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PubMed1997

C1Q synthesis by tissue mononuclear phagocytes from normal and from damaged rat liver: up-regulation by dexamethasone, down-regulation by interferon gamma, and lipopolysaccharide.

The subcomponent of complement C1, C1q, mediates complement activation via the classical pathway, and therefore may play an important role in the inflammatory processes in which complement activation is involved. The aim of our study was to investigate C1q synthesis by macrophages of normal and of acutely damaged livers. The localization of C1q in liver tissue was studied by immunohistochemistry. Rat liver tissue macrophages were isolated from normal as well as from acutely damaged (carbon tetrachloride model) liver, and were separated into small, monocyte-like phagocytes and large, mature tissue macrophages, as revealed by immunocytochemistry. C1q gene expression was studied by endogeneous labeling of newly synthesized proteins, immunoprecipitation, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and by reverse-transcription polymerase chain reaction (RT-PCR) of C1qB messenger RNA (mRNA). Semiquantitative analysis was performed by Northern blotting of total RNA and hybridization with the radioactively labeled RT-PCR product. C1 esterase inhibitor synthesis was studied in parallel. For comparison, C1q and C1-inhibitor synthesis were also investigated in blood monocytes and peritoneal macrophages. C1q was weakly detectable in sinusoidal cells of the normal liver. C1qB mRNA, as well as constitutive synthesis and secretion of C1q, was clearly detected in freshly isolated and cultured Kupffer cells from normal rat liver. In comparison, newly recruited "inflammatory" macrophages from damaged rat liver synthesized considerably lower amounts of the protein, similar to what was found in the monocyte-like macrophages of normal liver and in peritoneal macrophages. Monocyte C1qB mRNA was not detected even by RT-PCR, and remained undetectable during the time in culture. Similar behavior was observed for C1-inhibitor synthesis. Treatment of the cultures with interferon gamma (IFN-gamma) or lipopolysaccharide (LPS) strongly decreased, whereas treatment with dexamethasone strongly increased C1q gene expression in the macrophage populations, and induced C1qB mRNA in cultured monocytes, as revealed by RT-PCR. Kupffer cells of normal liver may produce considerable amounts of C1q, whereas the inflammatory macrophages of the acutely damaged liver may not be so important for the synthesis of C1q.

Animals↗
PubMed1984

Neutron scattering studies of subcomponent C1q of first component C1 of human complement and its association with subunit C1r2C1s2 within C1.

Neutron scattering studies are reported on subcomponent C1q of component C1 of human complement, and on C1, the complex of C1q with subunit C1r2C1s2. For C1q, the molecular weight was determined as 460,000. The radius of gyration at infinite contrast RC is 12.8 nm. The RC values for the proteolytically cleaved forms of C1q, namely the heads and the stalks, are 1.5 to 2 nm and 11 nm, respectively, and thus the axis-to-arm angle of C1q is estimated at 45 degrees. Neutron data for subunit C1r2C1s2 are published elsewhere. The neutron data on C1 lead to an RC value of 12.6 nm for proenzymic C1 and a molecular weight of 820,000. The wide-angle scattering curve of C1q exhibits a minimum at Q = 0.28 nm-1 and a maximum at 0.39 nm-1; on the addition of C1r2C1s2, this minimum disappears. The neutron data on C1 indicate that C1q and C1r2C1s2 have complexed with a large conformational change in one or both parts. No conformational changes can be detected on the activation of C1 by this method.

Complement Activating Enzymes↗
PubMed1977

Interactions between mycoplasma pneumoniae and the first components of complement.

Mycoplasma pneumoniae cells were rounded and killed by fresh guinea pig serum (GPS) which did not contain detectable amounts of antibody. The first component of complement (C1) was bound by M. pneumoniae in considerable amounts from both GPS and purified C1. The C1 bound by the cells was reacting with C4. Sequential addition of C1, C4, C2, and C-ethylenediaminetetraacetate to glass-grown M. pneumoniae cells resulted in rounding of a significant number of cells. M. orale and M. fermentans showed a reduced binding capacity for C1 as compared with M. pneumoniae. Both species were only slowly killed by fresh GPS, whereas M. hominis was as sensitive as M. pneumoniae. The results suggest an antibody-independent interaction between some components of the membrane surface of M. pneumoniae and C1, resulting in an activation of the complement system leading to the killing of the mycoplasma cells.

