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PubMed2000

[Meningococcemia associated with C7 deficiency].

We report a 20-year-old woman who developed meningococcemia. The patient developed fever, vomiting and skin rash, then was sent to our hospital for shock. Physical and laboratory examination revealed septic shock and DIC. Her blood culture grew Neisseria meningitidis (W135). She recovered promptly with PCG, gabexate mesilate and intensive care for shock. Hemolytic activities of the patient's complement were less than 12/CH50 during the course. Screening for each component of the complements suggested that this patient had deficiency of C7. Meningococcal disease has seldom seen in Japan. Early recognition is essential so that appropriate antibiotic therapy and supportive care can be promptly started because shock and death may ensure within hours after onset of symptoms.

Adult↗

PubMed1985

C56 formation in the reaction mixture of isolated complement components through the classical complement pathway.

The mechanism of hemolysis of unsensitized erythrocytes by a mixture of 9 isolated, human-derived complement components, C1s, C4, C2, C3, C5, C6, C7, C8 and C9 (C1s-C9) was studied. Of the tested erythrocytes, guinea pig erythrocytes (Egp) were the most susceptible to lysis by C1s-C9, followed by human and sheep erythrocytes. Contamination of the isolated complement components by C56 was ruled out. It was determined that a factor was generated in the reaction mixture of C1s, C4, C2, C3, C5 and C6 (C1s-C6), which had lytic activity against Egp when C7, C8 and C9 were added. We found that the lytic factor was similar to C56 in the following properties: (1) the activity of the lytic factor decreased when incubated with isolated C7 prior to its reaction with Egp; (2) the lytic factor did not bind to Egp by itself but it did bind in the presence of C7; (3) EDTA did not have any inhibitory effect on the lytic factor; (4) the activity of the lytic factor decreased by treatment with anti-C5 and anti-C6 but not by treatment with anti-C3 and anti-C4, and (5) gel filtration of the reaction mixture (C1s-C6) indicated that the elution volumes of the lytic factor and of isolated C56 were similar. Thus, it is likely that C56 is generated in the reaction mixture of C1s-C6 and the lytic factor binds to unsensitized erythrocytes together with C7, to form an intermediate EC567 which is susceptible to lysis by the action of C8 and C9.

Animals↗

PubMed1998

Characterization of soluble terminal complement complex assembled in C8beta-deficient plasma and serum.

Sera genetically deficient in either the alpha-gamma or the beta-subunit of complement component C8 virtually lack haemolytic activity. We have studied the formation and the structural organization of the soluble terminal complement complex (TCC) assembled in these sera following activation with cobra venom factor (CVF). The TCC concentration in the activated C8alpha-gamma and C8beta-deficient samples was 0.2% and 4%, respectively, when compared with zymosan-activated normal serum. TCC was purified from the activated C8beta-deficient samples by affinity chromatography and analysed by immunoblotting and enzyme immunoassay. No C8beta was detected in one TCC preparation, while 7% of the normal level was present in the other. The level of the other terminal components, including that of C8alpha-gamma, was normal. The ability of C8alpha-gamma to promote the assembly of TCC in the presence of a limited amount of C8beta or in the apparent absence of this subunit was confirmed using purified components, by mixing C5b6 and either of the purified C8 subunits together with C7 and C9. These data show that soluble TCC can be formed in C8beta-deficient sera that contain little or no C8beta.

Complement C5↗

PubMed1975

Studies of the inhibition of C56-initiated lysis (reactive lysis). IV. Antagonism of the inhibitory activity c567-INH by poly-L-lysine.

