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PubMed1988

Complement profiles in acute post-streptococcal glomerulonephritis.

It is well known that the hypocomplementemia of acute post-streptococcal glomerulonephritis (APSGN) is characterized by markedly reduced serum concentrations of C3 and moderately reduced levels of C5 and properdin (P). However, the extent of the activation of the classical pathway is not well defined and only limited data are available concerning serum concentrations of terminal components other than C5. In serial serum specimens from 14 children with APSGN, the presence and extent of C4 activation was directly assessed by measurement by rocket immunoelectrophoresis for C4 and C4 (C4d/C4 ratio). Elevated values for this ratio, indicating C4 activation, were found in 8 of 14 of the initial serum specimens, and in some patients the ratio remained elevated for several weeks. In contrast, the serum C4 level was low in only 1 specimen (the specimen with the highest C4d/C4 ratio). However, in 10 patients C4 concentrations within the normal range rose in serial serum specimens. Serum C2 concentrations were depressed in the initial specimens from 5 patients. The concentrations of 13 other complement component and control proteins were also measured in these specimens. Levels of terminal components, other than C5, in the initial serum specimens were normal except for depressed C8 in 3 of 13 patients and depressed C6 in 1 of 14. Of these 4 individuals, 3 had the lowest C3 levels in the study. It is concluded that the classical complement pathway is frequently activated in patients with APSGN early in the condition and that subtle abnormalities in C6 and C8 levels occasionally occur.

Adolescent↗
PubMedDate not supplied

Interaction of anti-leprosy drugs with the rat serum complement system.

Dapsone, clofazimine and rifampicin, the three most important constituents of multidrug therapy against leprosy, were studied with respect to their effects on the rat serum complement system, in vitro as well as in vivo. Of the three drugs only dapsone and clofazimine exhibited significant in vitro anti-complement activity and only at a very high, non-therapeutic dose of 0.24 mg/ml. On the contrary, rifampicin could not induce significant in vitro complement consumption. Furthermore, dapsone and clofazimine could reduce rat-serum-mediated rabbit erythrocyte haemolysis in the presence of Mg2+-EGTA, indicating that they could also affect the alternative pathway of complement activation. However, the latter pathway of complement consumption by these drugs seems to be insignificant because the factor-B-mediated complement-consumption system is minimal in rat sera. Immunoelectrophoretic study of mixtures of fresh rat sera and anti-leprosy drugs against specific anti-rat-C3 antisera demonstrated that dapsone and clofazimine could not cleave the C3 complement component. In a separate experiment we attempted to reconstitute the haemolytic complement activity consumed by dapsone and clofazimine by adding Crat-EDTA sera (a source of C3, C5, C6, C7, C8 and C9), but at most only 12% reconstitution of haemolytic activity could be achieved. We thus conclude that both dapsone and clofazimine could affect the complement system, predominantly through the earlier complement components and at very high, non-therapeutic doses. On the contrary, in-vivo experiments in rats showed that a combination of these three drugs, when given at a therapeutic dose or at 10 times the therapeutic dose for three months, did not affect the complement system.

Animals↗
PubMed1992

Induction of contact sensitivity by cell-associated immunocomplexes requires activation of the early complement components.

Lymph node cells collected from CBA/J mice 4 days after painting the skin with picryl chloride behave like antigen presenting cells and induce contact sensitivity when injected into naive recipient mice. The immunizing capacity of these '4-day' cells is due to T cells which carry on their membrane hapten-IgM immunocomplexes. Incubation of the cells with complement from mouse strains that express high C4 serum levels (C4H), abolishes their immunizing capacity. This effect is related to the activation of the early components of the classical complement pathway, as supported by experiments using C3 and C4-depleted or C5 and C6-genetically deficient mouse sera. The detection of different amounts of C3b and C4b on the surface of 4-day T cells after incubation with C4L and C4H sera supports the possibility that membrane bound activated complement components could modify the immunizing capacity of these cells. Results herein reported suggest that membrane-bound C3b and C4b are not per se inhibitory but interfere with the residual complement activating capacity of 4-day T cells. The role of complement activation by 4-day T cells is pivotal as complement depletion of recipient mice by cobra venom factor (CVF) inhibits the immunizing capacity of untreated 4-day T cells, while 4-day T cells treated with complement in vitro and injected together with C4a anaphylatoxin are able to immunize recipient mice.

Animals↗
PubMed1989

Mediator-induced activation of xanthine oxidase in endothelial cells.

