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PubMed1981

Complement levels in cigarette smokers: elevation of serum concentrations of C5, C9, and C1-inhibitor.

Serum levels of 13 individual complement component and control proteins were measured in 25 male cigarette smokers and 25 male non-smokers. A significant elevation of the mean serum levels of C5, C9 and C1-inhibitor was demonstrated for the smokers while levels of C1q, C2, C4, C3, C6, C8, Factor B, properdin, C3b inactivator and beta 1H did not differ significantly between the two groups. Serum level of C9 in individual smokers correlated significantly with both the present amount of consumption and cumulative consumption, while C5 level correlated with present consumption. The complement profile in the cigarette smoker is similar to that observed in certain inflammatory conditions. The elevation of C5, C9 and C1-inhibitor levels may reflect the presence of a low grade inflammatory process in the cigarette smoker.

Adolescent↗
PubMed1992

Mechanism of YadA-mediated serum resistance of Yersinia enterocolitica serotype O3.

Complement activation via the alternative pathway was analyzed with isogenic strains of Yersinia enterocolitica serotype O3 differing in plasmid content (p- or p+ strains) or selective lack of YadA expression (YadA- strain). The p+ strain was serum resistant, even after antibody-enhanced complement activation. Serum sensitivity was observed with the p- and YadA- strains but was more pronounced in the p- strain. The p+ strain deposited less C5b-9(m) complexes on its surface than the p- and YadA- strains. No size difference, however, was detected with solubilized C5b-9(m) complexes obtained from resistant and sensitive strains. At the C3 level, it became evident that surface-bound C3b was degraded faster into iC3b on the p+ strain than on the p- and YadA- strains. Our results demonstrate that YadA inhibits complement activation at the C3 and C9 level. As a result, reduced amounts of C5b-9(m) are generated on the surface of YadA-bearing bacteria. In addition, YadA seems to protect against the lytic action of those C5b-9(m) complexes whose deposition could not be prevented.

Adhesins, Bacterial↗
PubMed2000

Sublytic complement attack increases intracellular sodium in rat skeletal muscle.

BACKGROUND: Although excessive complement activation and deranged sodium homeostasis in skeletal muscle are characteristic in sepsis, their relationship has not been examined. This study was designed to determine if sublytic complement activation can directly mediate changes in myocellular sodium content. MATERIALS AND METHODS: Fast-twitch extensor digitorum longus muscles were freshly isolated from infant rats. Unsensitized muscles were incubated at 30 degrees C for 60 min in the media containing 10% human or rat serum under conditions of no complement activation, activation by zymosan, inactivation by heat, C7 or C9 deficiency, selective inhibition of complement pathway, and inhibition of Na(+)-K(+) ATPase by ouabain. Intracellular sodium ([Na(+)](i)) and potassium ([K(+)](i)) contents of the muscles, myocellular ATP, and LDH release from the muscles were then determined. RESULTS: Normal human serum significantly increased [Na(+)](i) and the [Na(+)](i)/[K(+)](i) ratio in the muscles as well as zymosan-activated serum. Heat inactivation, C7 deficiency, and inhibition of the alternative pathway completely abolished the cationic changes. Average LDH release was identical in all groups and less than 6%. Complement activation did not impair ouabain-sensitive Na(+)-K(+) ATPase activity in the muscles or alter myocellular ATP. Thus, the observed alterations are not likely due to dysfunction of Na(+)-K(+) pump or depletion of myocellular energy. Instead, alterations in [Na(+)](i) were dependent upon the amount of C9 added to C9-deficient serum, which suggests that the alterations are likely dependent on transmembrane pores created by membrane attack complexes (MAC). CONCLUSIONS: Sublytic amounts of MAC formed as a result of complement activation can directly alter [Na(+)](i) in ex vivo skeletal muscle.

Adenosine Triphosphate↗
PubMed1986

Restriction of the alternative pathway of human complement by intact Trypanosoma brucei subsp. gambiense.