Animals↗
PubMed1978

The presence of active C1 (C-1) on peripheral human lymphocytes.

We have shown that the first component of complement C1 is present in an active form on the surface of washed human peripheral lymphocytes but not on platelets or erythrocytes. This active C1 (C-1) was detected by its ability to transfer to sensitized cells carrying C4, i.e., EAC4, forming EAC-1,4. Active C1 was also able to consume C4. Treatment of these lymphocytes with 0.02 M EDTA removed C-1. EDTA-treated lymphocytes were able to bind exogenous purified human C-1. Comparative studies with sentized erythrocytes (EA) and EDTA treated lymphocytes showed that although fewer molecules of exogenous C1 could bind to the EDTA-treated lymphocytes than to EA, the consumption of C4 by C-1 bound to lymphocytes was significantly higher than that observed with EAC-1. When lymphocytes obtained from 2 patients with chronic lymphocytic leukemia and hypocomplementemia were tested, the release of C1, the C4 consumption and the binding of C-1 to EDTA-treated cells were highly inefficient.

Blood Platelets↗
PubMed1995

Control of contact activation on end-point immobilized heparin: the role of antithrombin and the specific antithrombin-binding sequence.

The uptake and activation of FXII from blood plasma was studied in small-diameter polyethylene tubing, surface-modified by end-point immobilization of heparin. Two preparations of heparin were used to modify the contact-activating properties of the plastic tubing: unfractionated, functionally active heparin and low-affinity heparin, lacking the specific antithrombin-binding sequence and virtually devoid of anticoagulant activity. The uptakes of FXII on the two heparin surfaces were similar. No activated FXII could be demonstrated on the unfractionated heparin surface, whereas on the low-affinity heparin surface nearly all FXII underwent spontaneous activation. The suppression of FXII activation on the unfractionated heparin surface was investigated by using plasma depleted of antithrombin, complement C1 esterase inhibitor, or both. The removal of antithrombin resulted in extensive activation of FXII, whereas the depletion of C1 esterase inhibitor had only a minor effect. Experiments with recalcified plasma showed rapid clot formation during exposure to the low-affinity heparin surface. After depletion of antithrombin, but not complement C1 esterase inhibitor, the recalcified plasma clotted in contact with the unfractionated heparin surface as well. We conclude that antithrombin and the antithrombin-binding sequence in the surface-immobilized heparin are essential for the prevention of surface activation of FXII and triggering of the intrinsic coagulation system.

Animals↗
PubMed1977

Biosynthesis of the first component of complement by human fibroblasts.

1. Haemolytic activity corresponding to that of the first component of complement (C1) was synthesized and secreted by all nine human fibroblast cell lines examined. No activity was found in the culture media of a variety of other human cell lines. 2. The component-C1 haemolytic activity secreted by the fibroblast lines behaved in an identical manner, in most respects, with that of the component-C1 haemolytic activity of human serum. The component-C1 haemolytic activity secreted by fibroblasts, however, was less susceptible to inhibition by rabbit fragment F(ab')(2) anti-(human subcomponent C1q) than was the component-C1 haemolytic activity of human serum. 3. Biosynthesis of fibroblast component-C1 haemolytic activity was inhibited by the presence of cycloheximide and regained on its removal. 4. Incorporation of radioactivity into proteins secreted by the fibroblasts and release of component-C1 haemolytic activity by the fibroblasts both increased in a linear manner until several days after the cultures had reached a state of confluent growth. 5. Radioactivity was incorporated into subcomponents C1q, C1r and C1s, as judged by the formation of specific immunoprecipitates and by absorption with immune aggregates. 6. The immunoprecipitates formed by using antisera against subcomponents C1r and C1s were run on polyacrylamide gels in sodium dodecyl sulphate, and this provided convincing physiochemical evidence for the biosynthesis of these subcomponents de novo. 7. The results obtained with immunoprecipitates formed by using anti-(subcomponent C1q) suggest that subcomponent C1q may be synthesized and secreted by fibroblast cell lines in vitro, in a form with a higher molecular weight than that of subcomponent C1q which is isolated by conventional techniques of protein fractionation from fresh serum.