The stable intermediate complex C56 can initiate the lysis (reactive lysis) of unsensitized erythrocytes (E) by the membrane attack machanism of complement. Certain serum constituents designated C567-INH inhibit reactive lysis by preventing the C567 complex, once formed, from attaching to a membrane surface. It is shown here that microgram quantities of poly-L-lysine (PLL), a synthetic polycation of molecular weight 180,000, can reverse the effests of C567-INH, and thereby potentiate formation of EC567 by erythrocytes, C56 and C7 in whole serum. Erythrocytes exposed to PLL in a preincubation step did not show either increased susceptibility to C567 or resistance to C567-INH, and reversal of C567-IHN by given amounts of PLL was not diminished as cell concentrations were greatly increased, indicating that the effect of PLL was predominantly directed against fluid phase rather than against erythrocyte membrane substrates. The effects of PLL and C567-INH were quantitatively reciprocal. Thus, PLL-induced potentiation of C56-induced lysis is a solute effect which seems to involve direct neutralization of naturally occurring serum inhibitors of the C567 trimolecular complex of complement. The use of PLL thus provides a suitable antagonist for C567-INH in reaction mixtures, and allows evaluation of the role of C567 and C567-INH in a variety of situations involving C-mediated lysis.

Alpha-Globulins↗

PubMed1982

Cooperative interaction of factor B and other complement components with mononuclear cells in the antibody-independent lysis of xenogeneic erythrocytes.

Synergistic cytotoxicity is a term used to describe a cytotoxic system in which xenogeneic erythrocyte target cells are lysed in the presence of nonimmune human mononuclear effector cells and antibody-depleted normal human serum. Neither the mononuclear cells nor the serum alone are cytolytic to the target erythrocytes. Previous studies have shown that the serum activity is not immunoglobulin and is heat-labile, suggesting a similarity to serum complement. In this report, sera deficient in various complement components as well as highly purified single complement components were tested with whole mononuclear cell populations and purified monocytes and lymphocytes to further characterize this cytotoxicity system. Whole mononuclear cell populations failed to mediate target cell lysis in sera deficient in C5 or factor B. However, C3-deficient serum, even in the presence of anti-C3 antibody, supported synergistic cytotoxicity normally. Purified lymphocytes were also normally cytotoxic in C3-deficient serum but failed to lyse targets in sera deficient in C5, C7, C8, or depleted of factor B. Purified monocytes failed to lyse the target cells only in factor B-depleted serum and could lyse the target cells in serum-free medium when purified factor B alone was added. Monocyte-mediated cytotoxicity induced by factor B was inhibited 73-100% by adding lymphocytes back to the purified monocytes. Thus, both lymphocytes and monocytes can serve as effector cells in this form of cytotoxicity but require cooperative interaction with different sets of complement components. In addition, lymphocytes can modulate the monocyte-mediated form of target cell lysis associated with factor B.

Animals↗

PubMed1985

Multimeric complement component C9 is necessary for killing of Escherichia coli J5 by terminal attack complex C5b-9.

We studied the molecular composition of the complement C5b-9 complex required for optimal killing of Escherichia coli strain J5. J5 cells were incubated in 3.3%, 6.6%, or 10.0% C8-deficient serum previously absorbed to remove specific antibody and lysozyme. This resulted in the stable deposition after washing of 310, 560, and 890 C5b67 molecules per colony-forming unit, respectively, as determined by binding of 125I-labeled C7. Organisms were then incubated with excess C8 and various amounts of 131I-labeled C9. Plots of the logarithm (base 10) of E. coli J5 cells killed (log kill) vs. C9 input were sigmoidal, confirming the multihit nature of the lethal process. When C9 was supplied in excess, 3300, 5700, and 9600 molecules of C9 were bound per organism for cells bearing 310, 560, and 890 C5b-8 complexes, respectively, leading to C9-to-C7 ratios of 11.0:1, 10.8:1, and 11.4:1 and to log kill values of 1.3, 2.1, and 3.9. However, at low inputs of C9 that lead to C9-to-C7 ratios of less than 3.3:1, no killing occurred, and this was independent of the number of C5b-9 complexes bound. Formation of multimeric C9 at C9-to-C7 ratios permissive for killing was confirmed by electron microscopy and by binding of 125I-labeled antibody with specificity for multimeric but not monomeric C9. These experiments are the first to demonstrate a biological function for C9 polymerization and suggest that multimeric C9 is necessary for optimal killing of E. coli J5 cells by C5b-9.

