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PubMed1986

Meningococcemia and acquired complement deficiency. Association in patients with hepatic failure.

We treated two patients with severe hepatic failure complicated by meningococcemia. Serum complement profiles performed on these patients found low total hemolytic complement assays, normal concentrations of C1q, and low or undetectable concentrations of C3 through C6, C8, C9, and factors B and I. These studies suggest that these patients developed meningococcemia in the setting of acquired complement deficiency from impaired synthesis of multiple complement system proteins.

Acute Disease↗

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↗

PubMed1993

Regulation of complement membrane attack complex formation in myocardial infarction.

Recent studies have suggested that the complement (C) system is involved in the development of tissue injury of myocardial infarction. As it is not known why the strictly controlled C system starts to react against autologous heart tissue, we have analyzed the expression of various membrane regulators of C (CR1, DAF, MCP, CD59, C8 binding protein) and the pattern of deposition of C components and plasma C regulators (C4b binding protein and vitronectin) in normal (n = 7) and infarcted (n = 13) human myocardium. In the infarcted myocardium deposits of the C membrane attack complex (MAC) were observed by immunofluorescence microscopy, and lesions resembling the transmembrane channels of MAC were detected by transmission electron microscopy. CD59 and C8 binding protein were strongly expressed by muscle cells of normal myocardial tissue. Little or no CR1, MCP, and DAF was observed on these cells. The assembly of MAC was accompanied by the deposition of vitronectin (S-protein) and C4b binding protein in the infarcted areas of myocardium. In accordance with our earlier results the expression of CD59 but not of C8 binding protein was clearly diminished in the lesions. The results show that C8 binding protein, vitronectin, and C4b binding protein do not prevent complement attack against the infarcted myocardium but rather become codeposited with the MAC. Ischemia-induced transformation of nonviable cells into complement activators, acquired loss of resistance to the MAC by shedding of CD59, and recruitment of multifunctional serum proteins by MAC could thus constitute a general process aimed at the clearance of injured tissue.

Aged↗

PubMed1996

Complement-induced endothelial dysfunction in rabbits: mechanisms, recovery, and gender differences.

Activation of complement and attenuation of endothelium-dependent relaxation occur in a number of pathophysiological conditions. The aim of this study was to investigate the mechanisms of human complement activation and loss of endothelium-dependent relaxation in rabbit tissue, the duration of this loss, and the effects of gender and serum concentration. In rabbit thoracic aortic rings precontracted with phenylephrine, human serum (HS) concentration dependently induced a loss of endothelium-dependent relaxation to the receptor-dependent vasodilator acetylcholine (ACh) and receptor-independent vasodilator calcium ionophore A23187. Serum-induced loss of ACh-dependent relaxation was decreased when rings were bathed in 1) HS depleted of factor B, C2, or C8, 2) heat-inactivated HS, or 3) HS with complement inhibitor sCR1 or sCR1[desLHR-A]. Superoxide dismutase had no effect on serum-induced loss of ACh-dependent relaxation. Serum-induced loss of ACh-dependent relaxation returned to control values after removal of HS. Serum-induced loss of ACh-dependent relaxation was greater in male than in female aortic rings. These results suggest that 1) complement activation directly attenuates endothelium-dependent relaxation via the classical and alternative pathways independent of superoxide anion formation, 2) this attenuation is concentration dependent, reversible, and dependent on formation of C5b-9, and 3) endothelial tissue from males is more susceptible than that from females to the acute effects of complement activation.

Acetylcholine↗

PubMed2000

Acute cocaine exposure up-regulates complement expression in rabbit heart.

