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PubMed1984

The role of natural agglutinins and trypanolytic activity in host specificity of Trypanosoma musculi.

Trypanolytic activity and agglutinins for T. musculi were demonstrated in sera from refractory hosts. The agglutinins in human and bovine serum were specific antibodies. The trypanolytic activity was a result of the ability of the trypanosomes to activate complement in these normal sera. The results suggested that Trypanosoma musculi activates human complement by the alternative pathway. The activity was inhibited by EDTA but not EGTA, and trypanosome lysis occurred in the absence of C2. In addition, conversion of C3 occurred in the presence of EGTA. The trypanolytic activity of bovine serum was similarly inhibited by EDTA but not EGTA. Trypanosome lysis failed to occur in C6 deficient rabbit serum, showing that the late components of complement are required for parasite lysis. Trypanosome lysis by human or bovine serum was inhibited by the addition of mouse serum but not rat serum. These observations suggest that the presence of trypanolytic activity and antibodies to this trypanosome in sera of normal mammals may be responsible for the restricted host range of the trypanosome, and that the absence of these antibodies and the ability of this parasite to evade the trypanolytic activity enables T. musculi to establish infections in the mouse.

Agglutination Tests↗
PubMed2001

ApoE(-/-) mice develop atherosclerosis in the absence of complement component C5.

Previous studies have suggested that the terminal complex of complement may contribute to the pathogenesis of atherosclerosis. C5b-9 complexes colocalize with the extracellular lipid in the aortic intima of hypercholesterolemic rabbits, and C6-deficient rabbits develop less atherosclerosis than controls. To test the role of complement in atherosclerosis in a different animal model, C5 deficient (C5def) mice were cross-bred with atherosclerosis susceptible apoE(-/-) mice, generating mice deficient in both apoE and C5 and control apoE(-/-) mice. Progeny were typed for C5 titer and serum cholesterol levels. Both male and female mice were fed a high fat diet from weaning until 22 weeks of age. At that time there were no significant differences in plasma cholesterol or triglycerides between apoE(-/-) control and apoE(-/-)/C5def groups. Morphometric analysis of the aortic root lesions gave mean (+/-SEM) lesion areas for male apoE(-/-) and apoE(-/-)/C5def mice of 468,176 +/- 21,982 and 375,182 +/- 53,089 microm(2), respectively (n = 10 each, P value = 0.123). In female apoE(-/-) mice (n = 5), the mean lesion area was 591,981 +/- 53,242 microm(2), compared to 618,578 +/- 83,457 microm(2) for female apoE(-/-)/C5def mice (n = 10) (P value = 0.835). Thus neither male nor female mice showed a significant change in lesion area when C5 was not present. In contrast to the case in the hypercholesterolemic rabbit, activation of the terminal complex of complement does not play a major role in the development of atherosclerosis in apoE(-/-) mice.

Animals↗
PubMed1975

Acute anaphylaxis associated with serum complement depletion.

A 45-year-old woman with rheumatoid arthritis developed anaphylaxis 6 min after receiving a subcutaneous injection of lidocaine, followed by an intra-articular injection of lidocaine mixed with methprednisolone acetate. One hour after the onset of anaphylaxis, serum complement component levels were markedly depressed and remained so far 18 hr. Circulating immune complexes and antibodies to lidocaine could not be demonstrated. Neither lidocaine nor methylprednisolone acetate activated the patient's complement system in vitro. Subsequently, total hemolytic activity (CH50) levels were variable, complement component protein concentrations of C1q, C1s, C4, C2, C3, C5, C6, C9, and Factor B were normal, but hemolytic activity of C4 and C2 was diminished. Serum C1 inhibitor concentrations were normal or slightly depressed. The patient has never had any symptoms suggestive of angiodema. It is postulated that the endogenous complement abnormality present in this patient may have contributed to the anaphylactic reaction.

Anaphylaxis↗
PubMed1987

Molecular mechanisms of cytotoxicity: comparison of complement and killer lymphocytes.

