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PubMed1990

Synthesis of complement by alveolar macrophages from patients with sarcoidosis.

Sarcoidosis is a granulomatous disorder of unknown aetiology. Alveolar macrophages (AM) in sarcoidosis release a variety of mediators important to the pathogenesis of the disease. Complement is essential for the inflammatory response and we investigated whether there were any major defects in the potential for sarcoidosis AM to synthesize complement in vitro. AM from 11 patients with active sarcoidosis and three healthy controls were cultured under serum-free conditions. There was a significant binding of polyclonal (anti-C5, -C6, -C7, -C8) and monoclonal anti-complement antibodies (anti-C3c and anti-C9 neoepitope (aE11] to agarose beads incubated with unstimulated AM for 24, 48, or 72 h. A significant and inhibitable production of soluble C3c, C5, C9, and S-protein was found in the harvested medium as detected by enzyme immunoassays. Activated C3 and C9 were also detected based on neoepitope expression. Presence of co-cultured agarose beads reduced the amount of soluble S-protein due to deposition on the agarose. We argue that the C9 neoepitope is an integral part of the terminal complement complex (TCC), both in the fluid and solid phase when bound to the agarose. In the fluid phase, SC5b-9 was generated, whereas the agarose-bound S-protein is assumed not to be associated with TCC on the beads. The results demonstrate for the first time that AM from sarcoidosis patients synthesize the functional alternative and terminal pathway of complement.

Adult↗
PubMed1981

Human seminal plasma inhibition of antibody complement-mediated killing and opsonization of Neisseria gonorrhoeae and other gram-negative organisms.

Seminal plasma diluted 1:5-1:1,000 gave marked inhibition of serum antibody complement-mediated bactericidal and opsonic effects against Neisseria gonorrhoeae and other gram-negative organisms. Serum that was bactericidal at a dilution of 1:5,120 was not bactericidal at a dilution of 1:10 when seminal plasma was added. Bactericidal action of immune human or rabbit sera, or purified immunoglobulin (Ig)G or IgM plus complement for six strains of N. gonorrhoeae, serogroups A, B, C, and Y of Neisseria meningitidis, Escherichia coli and other gram-negative rods was inhibited by seminal plasma. Using C8- or C7-deficient sera as antibody and complement sources, opsonization, phagocytosis, and killing of N. gonorrhoeae and E. coli 014-K7 were inhibited by seminal plasma. Opsonization, phagocytosis, and killing of Staphylococcus aureus 502A was not inhibited. For the gram-negative organisms, the early phase of the opsonization process, probably complement activation, appeared to be inhibited rather than the ingestion or polymorphonuclear leukocyte killing steps; addition of seminal plasma yielded a significant reduction in the percentage of polymorphonuclear cells with associated bacteria. Seminal plasma did not prevent attachment of IgG, IgM, or IgA antibodies to gonococci. It reduced serum hemolytic whole complement activity by 25%. The seminal plasma inhibitor was of low molecular weight and was stable at 56 degrees C for 30 min, but inhibitory activity was lost after heating to 100 degrees C for 10 min. It is likely that the inhibitory factor(s) is a low-molecular weight protease or protease inhibitor. Seminal plasma probably has an important role in inhibition of complement and antibody functions in the genital tract. It may enhance pathogenesis of agents of sexually transmitted diseases.

Antibodies, Bacterial↗
PubMed1993

The role of adhesion molecules in the regulation of antibody responses.

We used the T-cell-dependent antigen, bacteriophage (phage) phi X174, to study antibody synthesis in patients, guinea pigs, and dogs with complement component deficiencies (C2, C4, C3, C7); in patients with adhesion molecule deficiencies (CD11/CD18 or sialylated Lewisx); and in patients with the hyper IgM (HIM) syndrome (absence of functional gp39 expression by activated T cells). Patients and guinea pigs deficient in early complement components, patients deficient in CD11/CD18, and patients lacking functional gp39 on activated T cells responded to repeated phage immunizations with depressed antibody titers, lack of or inadequate amplification, and failure to switch from IgM to IgG, suggesting that defective T-cell-B-cell interaction is the cause of the antibody deficiency observed in these patients.

Animals↗
PubMed1993

[The complement system].

The complement system represents a multitude of activating factors, associated with the cellular membrane and providing for cell lysis. The system is composed of 21 serum proteins and 8 receptors and may be found in cells of various types. The major function of the system consists in its activation which entails a cascade of events terminated by cell lysis. Two complement system activation mechanisms are generally distinguished, one of which is classical and one is alternative. These two mechanisms converge after the activation of the third component (C3) or as a result of interaction between the terminal components (C5, C6, C7, C8 and C9) of the complement cascade. The complement system is linked with the fibrinolytic, blood coagulating and kinin systems.

