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PubMed1981

Human complement in the arachidonic acid transformation pathway in platelets.

Arachidonate-mediated release of 14C serotonin and thromboxane B2 (TXB2) is significantly enhanced in the presence of complement. Only purified complement components C5, C6, C7, C8, and C9 are required for this reactivity. No known activating mechanism of the classical or alternative pathway is required, nor is C3. In the absence of exogenously added complement, platelet membrane-bound complement components play an essential role in modulating arachidonate-mediated serotonin release. Incubation of platelet membranes with arachidonate and C5--C9 led to the production of dimers of the membrane attack complex (C5b--9) on the platelet surface. These macromolecular complexes were eluted from the platelet membrane and were identified physicochemically and morphologically. The possibility arises that C3 in association with C5--C9 is required for mobilization of the arachidonic acid from the phospholipid of the platelet membrane. Once the arachidonic acid is mobilized, C3 is no longer required, C5--C9 being sufficient to modulate this pathway leading to enhanced production of TXB2.

Animals↗
PubMed1994

Genomic structure of the human complement protein C8 gamma: homology to the lipocalin gene family.

Human C8 is one of five complement components (C5b, C6, C7, C8, C9) that interact to form the cytolytic C5b-9 complex on target cells. It contains three subunits (C8 alpha, C8 beta, C8 gamma) which are encoded in separate genes. In relation to other proteins of the complement system, C8 gamma is unusual in that it is not structurally related to any other component nor does it have an obvious function. Based on weak but significant sequence similarity, it is proposed to be a member of the lipocalin family of widely distributed proteins that bind and transport small hydrophobic ligands. In this study, the human C8 gamma gene has been characterized and found to contain seven exons spanning approximately 1.8 kb. S1 nuclease and anchored PCR were used to identify the transcription initiation site. This site is preceded by putative regulatory elements that include two SP1 binding sites, several glucocorticoid response elements, and two SV40 enhancer core consensus sequences. A comparison to genes of other lipocalins reveals a remarkably close correlation in exon number, lengths, and phases. A close correspondence in exon boundaries is also observed and suggests that C8 gamma contains the same discrete structural elements that define the characteristic beta-barrel shape of the lipocalins. These results establish that C8 gamma is indeed ancestrally related to the lipocalin family and strengthens the likelihood that its role in the complement system is to bind an as yet unidentified ligand.

Amino Acid Sequence↗
PubMed1978

Plasma levels of complement components and complement haemolytic activity in protein-energy malnutrition.

The plasma levels of complement haemolytic activity (CH50) of some complement components and of C3d, a C3 breakdown product, were measured in fifty-nine African children with various types of protein-energy malnutrition (PEM) including kwashiorkor, before and during recovery. A significant decrease of CH50, C3, C9 and factor B was observed in PEM without a concomitant decrease of C4 and C5. Increased plasma levels of C3d were also found in PEM patients. Two mechanisms seem to be involved in the impairment of the complement system in PEM: (1) a decreased synthesis of at least C3 and C9 as suggested by a significant correlation between C3 or C9, levels and those of albumin and cholinesterase; (2) an increased catabolism of C3 possibly due to an activation of the alternative complement pathway, as suggested by the increased level of C3d and the decreased level of factor B which are significantly correlated with C3 levels but not with albumin levels. These data support the possible role of a relative complement deficiency upon the decreased resistance to infections observed in malnourished children.

Child, Preschool↗
PubMed1989

Inhibition of the formation of the complement membrane-attack complex by a monoclonal antibody to the complement component C8 alpha subunit.

The effect of nine monoclonal antibodies to complement component C8 on the interaction of C9 with preformed cell-surface C5b-8 complexes and on the functional insertion of C8 into the membrane-attack complex (MAC) was investigated. None of the antibodies prevented C9 insertion into a preformed C5b-8 complex. One antibody (F1) directed to the C8 alpha subunit clearly inhibited formation of a functional MAC. It is proposed that this antibody prevents the C8 alpha subunit unfolding and distorting the bilayer to allow C9 insertion.