The exact mechanism of the cardiotoxic actions of cocaine remains unclear. The finding that the heart may be a source of injurious complement components led us to investigate whether cocaine promotes myocardial expression of complement. Rabbit isolated hearts were perfused for 70 min with either cocaine hydrochloride (1 or 10 microM), the synthetic isomer (+)-cocaine (10 microM), or procaine hydrochloride (10 or 30 microM). Compared with controls perfused with drug-free buffer, both cocaine and procaine significantly (P <. 05) increased myocardial C1q, C1r, C8, and C9 mRNA expression, whereas 10 microM (+)-cocaine had no effect on complement mRNA expression. Cocaine also significantly increased (P <.05) C3 mRNA transcription. In addition, in vivo administration of cocaine (1 mg/kg) for three consecutive days significantly increased myocardial complement mRNA expression. Cocaine and procaine also increased membrane attack complex (MAC) formation in the myocardium. The antioxidant 2-N-mercaptopropionyl glycine, attenuated the increases in complement mRNA expression induced by 1 microM cocaine and 10 microM procaine. In vivo heparin administration (300 U/kg i.v.), 2 h before removal of the heart and exposure to 1 microM cocaine, did not inhibit C1q, C1r, C3, and C8 mRNA transcription, but decreased MAC expression. It was determined previously that heparin reduces myocardial ischemia/reperfusion injury. Our results suggest that cocaine may cause myocardial injury by up-regulating local complement expression, possibly via the production of reactive oxygen species. Furthermore, the glycosaminoglycan heparin may modulate the cytotoxic effects of cocaine by impeding formation of the MAC.

Animals↗

PubMed1994

Silica induced suppression of the production of third and fifth components of the complement system by human lung cells in vitro.

Although investigations to date have demonstrated the ability of the monocyte/macrophage to synthesize complement components, only a limited number of studies on complement synthesis by nonhepatic tissue cells have been reported. To begin to fill this gap in our knowledge we have recently evaluated the ability of lung tissue cells to synthesize and secrete various complement components in vitro. Using 35S-methionine incorporation and immunoprecipitation techniques we have previously demonstrated the ability human lung type II pneumocytes (A549) and human lung fibroblasts (WI-38), to synthesize and secrete a variety of both early and terminal complement components, as well as several regulatory proteins including Clr, Cls, C4, C3, C5, C6, C7, C8, C9, Factor B, Factor H, Factor I and Cls inactivator. Our present studies demonstrate the capability of silica to regulate complement component production by A549 cells, but not complement component production by WI-38 cells. Specifically, using sensitive ELISAs we demonstrated that a non-toxic dose of silica had the capability to suppress the production of both C3 and C5 by A549 pneumocytes by 40-50 percent, but had no effect on C3 or C5 synthesis by WI-38 fibroblasts. Additionally, using 35S-methionine incorporation and TCA precipitation techniques, we demonstrated that suppression of C3 and C5 production by silica treated A549 pneumocytes was not a result of suppression of total protein synthesis. These studies demonstrate that silica, which has been implicated in pulmonary diseases, has the capability to regulate local complement production by lung tissue cells in vitro. In vivo, this suppression of complement production by the type II pneumocytes could alter the local tissue reservoir of complement components during infection and pulmonary injury, thus resulting in depressed pulmonary host defense.

Cell Line↗

PubMed1995

A new complementation group of mitomycin C-hypersensitive Chinese hamster cell mutants that closely resembles the phenotype of fanconi anemia cells.

Three Mitomycin C (MMC)-hypersensitive mutants (CL-V1B, CL-V5B, and CL-V101B) were isolated from Chinese hamster V79B cells by the replica plating technique. In comparison to the parental cell line, CL-V1B, CL-V5B, and CL-V101B show about a 22-, 32-, and 13-fold increased sensitivity to MMC, respectively (judged by the D10). These mutants are also sensitive to other DNA cross-linking agents, such as 1,2,3,4-diepoxybutane (9-, 19-, and 12-fold, respectively) and cis-diamminedichloroplatinum(II) (17-, 12-, and 6-fold, respectively). CL-V5B and CL-V101B display an exclusive sensitivity to DNA cross-linking agents, whereas CL-V1B also shows an increased sensitivity to monofunctional alkylating agents, such as methyl methanesulfonate (3-fold) and ethyl methanesulfonate (2-fold), and UV254mm (2-fold). Approximately 2-3-fold higher levels of spontaneous chromosomal aberrations are found in these three mutants in comparison to wild-type V79B cells. At a MMC survival level of 80%, CL-V5B demonstrates a 16-fold higher level of MMC-induced chromosomal damage than V79B. Despite phenotypical heterogeneity within this group of mutants, hybrid clones derived after fusion remained MMC sensitive, indicating that these mutants belong to the same complementation group. To determine whether the mutants represent a new complementation group among other Chinese hamster cell mutants that also display hypersensitivity to MMC, CL-V1B cells were fused with mutants representing different complementation groups i.e., irs1, irs3, irs1SF, UV20, UV41, V-H4, and V-C8 cells. In all cases, the derived hybrids regained MMC sensitivity similar to wild-type cells, indicating that the CL-V1B mutant represents a new complementation group. The phenotype of CL-V1B, CL-V5B, and CL-V101B cells closely resembles the phenotype of Fanconi anemia cells, suggesting that these hamster mutants could be defective in a gene that is involved in this disorder.