The membrane attack complex of complement is an amphiphilic fusion product of 5 glycoproteins, C5, C6, C7, C8 and C9. The membrane attack complex forms transmembrane channels that vary in size depending on the number of C9 molecules incorporated into the complex. The C5b-8 complex forms small channels and at high multiplicity can kill nucleated cells. At least 12 C9 molecules are required to form tubular poly C9 which evokes the ultrastructural image of the classical membrane lesion produced by complement. The membranes of erythrocytes and other blood cells contain a 70,000 dalton protein that can inhibit channel formation by the membrane attack complex. This protein is species specific and has been called homologous restriction factor. A cytotoxic protein immunochemically related to C9 was isolated from cytotoxic human large granular lymphocytes and from OKT3 activated human peripheral blood mononuclear cells. In the presence of Ca++, isolated C9 related protein (C9RP) formed circular structures that resembled poly C9. C9RP efficiently killed K562 cells, human melanoma cells, Raji cells and human large granular lymphocytes. The results suggest that the channel forming protein of cytotoxic lymphocytes and C9 of complement have a common evolutionary ancestry.

Complement C9↗
PubMed2005

Role of the surface charges D72 and K8 in the function and structural stability of the cytochrome c from Nostoc sp. PCC 7119.

We investigated the role of electrostatic charges at positions D72 and K8 in the function and structural stability of cytochrome c6 from Nostoc sp. PCC 7119 (cyt c6). A series of mutant forms was generated to span the possible combinations of charge neutralization (by mutation to alanine) and charge inversion (by mutation to lysine and aspartate, respectively) in these positions. All forms of cyt c6 were functionally characterized by laser flash absorption spectroscopy, and their stability was probed by urea-induced folding equilibrium relaxation experiments and differential scanning calorimetry. Neutralization or inversion of the positive charge at position K8 reduced the efficiency of electron transfer to photosystem I. This effect could not be reversed by compensating for the change in global charge that had been introduced by the mutation, indicating a specific role for K8 in the formation of the electron transfer complex between cyt c6 and photosystem I. Replacement of D72 by asparagine or lysine increased the efficiency of electron transfer to photosystem I, but destabilized the protein. D72 apparently participates in electrostatic interactions that stabilize the structure of cyt c6. The destabilizing effect was reduced when aspartate was replaced by the small amino acid alanine. Complementing the mutation D72A with a charge neutralization or inversion at position K8 led to mutant forms of cyt c6 that were more stable than the wild-type under all tested conditions.

Cytochromes c6↗
PubMed1985

Effect of different sulfonamides on the human serum complement system.

Incubation of normal human serum with different sulfonamides led to a dose-dependent inactivation of total hemolytic complement activity. A decrease of the activities of C1, C2, C3, C5 and one or several of the components C6-9 was observed after treatment of normal human serum with the sulfonamide sulfisomidine. Inactivation of complement components by sulfonamides seems to result from direct interaction with the drug as well as, to a minor extent, from activation of the alternative pathway. At relatively high concentrations, sulfonamides caused a conformational change in C3 and C4. The observed structural change is equivalent to that induced by cleavage of the internal thiolester bond in these molecules. The generation of such structurally altered C3 (C3b-like C3) as well as an antagonizing effect of sulfonamides towards the action of the regulatory protein factor I might be responsible for alternative pathway activation. The physiological relevance in vivo of the observed effects of sulfonamides remains to be assessed.

Complement C3↗
PubMed1994

Silica induced suppression of the production of third and fifth components of the complement system by human lung cells in vitro.