Animals↗
PubMed1996

Physical linkage and orientation of the human complement C8 alpha and C8 beta genes on chromosome 1p32.

Human C8 is one of five components (C5b, C6, C7, C8, C9) of the cytolytic C5b-9 complex of complement. It consists of three nonidentical subunits (C8 alpha, C8 beta, C8 gamma), which are encoded in separate genes. Genetic linkage and chromosomal localization studies previously established that C8 alpha and C8 beta are closely linked on chromosome 1p32. In this study, clones with inserts containing genes for both C8 alpha and C8 beta were isolated from a yeast artificial chromosome (YAC) human genomic DNA library and characterized in an effort to determine intergenic distance and orientation. One clone with a approximately 330-kb insert yielded restriction digest patterns for C8 alpha and C8 beta that agreed with those obtained previously from digests of human genomic DNA, thereby confirming the presence of intact copies of both genes. A second clone with a approximately 280-kb insert yielded similar results; however, it was truncated at the 5' end of the C8 alpha gene. Restriction digests of both clones were subjected to PFGE and Southern blot analysis using probes specific for the terminal exons of C8 alpha (exons 1 and 11) and C8 beta (exons 1 and 12). Results indicate the genes are physically linked (< 23 kb) and in a 3'-3' orientation. This is the same orientation as the ancestrally related C6 and C7 genes, which are also physically linked on chromosome 5p13.

Chromosome Mapping↗
PubMed1999

Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease.

In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individuals. In HD striatum, neurons, myelin and astrocytes were strongly stained with antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contrast, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and the internal capsule samples but not in normal brain. RT-PCR analysis and in-situ hybridisation were carried out to determine whether complement was synthesised locally by activated glial cells. By RT-PCR, we found that complement activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compared to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor and C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confirmed that C3 mRNA and C9 mRNA were expressed by reactive microglia in HD internal capsule. We propose that complement produced locally by reactive microglia is activated on the membranes of neurons, contributing to neuronal necrosis but also to proinflammatory activities. Complement opsonins (iC3b) and anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimulation of glial cells and phagocytes bearing specific complement receptors.

Adult↗
PubMed1999

An NcoI polymorphism in the human complement component 7 (C7) gene.

A novel polymorphic site has been found in the 3' untranslated region (UTR) of the human complement component 7 (C7) gene. The polymorphic site at 14-bp down-stream from the TAG stop codon was either C or A (Nco I-digested), with allele frequencies of 0.660 and 0.340. This NcoI polymorphism would be useful to perform a DNA marker haplotype study in patients with deficiencies of the complement genes, such as C6, C7, C9, which are located closely on chromosome 5p13.

Alleles↗
PubMed2005

Effects of endotoxin administration and cerebral hypoxia-ischemia on complement activity and local transcriptional regulation in neonatal rats.

It is not known whether up-regulation of complement components, either circulating or locally synthesized, contributes to an increased susceptibility to neonatal hypoxic-ischemic (HI) cerebral injury. Therefore, we tested the hypothesis that in neonatal rats subjected to a unilateral HI cerebral insult, prior administration of E. coli lipopolysaccharide (LPS) augments (1) complement-mediated serum hemolytic activity, and (2) C3 mRNA and C9 mRNA levels in hepatic and cerebral tissue. Pregnant rats were injected subcutaneously with sterile normal saline (NS) or 500 microg/kg of LPS on gestational days 18 and 19. Following birth, the pups received intraperitoneal injections of NS or 250 microg/kg of LPS on postnatal days 3 and 5. On postnatal day 7, each animal was subjected to ligation of the right common carotid artery followed by 2.5h of hypoxia (8% O(2)). At 3, 6,18, 24 and 48 h after hypoxia, the complement-mediated hemolytic activity of pooled serum was measured. Hepatic and cerebral C3 mRNA and C9 mRNA were quantified by qRT-PCR at 3, 6, and 18 h after HI. Serum hemolytic activity, hepatic C3 mRNA, and hepatic C9 mRNA were up-regulated after cerebral HI. LPS administration potentiated the effect of HI on serum hemolytic activity and increased cerebral C3 mRNA levels. Cerebral C9 mRNA was not detected and was not affected by HI, with or without the prior LPS administration. These observations support the theory that previously reported C9-mediated neurotoxicity following cerebral HI is induced by circulating, rather than locally synthesized C9.

