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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↗
PubMed1976

A new activity of complement component C3: cell-bound C3b potentiates lysis of erythrocytes by C5b,6 and terminal components.

EAC4b,3b (sheep erythrocytes carrying rabbit antibody and guinea pig complement component fragments C4b and C3) adsorb human C5b,6 reversibly; the avidity of binding varies inversely with ionic strength. We believe that the receptor of C5b,6 is contributed by the cell-bound C3b because the binding capacity of EAC4b,3b varies with C3b multiplicity and can be blocked with rabbit antibody to guinea pig C3. The fixation of C5b,6 to the erythrocyte-bound C3b serves to concentrate C5b,6 on the cell surface; as a consequence, the hemolytic efficiency of C5b,6 is almost 100 times greater when assayed with EAC4b,3b than with plain erythrocytes. This potentiation represents a hitherto unrecognized function of cell-bound C3b.

Animals↗
PubMed1989

The release of C5a in complement-activated serum does not require C6.

The influence of terminal complement components on the generation and release of the complement C5a fragment was investigated by comparing the levels of C5a in complement-activated serum with the levels of C5a produced in serum depleted of complement C6. In order to investigate the release of C5a, a modified C5a assay was developed that utilizes an anti-C5b monoclonal antibody to remove C5, C5b, and C5b-C5a complexes from samples prior to C5a assay. The modified assay was developed because the standard methodology, which includes an acid-precipitation step designed to dissociate C5a and C5b, cannot distinguish free C5a from the C5a that is bound to C5b. Therefore, the standard methodology is not capable of monitoring the influence of terminal components on C5a/C5b dissociation. Levels of C5a were measured in complement-activated whole human serum, in serum depleted of C6, and in serum containing inhibitory levels of anti-C6 Fab using both the modified C5a assay and the standard methodology. Sera were complement-activated with either zymosan to activate the alternative complement pathway or with antibody-coated sheep erythrocytes to activate the classical pathway. The levels of free C5a in C6-depleted sera after activation were equivalent to the C5a levels in activated whole serum, indicating that C6 is not required for the release of C5a from C5b. In addition, the quantity of C5a detected in zymosan-activated sera using the standard acid-precipitation methodology was greater than C5a levels when assayed using the modified immunoadsorption technique, confirming that acid-treatment enhances the C5a dissociation and promotes C5a recovery. Since the other terminal components, C7, C8, and C9, bind to C5b only after C5b only after C6 is bound, these results indicate that none of the terminal components are required for the release of C5a. Although the terminal components could influence the rate of C5a release, the quantity of C5a released in serum was entirely independent of terminal components.

Animals↗
PubMed1977

Enhancement of C56-initiated lysis by cell-bound C3 fragments: evidence for a mechanism independent of the prior binding of C56 to C3b.

Cell-bound C3b can reversibly bind C56, the activated complex of the fifth (C5) and sixth (C6) components of complement, and in this way potentiate C56-initiated lysis by favoring the formation of C567 at the cell surface. We report here another way in which cell-bound C3 fragments can enhance C56-initiated lysis, which involves C567 generated in the fluid phase rather than at the cell surface. Evidence for the involvement of fluid phase C567 was obtained by use of dextran sulfate, which is known to inhibit the hemolysis of E mediated by fluid phase C567. Dextran sulfate strongly inhibited the formation of C567 sites on cells bearing C4b and C3b (EAC4b3b) as well as on unmodified E when C56 and C7 were added simultaneously to the cells. By contrast, dextran sulfate had virtually no effect on the reaction sequence involving the prior binding of C56 to C3b and subsequent formation of C567 at the cell surface. Treatment of EAC4b3b with either anti-C3 Fab' fragments or the C3b inactivator reduced but did not eliminate the enhancement of hemolysis, raising the possibilities that a C3 fragment(s) other than C3b also can enhance C56-initiated lysis and/or that the enhancement is indirect without a requirement for an interaction between C567 and the cell-bound C3 fragment itself.

Complement C3↗
PubMed1979

Structural similarities between C6 and C7 of human complement.

A new method for the isolation of C6 and C7 by affinity chromatography of human serum with anti-C6 and anti-C7 coupled to Sepharose is described. C6 and C7 prepared by this method are hemolytically fully active, homogeneous proteins obtained in 25% yield. A comparison of the properties of isolated C6 and C7 gave the following results: The amino acid composition of the two proteins is very similar. The m.w. calculated from the amino acid content is 124,800 for C6 and 120,800 for C7. Both components are single chain glycoproteins migrating upon electrophoresis at pH 8.6 as beta 2-globulins, Both proteins are polymorphic as detected by isoelectrofocusing in polyacrylamide gels and range in their isoelectric points from pH 6.15 to 6.7. The UV spectra reveal only minor differences; the extinction coefficients are: EC6 = 1.71 cm2 X mg-1 and EC7 = 1.92 cm2 X mg-1. CD-spectra show 8% alpha-helix and 10% beta-structure for C6 and 10% alpha-helix and 14% beta-structure for C7. The structural similarities of C6 and C7 suggest their evolution from a common ancestral gene.

Chemical Phenomena↗
PubMed1976

Purification of the sixth and seventh component of human complement without loss of hemolytic activity.