We studied the interaction of African trypanosomes with human complement. Bloodstream forms of Trypanosoma brucei subsp. gambiense isolated from mice activated the alternative pathway of complement during a 30-min incubation in vitro. In human serum, all cells remained intact and motile during this period. C3 was detected on the surface by a direct binding assay with a monoclonal antibody which recognizes C3b and iC3b. C3 deposition could also be detected by this radioimmunoassay when parasites were incubated with purified C3. Such C3 binding was enhanced by factor B, factor D, and magnesium. Surface deposition of factor B was demonstrated both by flow immunofluorescence analysis and binding of radiolabeled factor B. C3 binding and factor B binding were inhibitable by EDTA but not by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N' -tetraacetic acid (EGTA). The inhibited binding could be restored by addition of magnesium. No human immunoglobulin G or mouse immunoglobulin was detected on the trypanosome surface. By flow cytometry, neither human C5 nor polymerized C9 was detected on trypanosomes incubated in serum, although this assay was able to detect C5 and C9 on the surface of complement-treated human erythrocytes. Using a radioimmunoassay which measures C5b-9 in serum, we found that there was no generation of SC5b-9 in serum which had been incubated with trypanosomes. We concluded that, although trypanosomes activate the alternative pathway of complement, they are not lysed, because the cascade does not continue beyond the establishment of C3 convertase.

Animals↗
PubMed1998

Complement activation and regulator expression after anoxic injury of human endothelial cells.

Complement activation is involved in the ischemia-reperfusion injury of various organs, but the mechanisms leading to activation of the complement system are incompletely understood. In this study we show that EA.hy 926 human endothelial cells cultured under anoxic conditions (24 or 48 h) become activators of the homologous complement system. Flow cytometric analysis indicated that C1q, C3c, C3d, C4, C5, C9 components of complement are deposited on anoxic but not on normoxic cells after incubation with normal human serum. Cell membrane-associated regulators of complement, membrane cofactor protein (CD46), decay-accelerating factor (CD55) and protectin (CD59) were expressed on EA.hy 926 cells grown under normal oxygen tension. Under anoxic conditions the expression of protectin was clearly decreased, whereas the expression of CD46 and CD55 diminished only slightly. Our results suggest that anoxia can convert human endothelial cells to activators of the complement system. The diminished expression of protectin, CD46 and CD55 can sensitize the cells to complement-mediated damage. Activation of the complement system due to the anoxic injury of human endothelial cells might be an important triggering mechanism in the pathogenesis of ischemia-reperfusion injury of human heart.

Antigens, CD↗
PubMed1997

Difficulties in the ascertainment of C9 deficiency: lessons to be drawn from a compound heterozygote C9-deficient subject.

A group of patients with long-surviving mismatched kidney allografts were investigated for complement function using haemolytic assays in agarose gels. One patient was found to have no alternative pathway activity but a low normal classical pathway. Surprisingly, investigation revealed that the patient's complement was normal for all components except C9, which was functionally absent. The patient was shown to be heterozygous for DNA markers in the C6, C7 and C9 region of chromosome 5 and therefore appears to be a compound heterozygote for two uncharacterized C9 deficiency genes. Serological analysis by ELISA revealed that he has trace concentrations of a non-functional C9 molecule. Western blot analysis was not sufficiently sensitive to permit detection of this molecule. We hypothesize that the patient is heterozygous for a complete deficiency of C9 and for a gene directing hyposynthesis of a defective C9. We also suggest that C9 deficiency may be more common among Caucasians than has been reported.

Complement C8↗
PubMed1986

Assembly of the membrane attack complex of complement on small unilamellar phospholipid vesicles.