Cell Line↗
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↗
PubMed2005

Complement-coated antibody-transfer (CCAT); serum IgA1 antibodies intercept and transport C4 and C3 fragments and preserve IgG1 deployment (PGD).

In periodontal disease, IgG1 and IgA1 antibodies produced in situ deposit on antigens in the affected tissues. Thus, there is an interest in the effect of co-deposited IgA1 antibodies on complement activation by IgG1-immune complexes. In the present study, we first analyzed the effect of IgA1-immune complexes on complement using human IgA1 antibodies to dansyl (with dansylated human serum albumin serving as the immobilized antigen). It was observed that these IgA1-immune complexes when incubated for prolonged times with 33% human serum as a source of complement received C4b and C3b deposition. As C4b and C3b deposited on the IgA1 antibodies and on the antigenic surface, the complement-coated IgA1 antibodies departed. These fluid-phase complement-coated IgA1 antibodies were transferred to antigen-coated microtiter-ELISA plates, where they became bound to the antigens. Thus, the complement-coated IgA1 antibodies retained their antigen-binding function, especially as a proportion of their covalently bound C3b progressively degraded to iC3b and C3d. Genetically engineered carbohydrate-deficient mutant human IgA1 antibodies were used to assess the role of carbohydrate in accepting the C4b and C3b depositions, and these studies indicated that the carbohydrate on the Fc-region of IgA1 played a positive role. Another interesting finding generated by this study was that when IgA1 was co-deposited with IgG1 antibodies, and serum complement was added, the IgG1 antibodies tended to remain on the antigenic surface. The co-deposited IgA1 antibodies not only controlled (reduced) the rate of the consumption of the first component of complement (C1) and of classical complement pathway activation by IgG1-immune complexes (and therein reduced the rate of complement-mediated dissolution of the IgG1-immune complexes), but also the co-deposited IgA1 antibodies simultaneously intercepted/accepted C4b and C3b, then departed, as complement began to cover the antigenic surfaces. The process in which complement-coated IgA1 antibodies transferred to non-complement-coated antigens is termed complement-coated antibody-transfer/transport (CCAT). In this way, IgA1 antibodies extended the efficiency of the complement system by insuring the specific IgA1 antibody-mediated transport of the captured biologically active complement fragments to those antigens stimulating the IgA1 antibody response but not yet neutralized (completely coated) with complement. Simultaneously by impeding the rate of C1 consumption and by intercepting C4b and C3b, IgA1 antibodies slowed C4b and C3b deposition on the antigenic surface and on the co-deposited IgG1 antibodies. Thus, in the presence of ongoing complement activation, the deposition of serum IgA1 antibodies enabled the co-deposited IgG1 antibodies to better maintain their ability to interact with antigens. We termed this latter phenomenon, preservation of IgG antibody deployment (PGD). In summary, co-deposited IgA1 antibodies maximized the efficiency of the complement system, transported their covalently bound complement fragments to specific antigens and sustained the effective deployment of IgG1 antibodies directed to those same antigens.

Antigens↗
PubMed1984

Lysis of horse red blood cells mediated by antibody-independent activation of the alternative pathway of chicken complement.

