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PubMed1986

Functional C8 associated with human platelets.

Haemolytic assay for C8 revealed its association in functionally active form with washed human platelets. Platelet-bound C8 haemolytic activity was inhibited by F(ab')2 anti-C8 and was undetectable in the platelet suspension obtained from three C8 deficient patients. Incubation of platelets from C8 deficient individuals in normal plasma did not restore C8 haemolytic activity, indicating that platelets do not absorb C8 from plasma in vitro during platelet preparation. Thrombin, a mediator of the platelet release reaction, did not induce the release of C8 from normal platelets. Conversely, lysis of EAC1-7.9 by platelet bound C8 was not accompanied by release of beta-thromboglobulin or serotonin from the platelets. C8 was detected in a homogenate prepared from platelets as well as in the supernatant collected after high speed centrifugation of the homogenate. The association of C8 with platelets as an individual component rather than as part of the C5b-9 membrane-attack complex was supported by the following evidence: platelet bound C8 eluted from a Sephacryl S-200 column at the same volume as C8 from normal human serum; F(ab')2 anti-C8, but not F(ab')2 anti-C5, inhibited platelet C8 activity; the platelet homogenate, which lysed EAC1-7.9, had no effect on EAC43 which are susceptible to the lytic activity of the C5b-9 complex.

Blood Platelets↗
PubMed1991

Evasion of Yersinia enterocolitica serotype 03 from complement-mediated killing.

Using isogenic strains of Y. enterocolitica serotype 03 (isolate 75) differing in LPS side chains (S and R), plasmid content (p+ and p-) or selective failure of YOP1 expression (YOP1-) we observed comparable C9 consumption via the alternative pathway by all strains. Differences became apparent in the bactericidal assays in which the 75S p+ strain was resistant whereas the plasmid-negative S and R strains were killed. Increased but submaximal resistance was observed with the 75R p+ and 75S YOP1- strains indicating that LPS side chains and plasmid-encoded factors other than YOP1 also contribute to serum resistance. Deposition of C9 and terminal complement complex (TCC) formation were greatly reduced on the resistant 75S p+ strain compared to the sensitive 75S p- strain. The 75S YOP1- variant behaved like the 75S p- strain with respect to C9 deposition and TCC formation suggesting that YOP1 prevents terminal C activation. A comparison of TCC deposited on resistant and sensitive Y. enterocolitica revealed no differences with respect to their salt- and protease-resistance and their size. We conclude from our experiments that serum resistance of 75S p+ depends on several surface components YOP1 being the most important. The YOP1 protein clearly interferes with C9 deposition and TCC formation and thereby contributes to serum resistance of plasmid-positive, YOP1 expressing Y. enterocolitica.

Centrifugation, Density Gradient↗
PubMedDate not supplied

The role of complement in the host's defense against Streptococcus pneumoniae.

In recent years there has been a growing realization that the complement systems plays an important role in the host's defense against infection and that it plays an especially critical role in both natural and acquired immunity to Streptococcus pneumoniae. The terminal components of the complement system, C3-C9, are responsible for most protective functions of the complement system. However, in order to subserve their protective functions, C3-C9 must first be activated. In vitro studies have shown that pneumococci are able to activate the terminal components of complement, C3-C9, by at least two different mechanisms, the classical and alternative pathways. Regardless of the pathway of their activation, C3-C9 produce anaphylatoxic, chemotactic, and opsonic activities in serum, each of which has the potential to play an important protective role in pneumococcal infections. Studies with experimental animals and the experience gained from study of complement deficiencies in humans have each fulfilled the promise of the in vitro studies by demonstrating that the complement system plays a biologically significant role in vivo in the host's defense against S. pneumoniae.

Animals↗
PubMed1993

Several vascular complement inhibitors are present on human sperm.