Light-scattering intensity was shown to be a reliable, direct, and quantitative technique for monitoring the assembly of the membrane attack complex of complement (proteins C5b-6, C7, C8, and C9) on small unilamellar phosphatidylcholine vesicles. The assembly on vesicles occurred in a simple fashion; complexes of C5b-7 bound noncooperatively to the vesicles, and final assembly of C5b-9 did not induce vesicle aggregation or fragmentation. When C5b-6 and C7 were mixed in the presence of vesicles but at molar protein/vesicle ratios of less than 1, there was quantitative binding of C5b-7 to the vesicles with no concomitant aggregation of C5b-7. If C7 was added at a slower rate, quantitative binding was obtained at molar C5b-7/vesicle ratios of up to 5. The latter observations (a) were consistent with the proposal that C5b-7 aggregation and membrane binding were competitive events and (b) defined conditions under which light-scattering intensity measurements could monitor C5b-9 assembly on vesicles without contribution from the fluid-phase assembly. The C8/C5b-7 ratio in the phospholipid-C5b-8 complex was 0.97 +/- 0.12, and the maximum ratio of C9/C5b-8 in the final complex was 16.2 +/- 2.0. One C9 molecule associated rapidly with each phospholipid-C5b-8, followed by slower incorporation of the remaining C9 molecules. The initial velocity of the slow phase of C9 addition was easily saturated with C9 and gave an activation energy of 37 kcal/mol. This was identical with the value measured for the analogous process in the fluid-phase assembly.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement C7↗
PubMed1984

Distributions and recoveries of complement components during cold ethanol fractionation of human plasma.

The distributions and recoveries of the hemolytic activities and quantities of protein of complement components during cold ethanol fractionation were studied. Most of the components were recovered in Cohn's fraction III, with slight activities in fractions I and IV. The hemolytic activities of C1 and C5 were recovered in high yields in fraction III. The recoveries of activities of late components of complement (C6-C9) in fraction II + III were also high. These results suggest that many complement components can be isolated from Cohn's ethanol fractions.

Cold Temperature↗
PubMed1985

Platelet-associated complement in chronic ITP.

Chronic ITP is due to antibody-induced destruction of platelets by the reticuloendothelial (RE) system. The role of complement in this process is unclear. We measured platelet-associated complement (PAC) components C3, C3bi, C4 and C9 in 16 patients with chronic ITP, in two of these patients prior to and after splenectomy. Competitive solid-phase radioimmunoassays using monoclonal antibody (anti-C3d, anti-C3bi neoantigen or anti-C9) or affinity-purified heterologous antibody (anti-C4) were used. Mean values (+/- SD) of normal subjects (ng/10(7) plts) were: PAC3d 17.6 +/- 6.8; PAC3bi 11.6 +/- 2.3; PAC4 1.6 +/- 0.5; PAC9 9.9 +/- 2.6. Significantly elevated (greater than 2 SD) PAC3, PAC3bi, PAC4 and PAC9 levels occurred in 12/16, 11/14, 10/14 and 5/9 chronic ITP patients. The PAC3, PAC3bi and PAC9 values correlated inversely with the patients' platelet counts (P less than 0.001); PAC4 levels did not. A positive correlation was also noted between PAC3, PAC3bi and PAC9 while PAC4 values showed no correlation. Two patients with preoperative elevation of all four PAC proteins showed normalization of PAC3, PAC3bi and PAC9 values after a splenectomy-induced remission; PAC4 levels remained elevated for up to 5 months after surgery. We conclude that in vivo C activation occurs in most chronic ITP patients with binding of C3 and C9 to the platelet surface. This in vivo C activation may promote more efficient phagocytosis (C3b) and possibly platelet lysis (C5-9) in some ITP patients.

Adult↗
PubMed1976

Increased ion permeability of planar lipid bilayer membranes after treatment with the C5b-9 cytolytic attack mechanism of complement.

The ion permeability of planar lipid bilayers, as measured electrically, was found to increase modestly upon treatment with purified complement complex C5b,6 and complement components C7 and C8. The subsequent addition C9 greatly amplified this change. No permeability changes occurred when components were added individually to the membrane, or when they were used in paired combinations, or when C5b, C7, C8, and C9 were admixed prior to addition. Thus, there is a significant parallel between the permeability changes induced in the model membrane and damage produced in biological membranes by the C5b-9 complement attack sequence. The efficiency of membrane action by C5b-9 was critically dependent on the order in whcih components were added to the membrane. There were also differences in the electrical properties of membranes treated with C5b-8 and C5b-9, though in both cases the enhanced bilayer permeability is best attributed to the formation of trans-membrane channels. Collectively, the data are consistent with the hypothesis that the mechanism of membrane action by complement involves the production of a stable channel across the lipid bilayer, resulting in cell death by colloid-osmotic lysis.