Although investigations to date have demonstrated the ability of the monocyte/macrophage to synthesize complement components, only a limited number of studies on complement synthesis by nonhepatic tissue cells have been reported. To begin to fill this gap in our knowledge we have recently evaluated the ability of lung tissue cells to synthesize and secrete various complement components in vitro. Using 35S-methionine incorporation and immunoprecipitation techniques we have previously demonstrated the ability human lung type II pneumocytes (A549) and human lung fibroblasts (WI-38), to synthesize and secrete a variety of both early and terminal complement components, as well as several regulatory proteins including Clr, Cls, C4, C3, C5, C6, C7, C8, C9, Factor B, Factor H, Factor I and Cls inactivator. Our present studies demonstrate the capability of silica to regulate complement component production by A549 cells, but not complement component production by WI-38 cells. Specifically, using sensitive ELISAs we demonstrated that a non-toxic dose of silica had the capability to suppress the production of both C3 and C5 by A549 pneumocytes by 40-50 percent, but had no effect on C3 or C5 synthesis by WI-38 fibroblasts. Additionally, using 35S-methionine incorporation and TCA precipitation techniques, we demonstrated that suppression of C3 and C5 production by silica treated A549 pneumocytes was not a result of suppression of total protein synthesis. These studies demonstrate that silica, which has been implicated in pulmonary diseases, has the capability to regulate local complement production by lung tissue cells in vitro. In vivo, this suppression of complement production by the type II pneumocytes could alter the local tissue reservoir of complement components during infection and pulmonary injury, thus resulting in depressed pulmonary host defense.

Cell Line↗
PubMed1998

The fluffy gene of Neurospora crassa encodes a Gal4p-type C6 zinc cluster protein required for conidial development.

Neurospora crassa fluffy (fl) mutants are unable to produce macroconidia. We cloned the fl gene to determine its role in regulating conidiation. A cosmid clone containing fl was identified by complementation. The sequence of fl revealed that it encodes a Gal4p-type C6 zinc cluster protein with greatest similarity to the N. crassa NIT4 protein that regulates genes required for nitrate utilization. Analysis of several fl mutant alleles demonstrated that null mutants are blocked in the budding phase of development required to produce conidiophores. fl mRNA is transiently induced just prior to the developmental commitment to budding growth. This timing of fl expression is consistent with a role for FL protein in activation of the previously characterized conidiation-specific (con) genes, con-6 and con-10. These data suggest that FL acts as a developmentally regulated transcription factor required for conidiophore morphogenesis.

Amino Acid Sequence↗
PubMed1975

Activation of the properdin pathway of complement in patients with gram-negative bacteremia.

To determine the pathway used for activation of complement component C3, serum levels of components C1, C4, C2, C3, C5, C6, and C9 and two properdin factors, properdin and factor B, were measured in 42 patients with gram-negative bacteremia, in 19 of whom shock subsequently developed. Mean levels of the classical components C1, C4, and C2 in bacteremic patients in whom shock subsequently developed did not differ significantly (p greater than 0.05) from those of patients with uncomplicated bacteremia. Levels of properdin, factor B and C3, C5, C6, and C9 were significantly (p less than 0.05) decreased in patients with shock in comparison with those with uncomplicated bacteremia. Taken together, these findings are consistent with activation of C3 and the terminal complement sequence, C5-C9, occurring primarily by the properdin pathway, in patients with gram-negative bacteremia eventuating in shock. Biologically active products released during activation of C3-C9 may contribute to the development of shock.

Bacteria↗
PubMed1975

Complement fixation by rheumatoid factor.

The capacity for fixation and activation of hemolytic complement by polyclonal IgM rheumatoid factors (RF) isolated from sera of patients with rheumatoid arthritis and monoclonal IgM-RF isolated from the cryoprecipitates of patients with IgM-IgG mixed cryoglobulinemia was examined. RF mixed with aggregated, reduced, and alkylated human IgG (Agg-R/A-IgG) in the fluid phase failed to significantly reduce the level of total hemolytic complement, CH50, or of individual complement components, C1, C2, C3, and C5. However, sheep erythrocytes (SRC) coated with Agg-R/A-IgG or with reduced and alkylated rabbit IgG anti-SRC antibody were hemolyzed by complement in the presence of polyclonal IgM-RF. Human and guinea pig complement worked equally well. The degree of hemolysis was in direct proportion to the hemagglutination titer of the RF against the same coated cells. Monoclonal IgM-RF, normal human IgM, and purified Waldenström macroglobulins without antiglobulin activity were all inert. Hemolysis of coated SRC by RF and complement was inhibited by prior treatment of the complement source with chelating agents, hydrazine, cobra venom factor, specific antisera to C1q, CR, C5, C6, or C8, or by heating at 56 degrees C for 30 min. Purified radiolabeled C4, C3, and C8 included in the complement source were bound to hemolysed SRC in direct proportion to the degree of hemolysis. These data indicate that polyclonal IgM-RF fix and activate complement via the classic pathway. The system described for assessing complement fixation by isolated RF is readily adaptable to use with whole human serum.