We have previously reported that the complement inhibitor SP-40,40 is present in human seminal plasma. We also speculated that other inhibitors of the vascular complement system may be present within semen for the purpose of providing protection for sperm against complement within the male and/or female genital tract. In this study, we examined human seminal plasma and spermatozoa for the presence of several major complement regulatory proteins. We detected the presence of decay-accelerating factor (DAF) and CD59 and have confirmed the presence of Membrane Cofactor Protein (MCP) and SP-40,40 on human sperm. As an approach to the possible functional significance of these inhibitors on sperm membranes, the presence of two key complement components, C3 and C9, in seminal plasma was used as a criterion for an active complement system. We failed to detect C9 in seminal plasma and showed that its concentration was less than 5% of the level detected in blood plasma. C3 was also undetectable in seminal plasma; as assessed by Western transfer, its level was less than 0.3% of that in blood plasma. The low level or indeed the absence of key components of the complement system in seminal plasma--together with the finding that human sperm possess an extensive array of the vascular complement inhibitors, some of known physiologic significance--strongly suggests that their role on sperm is to protect sperm from complement lysis in the female rather than the male genital tract.

Antigens, CD↗
PubMed1977

Interactions of C-reactive protein and complement with liposomes.

Interactions between C-reactive protein (CRP) and liposomal model membranes containing phosphatidylcholine were investigated. These interactions, in the presence of human serum, resulted in consumption of each of the components of the classical complement pathway (C1-C9) and also resulted in complement-dependent damage and release of trapped glucose from certain types of liposomes. CRP-initiated lysis of liposomes was strongly dependent upon membrane lipid composition. Optimal activity occurred with positively charged liposomes containing galactosylceramide (galactocerebroside); positively charged liposomes lacking galactocerebroside released much less glucose, while negatively charged liposomes, either with or without galactocerebroside, did not release glucose at all. Glucose release was inhibited by free phosphocholine. Lesser, but significant, "background" glucose release independent of the presence of CRP also was observed with positively charged liposomes containing galactocerebroside, and this was associated with marked preferential consumption of the later-acting complement components (C3-C9). C2-deficient human serum failed to support CRP-dependent glucose release, but glucose release was observed upon reconstitution of the serum with C2. Guinea pig complement also did not support CRP-mediated glucose release, but upon addition of human C1q substantial glucose release was observed. We conclude that (i) CRP can sensitize appropriate liposomes for complement-dependent damage via the primary complement pathway starting at the level of C1q; (ii) of those studied, liposomes that are most susceptible to membrane damage contain phosphatidylcholine, have a positive charge, and contain a ceramide glycolipid; and (iii) such liposomes also are sensitive, although to a much lesser degree, to complement-dependent lysis initiated in the absence of CRP and involving consumption of terminal in excess of early acting complement components.

C-Reactive Protein↗
PubMed1986

Interaction of complement with serum-sensitive and serum-resistant strains of Pseudomonas aeruginosa.

The interaction of complement with the following two strains of Pseudomonas aeruginosa was examined: 144M, a mucoid, serum-sensitive strain bearing short lipopolysaccharide O chains, and 144M-SR, a mucoid, serum-resistant strain bearing long lipopolysaccharide O chains isolated by repeated passage of 144M in increasing concentrations of pooled normal human serum (PNHS). While significant killing of 144M occurred in 5 to 40% PNHS, no killing of 144M-SR was observed. Both strains activated complement, especially 144M-SR which consumed 88.7, 96.4, and 100% of the available complement 3 (C3), C5, and C9, respectively, in 10% PNHS during a 60-min incubation at 37 degrees C. Although it activated more C3 than did 144M (54.9% consumption), 144M-SR bound only half as much C3 as 144M. Similarly, although 144M-SR activated more C9 than did 144M (50.0% consumption in 60 min), there was considerably less C9 attached to 144M-SR (2,990 molecules of C9 per bacterium) than to 144M (13,700 molecules per bacterium) after 60 min of incubation. Furthermore, only 162 molecules of the C9 bound to 144M-SR remained bound after treatment with 0.1% trypsin, while 5,692 molecules of the C9 bound to 144M remained bound under similar conditions. These results show that the serum resistance of 144M-SR does not represent a failure to activate complement efficiently, but instead reflects failure of the assembled terminal complement complex C5b-9 to insert stably into the outer membrane of this strain.

Blood Bactericidal Activity↗
PubMed1984

Measurement of the ratio of the eighth and ninth components of human complement on complement-lysed membranes.