Cell Membrane Permeability↗
PubMed1996

Protection of gingival epithelium against complement-mediated damage by strong expression of the membrane attack complex inhibitor protectin (CD59).

Adult periodontitis (AP) is a chronic inflammatory disease of the tooth-supporting apparatus. Activation products of the inflammation-inducing complement system have been detected in the gingival crevicular fluid at the site of gingival inflammation. In the present study, we examined whether evidence for ongoing complement activation in gingival tissues of patients with AP can be obtained. In light of the potential tissue-damaging effects of the complement system, we also examined how the gingival tissue is protected against the cytolytic activity of complement. Surgical and autopsy samples of AP (n = 18) and healthy (n = 11) gingiva were analyzed for the expression or deposition of the complement regulators protectin (CD59) and vitronectin (S-protein) and complement components C3d and C9 by indirect immunofluorescence microscopy with specific antibodies. In healthy gingiva, protection was strongly expressed on the membranes of epithelial cells and on the vascular endothelia of the underlying connective tissue. In AP, protectin was also strongly expressed by endothelial cells, but in the epithelia the expression was granular and weaker than in the healthy gingiva. Coarse granular deposits of complement components were seen in the subepithelial tissues of 61% (C3d), 39% (C9), and 33% (vitronectin) of AP patients, compared with 9% (one case in 11) in healthy controls. In addition, deposits of C3d, C9, and vitronectin were observed on the basement membranes of both pocket and oral epithelium of healthy and AP gingiva but not at sites of protectin expression. The results suggest an increased turnover of the complement system in the gingival tissues of AP patients. The gingival epithelium and connective tissue endothelia are well-protected against damage by the membrane attack complex of complement (MAC). Protection of the underlying connective tissue is insufficient, however, and may allow for deposition of MAC and autologous tissue damage in AP.

Adult↗
PubMed1987

Enhancement of complement-mediated lysis of dithiothreitol-treated erythrocytes involves increased C9 insertion and polymerization.

Treatment of human erythrocytes with dithiothreitol (DTT) increases the sensitivity of normal cells to complement (C)-mediated lysis. We have investigated the mechanism through which DTT increases cell susceptibility to complement by comparing the interactions of complement proteins with DTT-treated erythrocytes and with normal cells. In addition, we have studied the effect of DTT on the physical state of the erythrocyte membrane. Results indicated that the DTT primarily affects the interactions of the late components of complement with the cell membrane. In particular, the insertion efficiency of C9 and its ability to form tubular poly-C9 are enhanced on DTT-treated cells. Electron spin resonance (ESR) spectroscopic analyses of the treated and untreated membranes showed essentially no correlation between bulk membrane fluidity and the DTT-induced change in lytic susceptibility, suggesting no gross disruption of the membrane lipid structure by DTT. In view of the fact that DTT-treated erythrocytes have been proposed as a possible model for the abnormally complement-sensitive erythrocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) which are deficient in a 75,000 mol. wt membrane protein called decay accelerating factor (DAF), we explored the possibility that DAF might be affected by DTT. Studies with anti-DAF F(ab')2 antibodies indicated that DAF activity is protected from DTT-treatment. These results are reinforced by the observation that DTT-treatment of DAF-deficient Type III PNH-E also led to enhanced lysis of PNH-E, implying that DTT affects membrane structures other than DAF. Thus, we conclude: (1) that DTT increases the lytic susceptibility of human erythrocytes to late components of human complement by modifying membrane structures to facilitate C9 insertion and polymerization, and (2) that DTT-treated erythrocytes are not a suitable model for PNH erythrocytes.

Biopolymers↗
PubMed1998

Complement gene expression by rabbit heart: upregulation by ischemia and reperfusion.