Animals↗
PubMed2002

C-reactive-protein-associated increase in myocardial infarct size after ischemia/reperfusion.

C-Reactive protein (CRP), a marker for acute inflammation, is associated with increased risk of cardiovascular events. The mechanism underlying this association is uncertain. An acute inflammatory response was induced in rabbits by subcutaneous injection of croton oil (CO) 1 to 3 days before 30 min of regional myocardial ischemia/180 min of reperfusion. CO treatment increased plasma CRP from below the limit of detection to 2.5 +/- 0.5 mg/dl and was associated with an increase in infarct size expressed as percentage of risk region [32 +/- 6% vehicle controls (n = 7) to 47 +/- 9% CO-treated rabbits (n = 7; P < 0.05]. After 10 min of ischemia and 180 min reperfusion, no infarct was found in controls; however, an infarct of 7 +/- 1% was found in CO-treated rabbits (P < 0.05; CRP, 2.3 +/- 0.4 mg/dl). The CRP-related increase in infarct size was not observed in croton oil-treated, C6-deficient rabbits (n = 5/group), indicating the involvement of complement. In these rabbits, infarct size was 22 +/- 2% (P < 0.05) despite having plasma CRP of 4.3 +/- 0.4 mg/dl. The CRP-associated increase in infarct size was ameliorated by pretreatment with heparin (n = 7; infarct size 33 +/- 3%; CRP, 2.3 +/- 0.3 mg/dl; P < 0.05) or N-acetylheparin (n = 7; infarct size 23 +/- 4%; CRP, 3.1 +/- 0.5 mg/dl; P < 0.05). These observations may explain why increased serum CRP is associated with an augmented risk for cardiovascular events.

Animals↗
PubMed1989

Distribution of complement in the sclera.

In the present study, we compared hemolytic activities of C1, C4, C2, C3, C5, C6 and C7 in the anterior and posterior sclera. Additionally, we used radial immunodiffusion to measure levels of Factor B, IgG, IgA and albumin in the anterior and posterior sclera. Except for C1, complement levels were significantly higher in the posterior than anterior sclera. Additionally, levels of immunoglobulins as well as albumin were significantly higher in the posterior than anterior sclera. These results suggest that the posterior sclera has a better adjacent vascular supply than the anterior sclera. On the other hand, the results of this study show that the anterior sclera has more C1, the recognition unit of the classical pathway, than the posterior sclera. Because there is nearly twice as much C1 in the anterior sclera, it may be easier for antigen-antibody complexes, whether formed in the sclera itself or derived from the neighboring vessels, to set off the complement cascade in the anterior sclera. This finding may help explain why scleritis associated with immune complex disease is more common in the anterior than posterior sclera.

Adult↗
PubMed2005

Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis.

