffers and proteins. All divalent cations tested from the first transition period of the periodic table (i.e. Ca2+, Mn2+, Co2+, Ni2+, and Zn2+) effectively mediated the formation of functional macromolecular C1. Dose curves showed maximal C1 assembly and activation at ion concentrations of 30 to 50 microM for each of the above metal ions. However, when ion concentrations were increased above 50 microM, C1 assembly and activation became inhibited. The further to the right in the periodic table, the better inhibitor was the metal ion. Competition experiments indicated that the ion binding sites mediating inhibition are distinct from those promoting activation. Other metal ions that also effectively mediated C1 assembly and function were Cd2+ and Tb3+; however, Mg2+ and Ba2+ were ineffective. All metal ions that mediated C1 assembly and activation also promoted C2 consumption by C1 in normal human serum treated with aggregated IgG. In conclusion, the assembly and function of C1 can be mediated by numerous metal ions. In direct opposition to accepted theory, there is no specific requirement for calcium.

Calcium↗

PubMed2003

Association of the 3' UTR transcription factor LBP-1c/CP2/LSF polymorphism with late-onset Alzheimer's disease.

Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. To date, apolipoprotein E (apoE) is the only established susceptibility gene for late-onset AD. ApoE accounts for less than 50% of the risk of AD, indicating the presence of other unknown susceptibility loci. Linkage studies have indicated chromosome 12 as the most likely location for another late-onset AD locus. We examined seven polymorphisms in five candidate genes located in and around the linkage peaks on chromosome 12 in 564 cases and 523 controls. The genes included complement component 1R (C1R), vitamin D receptor (VDR), scavenger-receptor B1 (SR-B1), low-density lipoprotein receptor related protein 1 (LRP1), and transcription factor LBP-1c/CP2/LSF. We found no association with C1R, VDR, SR-B1, and LRP1 polymorphisms. However, the frequency of the A allele of the 3' (untranslated region) UTR LBP-1c/CP2/LSF polymorphism was higher in controls than cases (0.071 vs. 0.051; P = 0.042) with an adjusted odds ratio (OR) of 0.65 (95% confidence interval [CI]: 0.43-0.96; P = 0.0498). Our data suggest that the LBP-1c/CP2/LSF polymorphism may have a moderate protective effect against the risk of AD.

3' Untranslated Regions↗

PubMedDate not supplied

Specificity of substrate analogue inhibitors of human urinary kallikrein.

A series of acetyl-peptidyl-amides containing the amino acid sequence around the Arg-Ser kallikrein cleavage site of bovine kininogen were synthesized and tested for their ability to inhibit both the kinin-releasing activity and the amidase activity of purified human urinary kallikrein. The substrate analogues were competitive inhibitors for human urinary kallikrein and the heptapeptides (P4-P3'), hexapeptides (P3-P3'), and pentapeptides (P2-P3') gave Ki values of 140, 64, and 18 microM respectively, while the tetrapeptides (P1-P3'), tripeptides (P1'-P3') and dipeptides (P2'-P3') had little or no inhibitory activity. The effective analogues had neither kinin-like nor kinin-blocking activity on the rat uterus either before or after exposure to human urinary kallikrein. The effective human urinary kallikrein inhibitors were further examined for their effect on other serine proteases, including human plasma kallikrein, plasmin, complement components (C1s, C1r), bovine coagulation factors (IIa, IXa, and Xa), elastase, and trypsin. These peptides showed little inhibition of the circulating serine proteases but yielded a Ki for the nonspecific protease trypsin in the microM range. These results should provide the basis for the development of highly specific tissue kallikrein inhibitors to aid in elucidating the in vivo role(s) of tissue kallikreins.

Animals↗

PubMed1992

An association between homozygous C3 deficiency and low levels of anti-pneumococcal capsular polysaccharide antibodies.

Inherited deficiencies of complement components are associated with an increased risk of infection by encapsulated, high grade bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis. Hence, the levels of antibodies to bacterial capsular polysaccharide antigens were measured using ELISA in 65 patients with inherited deficiencies covering the classical, alternative and terminal components of the complement cascade. Three of the four C3-deficient individuals studied were found to be almost totally deficient in specific anti-pneumococcal capsular polysaccharide (PCP) antibodies. These individuals had a history of recurrent pneumococcal sepsis. While single individuals with C1r, C2 and C1Inh deficiency were found to have low anti-PCP antibody levels, no other group of complement deficiency had significantly reduced anti-PCP antibody levels compared with 100 controls. Antibody levels to the other two polysaccharides were not significantly lower in the patient groups. These findings suggest that C3 may be able to provide a stimulatory signal to promote the production of anti-PCP antibodies.

Adolescent↗

PubMedDate not supplied

Underlying complement deficiency in patients with disseminated gonococcal infection.

