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PubMed1991

Formation of ion-conducting channels by the membrane attack complex proteins of complement.

The effects of sequential additions of purified human complement proteins C5b-6, C7, C8, and C9 to assemble the C5b-9 membrane attack complex (MAC) of complement on electrical properties of planar lipid bilayers have been analyzed. The high resistance state of such membranes was impaired after assembly of large numbers of C5b-8 complexes as indicated by the appearance of rapidly fluctuating membrane currents. The C5b-8 induced conductance was voltage dependent and rectifying at higher voltages. Addition of C9 to membranes with very few C5b-8 complexes caused appearance of few discrete single channels of low conductance (5-25 pS) but after some time very large (greater than 0.5 nS) jumps in conductance could be monitored. This high macroscopic conductance state was dominated by 125-pS channels having a lifetime of approximately 1 s. The high conductance state was not stable and declined again after a period of 1-3 h. Incorporation of MAC extracted from complement-lysed erythrocytes into liposomes and subsequent transformation of such complexes into planar bilayers via an intermediate monolayer state resulted in channels with characteristics similar to the ones produced by sequential assembly of C5b-9. Comparison of the high-conductance C5b-9 channel characteristics (lifetime, ion preference, ionic-strength dependence) with those produced by poly(C9) (the circular or tubular aggregation product of C9) as published by Young, J.D.-E., Z.A. Cohn, and E.R. Podack. (1986. Science [Wash. DC]. 233:184-190.) indicates that the two are significantly different.

Animals↗
PubMed1977

C567-initiated cytolysis of lymphoid cells: description of the phenomenon and studies on its control by C567 inhibitors.

Cells of the Raji human lymphoblastoid line, when pretreated with the metabolic inhibitor puromycin were found to be susceptible to killing by the isolated proteins of the complement attack mechanism (C5-9). Incubation of 51Cr-labeled lymphoblastoid cells with purified C56 and C7 resulted in the formation of a lymphoblast-C567 (LC567) intermediate, and the addition of purified human C8 and C9 resulted in release of 51Cr from these cells. Serum C567 inhibitors (C567-INH), purified human lipoproteins, and dextran sulfate, each previously shown to inhibit the attachment of the C567 trimolecular complex to erythrocytes, also inhibited the formation of LC567, and as a consequence, C56-initiated cytotoxicity; the polycation protamine sulfate counteracted the inhibitory effect of dextran sulfate. Thus, the potential for damage of bystander nucleated cells exists when C56 is generated in solution, and is influenced by agents known to modulate the hemolytic activity of C567. It is suggested that these mechanisms may be involved in the control of the function as well as the viability of various nucleated cells.

Cell Line↗
PubMed1984

Genetic polymorphism of the seventh component of complement in a Japanese population.

Genetic polymorphism of C7 in a Japanese population has been described, using polyacrylamide gel isoelectric focusing electrophoresis followed by an electrophoretic blotting technique. Phenotypes of C7 were classified into six common patterns, and observed phenotypes were produced by autosomal codominant at a single locus with three alleles. Three common alleles, designated C7*B, C7*M and C7*A, were found, and gene frequencies calculated from 494 individuals showed C7*B = 0.858, C7*M = 0.096 and C7*A = 0.046, respectively. It is noteworthy that both C7*M and C7*A have polymorphic frequencies in the Japanese population. The distribution of phenotypes fitted the Hardy-Weinberg equilibrium. Results indicate that the electrophoretic blotting technique, which has high specificity and sensitivity, is applicable in the study of heterogeneity of protein antigens.

Adult↗
PubMed1983

Complement components in 100 newborns and their mothers determined by electroimmunoassay.

Samples of blood were obtained from 100 healthy full-term women in labour and, after delivery, from the umbilical cord of their infants. By electroimmunoassay, complement components were quantitated in serum (C1q, C1r, C1s, C1 IA, C2, P, D. I, H, C6 and C7) or in EDTA-plasma (C4, C3, B, C5. and C). The concentrations of C7 in cord serum was twice that found by others using a functional assay. Concentrations of C1r, I and C6 in the cord sample were 50-60 per cent of those in healthy blood donors used as reference, and that of D was about 130 per cent. The cord serum and plasma concentrations of the remaining components agreed with previously reported values. The maternal levels of C2, C4, C3, B, H, C5 were 40-60 per cent higher than those of the reference.

Complement C4↗
PubMedDate not supplied

Evidence suggesting the occurrence of C3-independent intravascular immune hemolysis. Reactive hemolysis in vivo.