Neisseria meningitidis (meningococcus) is an important cause of meningitis and sepsis. Currently, there is no effective vaccine against serogroup B meningococcal infection. Host defense against neisseriae requires the complement system (C) as indicated by the fact that individuals deficient in properdin or late C components (C6-9) have an increased susceptibility to recurrent neisserial infections. Because the classical pathway (CP) is required to initiate efficient complement activation on neisseriae, meningococci should be able to evade it to cause disease. To test this hypothesis, we studied the interactions of meningococci with the major CP inhibitor C4b-binding protein (C4bp). We tested C4bp binding to wild-type group B meningococcus strain (H44/76) and to 11 isogenic mutants thereof that differed in capsule expression, lipo-oligosaccharide sialylation, and/or expression of either porin (Por) A or PorB3. All strains expressing PorA bound radiolabeled C4bp, whereas the strains lacking PorA bound significantly less C4bp. Increased binding was observed under hypotonic conditions. Deleting PorB3 did not influence C4bp binding, but the presence of polysialic acid capsule reduced C4bp binding by 50%. Bound C4bp remained functionally active in that it promoted the inactivation of C4b by factor I. PorA-expressing strains were also more resistant to C lysis than PorA-negative strains in a serum bactericidal assay. Binding of C4bp thus helps Neisseria meningitidis to escape CP complement activation.

Amino Acid Sequence↗
PubMed1987

Complement activity in normal rabbit bronchoalveolar fluid. Description of an inhibitor of C3 activation.

Hemolytically active C4, C3, C5, and C6, and trace amounts of C1, were present in bronchoalveolar lavage fluid from healthy adult rabbits. Both the alternative and classical pathways were functionally intact through C5. Complement depletion by intravascularly administered cobra venom factor caused a parallel decrease in lavageable C5 from the rabbit's lungs. Whereas BALF C5 had specific activity comparable to serum C5, that of BALF C3 was lower than predicted. This was found to be due to the action of a substance that selectively blocked C3 activation. The inhibitor did not cause irreversible inactivation of C3, and it had no effect on C5 activity. It blocked the formation of EAC423 from EAC42 + C3, but not the lysis of preformed EAC423 + C5-9 or EAC423 rosetting with rabbit neutrophils. Hydrophobic chromatography of BALF separated the activity of the inhibitor from that of C3. Further chromatography showed that it had a net negative charge at physiologic pH, and molecular weight between 14 and 30 kilodaltons. The presence of an inhibitor of C3 activation in the airways would provide control of complement activation in an environment that is constantly exposed to bacteria, dust, and other potential inflammatory stimuli.

Animals↗
PubMed1991

Biochemical characterization of a spearmint mutant that resembles peppermint in monoterpene content.

A radiation-induced mutant of Scotch spearmint (Mentha x gracilis) was shown to produce an essential oil containing principally C3-oxygenated p-menthane monoterpenes that are typical of peppermint, instead of the C6-oxygenated monoterpene family characteristic of spearmint. In vitro measurement of all of the enzymes responsible for the production of both the C3-oxygenated and C6-oxygenated families of monoterpenes from the common precursor (-)-limonene indicated that a virtually identical complement of enzymes was present in wild type and mutant, with the exception of the microsomal, cytochrome P-450-dependent (-)-limonene hydroxylase; the C6-hydroxylase producing (-)-trans-carveol in the wild type had been replaced by a C3-hydroxylase producing (-)-trans-isopiperitenol in the mutant. Additionally, the mutant, but not the wild type, could carry out the cytochrome P-450-dependent epoxidation of the alpha,beta-unsaturated bond of the ketones formed via C3-hydroxylation. Although present in the wild type, the enzymes of the C3-pathway that convert trans-isopiperitenol to menthol isomers are synthetically inactive because of the absence of the key C3-oxygenated intermediate generated by hydroxylation of limonene. These results, which clarify the origins of the C3- and C6-oxygenation patterns, also allow correction of a number of earlier biogenetic proposals for the formation of monoterpenes in Mentha.

Journal Article↗
PubMed1973

Membrane lesions in immune lysis: surface rings, globule aggregates and transient openings.