Alkylating Agents↗

PubMed1997

The development of the complement system after 28 weeks' gestation.

OBJECTIVE: To assess the levels and development of the various complement components in preterm infants, particularly among those born before 34 weeks' gestation. SUBJECTS AND METHODS: We measured the complement system's activities (CH50 and AP50) as well as its various components (C1q,r,s, C2-C9, Factor B, and properdin) in 25 preterm infants [gestational age (GA) 28-33 weeks], 35 preterm infants (GA 34-36 weeks), 50 full-term newborn infants (GA 37-42 weeks), and 49 healthy adults as control subjects. RESULTS AND CONCLUSIONS: The results of these studies are: (i) complement levels and activity were significantly reduced in preterm and full-term neonates when compared with adult levels, with the exception of C7 which was within the normal range in most infants. C8 and C9 were the most markedly reduced at all gestational ages. (ii) Complement levels correlated significantly with gestational age, but not with birth-weight, type of delivery, or gender. (iii) Between 28 and 33 weeks' gestation, there appeared to be almost no development of the complement system.

Adult↗

PubMed2005

cDNA cloning and phylogenetic analysis of the sixth complement component in rainbow trout.

The sixth complement protein (C6) is an essential component of the membrane attack complex (MAC); the end product of the lytic pathway of complement activation. The MAC complex constitutes a supramolecular assembly containing the five precursor proteins C5b, C6, C7, C8, and C9. Once assembled on the target surface it forms transmembrane channels that cause membrane damage and cytolysis of complement-opsonized pathogens. Besides mediating direct pathogen elimination, exposure of cells to sublytic doses of MAC can trigger diverse cellular responses such as, cell activation, induction of apoptosis, cell cycle re-entry and proliferation in various biological settings. The terminal complement components (C6-C9) are structurally related proteins, differing in size and complexity. In order to study their evolution, we report here the cloning and molecular characterization of C6 component in rainbow trout. The deduced amino acid sequence of trout C6 exhibits 55 and 44% identity with zebra fish and human orthologs, respectively. The 'domain' architecture of trout C6 resembles that of mammalian counterparts, and the cysteine backbone is also conserved. Finally, trout C6 gene appears to exist as a single copy in the trout genome, and is expressed in a wide range of trout tissues.

Amino Acid Sequence↗

PubMed1989

Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups.

46 patients in whom meningococcal disease due to serogroups X, Y, Z, W135, or 29E had developed after the age of 10 years were investigated retrospectively for complement deficiency. Complement deficiency was found in half of the patients: properdin deficiency in 9 patients, C3 deficiency syndromes in 5, and homozygous deficiency of a terminal component (C5, C6, C7, or C8) in 9. Meningococcal infections recurred in 5 of the 9 patients with terminal complement component deficiencies but not in the other complement-deficient patients. The findings show that meningococcal disease due to uncommon serogroups is often associated with complement deficiency.

Adolescent↗

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↗

PubMed1994

Recombinant soluble CD59 inhibits reactive haemolysis with complement.