The authors present circumstantial evidence for the involvement of reactive hemolysis, i.e., C3-independent binding of the cytolytic C5b-9 complement complex to bystander red cells (RBC), in a case of intravascular immune hemolysis. Fresh serum obtained from a 6-year-old patient during the hemolytic episode, but not obtained thereafter, induced C5b-9-dependent hemolysis of human RBCs but the indirect C3 antiglobulin test remained negative. Particles (presumably RBC ghosts) isolated from the patient's plasma anticoagulated with EDTA at the peak of hemolysis were coated with C5b-9 complexes, whereas the direct antiglobulin test was strongly positive for IgA, only weakly positive for IgG, and negative for C3. Moreover, neither the autoantibodies isolated by elution (IgG plus IgA), nor free serum autoantibodies (IgA alone) activated complement in vitro. Additionally, serum samples collected later during the 12-month period of observation contained normal levels of C3, C4, C8, and C9, but markedly reduced levels of C7. These serums all produced strong reactive lysis in agarose plates, but not in test tubes. These results appear compatible with the working hypothesis that the intravascular hemolytic episode in this patient might have arisen through a local initiation of complement activation with subsequent C3-independent binding of C5b-9 to and hemolysis of bystander RBCs.

Anemia, Hemolytic, Autoimmune↗
PubMed1993

Meningococcal disease in patients with late complement component deficiency: studies in the U.S.S.R.

The purpose of this study was to examine the occurrence of late complement component deficiency (LCCD) states in the USSR. Thirty deficient individuals were detected: 27 with C8 beta and 3 with C7 deficiency. Among individuals with a first episode of meningococcal infection, about 1% had LCCD, whereas among patients with recurrent bacterial meningitis the prevalence of LCCD rose to approximately 50%. This corresponds to a prevalence for LCCD of approximately 12 per 100,000 in the general population. The individuals with LCCD identified in this study experienced about 77 episodes of meningococcal disease and acute bacterial meningitis. Mathematical analysis of the morbidity from meningococcal disease in individuals with LCCD demonstrated that the probability of disease did not change with the age of the patient and was not affected by prior episodes of infection. This finding suggest that in contrast to the situation in the general population, prior infection fails to protect the deficient individual from recurrent disease. In comparison to complement-sufficient persons, the course of disease in individuals with LCCD is less severe, as shown by a reduction in the number of episodes of endotoxic shock and mortality as well as their more rapid recovery. These findings suggest that exuberant complement activation and concomitant formation of membrane attack complexes during meningococcal infection in complement-sufficient patients plays an important role in the activation and injury of peripheral blood cells and endothelial cells during endotoxic shock.

Adolescent↗
PubMed1975

Cyanate as an inactivator of complement proteins.

Sodium cyanate added to normal human serum or serum from patients with sickle-cell disease resulted in the functional inactivation of C3, C5, C6, C7, and the C3b inactivator, but not C8 and C9. Final concentrations as low as 0.5 mM in serum caused inactivation of 12 to 64% of the C3 after 8 hr at 37 degrees C. The activity of the inactivated C3, C5, and C3b inactivator was not restored by dialysis. Most of the functional activity of C3 in cyanate-treated sera was destroyed by very small quantities of 14C-labeled cyanate that was bound to the protein. C3 inactivation by cyanate occurred in heated sera (50 degrees C, 30 min) and sera treated with EDTA, probably indicating that one mechanism for inactivation was by a direct carbamylation reaction. Both C3 and C5 showed two anodal-migrating forms in two dimensional antigen-antibody crossed electrophoresis in some sera treated with low concentrations of cyanate. Measurements of circular dichroism of highly purified carbamylated C3 showed no detectable changes in structure even though most of the functional activity was destroyed. Purified, inactive C3 that was carbamylated with 14C-labeled cyanate was capable of binding to EAC142, but the resulting EAC1423 was weakly positive for immune adherence and negative for agglutination with anti-C3 antiserum. Unlabeled, cell-bound C3b on EAC142 was not susceptible to cyanate action as shown by no loss in immune adherence and positive agglutination with anti-C3 antiserum. The C3b inactivator was more susceptible to cyanate than C3 in a short time period, whereas both were inactivated after 8 hr. Since cyanate is currently being evaluated as a treatment for sickle-cell disease, the inactivation of C3 by the drug is an important consideration for such patients who are already deficient in C3 dependent heat-labile opsonins that aid in host defense.