Rat pulmonary artery endothelial cells incubated with human serum that has been complement-activated by addition of cobra venom factor reveal a pronounced conversion of xanthine dehydrogenase to xanthine oxidase. This process requires the availability of the fifth component of complement (C5) but not the presence of other components (C2 and C6-C9). The phenomenon can be reproduced by addition to endothelial cells of purified human recombinant C5a but not C5a desArg or C3a. The enzyme conversion process is relatively rapid (occurring within 5-10 min), requires the presence of intact endothelial cells, and does not require protein synthesis. Similar effects on endothelial cells have been obtained with human recombinant tumor necrosis factor alpha and the chemotactic peptide N-formyl-Met-Leu-Phe. In contrast, bradykinin, recombinant human interleukin 1 beta, and phorbol ester lack this biological activity. These findings suggest novel effects of inflammatory mediators on endothelial cells.

Animals↗
PubMed1989

Mouse strains with typical mammalian levels of complement activity.

Common laboratory mouse strains have very low complement levels relative to humans, rats, guinea pigs, rabbits and other mammals, which limits the value of the mouse as an experimental model. We therefore tested serum complement levels of 43 mouse strains and 11 rat strains, for the purpose of selecting a convenient laboratory animal having high complement levels. Total complement activity was determined with both erythrocytes and human tumor cells as targets. Eight mouse strains were identified that have complement levels comparable to those of other mammals. These mouse sera lyse tumor cell targets as well as sera from humans, rats or guinea pigs, although they are somewhat less active than rabbit sera. They are relatively inefficient in lysing erythrocyte targets, yet are as active as rabbit serum in this assay. Target cell lysis was demonstrated to be via the classical pathway of complement activation. Of the eight 'high complement' mouse strains, four were recently derived from wild mice, and one, SF/CamEi, was derived from wild mice in 1951. The three other strains, BUB/BnJ, DA/HuSn and RIIIS/J, were developed more than 40 years ago, but apparently were not tested previously for complement activity. Using the BUB mouse as a representative of the 'high complement' mice, we assayed levels of the nine complement components, in an attempt to identify the cause of high complement activity. No difference in levels of C1, C2, C4, C8 or C9 was detected between BUB and BDF1 mice. C2 activity was very low in both strains. C3, C5, C6 and C7 activities were higher in BUB mice than in BDF1 mice, indicating that variation in these complement components is responsible for the difference in total complement activity. The genes determining the 'high complement' phenotype appeared to be semi-dominant in F1 hybrids. The 'high-complement' mouse strains, and recombinant strains derived from them, will be useful in a wide range of biomedical research.

Animals↗
PubMed1999

Complement (C5b-9) induces glomerular epithelial cell DNA synthesis but not proliferation in vitro.

BACKGROUND: The C5b-9 membrane attack complex of complement is the principal mediator of injury induced experimentally by antibodies directed at glomerular cell membranes. In experimental membranous nephropathy, C5b-9 induced injury to the glomerular visceral epithelial cell (VEC) is associated with DNA synthesis, but not cytokinesis. In the current study we determined if C5b-9 increases DNA synthesis in VEC in vitro, and defined the mechanisms involved. METHODS: Rat VEC in vitro were divided into three groups: (1) sensitized with anti-VEC antibody and exposed to sublytic concentrations of C +/PVG serum (normal complement components); (2) anti-VEC antibody and control C-/PVG serum (C6 deficient); (3) no anti-VEC antibody. DNA synthesis (BrdU staining), mitosis (mitotic figures) and cytokinesis (cell counts) were measured at 24 and 48 hours. To examine the expression of specific S-phase and M-phase cell cycle regulatory proteins and their inhibitors, immunostaining and Western blot analysis was performed for cyclin A, CDK2, p21 and p27, cyclin B and cdc2. RESULTS: In the absence of growth factors, sublytic C5b-9 attack did not increase proliferation. In contrast, sublytic C5b-9 attack (group 1) augmented growth factor induced DNA synthesis by 50% compared to controls (groups 2 and 3; P < 0.001), and was accompanied by increased levels of cyclin A and CDK2, and a decrease in the cyclin kinase inhibitor p27 (but not p21). Sublytic C5b-9 attack reduced the expression of the M phase cell cycle proteins, cyclin B and cdc2, accompanied by reduced mitosis (mitotic figures) and cytokinesis (cell number). CONCLUSIONS: Our results show that the C5b-9 augmented growth factor entry into the S phase in VEC is regulated by changes in specific cell cycle regulatory proteins. However, antibody and complement decreased the M phase cell cycle proteins, and prevented VEC mitosis and cytokinesis, suggesting a delay or arrest at the G2/M phase.