Three soluble forms of membrane attack complex inhibitory factor (MACIF or CD59) were prepared using recombinant baculovirus-infected insect cells. They consisted of 70, 77 and 86 amino acids, starting from the amino terminus of naturally occurring CD59, and were designated recombinant (r) CD59 70, 77 and 86, respectively. All three rCD59 lacked a glycosyl-phosphatidylinositol (GPI) anchor, unlike membrane CD59 which has a GPI anchor at the anchor at the carboxyl terminus (77th amino acid). Their activities in inhibiting complement activation were assayed with C5b-7 intermediate cells and C8 and C9 components. The inhibitory activity of rCD59 70 was as high as that of rCD59 77 and twice that of rCD59 86. In addition, it was one-fourth and one-hundredth lower than the activities of urine and erythrocyte CD59, respectively. However, when assayed in the presence of human serum at a final concentration of 50% (v/v), the activities of both urine and erythrocyte CD59 were greatly decreased to to one-tenth of that of rCD59 70. Purified rCD59 70 molecules were all glycosylated, but rCD59 77 and 86 were mixtures of glycosylated and non-glycosylated molecules. The inhibitory activities of rCD59 77 and 86 were the same for the glycosylated and non-glycosylated forms. These results suggest that the soluble rCD59 provide a means for elucidating the biological roles of CD59.

Amino Acid Sequence↗

PubMed1973

The membrane attack mechanism of complement. Verification of a stable C5-9 complex in free solution.

The membrane attack mechanism of complement, C5 to C9, has previously been postulated to associate on the target cell surface to a stable decamolecular complex with a calculated mol wt of 995,000. A soluble and stable complex consisting of C5, C6, C7, C8, and C9 has now been demonstrated to arise as a consequence of complement activation by the classical or alternate pathway. It has a sedimentation coefficient of 22.5S and a mol wt of 1 million daltons, and it migrates on electrophoresis at pH 8.6 as an alpha-globulin. The stable and soluble C5b-9 complex cannot bind to erythrocytes and has no demonstrable cytolytic activity. However, due to partially unsaturated binding sites for C9, it can bind additional C9 and thus function as an inhibitor of lysis of EAC1-8 by C9. These results support the concept according to which the membrane-bound attack system of complement represents a stable, decamolecular assembly of C5b-9. Unlike its analogue in free solution, the membrane-bound complex is cytolytically active.

Cell-Free System↗

PubMed1990

Synthesis of C3, C5, C6, C7, C8, and C9 by human fibroblasts.

We investigated the ability of human fibroblasts to produce the components of the final common pathway (C3-C9) of complement in vitro by co-culturing an alternative complement activator (agarose beads) with the cells. The test system involved incubation of beads with anti-complement antibodies followed by radioactive-labelled anti-Ig detection antibodies. Subsequently, the beads were examined in a radioimmunoassay. Our results indicate that human fibroblasts produce C3, C5, C6, C7, C8, and C9. A neoepitope selectively expressed on activated C9 was detected, indicating assembly of the terminal complement complex and thus formation of a functional terminal complement pathway by the fibroblasts.

Antibodies, Monoclonal↗

PubMed1992

Analysis of high complement levels in Mus hortulanus and BUB mice.

BUB/BnJ mice were previously identified as having exceptionally potent complement activity, relative to common mouse strains, in the lysis of antibody-coated human tumor cells. We describe herein our investigation into the molecular and genetic basis for this difference between mouse strains, and also our results with wild mice and mouse strains recently derived from the wild, to determine whether low complement levels are characteristic of wild mice. BUB complement was compared with complement from BALB/c and C57BL/6 mice. BUB mice had higher levels of most individual classical pathway components, except for C1, than the other two strains, but the difference was generally only 2-3-fold, so insufficient to fully explain the difference observed with tumor target cells. CH50 titers on antibody-coated sheep erythrocytes also demonstrated only a 2-4-fold difference. However, CH50 titers on antibody-coated human erythrocyte target cells demonstrated a difference similar in magnitude to that seen with human tumor targets. These results suggest that the difference between mouse strains depends partly on the use of human, rather than sheep, target cells. In an assay for alternative complement pathway activity using neuraminidase-treated human erythrocytes as targets, complements of BALB/c and BUB mice were similar in activity, suggesting that the difference between mouse strains is manifested in the early steps of complement activation. Analysis of F1 and backcross mice suggested that the difference in complement level between BUB and BALB/c or C57BL/6 mice is controlled by semi-dominant genes, and cannot be attributed to a single gene. Wild mice and mice recently derived from the wild generally had low complement levels, similar to most laboratory mice. However, three strains of aboriginal mice, including Mus hortulanus (spicilegus) and Mus spretus, had complement levels higher than that of BUB mice, and as high as sera from the rabbit or rat, which are the most potent known complement sources for the lysis of human tumor cells. In comparison with BUB mouse sera, M. hortulanus sera had at least four-fold higher levels of C3, C6, C8 and C9, and some or all of these differences may explain its higher total complement activity. In the lysis of antibody-coated human erythrocytes, M. hortulanus serum was more potent than any other complement source tested, including sera of the guinea pig, rat, rabbit or human. These strains may be useful in investigating the role of complement in various pathological processes, and in investigating the genetic regulation of the complement system.