Activation of the complement system has been implicated in the pathogenesis of myocardial ischemia/reperfusion injury. It has always been assumed that liver is the primary source of complement components. In the present study, we used the reverse-transcriptase polymerase chain reaction technique to establish that the mRNAs for complement proteins C3 and C9 are expressed in rabbit heart. Rabbit liver, brain, spleen, and kidney were also shown to express C3 and C9 mRNAs. We used Western blotting to establish that these mRNAs in heart are translated into the corresponding proteins. We further established that dramatic upregulation of the mRNAs occurred in Langendorff-perfused isolated hearts subjected to ischemia and reperfusion. C3 mRNA was always expressed at higher levels than was C9 mRNA, but C9 mRNA showed greater upregulation under stress. Compared with levels in control hearts subjected to 5 minutes of normoxic perfusion, hearts subjected to 0.5 hours of ischemia followed by 1 hour of reperfusion had a 4.72-fold increase in C3 mRNA and a 19.5-fold increase in C9 mRNA. By contrast, C3 mRNA in hearts subjected to 3.5 hours of normoxic perfusion showed no change, and those subjected to 3.5 hours of ischemia showed only a 1.72-fold increase, whereas C9 mRNA levels increased by 5.17-fold after 3.5 hours of normoxic perfusion and 12.5-fold after 3.5 hours of ischemia. The results of this study demonstrate for the first time that heart tissue is capable of expressing genes and proteins of the complement system, although it is not yet known which cell types are responsible. They further demonstrate that ischemia and reperfusion of the heart promotes a rapid upregulation of the mRNAs encoding the complement proteins C3 and C9 and that these abnormal levels considerably exceed those of normal liver. These observations are consistent with the hypothesis that local production of complement proteins may contribute significantly to the degree of ischemic injury to the myocardium and that complement expression is augmented by reperfusion.

Animals↗
PubMed1986

Restriction in the lytic efficiency of complement of different erythrocyte targets: a re-examination of the activities of horse C8 and C9.

Differences in the lytic efficiency of different complement sources have frequently been observed. This effect has been shown to be related to both the species of the target erythrocyte and the species composition of terminal complement components within the 5b-9 membrane attack complex. The majority of studies have indicated that the source of C9 is critical in controlling the range of erythrocyte species that can be lysed efficiently. One exception to this general finding was the report by Lachmann et al., 1973 (Immunology 24, 135-145), using horse serum as a complement source. In that study, horse C8 rather than C9 was implicated as the critical component. In this study, we have re-examined this observation and find that the restricted hemolytic potential of horse complement correlates absolutely with the presence of horse C9. The reason for the differences between our findings and those of the earlier study are discussed.

Animals↗
PubMed1981

Further studies on C9 deficiency.

Further studies were carried out on the C9 deficiency (C9D). Her serum complement activity (CH50) was 15.7 units when assayed in high ionic strength buffer and 8.8 or less than 5.0 units when assayed in low ionic strength buffer containing glucose or sucrose, respectively. It was revealed that this buffer-dependent CH50 variation of C9D serum was due to the effect of the buffer on the spontaneous lysis of EAC1-8. The serum bactericidal activity of C9D was low, but the addition of specific antibody against bacteria increased the activity indicating an important role of antibody in the serum bactericidal activity. Neither C9 inactivator(s) nor antibody against C9 was detected in the serum, indicating that the case had a defect of C9 synthesis. However, the estimation of C9 levels in the sera of her family could not reveal the mode of inheritance of C9D.

Adult↗
PubMed1985

Membrane attack complex of complement in dermatitis herpetiformis.

The assembly of membrane attack complex (MAC) of complement implies activation of complement to the attachment of C9 and the presence of MAC on tissue suggests a possible pathogenic role for complement in disease since MAC is able to damage membranes. We examined normal skin of five patients with dermatitis herpetiformis for the presence of MAC using a monoclonal antibody (poly C9-MA) that recognizes a neoantigen of C9 that is not present on monomeric C9 but is common to both isolated MAC and to polymerized C9. Granular deposits of polymerized C9 were found at the sites of IgA deposition in the dermal papillae of normal skin from all patients. The pathologic importance of this finding is uncertain.

Antibodies, Monoclonal↗