Anemia, Sickle Cell↗
PubMed1976

Activation of therminal components of human complement by a trypsin-activated complex of human factor B and cobra venom factor.

Cleavage of C3 by CVF-B was demonstrated by hemolytic, immunoelectrophoretic and immune adherence reactions. No cleavage of C5 was detected by immunoelectrophoresis, but C5 hemolytic activity, assayed with EAC1423, decreased although less than C3 hemolytic activity. The co-existence of C3 with limiting amounts of C5 did not reduce the final degree of hemolysis of guinea pig erythrocytes (GPE) induced by late-acting components C6 through C9 and CVF-B. Thus, a CVF-B hemolytic system composed of GPE, C5 through C9 and CVF-B provided a method for titration of terminal components of human complement. CVF-B was able to generate hemolytically active sites of C567 on GPE by activation of C5, C6 and C7. The complex C567 in the fluid-phase decayed within 1 min but C567 on GPE was quite stable. Originally insensitive sheep erythrocytes became sensitive to the CVF-B hemolytic system if C3b sites were present, suggesting that cell-bound C3b played a role in orienting the positions of C567 to be fixed. CVF-B could be recovered quantitatively from the supernatant of the reaction mixture in which the hemolytically active intermediate GPEC-5678 had been formed through the interaction between C5 to C8 and CVF-B.

Animals↗
PubMed1984

Phenotypic genetics of complement components.

Both charge and size-dependent electrophoretic techniques have been used to investigate genetic polymorphisms of complement proteins. Of the seventeen complement proteins, ten have been shown to have genetic variants and only one (C9) has been extensively investigated without revealing variants. These investigations give information on the numbers of cistrons and their linkage relations. They demonstrate or confirm the linkage of C2, Factor B and C4 to the MHC. In the cases of both human and mouse C4, it has been shown that the loci are (usually) duplicated. C4 in humans is extremely polymorphic and exhibits a number of strong allelically associated haplotypes. Some of these have only one expressed C4 gene and are associated with disease susceptibility. C8 has at least two cistrons coding for associating subunits. C6 and C7 are linked in several species and sometimes C7 is duplicated. This gene pair is discussed in relation to natural selection and gene conversion.

Animals↗
PubMed1984

Freeze-thaw activation of the complement attack phase: II. Comparison of convertase generated C--56 with C--56 generated by freezing and thawing.

The activation of the C-attack phase does not necessarily involve the components of the C5 convertases. C--56 hemolytic activity was generated from the same source of C7 depleted serum by the alternative pathway convertase or by freezing and thawing resp. In contrast to activation by the convertase, biological activities of C5a (chemotaxis, serotonin release) were not detected following activation by freezing. The yields of C--56 hemolytic activities were similar and the properties of the activated products were identical. No difference was found in the molecular weight, in the hydrophobicity or with respect to charge. The two activities were in the absence of C7 stable at 37 degrees C and decayed rapidly in the presence of C7. It is proposed that a conformational change in the tertiary structure of the molecule(s) is the critical event in the formation of an active C--56 complex. In this light the cleavage of C5a from the native molecule by the convertase appears as a side reaction, not by itself essential for activation.

Complement Activating Enzymes↗
PubMed1988

Studies on serum resistance in Escherichia coli.

Serum-sensitive mutants and their serum-resistant smooth parental E. coli strains (Wf8, Wf26, and WF 52) have been investigated in respect to their binding of different complement components. These pairs consisting of a wild-type and its mutants represent a better model for the investigation of the mechanism of serum resistance than the comparison of unrelated strains. Both strains of a pair bind equivalent amounts of C3. In binding assays using radiolabeled terminal components C6, C7, C8, and C9, the serum-sensitive strains do bind more late acting components than their resistant parental strains. An active membrane attack complex stably bound to the cell surface was found on the mutants, whereas with wild-type bacteria a complex could be isolated from the supernatant which is composed of the late acting complement components and S-protein. This complex is released from the surface of the wild-type bacteria without participation of C9.

Blood Bactericidal Activity↗
PubMed1979

Quantitation of the membrane attack complex of complement in an air-driven ultracentrifuge.