Cell Membrane↗

PubMedDate not supplied

Some aspects of the humoral immunity and the phagocytic function in newborn infants.

Newborn infants, particularly those born prematurely, are prone to develop life-threatening pyogenic infections. Different studies have demonstrated impairment of various aspects of the humoral immunity and the phagocytic activity of neutrophils in newborns. We conducted a comprehensive study evaluating the complement function (CH50 and AP50) and the level of the vast majority of the complement components (Clq, Clr, Cls, C2-C9, FB and properdin) in preterm and full-term newborn infants as compared to adults. Furthermore, we investigated the effect of autologous and heterologous serum on the bactericidal activity of neutrophils, by crossing newborn serum with adult cells and vice versa. Results showed that preterm and full-term newborns have an impaired complement activity as compared to adults (CH50 P < 0.05, AP50 < 0.01) and significantly reduced complement components except for C7, which was found to be normal in full-term infants and in most appropriate-for-gestational age preterm newborns at 34-36 weeks. A statistically significant correlation was found between gestational age and the level of most of the complement components. CH50 and AP50 also showed a positive trend which, however, was not statistically significant. No correlation was found between birthweight and complement activity or complement component levels. The neutrophil bactericidal activity of full-term newborns was about one-third that of adults (P < 0.001). Adult serum improved the bactericidal activity of newborn neutrophils by 93%, indicating a considerable neonatal humoral defect. Conversely, neonatal serum blunted the adult bactericidal activity by 86%. Our results support the fact that both humoral and phagocytic functions in newborn infants are impaired, which may possibly account for their increased tendency to develop severe pyogenic infections.

Adult↗

PubMed1989

Characterization of the enhanced susceptibility of paroxysmal nocturnal hemoglobinuria erythrocytes to complement-mediated hemolysis initiated by cobra venom factor.

When whole serum C is activated by cobra venom factor complexes (CoFBb), paroxysmal nocturnal hemoglobinuria (PNH) III E (the most C-sensitive type) are hemolyzed, but normal and PNH II E (the intermediately sensitive type) are not. Previous studies have shown that after exposure to CoFBb and serum, PNH III E bind relatively large amounts of the trimolecular C complex, C5b67, whereas normal and PNH II E bind virtually none. In the studies reported herein, we have observed that when normal and PNH III E are incubated with isolated C5, C6, and 125I-C7 in the presence CoFBb, the normal E bind more C5b-7 than the PNH cells. When C7-deficient serum is included in the reaction mixture, however, the PNH E are once again observed to bind much greater amounts of C5b-7. These observations suggest that plasma and membrane factors act in concert to restrict the assembly of the trimolecular C5b-7 complex on human E. PNH III E appear to be deficient in the membrane component of this inhibitory system.

Animals↗

PubMed1977

Complement system in human colostrum: presence of nine complement components and factors of alternative pathway in human colostrum.

Evidence has been obtained for the presence in human colostrum of all nine components of complement (C), C1 through C9, and factors of the alternative pathway. Samples of colostrums collected from five women at 1-4 days after normal parturition were assayed for the haemolytic activities of individual components. As compared with normal human sera, the activities of each component ranged from 0.03 to 7% of those in sera. The activities of C4, C7 and C9 were relatively high, while that of C1 was extremely low. In most of the cases, the activities of individual components gradually increased following delivery, when expressed as the activity per unit weight (g) of protein in the colostrum. When the colostrums were treated with cobra venom factor, most of the colostrums showed 10-20% reduction in the C3 activity. This finding indicates the presence of factors such as B and D which are involved in the activation of C through the alternative pathway. The role as a defense factor of the C system in human colostrum and milk is discussed in connection with the ability of secretory IgA to react with C.

Colostrum↗

PubMed1997

The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure.