Animals↗
PubMed1980

Membrane attack complex of complement: a structural analysis of its assembly.

This study was conducted to gain insight into the process of assembly of the membrane attack complex (MAC) of complement through structural analysis. Four intermediate complexes and the MAC were examined by electron microscopy and by sucrose density-gradient ultracentrifugation. The C5b-6 complex has a sedimentation rate of 11S, an elongated, slightly curved shape and dimensions of 160 x 60 x 60 A. At protein concentrattions greater than 1 mg/ml, and physiologic ionic strength and pH, the complex forms paracrystals that have the appearance of parallel strands. Equimolar quantities of C5b-6 and C7 mixed in the absence of lipids or detergents give rise to C5b-7 protein micelles which are soluble in aqueous media and have a sedimentation rate of 36S, suggesting a tetrameric composition. Ultrastructurally, C5b-7 protein micelles consist of four half-rings, each measuring 200 x 50 A, which are connected to one another by short stalks extending from the convex side of the half-rings. C5b-7 bound to dioleoyl lecithin (DOL) vesicles has a similar ultrastructural appearance. After extraction with deoxycholate (DOC), C5b-7 has a sedimentation velocity of 36S which further suggests the occurrence of C5b-7 in the form of tetrameric protein micelles. Attachment of C8 to vesicle-bound C5b-7 results in dissociation of the protein micelles. An individual C5b-8 complex appears as a half-ring attached to the DOL-vesicle via a 100-A-long and 30-A-wide stalk. After extraction from the DOL-vesicles with DOC, C5b-8 has a sedimentation velocity of approximately 18S. Binding of C9 to DOL-vesicle bound C5b-8 induces the formation of the typical ultrastructural complement lesions. C5b-9 extracted from the vesicles with DOC has a sedimentation rate of 33S, which is characteristic of the C5b-9 dimer. It is concluded that dimerization is a function of C9. C5b-9 monomers are visualized when a single C5b-9 complex or an odd number of complexes were bound per DOL-vesicle. The C5b-9 monomer has an ultrastructural appearance that is theoretically expected of a half-dimer: a 200- x 50-A half-ring which is attached to the DOL-vesicle by a 100- x 80-A appendage. Extracted with DOC, the C5b-9 monomer has a sedimentation rate of 23S. At a higher multiplicity of MAC per DOL-vesicle, large structural defects in the lipid bilayer are seen which are attributed to direct physical destruction of membranes by the known lipid-binding capacity of the MAC. It is proposed that protein micelle formation at the C5b-7 stage of MAC assembly and dissociation of these micelles upon binding of C8 are events that facilitate dimerization of C5b-9 and thus MAC formation.

Binding Sites↗
PubMed2002

Protection of hDAF-transgenic porcine endothelial cells against activation by human complement: role of the membrane attack complex.