Horse red blood cells (HRBC) were found to be lysed when incubated with fresh normal chicken serum (NCS). By comparison of the properties of the lysis of HRBC with those of the complement-dependent lysis of sheep red blood cells (SRBC) sensitized with haemolytic antibody via the classical pathway, the following differences were observed between the two haemolytic phenomena. (i) The lysis of HRBC was independent on antibody in contrast to the antibody dependence of the lysis of sensitized SRBC. (ii) The lysis of HRBC was dependent on Mg but not on Ca ion, whereas the lysis of sensitized SRBC required both Mg and Ca ions. (iii) Treatment of NCS with carrageenan that acts as an inactivator of the first component of complement (C1) inhibited the lysis of sensitized SRBC but not the lysis of HRBC. (iv) C1 was consumed in the lysis of sensitized SRBC but not in the lysis of HRBC. (v) Cobra venom factor (CVF), C3 inactivator via the alternative complement pathway, inhibited the lysis of HRBC but not the lysis of sensitized SRBC. (vi) Minimal reaction times for the lysis of HRBC and for the lysis of sensitized SRBC were 90 and 60 min, respectively. These findings indicate that the lysis of HRBC was caused by the antibody-independent activation of complement via the alternative pathway.

Animals↗
PubMed1983

Measurement of antibody-dependent binding, proteolysis, and turnover of C1s on liposomal antigens localizes the fluidity-dependent step in C1 activation.

The antibody-dependent binding and activation of the first component of human complement (C1) by liposomes containing nitroxide spin-label lipid haptens have been simultaneously measured. The liposomes were either fluid (dimyristoylphosphatidylcholine) or solid (dipalmitoylphosphatidylcholine) at the temperature of the experiments (32 degrees C). In 10 minutes fluid liposomes activate 40% of the C1 whereas solid liposomes only activate 10% of the C1. The fraction of C1 bound at the end of the activation incubation is approx. 2% for fluid liposomes and approx. 4% for solid liposomes. This binding is consistent with the relative amounts of antibody which bind to these two types of liposomes. These results demonstrate turnover of C1 or C1r2s2 on the liposome surface. It is concluded that the differential activation of C1 is due to a difference in the rate of activation of C1 after it is bound to the liposome surface. Lower limits for the activation rate constant for C1 bound to fluid and solid liposomes are estimated to be 8 X 10(-2) s-1 and 1 X 10(-2) s-1, respectively.

Animals↗
PubMed1981

Stoichiometry and sedimentation properties of the complex formed between the C1q and C1r2C1s2 subcomponents of the first component of complement.

We have examined the functional and hydrodynamic properties of the first component of human complement, C1, and the activated first component, C1-, reassembled in the presence of Ca++ from C1q and either the C1r2C1s2 or the C1r-2C1s-2 tetramer. Reconstituted C1 has hemolytic activity similar to C1 in serum. As long as either tetramer is in excess and the total concentration is low, we find that only a 1:1 complex is formed between C1q and either the unactivated or activated tetramer. This complex sediments at 15.9 +/- 0.2 Svedbergs and has a complex sediments at 15.9 +/- 0.2 Svedbergs and has a m.w. of 739,000 +/- 37,000. The boundary shape of the sedimenting C1- preparation was broader than that of C1 suggesting the association constant between C1r2C1s2 and C1q may have decreased upon activation. At elevated concentrations, with more than a molar excess of C1q, C1 aggregated to form both 16S and 23S species.

Animals↗
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↗
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↗
PubMed1975

Complement-mediated bactericidal system: evidence for a new pathway of complement action.

The early components of human complement (C1, C4, and C2) plus certain serum euglobulins will kill pathogenic strains of Shigella sonnei. Serum from patients with hereditary C3 deficiencies and specific antiserums to C3, C5, and C6 were utilized to demonstrate the absence of requirements for late-acting complement components in this unusual bactericidal system.

Antibodies, Bacterial↗
PubMed1987

Antibody-independent activation of the classical pathway of complement by Epstein-Barr virus.

A purified preparation of Epstein-Barr virus (EBV) has been shown to activate the classical complement pathway by direct interaction with the first component of complement, C1, without the intervention of antibody. No evidence was found for activation of the alternative pathway. Following classical pathway activation the specific affinity of EBV for B cells can be presumed to be lost since the virus will become opsonized for clearance by phagocytic cells bearing complement receptors, CR1 and CR3. This activation is further evidence that complement plays a role in defence mechanisms independently of antibody activity.

Antigens, Viral↗