Animals↗
PubMed2005

Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization.

Choroidal neovascularization (CNV), or choroidal angiogenesis, is the hallmark of age-related macular degeneration and a leading cause of visual loss after age 55. The pathogenesis of new choroidal vessel formation is poorly understood. Although inflammation has been implicated in the development of CNV, the role of complement in CNV has not been explored experimentally. A reliable way to produce CNV in animals is to rupture Bruch's membrane with laser photocoagulation. A murine model of laser-induced CNV in C57BL/6 mice revealed the deposition of C3 and membrane attack complex (MAC) in the neovascular complex. CNV was inhibited by complement depletion using cobra venom factor and did not develop in C3(-/-) mice. Anti-murine C6 Abs in C57BL/6 mice inhibited MAC formation and also resulted in the inhibition of CNV. Vascular endothelial growth factor, TGF-beta2, and beta-fibroblast growth factor were elevated in C57BL/6 mice after laser-induced CNV; complement depletion resulted in a marked reduction in the level of these angiogenic factors. Thus, activation of complement, specifically the formation of MAC, is essential for the development of laser- induced choroidal angiogenesis in mice. It is possible that a similar mechanism may be involved in the pathophysiology of other angiogenesis essential diseases.

Animals↗
PubMed1987

Interactions of purified Serratia marcescens metalloproteases with fresh human serum and with purified human serum proteins.

Exposure of fresh human serum to two purified metalloproteases of S. marcescens strains SF 178 and SH 186 (both of serotype O6/O14:H12) at 35 degrees C, 3 h, resulted in altered electrophoretic mobility of the protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin, alpha 2-HS-glycoprotein, and complement (C) components C1q, C1s, C3a, C3c, C4, C5, and C9, but not C6, C7, C8, and properdin, as determined with electroimmunoassays (Laurell technique). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the partial degradation of the heavy (H) chain of purified human immunoglobulin IgG by the metalloproteases of S. marcescens strains SF 178 and SV O1 (serotype O13/O19:H1), but not by the metalloproteases of strains SH 186 and SE 182 (serotype O9B:H11) following extended incubation (35 degrees C, 22 h). Human IgA and IgM were refractory. Purified human C components, C3, C4, C5, C6, C7, C8, and C9, as well as purified human alpha 1-antitrypsin, alpha 2-macroglobulin, transferrin, and lactoferrin were attacked by the S. marcescens metalloproteases SF 178 and SH 186 at 35 degrees C for 5 h, as demonstrated with the SDS-PAGE procedure; haptoglobin and C-reactive protein were resistant.

Acute-Phase Proteins↗
PubMed2002

The membrane attack complex of complement induces caspase activation and apoptosis.

Activation of the terminal pathway of the complement system leads to insertion of terminal complement complexes (C5b-9) into the cell membrane, which may induce cytolysis. Recent data indicate that the terminal complement pathway can also result in apoptosis in vivo. To further define the cell death pathway induced by complement, we examined induction of apoptosis by complement in vitro. Rat mesangial cells opsonized with a complement-activating antibody and exposed to rat serum as a complement source underwent apoptotic cell death in a time- and dose-dependent fashion, as demonstrated by membrane exposure of phosphatidylserine and fragmentation of nuclei. No significant apoptosis was detected in either cultures treated with C6-deficient serum or in control cultures. The pan-caspase-inhibitor zVAD-fmk inhibited complement-induced apoptosis completely. In line with this observation, complement induced cleavage and activation of caspase 3. Importantly, cellular exposure to purified cytolytically inactive C5b-9, in the absence of antibody and early complement components, also resulted into caspase activation and apoptosis. Together, these results indicate that C5b-9 is involved in induction of apoptosis via a caspase-dependent pathway. Apoptosis as a consequence of complement-mediated cell damage may provide an explanation for the presence of apoptosis in inflammatory processes, for instance in hyperacute xenograft rejection.

Amino Acid Chloromethyl Ketones↗
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↗
PubMed1975

Serum complement and immunity in experimental simian malaria. II. Preferential activation of early components and failure of depletion of late components to inhibit protective immunity.