Xenograft rejection in the discordant pig-to-primate model is dependent on binding of natural antibodies to gal-alpha [1-3]-gal epitopes on the porcine endothelial cell (EC). This leads to complement activation and deposition of activation products onto the membrane and results in perturbation of EC function and thrombus formation. Here we investigated the ability of human complement activation products to directly induce activation of porcine EC, with subsequent upregulation of adhesion and pro-coagulant molecules. Porcine aortic EC were isolated from wild-type and hDAF-transgenic pigs and incubated with human serum, either in the presence or absence of the soluble complement inhibitor TP10 (sCR1). Recombinant C5a, C1q-IgG immune complexes, C6-deficient human serum and serum containing anti-C9 Ab were used to identify EC activating complement products. Heat-inactivated human serum was used as a negative control. Cells were stained with antibodies against human C3, the MAC or with antibodies cross-reactive for porcine E-Selectin, VCAM-1 or Tissue Factor, and analyzed by flow cytometry. We found upregulation of E-Selectin and Tissue Factor on wild-type EC after incubation with human serum. This effect coincided with the deposition of C3 and MAC on the membrane of these cells. The addition of TP10 inhibited EC activation by up to 95%. In contrast, greatly reduced C3 and MAC deposition was detected on hDAF transgenic cells, and no complement-mediated EC activation was seen. Experiments with C6-deficient serum and incubation with anti-C9 Ab indicate a major role of the MAC in serum-mediated EC activation, whereas neither C5a nor C1q-IgG caused activation of EC. These data provide further explanation of the protective role of human DAF in the pig-to-primate xenotransplantation model.

Animals↗
PubMed2004

Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.

BACKGROUND: Mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed cryoglobulinemia with renal disease closely resembling human cryoglobulin-associated membranoproliferative glomerulonephritis (MPGN), including glomerular deposits of immunoglobulins and complement. We assessed the effect of complement inhibition through overexpression of Crry (complement receptor-1 related gene/protein Y), which blocks the classic and alternative pathway of complement activation through inhibition of the C3 convertase, in cryoglobulinemia-associated immune complex glomerulonephritis. METHODS: TSLP transgenic mice were crossbred with animals overexpressing Crry. Mice were sacrificed after 50 days (females) or 120 days (males), and kidneys, blood, and urine were collected from seven mice of each experimental group (wild type, Crry transgenic, TSLP transgenic, and Crry/TSLP doubly transgenic). RESULTS: TSLP/Crry doubly transgenic animals demonstrated expected serum levels of Crry. Renal involvement, both in TSLP transgenic and TSLP/Crry doubly transgenic animals, was characterized by glomerular matrix expansion, macrophage influx, activation of mesangial cells, and deposition of immunoglobulins and complement. Overexpression of Crry did not result in significant improvement of renal pathology or laboratory findings. Expression of recombinant soluble Crry was confirmed by enzyme-linked immunosorbent assay (ELISA) in Crry transgenic animals. However, formation of the membrane attack complex C5b-9 as a marker of terminal active complement components and represented by glomerular C9 staining could not be inhibited in Crry transgenic TSLP mice. CONCLUSION: These results indicate that overexpression of Crry was not sufficient to prevent renal injury in TSLP transgenic mice. We suggest that the inhibitory capacity of Crry may be overwhelmed by chronic complement activation. Further studies need to address the role of complement in cryoglobulinemic glomerulonephritis before therapeutic complement inhibition can be attempted.

Animals↗
PubMed1984

Relation of clinical activity of rheumatoid arthritis to immune complexes, complement components and anti-immunoglobulins.

Circulating immune complexes by fluid phase Clq binding assay, complement components and anti-immunoglobulin levels were studied in sera of 35 patients with rheumatoid arthritis (RA). In 23 of the 35 sera (65.7%), circulating immune complexes were positive, and the mean +/- SD of Clq binding activity (ClqBA), 44.5 +/- 19.4%, was significantly high compared to that of healthy persons, 17.4 +/- 8.2%. Antigenic determination of complement components revealed that Clq, C3, C5, C9, factor B and Cl esterase inhibitor (ClINH) were significantly high in sera of RA, but C4 and properdin were not. The disease activity correlated with ClqBA, IgG- and IgM-anti-immunoglobulins, C9 and serum IgG. On the other hand, ClqBA correlated with both IgG- and IgM-anti-immunoglobulin levels but not with complement components.

Adolescent↗
PubMed1988

Complement depletion and persistent hemodynamic-hematologic responses in protamine-heparin reactions.