Procedures for the isolation of the human complement proteins C6 and C7 have been described. These procedures allow isolation of the two proteins without any loss of hemolytic activity. Apparent activity gains of 160% and 140% were observed for C6 and C7, respectively, when the activity of the isolated proteins was compared with their activity in serum. The recovery of C6 was 3.5 to 11% and that of C7 was 7 to 13% of the amount present in serum. C6 has a m.w.of 128,000 and an electrophoretic mobility at pH 8.6 of -2.6 times 10(-5) cm2 s-1 v-1. C7 has a m.w. of 121,000 and an identical electrophoretic mobility. With 3 times 10(7) assay cells, 63% hemolysis was achieved with 1 ng of C6 and 3.8 ng C7. On polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and after reduction with mercaptoethanol, C6 and C7 behaved as single polypeptide chain proteins.

Complement C6↗
PubMed1987

Terminal complement components play a role in the expression of C5a.

This study examined the expression of C5a detected antigenically (RIA) and functionally (PMN-myeloperoxidase release) consequent to classical or alternative pathway convertase cleavage. Maximal C5a expression occurred when C5 was cleaved in the presence of the later-acting complement components, C6, C7, and C8. This effect was detected by using both purified components and normal human serum immunochemically depleted of C7 or C8 and reconstituted with the purified component. C6 alone was not sufficient to augment C5a expression. Subsequent incubation of C6 and C7 with C5 cleaved in the absence of the terminal components was not sufficient for C5a release. Repeated freezing and thawing of C5 cleaved in the absence of C6 and C7 produced C5a equivalent to that detected when convertase cleavage occurred in the presence of the terminal components. Mild detergent treatment of convertase-cleaved C5 was not sufficient for C5a release. We believe that these data indicate a role for the terminal complement components in the expression of both C5a antigen and function. The mechanism for this effect is not known, but it may involve conformational changes in the C5 molecule that occur during membrane attack complex formation.

Complement C5↗
PubMed1975

Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction.

Experiments were conducted to characterize the antibody-independent activation of complement in human serum by isolated human heart mitochondrial membranes in vitro and to determine whether similar patterns of complement consumption occurred in patients after acute myocardial infarction. Direct evidence for the interaction of C1 and heart mitochondrial membranes was obtained by mitochondria-C1 binding and elution experiments. Exposure of normal human sera to isolated human heart mitochondria at 37 degrees C resulted in the consumption of C1, C4, C2, and C3 without significant consumption of the terminal components of the complement system (C6 through C9). The consumption occurred in the absence of detectable anti-heart mitochondria autoantibody, was demonstrated to be calcium dependent, and was inhibited by either 0.01 M EDTA or ethylene glycol bis(bets-aminoethyl ether) N,N,N',N',-tetraacetic acid (EDTA). Although specific absorption of C1q from human sera inhibited the mitochondria-dependent activation of C4, C3 donsumption was not affected. These data indicate that the consumption of C4 and C2 likely occurred due to the mitochondrial membrane-mediated activation of C1, but that the consumption of the C3 did not necessarily involve either the classical or alternative complement pathways. After the in vitro characterization of the mitochondria-dependent activation of the complement system, additional studies were performed to determine whether similar consumption occurred in patients after acute myocaridal infarction. During a 72-h period after hospital admission significant decreases in C1, C4, and C3 occurred in six patients with recent chest pain but no evidence of acute myocardial infarction. These studies suggest that myocardial cell necrosis results in the release of subcellular membrane constituents capable of activating the complement system in the absence of detectable anti-heart autoantibodies; such activation may be responsible in part for the development of acute inflammation and evolution of the infarct size following coronary artery occulusion.

Autoantibodies↗
PubMed1977

Deviated lysis (d.l.): III. Kinetics of interaction of d.l. activity with chicken erythrocytes: evidence for E formation.

The interaction of d.l. activity with chicken red cells (CE) generates a cell intermediate with the properties of classical E*. Generation of CE* by d.l. activity at 37 degrees C is rapid, while there is a considerable lag in the conversion of CE* to ghost and hemoglobin. Conversion of CE* to ghosts can be blocked by high concentration of EDTA and/or 0 degrees C. CE* contain at least C6 and C9 on their surface.

Animals↗
PubMed1991

Human umbilical vein endothelial cells synthesize functional C3, C5, C6, C8 and C9 in vitro.

Human endothelial cells (EC), cultured serum-free, synthesize de novo protein which increasingly bind to agarose beads (an alternative pathway activator), until a plateau phase is reached after 24-48 h. EC synthesize functional C3, C5, C6, C8 and C9, which were detected on co-cultured agarose beads, using relevant polyclonal anti-complement antibodies. Two monoclonal anti-C9 neoepitope antibodies (aE11, poly C9-MA) bound to the co-cultured beads, showing that the terminal complement complex (TCC) (C5b-9) was assembled on the beads. This also suggests that C7 is synthesized. There seems to be a positive correlation between the amount of agarose-bound labelled protein and agarose-bound complement. The results indicate that EC produce and secrete the components for the functional alternative and terminal pathways of complement.

Antibodies, Monoclonal↗