Complement Activation↗
PubMed1996

Discordant renal histopathologic findings and complement profiles in membranoproliferative glomerulonephritis type III.

Patients with membranoproliferative glomerulonephritis (MPGN) type III and a low serum C3 concentration tend to have evidence for a nephritic factor of the terminal complement pathway (Nft). Complement profiles were studied in three patients with MPGN type III and low serum C3 concentrations. Serum C3 concentrations were 52, 21, and 14 mg/dL (normal range, 83 to 177 mg/dL). Serum Clq, C2, C4, properdin, and C5 concentrations were normal in all patients, whereas two had a slight decrease of C7 or C8. This pattern of complement activation resembles that seen with MPGN type II in which a nephritic factor activates the amplification loop (NFa). We conclude that in patients with MPGN type III the previously reported profile/presence of Nft is not always found, at least in the chronic stage of the disease, despite a low C3 value.

Biopsy↗
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↗
PubMed1991

Metalloproteases of Serratia liquefaciens: degradation of purified human serum proteins.

Two representative strains of Serratia liquefaciens, SL 5 (serotype O5:H1) and SL 11 (serotype O1:H1), produced proteases characterized by molecular weights of 52.5 kilodaltons and isoelectric points of 6.2; both enzymes were inhibited by 50 mM EDTA. As demonstrated with SDS-PAGE electrophoresis, the two metalloproteases attacked the following purified human serum proteins: complement components C3, C4, C5, C6, C7, C8, and C9, transferrin, alpha 1-antitrypsin, alpha 2-macroglobulin, fibronectin, type III fibrinogen, immunoglobulin G (heavy chains), and IgM (heavy chains). However, C1q, IgA, haptoglobin, and C-reactive protein were refractory.

Blood Proteins↗
PubMed1977

C5-dependent enhancement of rosette formation and phagocytosis by human polymorphonuclear leukocytes.

Using purified human complement components, the participation of C5 in phagocytosis was investigated. The addition of C5 to EAC 1423 increased both rosette formation and phagocytosis of the intermediates by human polymorphonuclear leukocytes. The opsonizing activity of C5b was not affected after decay of its hemolytic activity. Both C3- and C5-dependent phagocytosis is abolished either in the presence of chelating agents or by pretreatment of the polymorphonuclear leukocytes with trypsin. The enhancing effect of C5b in phagocytosis can be reduced either by further reaction with C6 and C7 or with anti-C5 F(ab)2 fragments.

Antibodies↗
PubMed1993

Linkage between complement components 6 and 7 and glutamic pyruvate transaminase in the marsupial Monodelphis domestica.

The sixth and seventh components of complement were found to be polymorphic and tightly linked in the laboratory opossum (Monodelphis domestica), as they are in eutherian mammals. In addition, strong evidence for linkage of the C6-C7 haplotype to the gene for glutamic pyruvate transaminase (GPT) was obtained for females but not for males. This result, combined with previous observations, established as a generality that recombination is severely reduced in females of this species by comparison with males. It also establishes synteny of C6-C7 and GPT in a marsupial species, as exists in mice. Because these loci are not syntenic in humans, the results imply that this synteny is ancestral to the separation of marsupials and eutherians and that it was broken relatively recently in the mammalian lineage leading to human beings. The newly described C6 and C7 polymorphisms provide additional power for developing a linkage map for M. domestica and for localizing genes that confer susceptibility to diseases for which this species is used as a model.

Alanine Transaminase↗
PubMed2000

Terminal complement complexes concomitantly stimulate proliferation and rescue of Schwann cells from apoptosis.