The complement system was evaluated in 22 individuals with disseminated gonococcal infection. Three of the 22 patients exhibited a total serum complement activity that was greater than 2 SD below the normal mean. Of these three, one had a complete deficiency of C1r, a second patient had pre-existing systemic lupus erythematosus with low levels of C4, and the third had a C8 concentration that was 60% of normal. We conclude that the prevalence of inherited or acquired complement deficiency among patients with disseminated gonococcal infection exceeds that among the general population and is an important host factor predisposing to systemic infection with Neisseria gonorrhoeae.

Adolescent↗

PubMed1999

Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor.

Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.

Aged↗

PubMed1989

Synthesis and regulation of C1 inhibitor in human skin fibroblasts.

Proteins of the C1 complex, C1q, C1r, and C1s, of the classical pathway of complement activation are known to be synthesized in human skin fibroblasts. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrate that human skin fibroblasts synthesize and secrete C1 inhibitor with an apparent molecular mass of 78 kDa in the cell lysate and 102 kDa in the extracellular medium. This C1 inhibitor had the capacity to bind activated C1s. Fibroblasts synthesized 30- to 50-fold more C1 inhibitor than was synthesized in monocytes. As previously reported, fibroblasts also synthesized C1r and C1s. IFN-gamma, IFN-beta 1, and TNF had significant, but distinct, effects on synthesis of C1 inhibitor, C1r, and C1s. Incubation of the cells with IFN-gamma, 1000 U/ml, for 24 h induced increases in the synthesis of C1 inhibitor, C1r, and C1s by 4.2-, 1.9- and 1.6-fold, respectively. IFN-beta 1 had effects similar to IFN-gamma, although smaller in magnitude. TNF, 12.5 ng/ml, induced increases in the synthesis of C1 inhibitor, C1r, and C1s by 1.5-, 1.4- and 2.6-fold. IL-1, IFN-beta 2 (IL-6), and LPS did not affect synthesis of C1 inhibitor, C1r, or C1s. Fibroblasts are present in large amounts in most tissues. Synthesis of C1 inhibitor, C1r, and C1s by these cells could provide a source of these important proteins in body tissues. In addition, fibroblasts should be a good model for the in vitro study of genetic diseases involving the synthesis of these proteins.

Adult↗

PubMed1985

Combined IgG2, IgG4 and IgA deficiency: low C1q concentrations and the presence of excess C1r and C1s in an adult patient with recurrent pneumococcal infections.

The complement (C) profile was investigated in an adult patient with combined IgG2, IgG4 and IgA deficiency and recurrent pneumococcal infections. The analysis revealed no gross impairment of the classic and alternative pathways of C activation. However, the concentrations of circulating C1q were persistently decreased, and the sera contained an excess of C1r-C1s complexes, resembling the C1 aberrations previously found in children with recurrent acute otitis media. The concentrations of C4 in the patient were persistently low. This could be ascribed to partial C4 deficiency with lack of C4A variants. The patient's IgG and IgM antibody responses to pneumococcal capsular polysaccharides and to other bacterial carbohydrate antigens were very poor. Interestingly, pneumococcal C-polysaccharide (CPS) could be detected in serum obtained during infection-free periods. Since CPS has been shown to bind C1q without causing C1 activation, the possibility was considered that the C1 aberrations in serum were due to circulating CPS. After administration of intramuscular gammaglobulin to the patient, the serum C1q levels were observed to return to normal.

Adolescent↗

PubMed1995

Regulation of the function of the first component of complement by human C1q receptor.

A membrane-associated receptor for the C1q subcomponent of complement is widely distributed among different cell types. While a number of possible physiological functions of the C1q receptor (C1qR) on different cell types have been described, the way in which C1qR regulates complement activity remains unclear. This report describes the mechanism by which C1qR regulates activation of the first component of complement, C1. Using purified components of complement, we were able to show that membrane-associated C1qR as well as detergent-solubilized C1qR, purified from polymorphonuclear leukocytes, human umbilical vein endothelial cells or an endothelial cell line, EA.hy 926, are able to inhibit complement-mediated lysis of C1q-sensitized erythrocytes. Using hemolytic assays, we were able to demonstrate that C1qR prevents the association of C1q with C1r and C1s to form macromolecular C1. In addition, incubation of C1qR with the collagen-like stalks, but not with the globular heads of C1q, inhibits the effect of C1qR. This demonstrates that C1qR exerts its complement inhibitory effect by binding to the collagen-like stalk of C1q. No complement regulatory effect of C1qR was observed on preformed macromolecular C1. These data suggest that besides such-well-known complement regulatory molecules as CD55 (DAF), CD46 (MCP), CD35 (CR1) and CD59 (HRF), C1qR too is able to regulate complement activity.

Carrier Proteins↗