It is known that there are 100 A-wide circular structures associated with the erythrocyte membrane in immune lysis. To determine whether these structures were functional holes extending through the membrane, freeze-etch electron microscopy was carried out. Sheep erythrocytes incubated with either rabbit complement or rabbit antibody (anti-sheep erythrocyte antibody) did not hemolyze and did not reveal any abnormalities in freeze-etch or negative-stain electron microscopy. Erythrocytes incubated with both complement and antibody revealed rings on the extracellular surface (etch face) of the cell membrane. Allowing for the 30 A-thick Pt/C replica, the dimensions of the surface rings were similar to those seen by negative staining. The ring's central depression was level with the plane of the membrane; some rings were closed circles, others were crescent shaped. The cleavage face of the extracellular leaflet revealed globule aggregates, each aggregate appearing to be composed of about four fused globules. The cleavage face of the cytoplasmic leaflet was normal. When immune lysis was carried out in the presence of ferritin, ferritin was subsequently detected in all lysed erythrocytes. If ferritin was added after immune lysis was complete, only 15% of the cells were permeated by ferritin, indicating that transient openings exist in the cell membrane during immune lysis. No abnormal structures were detected when C6-deficient rabbit serum was used as a source of complement. It is concluded that antibody and complement produce surface rings, prelytic leakage of K(+), colloid osmotic swelling, membrane disruption, and membrane resealing; the surface rings persist after these events.

Animals↗
PubMed1969

Immunological induction of increased vascular permeability. II. Two mechanisms of histamine release from rabbit platelets involving complement.

Two mechanisms have been described whereby rabbit platelets in vitro may be induced to release their contained histamine by the reaction of antigen and antibody. Both processes require the participation of the complement system. In the first, the adherence of platelets to particulate antigens such as zymosan or erythrocytes which have fixed complement through the third component was followed by histamine release. Plasma lacking C6 activity was fully active in this system. In the second mechanism, the reaction of soluble antigen with antibody in the presence of plasma also caused release of histamine from platelets and platelet clumping was observed. The release process, which appeared to follow the adherence of platelets to the immune complex, required the action of C6 and perhaps the later-acting components. No evidence could be obtained that a soluble factor was produced which caused the release. Instead, an inhibitor of the release process was detected after incubation of antigen, antibody, and plasma. Antibody preparations capable of giving complement-dependent PCA reactions in rabbits were also shown to induce the release of histamine from platelets in vitro.

Animals↗
PubMed1990

Scleral fibroblasts. Human leukocyte antigen expression and complement production.

The authors investigated the ability of recombinant human gamma-interferon (rhIFN-gamma) to influence production of complement and expression of human leukocyte antigens (HLA) by human scleral fibroblasts in culture. Cell cultures were established by explanting sclera from normal human donor eyes. To study complement production, fibroblasts were treated with 500 units/ml rhIFN-gamma in cell culture, and media were tested for complement components by hemolytic assay after 0, 1, 3, 6, 9, and 11 days. To induce Class II HLAs, fibroblasts were exposed to rhIFN-gamma at concentrations ranging from 10-500 units/ml and incubated for 1, 3, and 6 days. The HLAs were detected by immunofluorescence in conjunction with flow cytometry. Class I antigen was detected using a monoclonal antibody directed against beta 2-microglobulin. Class II histocompatibility antigens were identified using monoclonal antibodies specific for HLA-DR, -DP, and -DQ. Although complement component C1 was produced constitutively in cell culture, the addition of rhIFN-gamma resulted in an increase in production. Complement components C2 and C4 were detected only after treatment with rhIFN-gamma. Complement production was completely inhibited by cycloheximide, and C3, C5, C6, and C7 were not present in cell culture media with or without rhIFN-gamma. Class I antigen was present on all cells before induction, and an increase in expression was noted after exposure to rhIFN-gamma. Class II antigens were absent before induction with rhIFN-gamma. After treatment with rhIFN-gamma, scleral fibroblasts expressed HLA-DR, -DP, and -DQ in a dose-dependent, time-related fashion. These findings suggest that rhIFN-gamma has multiple effects on scleral fibroblasts: (1) increased production of C1, (2) production of C2 and C4, (3) up-regulation of Class I antigen expression, and (4) expression of Class II antigens. They also suggest that scleral fibroblasts have the potential to participate in immunologic diseases of the eye.

Adult↗