Hypotension, bradycardia, pulmonary artery hypertension, neutropenia, and thrombocytopenia have been suspected to be due to complement activation following protamine reversal of heparin. This investigation examined these phenomena in complement-depleted animals. Eight dogs received intraperitoneal naja n. naja cobra venom factor (CVF), 20 U/kg, 48 and 24 hr prior to anticoagulation with sodium heparin, 150 IU/kg, and reversal 30 min later with protamine sulfate, 1.5 mg/kg. Decomplementation was confirmed in all dogs. Systemic blood pressure (BP), pulse (HR), pulmonary artery systolic and diastolic pressures, (PAS, PAD), cardiac output (CO), platelet count (PTC), and white blood count (WBC) with differential were monitored. The maximal mean changes for the entire group were BP, -43 mm Hg; HR, -16; PAS, +6 mm Hg; PAD, +3 mm Hg; CO, -27%; PTC, -49%; and WBC, -48%. These hemodynamic and hematologic responses, occurring in the face of CVF-induced decomplementation, support the conclusion that complement components C3 and C5-C9 are not influential factors contributing to these protamine-heparin-induced events.

Animals↗
PubMed1991

The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes.

We have studied the complement-activating properties of liposomes. We show that surface charge is a key determinant of complement-activating liposomes. The nature of the charge, whether negative or positive, appears to dictate which pathway of the complement system is activated. Phosphatidylcholine:cholesterol (PC:CHOL, 55:45 mol/mol) liposomes were made to exhibit a positive or negative surface charge by the addition of cationic or anionic lipids, respectively. Normal human or guinea pig serum was incubated with liposomes, followed by determining the residual hemolytic activity of the serum as a measure of complement activation. Negatively charged liposomes containing phosphatidyl-glycerol, phosphatidic acid, cardiolipin, phosphatidylinositol, or phosphatidylserine activated complement in a Ca(2+)-dependent manner suggesting activation occurred via the classical pathway. Positively charged liposomes containing stearylamine or 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane activated complement via the alternative pathway. Neutral liposomes, PC:CHOL (55:45) and PC:CHOL:dipalmitoylphosphatidylethanolamine (35:45:20), failed to activate complement as measured by the hemolytic assays. We show that unsaturated liposomes are more potent complement activators than saturated liposomes and that 45 mol% cholesterol promotes complement protein-liposome interactions. Immunoblot analysis of phosphatidylglycerol-containing liposomes showed that C3b and C9 were associated with these liposomes. Thus, the complement consumption measured in the hemolytic assays represents active cleavage of the complement components and not passive adsorption to the liposome surface. These studies suggest that membranes composed of net charged phospholipids can activate the complement system. This observation underlines the importance in biologic membranes of complement regulatory proteins that protect normal cells from complement attack.

Animals↗
PubMed1982

Immunofluorescence studies on complement components in lichen amyloidosus.

Immunofluorescence studies were carried out in 7 cases of lichen amyloidosus, chiefly to detect deposition of complement components in the cutaneous lesions. Examination of skin biopsy specimens revealed deposition of Clq, C3, C9 and IgM in all the patients studied. Complement and immunoglobulin levels by assays of simultaneously obtained serum samples were found to be almost within the normal limits.

Adult↗
PubMed1975

Phylogeny of complement components in non-human primates.

The antigenic properties and functional activities of complement components were analyzed in primates to determine their relative evolutionary development. The sera of eight different sub-human primate species were examined by double diffusion in agar and compared to a pool of human serum with rabbit and goat antisera to human complement components Clq, Cls, C4, C2 C3, C5, C6, C8, C9, properdin, factor B (B), and C1 inhibitor. There are no apparent antigenic differences in complement proteins between man and the apes except for C1q. Old world monkeys are antigenically deficient in Clq,C1s, C9, and variably deficient in C4, C3, and C8. New World monkeys are antigenically deficient in all components (measured) except C5, C6, and properdin factor B. Prosimians are antigenically deficient in all components. Functional analyses of complement components showed similar levels in man and primates, except in prosimians. There is a dissociation between hemolytic assays and antigenic analyses, suggesting that functional sites may be separate from antigenic sites.

Absorption↗
PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