A sensitive assay of complement (C) activation via either the classical or alternative pathway was developed by evaluating assembly of the terminal complexes (C5b-9)2 or SC5b-9. Activation of serum containing [125I]C7 resulted in the formation of a stable, radiolabeled complex which was separable from its precursors by sedimentation in an air-driven ultracentrifuge. The radioactivity in the sediment was directly proportional to the amount of complex formed and assembly of the complex could be detected after C activation by aggregated IgG in concentrations as low as 10 micrograms/ml. Mild detergents such as Triton X-100 could be included in the reaction mixture, because they affected neither the assembly nor the integrity of the complexes. The assay, which detects both assembly of the membrane attack complex (MAC or (C5b-9)2) on target membranes and formation of SC5b-9 in fluid phase, measures the potential of certain substances to trigger the cytolytic phase of C regardless of whether the classical or alternative pathway was activated. However, by using serum depleted of either factor B or C1q, activation of either pathway can be assessed individually.

Cell Membrane↗
PubMed1993

Antibody response to meningococcal polysaccharides A and C in patients with complement defects.

Patients with defects of terminal complement components are particularly exposed to the risk of developing neisserial infections and seem to respond poorly to meningococcal capsular polysaccharide (PS) C via natural immunization. The sole meningococcal PSC is, on the other hand, an excellent immunogen in normal people. Considering the great importance of vaccine prophylaxis for the prevention of meningococcal infections in patients with complement defects, it is crucial to study the antibody response to the sole meningococcal PS in these patients. We therefore analysed the levels of anti-PSA and PSC antibodies in the members of four families including patients with homozygous and heterozygous defects of C7, C8 or factor H, before and after vaccination with the sole PSA + C. Surprisingly, we found the highest levels of antibodies before vaccination in homozygous subjects, followed by heterozygous and normal controls, whereas, after vaccination, homozygous subjects showed the lowest increase of specific antibodies, indicating their relative incapability to respond to sole meningococcal PS. In conclusion, this study demonstrates (1) the capacity to respond to meningococcal PS via natural immunization by patients with total complement defects, and (2) the low responsiveness to meningococcal PS via vaccine immunization by the same patients. We propose that vaccination should be given to patients lacking specific antibodies and their serological response should be assessed. In addition this study confirms previous observations on a likely lower immunogenic power of meningococcal serogroup C via natural immunization compared with the better immunogenicity of the sole PSC.

Adolescent↗
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↗
PubMed1983

Absence of the seventh component of complement in a patient with chronic meningococcemia presenting as vasculitis.

A previously healthy 40-year-old man presenting with fever, arthritis, and cutaneous vasculitis was found to have chronic meningococcemia. Evaluation of his complement system showed an absence of functional and antigenic C7, compatible with a complete deficiency of the seventh component of complement. Study of the patient's family spanning four generations showed heterozygous deficiency of C7 in five members. Chronic neisserial infection can be associated with C7 deficiency and must be distinguished from other causes of cutaneous vasculitis.

Adult↗
PubMed1982

Studies on the mechanism of bacterial resistance to complement-mediated killing. I. Terminal complement components are deposited and released from Salmonella minnesota S218 without causing bacterial death.

The mechanism of resistance of gram-negative bacteria to killing by complement was investigated. Complement consumption and uptake of purified, radiolabeled complement components on bacteria was studied using a serum- sensitive and a serum-resistant strain of Salmonella minnesota. Twice as many molecules of (125)I C3 were bound per colony-forming unit (CFU) of the smooth, serum-resistant S. minnesota S218 as were bound per CFU of the rough, serum-sensitive S. minnesota Re595 in 10 percent pooled normal human serum (PNHS), although 75-80 percent of C3 was consumed by both organisms. Hemolytic titrations documented total consumption of C9 by 5 min and more than 95 percent consumption of C5 and C7 by 15 min in the reaction with S218 with 10 percent PNHS. In contrast, negligible C5 depletion, 10 percent C7 consumption, and only a 26 percent decrease in C9 titer occurred with the serum-sensitive Re595. Binding of (125)I C5, (125)I C7, and (125)I C9 to S218 and Re595 was measured in 10 percent PNHS. A total of 6,600 molecules C5/CFU, 5,200 molecules C7/CFU, and 3,100 molecules C9/CFU bound to S218 after 5-10 min of incubation at 37 degrees C, but 50-70 percent of the C5, C7, and C9 bound to S218 was released from the organism during incubation at 37 degrees C for 60 min. Binding of 2,000 molecules C5/CFU, 1,900 molecules C7/CFU, and 9,000 molecules C9/CFU to Re595 was achieved by 20 min and was stable. The ratio of bound C9 molecules to bound C7 molecules, measured using (131)I C9 and (125)I C7, was constant for both organisms after 15 min and was 4.3:1 on Re595 and 0.65:1 on S218 in 10 percent PNHS. With addition of increasing amounts of purified, unlabeled (29 to 10 percent PNHS, there was no change in the C9:C7 ratio on Re595. However, with S218 there was a linear increase of the C9:C7 ratio, which approached the ratio on Re595. There was no (14)C release from S218 incubated in PNHS, nor was there evidence by electron microscopy of outer membrane damage to S218. Therefore, S. minnesota S218 is resistant to killing by PNHS, despite the fact that the organism consumes terminal complement components efficiently and that terminal components are deposited on the surface in significant amounts. The C5b-9 complex is released from the surface of S218 without causing lethal outer membrane damage.

