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PubMed1980

Bactericidal screening test for late complement component deficiencies or defects.

Congenital complement deficiency has been described in disseminated Neisseria infections. Its occurrences in humans with other kinds of infections have not been described. In the past, CH50 determinations have been used to detect these deficiencies, but this procedure is time consuming and cumbersome. A method of determining the presence of late component deficiencies or defects is described which is easy and inexpensive to perform. An agar pour plate with a serum-sensitive Escherichia coli strain is made, and 2.5-mm wells are put in the agar. Unknown fresh sera are used to fill the wells. An absence of a zone of bacterial growth inhibition around the well after incubation at 37 degrees C overnight indicates a late component defect or deficiency in the test serum. By applying this assay to 35 selected patients, four deficient patients were identified. One had a congenital C5 deficiency and three had C6 deficidencies. It is suggested that the assay be used as a screening test to study the relationship between congenital complement deficiencies and various kinds of infections, especially those caused by organisms which are partially serum sensitive.

Bacteriological Techniques↗
PubMed1976

Deviated lysis: Transfer of complement lytic activity to unsensitized cells II. Generation of the activity by inulin and by antigen antibody complexes.

Deviated lysis (d.l.) activity, i.e. lysis of unsensitized cells by lytic C activity, was generated via the classical pathway of Cactivation (ag ab complexes) and via the alternative pathway (inulin). The activity was observed on the surface of the activating particles and in the fluid phase. The activity was relatively stable at 32 degrees C. Its generation involved the C components C6 through C9 and possibly also C5.

Animals↗
PubMed1984

Complement lysis of nucleated cells: effect of temperature and puromycin on the number of channels required for cytolysis.

We have previously shown that lysis of a nucleated mammalian cell requires several complement channels unlike lysis of erythrocytes and that this difference is due primarily to rapid elimination of channels from the plasma membrane. We have now investigated this problem further by studying the rate of channel elimination at low temp, the osmotic fragility of the cells, and the effectiveness of the membrane-associated ion pumps. When complement channels were formed for 3 min at 37 degrees C, followed by prolonged incubation at 2 degrees C, the C6 lytic dose-response curves indicated that a single channel was required for lysis of a cell, whereas multiple channels were required when the entire process was carried out at 30 degrees C. The shift from multi- to one-hit lytic behavior can be explained by the drastic reduction in the rate of channel elimination at low temp. C6 lytic dose-response curves with puromycin-treated cells were also found to display one-hit behavior, but, in this case, the rate of channel elimination was reduced only about 35-40% (which would not suffice to explain the one-hit lytic characteristics). However, cell death was more extensive for puromycin-treated cells than normal cells after incubation in buffers of low ionic strength, suggesting that an increase in osmotic fragility may be a contributing factor in the shift from multi- to one-hit behavior. Blocking of the membrane-associated Na+/K+-ATPases with ouabain did not affect the multi-channel requirement. Presumably, this means that the ion pumping rate does not significantly influence the number of channels required for lysis.

Biological Transport, Active↗
PubMed2000

Cleavage of the fifth component of complement and generation of a functionally active C5b6-like complex by human leukocyte elastase.

Activation by complement C3/C5 convertases of the fifth component of human complement, C5, leads to two active cleavage products: C5a, a chemotactic peptide, and C5b, the activated form of C5. Human leukocyte elastase (HLE) has long been known to also release from C5 a chemotactic, C5a-like fragment. This, however, cannot be identical with C5a, since HLE does not cleave peptide bonds at the carboxyl group of arginine, the cleavage site that separates C5a and C5b after the exposure to the complement convertases. Therefore, the question arose whether HLE is capable of releasing a functionally C5b-like product from C5. The results show that this is, indeed, so. Treatment of human C5 with HLE in the presence of C6 leads to the formation on an active C5b6-like complex that lyses non-sensitized guinea pig red cells upon addition of the terminal components C7, C8, and C9. However, since C6 is highly sensitive to the hydrolytic action of HLE, the yield of the activation complex is rather low. The results offer a third possibility for the activation of C5: 1) classical cleavage at Arg74 by complement convertases, 2) oxidation of methionine residues without cleavage, and, as shown here, 3) cleavage by elastase at (a) site(s) distal from Arg74. The three procedures may modulate the relative yield of the two activities generated from C5, C5a-like and C5b-like effects.

Animals↗
PubMed2006

Polyglycolic acid-induced inflammation: role of hydrolysis and resulting complement activation.