The role of complement in the control of parasitemia was examined. Depletion of late components (3-9) by cobra venom factor did not alter either the degree or course of parasitemia during the pre-immune or immune stages of infection. The pattern of consumption of complement components was therefore examined. Concomitant with schizont rupture there was depletion of early-acting components (C1, C4, and C2) of the clasical complement pathway. The magnitude and remporal relationships of the fall were similar for these three components. Serum levels returned to prerupture values over 36-48 hr, and then the cycle was repeated. There was no simultaneous change in the levels of C3, C3 proactivator, or C6. These results delineate a new pattern of cyclical consumption of early components of the classical complement pathway associated temporally with schizont rupture and suggest that the late-acting components are not required for protective host immunity in malaria.

Acute Disease↗
PubMed2002

Structurally and functionally conserved domains in the diverse hydrophilic carboxy-terminal halves of various yeast and fungal Na+/H+ antiporters (Nha1p).

Genes encoding the Na(+)/H(+) antiporter (Nha1p) from Candida tropicalis (C.t.), Hansenula anomala (H.a.) (also named Pichia anomala), and Aspergillus nidulans (A.n.) were cloned, and the nucleotide sequences were determined. The deduced primary sequences revealed highly conserved hydrophobic regions and rather diverse hydrophilic regions. Among the seven known Nha1p sequences, Schizosaccharomyces pombe (S.p.) Nha1p is exceptional in lacking the hydrophilic region. Within the diverse hydrophilic regions, we found six conserved regions (C1-C6). Expression of C.t. Nha1p in Saccharomyces cerevisiae (S.c.) cells lacking NHA1 and ENA1 (Na(+)-ATPase) complemented the salinity-sensitive phenotype, suggesting that C.t. Nha1p is functionally related to S.c. Nha1p. Expression of various truncated forms of the C-terminal half of S.c. and C.t. Nha1p showed essentially the same phenotype for both species: deletion of the C4-C6 region caused cell growth to be more resistant to high salinity than the wild type, suggesting an inhibitory function of these domains on the antiporter activity. However, complete loss of C1-C6 caused a severe growth defect under conditions of high salinity, suggesting a defect in antiporter activity. The DeltaC2-C6 form of C.t. Nha1p, containing only C1, restored the retarded cell growth at high salinity more than the control vector alone, but to a value lower than the wild type. These results suggest an essential role for C1 and an activating role of the C2-C3 region in the functional expression of Nha1. High expression of the DeltaC2-C6 form of S.c. Nha1p was toxic for yeast cells, although low expression was not, suggesting that the overexpression of C1 is toxic. The results in this study suggest that the diverse hydrophilic region of yeast and fungal Nha1p has six conserved domains with conserved functions in terms of expression of Nha1p activity.

Amino Acid Sequence↗
PubMed2003

Mutant human cells with constitutive activation of NF-kappaB.

We have used a genetic approach to generate eight different mutant human cell lines in which NF-kappaB is constitutively activated. These independent clones have different phenotypes and belong to several different genetic complementation groups. In one clone inhibitor of kappaB(IkappaB) kinase is constitutively active, but in the seven others it is not, despite the fact that IkappaB is degraded in all eight clones. Thus, IkappaB kinase-independent mechanisms of IkappaB degradation and NF-kappaB activation are predominant in these mutants. Biochemical analyses of the mutants revealed that they fall into at least five different categories, differing in the sets of upstream kinases that are activated, confirming multiple mechanisms of NF-kappaB activation. By introducing a retroviral cDNA library into the Ras C6 cell line, with constitutively active NF-kappaB, followed by selection for functional complementation, we isolated a cDNA encoding a C-terminal fragment of enolase 1 and identified it as negative regulator of NF-kappaB.

Cell Line↗
PubMed1983

Lysis of paroxysmal nocturnal hemoglobinuria erythrocytes by acid-activated serum.

Erythrocytes from paroxysmal nocturnal hemoglobinuria patients (PNH-E) are much more susceptible to lysis by acid-activated human serum than normal human erythrocytes. Acidification of normal human serum to pH 6.4 in the absence of erythrocytes generates this lytic activity independently of the alternative pathway of complement activation. A shift of pH of a mixture of purified human C5 and C6 to 6.4 at 0 degrees C generates a similar activity C(56)a that lyses PNH-E together with C7-C9 much more efficiently than normal erythrocytes. Since acid-activation of normal human serum occurs in the absence of C3, the acid-activated C56 appears to be the lytic principle in acidified human serum.