The consequences of sublytic terminal complement complex (TCC) assembly on Schwann cell proliferation and apoptosis were examined by using purified complement proteins (C5*-9) or antibody-sensitized Schwann cells in the presence of a serum that was depleted of the seventh component of complement (C7dHS) and reconstituted with purified C7. Stimulation of cultured Schwann cells with antibody plus 10% C7dHS and C7 or C5*-9 induced DNA synthesis over antibody plus 10% C7dHS alone or in Schwann cells in which C5*-9 insertion was inhibited by heat inactivation, respectively. Cell cycle analysis with propidium iodide showed that, at 24 h, viable Schwann cells in defined medium were synchronized in G1/G0 phase. C5*-9 shifted 64% of these cells into S or G2/M phases in a manner similar to beta-neuregulin (beta-NRG), a known Schwann cell mitogen. Furthermore, antibody with 10% C7dHS and C7 or purified C5*-9 induced proliferation of viable Schwann cells. These effects were mediated by signal-transduction pathways involving p44 ERK1 (extracellular-regulated kinase 1), Gi proteins, and protein kinase C. Culturing in defined medium for 24 h resulted in apoptosis of up to 50% of Schwann cells that was prevented by treatment with beta-NRG or TCC. Sublytic C5*-9 significantly inhibited apoptosis 41% by 24 h, as determined by a terminal deoxyuridine triphosphate-biotin nick end labeling assay, and also decreased annexin-V binding at 4 h. Collectively, these data suggest that sublytic TCC, like beta-NRG, is a potent Schwann cell trophic factor that is capable of stimulating mitogenesis and apoptotic rescue. TCC assembly on Schwann cells during inflammatory demyelination of peripheral nerves may promote survival of mature cells to enhance repair and remyelination processes.

Animals↗
PubMed1985

Transmembrane channel-formation by five complement proteins.

Five serum proteins act in concert to form the membrane attack complex (MAC) of complement. The precursor proteins, C5, C6, C7, C8 and C9, are hydrophilic glycoproteins with molecular weights ranging from 70,000 to 180,000. When C5 is cleaved by the serine protease C5 convertase, nascent C5b is produced which forms together with C6 a soluble and stable bimolecular complex (C5b,6). Upon binding of C5b,6 to C7 a trimolecular complex (C5b-7) is formed, which expresses a metastable membrane binding site. Membrane-bound C5b-7 constitutes the receptor for C8 and the tetramolecular C5b-8 complex binds and polymerizes C9. During the assembly process the proteins undergo hydrophilic-amphiphilic transition and the end product consists of C5b-8 (Mr approx. 550,000) and of tubular poly C9 (Mr approx. 1,100,000). The functional channel size varies but its maximal diameter is approximately 10 nm. C9 polymerization appears to involve initial reversible associations of several C9 molecules, which leads to temperature dependent, constrained unfolding. Unfolded C9 monomers then associate laterally with each other and polymerization terminates with closure of the circular structure, which consists of 12-18 C9 monomers. Amino acid composition and sequence indicate that the N-terminal half of the single chain C9 molecule is hydrophilic and the C-terminal half rather hydrophobic. Phospholipid binding and insertion into membranes are functions of the C-terminal portion of the molecule.

Amino Acid Sequence↗
PubMed2000

Human complement protein C8 gamma.

Human C8 gamma is a 22 kDa subunit of complement component C8, which is one of five components (C5b, C6, C7, C8, C9) that interact to form the cytolytic membrane attack complex (MAC) of complement. C8 contains three nonidentical subunits (alpha, beta, gamma) that are products of different genes. These subunits are arranged asymmetrically to form a disulfide-linked C8 alpha-gamma dimer that is noncovalently associated with C8 beta. C8 alpha and C8 beta are homologous to C6, C7 and C9 and together these proteins comprise what is referred to as the 'MAC protein family'. By comparison, C8 gamma is distinct in that it belongs to the lipocalin family of small, secreted proteins which have the common ability to bind small hydrophobic ligands. While specific roles have been identified for C8 alpha and C8 beta in the formation and function of the MAC, a function for C8 gamma and the identity of its ligand are unknown. This review summarizes the current status of C8 gamma structure and function and the progress made from efforts to determine its role in the complement system.

Amino Acid Sequence↗
PubMed1989

Assembly of complement components C5b-8 and C5b-9 on lipid bilayer membranes: visualization by freeze-etch electron microscopy.

We have visualized by freeze-etch electron microscopy the macromolecular complexes of complement, C5b-8 and C5b-9, respectively, assembled on synthetic phospholipid bilayers. These complexes were formed sequentially by using purified human complement components C5b-6 followed by C7, C8, and C9. Complexes of C5b-8 were observed on the external surface (ES) of vesicles as 12-nm particles that tended to form polydisperse aggregates. The aggregates were sometimes of a regular chainlike structure containing varying numbers of paired subunits. Etching of vesicles containing C5b-9 complexes revealed on the ES large rings of approximately 27-nm outer diameter. One or two knobs usually were attached to the perimeter of the rings. Splitting of the membrane resulted in partitioning of the C5b-9 with the outer leaflet. Thus, round holes of approximately 17-nm diameter were present in the protoplasmic face (PF), and raised circular stumps of a matching size were present on the exoplasmic face (EF) of C5b-9 vesicles. C5b-9 complexes were frequently localized in regions of the lowest lipid order. That is, in micrographs of the EF and ES, single C5b-9 complexes were located where the ripples of the P beta' phase bend or reach a dead end, and linear arrays of C5b-9 complexes outlined disclination-like structures in the lattice; the holes in the PF mirrored this distribution. The membrane immediately surrounding C5b-9 rings was often sunk inwardly over an area much larger than that of the ring itself.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1988

Molecular mechanisms of lymphocyte-mediated killing.