Tissue and organ replacement have quickly outpaced available supply. Tissue bioengineering holds the promise for additional tissue availability. Various scaffolds are currently used, whereas polyglycolic acid (PGA), which is currently used in absorbable sutures and orthopedic pins, provides an excellent support for tissue development. Unfortunately, PGA can induce a local inflammatory response following implantation. Therefore, we investigated the molecular mechanism of inflammation in vitro and in vivo. Degraded PGA induced an acute peritonitis, characterized by neutrophil (PMN) infiltration following intraperitoneal injection in mice. Similar observations were observed using the metabolite of PGA, glycolide. Dissolved PGA or glycolide, but not native PGA, activated the classical complement pathway in human sera, as determined by classical complement pathway hemolytic assays, C3a and C5a production, and C3 and immunoglobulin deposition. To investigate whether these in vitro observations translated to in vivo findings, we used genetically engineered mice. Intraperitoneal administration of glycolide or dissolved PGA in mice deficient in C1q, factor D, C1q and factor D, or C2 and factor B demonstrated significantly reduced PMN infiltration compared to congenic controls (WT). Mice deficient in C6 also demonstrated acute peritonitis. However, treatment of WT or C6 deficient mice with a monoclonal antibody against C5 prevented the inflammatory response. These data suggest that the hydrolysis of PGA to glycolide activates the classical complement pathway. Furthermore, complement is amplified via the alternative pathway and inflammation is induced by C5a generation. Inhibition of C5a may provide a potential therapeutic approach to limit the inflammation associated with PGA-derived materials following implantation.

Animals↗
PubMed2003

[Immunological study in sickle cell disease patients: importance of the complement system].

Ten Tunisian patients, with homozygote sickle cell disease and asplenia were studied to investigate and to determine possible immunological function defects. Obtained results directed us to an abnormality of the alternate complement pathway activation which is expressed by a decreased hémolytic activity, while the classic pathway is normal. Quantification of C3, C4, C5, C6, C7 and factor B by immunochemical assay were normal, whereas factor B functional activity was depressed to a mean level of about half of normal in eight patients, IgG was increased in one subject and IgA in two others. Numeration of Band T cells revealed slight decrease in proportion of CD3 and CD4 at one patient associated with an increase in B cells, but normal or increased absolute numbers of all cells population.

Adolescent↗
PubMed1984

Freeze-thaw activation of the complement attack phase: I. Separation of two steps in the formation of the active C--56 complex.

The activation of the attack phase of C, C5-C9, is generally assumed to be dependent on the enzymes of the C activation pathways which cleave C5 into C5b and C5a. C5b will then form a complex with C6 that binds to membranes and, in the presence of C7-C9, effects cell lysis. In contrast, however, a variety of physicochemical means was found to activate C5 + C6 independently of the convertases and without apparent generation of the C5a peptide. By freezing and thawing of C5 + C6 a hemolytic C--56 activity was generated: (C--56 ).f The activation proceeded in two steps: (1) during a preincubation period of the two components the time and temperature dependent formation of an activatable intermediate was observed and (2) the intermediate C--56 could then be endowed with hemolytic activity by freezing and thawing. The intermediate as well as the activated (C--56)f complex was separated from C5 and C6 by anion exchange chromatography. While the isolated intermediate was labile, the active product after freezing and thawing was stable.

Complement Activation↗
PubMed1977

C5-dependent enhancement of rosette formation and phagocytosis by human polymorphonuclear leukocytes.

Using purified human complement components, the participation of C5 in phagocytosis was investigated. The addition of C5 to EAC 1423 increased both rosette formation and phagocytosis of the intermediates by human polymorphonuclear leukocytes. The opsonizing activity of C5b was not affected after decay of its hemolytic activity. Both C3- and C5-dependent phagocytosis is abolished either in the presence of chelating agents or by pretreatment of the polymorphonuclear leukocytes with trypsin. The enhancing effect of C5b in phagocytosis can be reduced either by further reaction with C6 and C7 or with anti-C5 F(ab)2 fragments.

Antibodies↗
PubMed1992

Complement profile in primary biliary cirrhosis.