Adsorption↗
PubMed1990

Functional properties of the asialo-fifth component of human complement.

Removal of exposed, terminal sialic acid (SA) from carbohydrate chains N-glycosidically linked to asparagine residues of highly pure human C5 with bacterial sialidase increased C-mediated hemolysis of antibody-sensitized sheep E maximally 2.77-fold. Sialidase-treated C5 used as a reagent for the titration of C6, C7, C8, and C9 resulted in increased titers of all these components compared to buffer-treated C5. As determined by a fluorometric method, ca. 65% of the SA was enzymically hydrolyzed under optimal conditions. Endoglycosidase F incubated with C5 followed by monosaccharide analyses by anion exchange chromatography with pulsed amperometric detection revealed both high mannose and complex (terminate in SA) oligosaccharides were hydrolyzed; no effect was found on the functional activity of C5. Approximately 4% of the complex oligosaccharides were hydrolyzed from C5. Comparison of sialidase- and buffer-treated C5 decay rates from EAC1gp(4b,oxy2a,3b)hu resulted in two linear components of the decay curve with sialidase-treated C5, but one linear component with buffer-treated C5. Of the sialidase-treated 125I-C5 15% was bound to EAC1gp(4b,oxy2a,3b)hu compared to 9.3% of buffer-treated 125I-C5. Furthermore, 27% of sialidase-treated 125I-C5 was bound to EAC1gp,4bhu compared to 16.6% of buffer-treated 125I-C5, but no lysis occurred after the addition of C6-C9. The mechanism of increased hemolytic activity after removal of SA from C5 is: the Tmax is prolonged at 30 degrees C (ca. 15 min vs 9 min), and a higher percentage of C5 binds to cellular intermediates compared to buffer-treated C5.

Asialoglycoproteins↗
PubMed1986

Fluid-phase assembly of the membrane attack complex of complement.

The dynamics and protein stoichiometry of the fluid-phase assembly of the membrane attack complex of complement were characterized by using light-scattering intensity measurements. The assembly proceeded in an ordered manner with generation of stable and highly reproducible intermediates. In the absence of phospholipid or C8, mixtures of C5b-6 and C7 self-associated to fluid phase-C5b-7 which had a weight-average molecular weight of (4.1 +/- 0.2) X 10(6). This corresponded to an average of nine C5b-7 complexes per particle. The particles appeared heterodisperse on sucrose gradients with S20,W values ranging from 21 to 39 S. Addition of C8 and C9 caused no further aggregation or disassembly of the particles. When excess C8 was added to the aggregated C5b-7, the ratio of C8 incorporated per C5b-7 moiety was 0.98 +/- 0.03. At saturating levels of C9, the C9/C5b-8 ratio in the particles was 7.2 +/- 0.6. Incorporation of C8 caused a small increase in the Z-averaged particle diffusion coefficient [(9.9-10.3) X 10(-8) cm2/s], indicating that it added in a manner that "filled in the gaps" in the C5b-7 particles. C9 caused only small decreases in the particle diffusion coefficient and substantially decreased the f/fmin ratio. The time course for C9 incorporation into fluid phase-C5b-8 indicated an initial rapid phase followed by a slow phase. The rapid phase corresponded to the incorporation of about one C9 for every two C5b-8 complexes. This suggested that one C9 binding site was accessible on about half of the C5b-8 complexes. This may imply that only about half of the C5b-8 complexes were capable of C9 polymerization so that the ratio of C9 incorporated per functional C5b-8 was (14 +/- 2)/1. The initial velocity of the slow phase of C9 addition gave an activation energy of 37 kcal/mol. The activation energy for C5b-8-independent polymerization of C9 had a similar value of 41 kcal/mol. Light-scattering intensity measurements seemed to be a highly reliable method for quantitative characterization of the fluid-phase assembly.

Complement C7↗