Lymphocytes kill tumor cells and other target cells by a contact-dependent mechanism. Killer lymphocytes acquire cytoplasmic granules upon lymphokine stimulation and these granules in turn contain potent cytotoxic mediators, some of which have been characterized recently. These include (i) a pore-forming protein (perforin) of 70 kDa that polymerizes into transmembrane tubules in the presence of calcium and that is structurally related to the terminal components (C5b-6, C7, C8 and C9) of the complement cascade, (ii) a cytokine related to tumor necrosis factor and lymphotoxin that causes DNA fragmentation in target cells, and (iii) a family of serine esterases presently without any known function. The relevance of these mediators in lymphocyte-mediated killing is currently being investigated. The identification and characterization of additional putative mediators of cytotoxicity in the future will undoubtedly provide us with a better understanding of the molecular basis of cell-mediated killing.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1987

Thromboxane B2 synthesis in human platelets induced by the late complement components C5b-9.

Sublytic doses of purified C5b6, C7, C8 and C9 induce the release of thromboxane B2 (TXB2) in human platelets. In the present study, we attempted to analyze the signal by which C5b-9 triggers the prostanoid synthesis in platelets. TXB2 release was accompanied by liberation of Ca++ from intracellular stores. Influx of Ca++ was not observed, indicating that C5b-9 did not form a channel large enough to permit passage of Ca++ ions. Therefore, channel formation is apparently not required for cell stimulation.

Arachidonic Acid↗
PubMed1993

Structure of the human C6 gene.

The terminal components of the complement system (C6-C9) are related proteins, differing in size and complexity. They seem to be typical mosaic proteins, composed of modules which are homologous with parts of other proteins. Individual elements in a mosaic protein are often bounded by introns in the gene, and where they are duplicated within a polypeptide, partial gene duplication within the gene is responsible. It is often found in such genes that the intron/exon boundaries are of the class 1 type. We have examined the boundaries of 17 of the 18 exons of C6 and five of C7. When considered with published data for C9, only one of the protein elements appears to follow the conventional pattern. These data suggest a more complex evolutionary history for the genes of the terminal complement components than had been anticipated and challenge the notions both that discovery of a recognized protein module is of predictive value in relation to gene structure and that these genes evolved from the simple to the complex.

Amino Acid Sequence↗
PubMed1985

Quantification of the terminal complement complex in human plasma by an enzyme-linked immunosorbent assay based on monoclonal antibodies against a neoantigen of the complex.

The fluid-phase terminal complement complex (TCC), consisting of the components C5b, C6, C7, C8, C9, and the S-protein, has recently been detected in normal human plasma by using antibodies against native terminal complement components. Increased amounts of TCC were then found in several patients with in vivo activation of complement. We now describe a sensitive, specific, and reliable enzyme-linked immunosorbent assay for quantification of the TCC, based on monoclonal antibodies against a neoantigen of the complex. The results indicate that the TCC is present in normal human plasma and in increased amounts in patients with complement activation in vivo, thus confirming previously obtained results. The assay is easy to perform and can be used for examination of large numbers of plasma samples.

Antibodies, Monoclonal↗
PubMed1992

Complement profile in primary biliary cirrhosis.

PBC is a chronic progressive liver disease of unknown etiology. Several abnormalities found in PBC support the hypothesis that it may be considered an autoimmune disease. Despite the complex and interesting relationship that exists between autoimmune disorders and the complement system, very few reports on the level of the serum complement component in PBC have been published, and most of these comprised only a few patients or analyzed only a scant number of the complement components. In the present study, sera of 73 PBC patients were analyzed for the levels of 10 complement components. It was found that the levels of most of the serum complement components, including C1q, C2, C3, C5, C7, properdin and factor B were significantly elevated in patients with PBC in comparison to healthy controls. The level of C4 was slightly lower than that of the normal controls (p = 0.019), while the levels of C6 and C8 were within the normal range. The number of PBC patients with serum levels of C4 and C6 < 60% of normal pooled serum was higher than in the respective control groups (6/69 compared with 0/26 and 4/71 compared with 0/27, respectively). However, the difference was not statistically significant. Thus, our study shows alterations in the levels of most complement components in PBC, the reasons for which are discussed.

Autoimmune Diseases↗