PBC is a chronic progressive liver disease of unknown etiology. Several abnormalities found in PBC support the hypothesis that it may be considered an autoimmune disease. Despite the complex and interesting relationship that exists between autoimmune disorders and the complement system, very few reports on the level of the serum complement component in PBC have been published, and most of these comprised only a few patients or analyzed only a scant number of the complement components. In the present study, sera of 73 PBC patients were analyzed for the levels of 10 complement components. It was found that the levels of most of the serum complement components, including C1q, C2, C3, C5, C7, properdin and factor B were significantly elevated in patients with PBC in comparison to healthy controls. The level of C4 was slightly lower than that of the normal controls (p = 0.019), while the levels of C6 and C8 were within the normal range. The number of PBC patients with serum levels of C4 and C6 < 60% of normal pooled serum was higher than in the respective control groups (6/69 compared with 0/26 and 4/71 compared with 0/27, respectively). However, the difference was not statistically significant. Thus, our study shows alterations in the levels of most complement components in PBC, the reasons for which are discussed.

Autoimmune Diseases↗
PubMed1993

Linkage between complement components 6 and 7 and glutamic pyruvate transaminase in the marsupial Monodelphis domestica.

The sixth and seventh components of complement were found to be polymorphic and tightly linked in the laboratory opossum (Monodelphis domestica), as they are in eutherian mammals. In addition, strong evidence for linkage of the C6-C7 haplotype to the gene for glutamic pyruvate transaminase (GPT) was obtained for females but not for males. This result, combined with previous observations, established as a generality that recombination is severely reduced in females of this species by comparison with males. It also establishes synteny of C6-C7 and GPT in a marsupial species, as exists in mice. Because these loci are not syntenic in humans, the results imply that this synteny is ancestral to the separation of marsupials and eutherians and that it was broken relatively recently in the mammalian lineage leading to human beings. The newly described C6 and C7 polymorphisms provide additional power for developing a linkage map for M. domestica and for localizing genes that confer susceptibility to diseases for which this species is used as a model.

Alanine Transaminase↗
PubMed1981

Activation of the fifth and sixth component of the complement system: similarities between C5b6 and C(56)a with respect to lytic enhancement by cell-bound C3b or A2C, and species preferences of target cell.

Brief shift of purified C5 and C6 at 0 degrees C to pH 6.4, followed by immediate neutralization, results in the generation of a factor, designated C(56)a, that lyses erythrocytes together with C7, C8, and C9. We compared C(56)a and C5b6 generated by an alternative-pathway convertase, with regard to their action on different target cells. We found tht C(56)a is similar to C5b6 in the following properties: 1) Together with C7, C(56)a forms a stable intermediate on either sheep or guinea pig erythrocytes. 2) Membrane-bound C3b, or A2C incorporated in the membrane, enhances lysis by C(56)a-9, as well as lysis by C5b6-9. We also found that the lysis of EC(56)a7 or EC5b67 intermediates by C8 and C9 depends on the species of the erythrocytes and the species of C8 and C9. Thus, lysis of sheep erythrocytes is more efficient with guinea pig C8 and C9 than with human C8 and C9. In the case of guinea pig erythrocytes, this relationship is reversed, i.e., these cells lyse more efficiently when human C8 and C9 are used. Enhancement of lysis by membrane-bound C3b or A2C does not abrogate this species incompatibility pattern.

Animals↗
PubMed1978

The complement profile in relation to the "reactor" state: a study in the immediate post-partum period.

C56 (activated "reactor") could be generated by adding zymosan to only nineteen out of the fifty serum samples obtained from southern Chinese women 3 to 5 days after a normal spontaneous delivery. As a group, post-partum sera showed a 25% increase in total haemolytic complement, an almost two-fold increase in haemolytic C5, C4 and C8 plus C9 activity, a 50% increase in antigenic C3 and haemolytic C2, C1 and factor B activity, a less than 20% increase in haemolytic C6 and C7 activity, and a 20% decrease in factor D and C1 inhibitor activity. Consequently, their C5:C7 ratios were significantly elevated. This finding supports, in part, the theory that the "reactor" state or ability to generate C56 depends on a relative excess of C56 over C7. However, comparison of the complement profile between sera with and those without "reactor" activity did not reveal any difference, except a greater elevation of C5 in the latter. It appears possible that a grossly excessive level of C5 may, in fact, be unfavourable to the generation of C56.

Complement C5↗
PubMed1993

Immobilization of Schistosoma mansoni miracidia by activation of the alternate complement pathway at unusually high serum dilution.