The ninth component of human complement (C9) is the last of the terminal complement components creating the membrane attack complex. C9 is a single-chain serum protein that is encoded by a gene located on chromosome 5p. Deficiency of terminal complement components is generally associated with recurrent neisseria infections. We studied a previously described Swiss family with inherited C9 deficiency. To identify the genetic basis of C9 deficiency, we developed an approach using exon-specific PCR and direct DNA sequencing. As a cause of C9 deficiency, we found two different point mutations, both generating TGA stop codons in the coding sequence. One mutation, a C to A exchange, was detected in exon 2 at cDNA position 166, the other, a C to T exchange, was located in exon 4 (cDNA position 464). In family studies of three first-degree relatives with heterozygous C9 deficiency, we demonstrated that the two mutations are segregating independently. Therefore, these mutations are sufficient to explain the complete deficiency of both the probands studied. DNA sequencing of the exon-intron junctions revealed a number of revisions regarding the boundaries between exons 4, 5, and 6 as well as between exons 10 and 11. No additional introns were detected in exons 6 and 10. Furthermore, DNA marker studies were conducted using known polymorphisms of the C6, C7, and C9 genes, confirming the linkage of the observed C9 mutations with defined haplotypes.

Base Sequence↗

PubMed2003

Serum-resistant strains of Borrelia burgdorferi evade complement-mediated killing by expressing a CD59-like complement inhibitory molecule.

Borrelia burgdorferi, the etiological agent of Lyme disease, comprises three genospecies, Borrelia garinii, afzelii, and burgdorferi sensu strictu, that exhibit different pathogenicity and differ in the susceptibility to C-mediated killing. We examined C-sensitive and C-resistant strains of B. burgdorferi for deposition of C3 and late C components by fluorescence microscope and flow cytometry. Despite comparable deposition of C3 on the two strains, the resistant strain exhibited reduced staining for C6 and C7, barely detectable C9, and undetectable poly C9. Based on these findings, we searched for a protein that inhibits assembly of C membrane attack complex and documented an anti-human CD59-reactive molecule on the surface of C-resistant spirochetes by flow cytometry and electron microscopy. A molecule of 80 kDa recognized by polyclonal and monoclonal anti-CD59 Abs was identified in the membrane extract of C-resistant strains by SDS-PAGE and Western blot analysis. The molecule was released from the bacterial wall using deoxycholate and trypsin, suggesting its insertion into the bacterial membrane. The CD59-like molecule acts as C inhibitor on Borrelia because incubation with F(ab')(2) anti-CD59 renders the serum-resistant strain exquisitely susceptible to C-mediated killing and guinea pig erythrocytes bearing C5b-8, unlike the RBC coated with C5b-7, are protected from reactive lysis by the bacterial extract. Western blot analysis revealed preferential binding of the C inhibitory molecule to C9 and weak interaction with C8 beta.

Antibodies, Blocking↗

PubMed1995

Hemolytically inactive C5b67 complex: an agonist of polymorphonuclear leukocytes.

The activity of hemolytically inactive C5b67, designated iC5b67, was evaluated as an agonist for functional responses of human polymorphonuclear leukocytes (PMN). C5b67 was formed from purified human complement components and decayed in phosphate-buffered saline (PBS) until it had no lytic activity for sheep erythrocytes in a standard assay. iC5b67, at nanomolar concentrations, stimulated PMN chemotaxis and Ca2+ fluxes, but inhibited superoxide production and failed to upregulate CR1 and CR3. There was no significant contamination of the iC5b67 with C5a to explain these results. Neither isolated C5b6 nor C7 alone exhibited the activities of iC5b67, while insolubilized anti-C7 could remove the PMN agonist activity from the iC5b67 preparation. Binding studies to define a specific receptor for iC5b67 on PMN were hampered by the very hydrophobic nature of the ligand. 125I-iC5b67, by contrast to hemolytically active 125I-C5b67, was unable to insert in erythrocytes, suggesting that iC5b67 need not insert in the PMN membrane to induce signaling. Two lines of evidence suggest that iC5b67 and C5a and FMLP share common steps in intracellular signaling (1) pretreatment of PMN with iC5b67 deactivates PMN for C5a- and FMLP-induced chemotaxis; and (2) pretreatment of PMN with pertussis toxin inhibits iC5b67-induced chemotaxis. Thus, iC5b67 has important effects on the activity of PMN and G-proteins and Ca2+ are involved in the signaling.