The mole ratio of the eighth (C8) and ninth (C9) components of human complement on membranes carrying the cytolytic C5b-9 complex was measured by direct binding assays. Erythrocytes from two different species were used as the membrane system. Antibody-treated sheep erythrocytes carrying a relatively small number of precursive membrane-bound C5b-7 complexes were prepared by exposure to human C8-depleted serum. These complexes were subsequently converted to C5b-8 by addition of saturating amounts of C8. Parallel binding assays using 125I-C8 were used to determine the exact amount bound and thus the number of C5b-8 complexes per cell. These cells were subsequently incubated with excess 125I-C9 and the amount bound relative to C8 on the membrane was measured. Results indicated the C8:C9 ratio remained constant at approximately 1:4 as the number of complexes varied from 40 to 310 per cell. Similar results were obtained regardless of whether C8 and C9 were added sequentially or simultaneously to cells bearing C5b-7. For comparison, experiments were also performed using membranes that contained a high number of complexes. Here, rabbit erythrocytes which carried approximately 25 000 C5b-7 per cell were incubated with limited amounts of C8 to form C5b-8 complexes on the membrane surface, the exact number of which was measured by 125I-C8 binding assays. When erythrocytes prepared in this manner were incubated with excess 125I-C9, the ratio of C8:C9 on the membrane was found to be essentially constant at approximately 1:3 as the number of these complexes varied from 50 to 4000 per cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed2000

Complement component 9 deficiency is not a susceptibility factor for SLE.

Almost all complement component 9 (C9) deficiency in Japan shows Arg95 Stop mutation of C9 gene. Therefore, we studied the prevalence of Arg95Stop mutation of C9 gene among 78 patients with SLE to elucidate the association of SLE and C9 deficiency. The Arg95Stop carrier frequency showed no significant difference between SLE patients and controls. Thus, C9 deficiency is not implicated in SLE susceptibility.

Complement C9↗
PubMed1977

Lytic activity of C5-9 complexes for erythrocytes from the species other than sheep: C9 rather than C8-dependent variation in lytic activity.

With the reactive lysis system, a form of hemolysis mediated solely by the late-acting complement components (C56, C7, C8, and C9), guinea pig C9 (C9gp) was found to be very inefficient in inducing the lysis of guinea pig and mouse erythrocytes bearing human C5-8. By contrast, C9gp could efficiently induce the lysis of sheep and goat erythrocytes bearing human C5-8. By contrast, C9gp could efficiently induce the lysis of sheep and goat erythrocytes bearing human C5-8. Human C9 was efficient in the lysis of erythrocytes from the species mentioned above. Further study showed: 1) the observed inefficiency in the lysis of guinea pig erythrocytes was not due to incompatibility between human C7 or C8 and C9gp; 2) C9gp could efficiently bind to guinea pig erythrocytes bearing human C5-8 but was inactive in the subsequent lytic process. The present finding emphasizes a role for C9 in complement-mediated membrane damage which may not be a simple effector function of C8 action.

Animals↗
PubMed1994

Identity of a peptide domain of human C9 that is bound by the cell-surface complement inhibitor, CD59.

The CD59 antigen is a plasma membrane glycoprotein that serves as an inhibitor of the C5b-9 complex of complement. This inhibitory activity appears related to the capacity of CD59 to bind with high affinity to sites that are nascently exposed in the alpha-chain subunit of human C8, as well as within the C9b domain (amino acid residues 245-538) of human C9, during assembly of the C5b-9 complex on the target membrane (Ninomiya, H., and Sims, P. J. (1992) J. Biol. Chem. 267, 13675-13680). The CD59 binding site in C9 was first investigated by N-terminal sequencing of CD59-binding peptides generated by limited digest of the isolated C9b domain. These experiments revealed a 17-kDa fragment (starting at C9 residue Thr-320) that retained affinity for CD59, suggesting the possibility for localizing the CD59 binding site by mapping with small C9-derived peptides. Peptides spanning the entire C9b sequence were expressed in Escherichia coli and then probed with CD59. CD59 bound specifically to all peptides starting N-terminal to C9 residue 359 with C termini extending beyond residue 411. Little to no CD59 binding was observed for various C9-derived peptides that started C-terminal to residue 359 or that were truncated N-terminal to residue 411. Affinity-purified antibody against C9 residues 320-411 inhibited CD59 binding to C9 by > 50% and completely inhibited its binding to the isolated C9b domain. Little to no specific binding of CD59 was detected for peptides restricted to the putative hinge domain within C9b (residues 245-271). These results indicate that a CD59 binding site is located between residues 320 and 411 of the C9 polypeptide and suggest that the affinity of this site is principally determined by residues 359-411.

Amino Acid Sequence↗