Animals↗

PubMed1992

Peptides related to the carboxyl terminus of human platelet factor IV with antibacterial activity.

A peptide (C13) corresponding to the last 13 amino acids of the carboxyl terminus of human platelet factor IV was found to be antibacterial. Amino acid substitutions predicted to disrupt either the amphipathic or alpha-helical nature of C13 rendered the peptide inactive. Antibacterial activity was demonstrated in normal human serum on bacteria which had been previously exposed to low levels of cefepime, a beta-lactam antibiotic. Peptide analogues were examined for more potent antibacterial activity in an antibacterial assay that employed normal human serum and low levels of cefepime. A peptide analogue (C18G) with 80-fold more antibacterial activity than C13 was identified. Studies in C8-deficient sera confirmed an essential role of human serum complement for optimal antibacterial activity. Additional studies showed low levels of cefepime, although not essential, enhanced the antibacterial activity of C18G. Animal protection experiments demonstrated that either peptide C18G or an analogue with all D amino acids (C18X) significantly increased the survival of neutropenic mice when coadministered with a low level of cefepime. This work has resulted in the identification of a new group of antibacterial peptides.

Amino Acid Sequence↗

PubMed1987

Molecular mechanisms of cytotoxicity: comparison of complement and killer lymphocytes.

The membrane attack complex of complement is an amphiphilic fusion product of 5 glycoproteins, C5, C6, C7, C8 and C9. The membrane attack complex forms transmembrane channels that vary in size depending on the number of C9 molecules incorporated into the complex. The C5b-8 complex forms small channels and at high multiplicity can kill nucleated cells. At least 12 C9 molecules are required to form tubular poly C9 which evokes the ultrastructural image of the classical membrane lesion produced by complement. The membranes of erythrocytes and other blood cells contain a 70,000 dalton protein that can inhibit channel formation by the membrane attack complex. This protein is species specific and has been called homologous restriction factor. A cytotoxic protein immunochemically related to C9 was isolated from cytotoxic human large granular lymphocytes and from OKT3 activated human peripheral blood mononuclear cells. In the presence of Ca++, isolated C9 related protein (C9RP) formed circular structures that resembled poly C9. C9RP efficiently killed K562 cells, human melanoma cells, Raji cells and human large granular lymphocytes. The results suggest that the channel forming protein of cytotoxic lymphocytes and C9 of complement have a common evolutionary ancestry.

Complement C9↗

PubMed1978

The complement profile in relation to the "reactor" state: a study in the immediate post-partum period.

C56 (activated "reactor") could be generated by adding zymosan to only nineteen out of the fifty serum samples obtained from southern Chinese women 3 to 5 days after a normal spontaneous delivery. As a group, post-partum sera showed a 25% increase in total haemolytic complement, an almost two-fold increase in haemolytic C5, C4 and C8 plus C9 activity, a 50% increase in antigenic C3 and haemolytic C2, C1 and factor B activity, a less than 20% increase in haemolytic C6 and C7 activity, and a 20% decrease in factor D and C1 inhibitor activity. Consequently, their C5:C7 ratios were significantly elevated. This finding supports, in part, the theory that the "reactor" state or ability to generate C56 depends on a relative excess of C56 over C7. However, comparison of the complement profile between sera with and those without "reactor" activity did not reveal any difference, except a greater elevation of C5 in the latter. It appears possible that a grossly excessive level of C5 may, in fact, be unfavourable to the generation of C56.

Complement C5↗