Chemotaxis, Leukocyte↗

PubMed1992

Properties of a low molecular weight complement component C6 found in human subjects with subtotal C6 deficiency.

A sensitive ELISA assay was used to quantitate serum complement component C6 concentrations. Levels in the range 0.3-3 micrograms/ml were measured in samples from eight individuals (four separate pedigrees) and two subjects with subtotal combined C6/C7 deficiency who have been reported previously. We defined C6 levels in this range as subtotal C6 deficiency (C6SD). In contrast, C6 deficiency with levels below 0.03 micrograms/ml was defined as C6Q0. C6Q0 has been found in 29 unrelated cases which have already been reported. Investigations of the properties of the C6 found in the C6SD subjects showed it to be haemolytically active and able to incorporate into the terminal complement complex. The protein had a relative molecular weight (Mr) of approximately 86% of normal C6 and this Mr was identical to that of the C6 of one combined deficient subject. The Mr of the C6 of the other combined deficient subject was previously estimated as 79% of the Mr of normal C6. Isoelectric focusing (IEF) analysis with band development by haemolytic overlay revealed that all C6SD samples produced an identical weak C6 band pattern anodal to normal C6A bands. The C7 IEF patterns of the two combined deficient subjects were identical, and the C6 IEF patterns of both were identical to those of the C6SD subjects. Thus the C6 of the combined deficient subjects is probably the same abnormal protein found in the C6SD individuals. None of the C6SD or combined deficient subjects have had meningococcal disease and it may be that low C6 levels afford some protection.

Adult↗

PubMed1981

Hemolytic complement and its components in Syrian hamsters: a study of five strains uninfected and infected with Brugia pahangi.

Complement profiles were tested in outbred (LVG) Syrian hamsters (Mesocricetus auratus) and compared to the MHA, LHC, PD4, and CB inbred strains. The total C and C component concentrations in the sera varied among the strains and were in the following ranges in untreated animals (in CH50 units per ml): total C, 140-260 (undetectable in PD4 and CB); Cl, 14,000-25,000; C2, 200-800 (except PD 4 and CB); C3, 40,000 and 80,000; C4, 2,000-2,800 (except PD4 and CB); C4, 40,000-80,000; C6, 3,600-6,000 (undetectable in PD4 and CB); C7, 50,000-350,000; C8, 10,000-30,000; C9, 30,000-60,000. The PD4 and CB strains had undetectable total C and C6, and their exact C2 and C4 levels could not be determined, but were lower than in the other strains. The MHA strain had the highest total C levels, but had significantly lower (1/3 or less) C7 levels than the other strains of hamsters. Infection of hamsters with the filarid nematode Brugia pahangi for four to five months produced moderate decreases in the total C and C3 levels, but varied changes in other C components. Six infected and three uninfected animals died during the experiment from spontaneous enteritis and weight loss.

Animals↗

PubMed1993

Complement component C5 modulates the systemic tumor necrosis factor response in murine endotoxic shock.