Free-swimming Schistosoma mansoni miracidia were immobilized by adding normal mammalian serum to the water. Miracidial immobilizing activity (MIA) was shown to result from activating the alternate pathway of complement (APC). MIA in normal sera was heat-sensitive and antibody independent; it was greatly reduced in factor B-depleted or C6-depleted, but not in C1-depleted, human serum. Addition of purified factor B to B-depleted serum totally restored MIA. Half-maximal MIA in normal human, rabbit, and guinea pig sera was detectable at final dilutions exceeding 1/100, 1/200, and 1/500, respectively, and normal rat serum was particularly potent, with MIA at dilutions exceeding 1/2000. Detection of APC activity at such high dilutions is quite extraordinary and attributed to the hypotonic conditions. We confirmed and extended previous findings that heat-inactivated infection sera also display MIA. Immobilizing activity in irradiated-cercarial vaccine rat serum cofractionated with rat IgG and anti-SWAP antibody activity. Antibody-dependent MIA titres were much lower than for APC-dependent MIA. Based upon light microscope and transmission EM studies, immobilization of miracidia by APC activation was attributed to severe tegumental damage. Miracidia within egg shells were insensitive to MIA.

Animals↗
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

C7 deficiency in an Irish family: a deletion defect which is predominant in the Irish.

Human deficiencies of terminal complement components are known to be associated with increased susceptibility to Neisseria meningitidis infection. Polymorphic DNA marker studies in complement deficient investigations allow identification of haplotypes associated with the deficiency and enable the possible identification of heterozygote carriers of the defect. We report studies of an Irish family in which the index case had suffered recurrent meningococcal disease and was found to be deficient in the seventh component of complement (C7). The availability of all family members enabled us to determine the segregating haplotypes. The defects in the family segregated with two very closely related C6 and C7 DNA haplotypes, one of which is known to be associated with the large Irish C7 DNA deletion defect. The index case and two C7 deficient siblings were found to be homozygous for this defect, a deletion that spans approx. 6.8 kbp and encompasses exons 7 and 8. The deletion defect of exons 7 and 8 of C7 has been found in homozygous form in another C7 deficient Irish individual, and is present in heterozygous form in C7 deficient members of a third Irish family. Therefore, this deletion defect occurs in five of the six deficient chromosomes of these three unrelated Irish families, raising the interesting question of how prevalent this defect may be within the Irish community.

Blotting, Southern↗
PubMed1987

Release of leukotriene B4 from sublethally injured oligodendrocytes by terminal complement complexes.

In the present study, the interaction of the terminal complement complexes with oligodendrocytes was investigated for observation of its effect on membrane lipid hydrolysis. [14C]Arachidonic acid was incorporated into the membrane lipids of cultured oligodendrocytes before sensitization with anti-galactocerebroside antiserum. Cells were then exposed to excess C6-deficient rabbit serum reconstituted with limiting doses of C6 to form various numbers of C5b-9 complexes. Qualitative analysis of the supernatants by HPLC revealed the presence of compounds that coeluted with arachidonic acid and its oxygenated derivatives, prostaglandin E2, leukotrienes E4 and B4, and 15-hydroxyeicosatetraenoic acid. The kinetics of leukotriene B4 release by excess C5b-8 was quantitated by radioimmunoassay. Leukotriene B4 release approached a maximum around 30 min, and C6 dose-response studies performed at 1 h showed that maximal levels of leukotriene B4 were detected over a range of sublytic C5b-9 attack. Maximal release of leukotriene B4 was also achieved by C5b-8 without further enhancement by addition of lytic doses of C9. Results indicate that sublytic attack of oligodendrocytes by complement induces release of lipid-derived inflammatory mediators.

Animals↗
PubMed1985

Immune immobilization of Treponema pallidum: antibody and complement interactions revisited.

The Treponema pallidum immobilization test was designed for serodiagnosis of syphilis and is dependent upon specific antibody and a heat labile component of normal serum. Investigators have shown the component to be dependent upon divalent cations and it is presumed to be complement. Experiments were performed to reevaluate the interactions of antibody and complement and the mechanism of immobilization. The loss of treponemal motility was correlated to the loss of complement activity in the reaction mixture. When motility of treponemes incubated with immune serum IgG and complement had dropped to 50% (3.4 h), 72% of the available complement had been consumed. At the same time, treponemes incubated with normal serum IgG and complement were 82% motile and only 51% of the complement had been consumed. C6 deficient rabbit serum and C4 deficient guinea pig serum were used in conjunction with immune serum IgG to determine which components of the complement cascade were necessary for immobilization. Treponemes were not immobilized by either sera. Results suggest that the heat labile factor in normal sera is complement, that both early and late components of the complement cascade are necessary, and that the reaction proceeds via the classical complement pathway. Although T. pallidum is susceptible to the actions of antibody and complement, the organisms must interact with these components for at least 2 h before immobilization will result.

Animals↗