Animals↗
PubMed1998

Induced expression of neuronal membrane attack complex and cell death by Alzheimer's beta-amyloid peptide.

beta-amyloid peptide (A beta) and complement-derived membrane attack complex (MAC) are co-localized in senile plaques of brains from Alzheimer's disease (AD) patients. But the relationship between A beta and complement activation is unclear. We have used human neurotypic cells, differentiated SH-SY5Y, as a model system to examine regulation of neuronal MAC expression and cell death by A beta. We demonstrated that mRNAs (C1q, C2, C3, C4, C5, C6, C7, C8 and C9) and proteins (C1q, C3 and C9) for the major components of the classical complement cascade are present in the SH-SY5Y neurotypic cells, indicating that neuronal cells can synthesize the necessary proteins required for MAC formation. Furthermore, immunocytochemical studies showed the A beta-induced neuronal MAC expression on the SH-SY5Y cells after CD59 was removed by PIPLC or blocked by anti-CD59 antibody. Meanwhile, increased A beta-induced neuronal cell death was observed following treatment with anti-CD59. Taken together, these results suggest that A beta activates neuronal complement cascade to induce MAC, and a deficiency of endogenous complement regulatory proteins, e.g., CD59, may increase the vulnerability of neurons to complement-mediated cytotoxicity.

Alzheimer Disease↗
PubMed1989

Detection of refolding conformers of complement protein C9 during insertion into membranes.

Human complement protein C9 is a hydrophilic serum glycoprotein responsible for efficient expression of the cytotoxic and cytolytic functions of complement. It assembles on the surface of a target cell together with C5, C6, C7 and C8 to form the membrane attack complex (MAC) and therefore has to change structure to become an integral membrane protein. As the protein assumes a stable structure in an aqueous environment, the question arises as to how it can enter the hydrophobic interior of a membrane. During MAC assembly C9 polymerizes into a circular structure, termed poly(C9) (ref. 8), which is responsible for the cylindrical electron microscopic appearance of the MAC. The suggestion has been made that C9 must at least partly unfold in order to enter a membrane and also that polymerization of the molecule is intimately linked to insertion and cytotoxicity. The extent of unfolding and the mechanism of polymerization are not understood, nor is it known precisely which parts of the molecule participate in the proposed structural changes. We have been able to capture refolding C9 conformers during membrane insertion with the help of sequence-specific anti-peptide antibodies. Some of these antibodies inhibit C9-mediated haemolysis but not C9 polymerization, while others have the opposite effect. This suggests that the two processes are independent.

Complement C9↗
PubMed1985

Human monocyte recognition of complement-coated lymphoblastoid cells.

The macrophage system in man plays a significant role in the detection of foreign cells. The mechanisms by which macrophages recognize malignant cells, however, are not well understood. We used human monocytes and four lymphoblastoid cell (LC) lines derived from human acute lymphocytic leukemia to investigate the initial recognition of tumor cells by monocytes. IgM antibody mediated the binding of these cells to monocytes only in the presence of complement. The stepwise addition of complement components to IgM-coated LC indicated that C3 was necessary to monocyte binding. Similarly, monocyte recognition of IgM-coated LC was maximal in the presence of sera from patients with congenital C5 or C6 deficiency, but absent in the presence of sera deficient C4 or from a patient with congenital C2 deficiency. Complement activation was associated with C3 consumption and the deposition of substantial amounts of C3 on to LC. Although 3H-C3 bound to LC appeared stable for 2 hours, approximately 4.0 +/- 2 X 10(5) 3H-C3 per LC was necessary for monocyte recognition, compared to approximately 2.7 +/- 0.5 X 10(3) 3H-C3 per RBC. The data indicate that LC can be recognized by monocytes through complement by mechanisms similar to nonmalignant target cells. However, substantial amounts of C3 are necessary to induce monocyte recognition of IgM-coated LC and, thus, such complement mediated recognition may be inefficient.

Cell Communication↗
PubMed1986

Genetic polymorphism of the seventh component of complement: a new variant.

Genetic polymorphism of the seventh component of complement (C7) was studied by the methods of agarose gel isoelectric focusing and immunoblotting. Serum or plasma samples were treated with neuraminidase prior to isoelectric focusing. A cathodal variant, named C7 5, was recognized in the treated samples. Family study indicates that the C7 5 component is genetically determined. The allele frequencies calculated from 183 healthy Japanese individuals were C7*1 = 0.809, C7*2 = 0.104, C7*4 = 0.038, and C7*5 = 0.049. An association between C7 and C6 alleles was not found.

Alleles↗