Patients with disseminated Neisseria meningitidis infections (meningococcemia) suffer from a fulminant shock syndrome that is accompanied by extraordinarily high concentrations in serum of tumor necrosis factor (TNF). People with homozygous deficiencies of late complement components (C5, C6, C7, and C8) experience a high incidence of disseminated neisserial infections yet suffer from an attenuated form of the disease. The mechanisms that account for this disparity in host response are unclear, but they may in part be related to differences in the systemic TNF response that are modulated by terminal complement components (C5 to C9). The role of C5 in the modulation of the systemic endotoxin-induced TNF response was studied with matched strains of C5-deficient (B10 D2/Osn) and complement-sufficient (B10 D2/Nsn) mice. Following lipopolysaccharide (LPS) administration, complement-sufficient mice exhibited more rapid increases in pulmonary and hepatic vascular permeabilities than did C5-deficient controls. Complement-sufficient mice developed acute passive hepatic congestion, they appeared more ill than C5-deficient mice, and they exhibited a twofold greater rise in serum TNF activity compared with that by C5-deficient mice. C5-deficient mice reconstituted with normal serum before an LPS injection exhibited pulmonary and hepatic vascular permeability increases and serum TNF levels approaching those observed in complement-sufficient mice. Alveolar and peritoneal macrophages isolated from complement-sufficient and C5-deficient mice and incubated in heat-inactivated serum did not exhibit differences in TNF mRNA expression or secreted TNF activity following stimulation with LPS. However, incubation of macrophages in complement-sufficient mouse serum (before LPS stimulation) resulted in increased TNF mRNA expression and TNF activity compared with those in cells incubated in C5-deficient serum. In vitro studies employing human complement components and peripheral blood monocytes revealed that recombinant C5a, in the presence or absence of LPS, can induce increased concentrations of TNF and that C5b to C9 had no additional modulatory effect on the TNF response. These data suggest that C5 modulates the endotoxin-triggered TNF response. The role of complement components distal to C5 (i.e., C5b to C9) in the endotoxin-triggered TNF response remains unclear.

Animals↗

PubMed1989

Secretion of the terminal complement proteins, C5-C9, by human platelets.

The terminal complement components, C8 and C9, and to a lesser extent C5, C6, and C7, but minimal amounts of C3, were shown to be associated with washed human platelets. In unactivated platelets, the complement components were detected in the platelet pellet by hemolytic assays after centrifugation and disruption of the platelets by freeze-thawing. However, after platelets had been activated by collagen, thrombin, or aggregated IgG to induce aggregation, the complement components were released into the supernatant. The rank order of hemolytic activity of C9, C8, C7, C6, and C5 detected in the supernatants of activated platelets was quite different from that found in serum from the same donors, in the same assays. In particular, the serum C7 hemolytic titer was more than twice the serum C9 hemolytic titer, whereas the activity of C9 detected from platelets was more than twice that of C7. This argues against a purely nonspecific uptake of these proteins by platelets from plasma. The functional role of terminal complement components released from platelets during activation is unknown, but it is tempting to speculate that these proteins may have a role in platelet-dependent immunological tissue injury. Because the C5b-9 membrane attack complex activates platelets, it is possible that release of terminal complement proteins serves to amplify platelet activation and may also play a role in diseases in which complement membrane attack complexes have been implicated.

Blood Platelets↗

PubMed2003

Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration.

The complement system consists of >30 proteins that interact in a carefully regulated manner to destroy invading bacteria and prevent the deposition of immune complexes in normal tissue. This complex system can be activated by diverse mechanisms proceeding through distinct pathways, yet all converge on a final common pathway in which five proteins assemble into a multimolecular complex, the membrane attack complex (MAC). The MAC inserts into cell membranes to form a functional pore, resulting in ion flux and ultimately osmotic lysis. Immunohistochemical evidence of the MAC decorating neurons in cortical gray matter has been identified in multiple CNS diseases, yet the deleterious consequences, if any, of MAC deposition in the cortex of mammalian brain in vivo are unknown. Here we demonstrate that the sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioral and electrographic seizures as well as cytotoxicity. The onset of seizures occurred during or shortly after the infusion of C8/C9. Neither seizures nor cytotoxicity resulted from the simultaneous infusion of all five proteins premixed in vitro. The requirement for the sequential infusion of all five proteins together with the temporal relationship of seizure onset to infusions of C8/C9 implies that the MAC was formed in vivo and triggered both seizures and cytotoxicity. Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain.

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↗