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PubMed1992

Bacterial evasion of the antibody response: human IgG antibodies neutralize soluble but not bacteria-associated group B streptococcal C5a-ase.

Most strains of group B streptococci (GBS) possess an enzyme that inactivates the human anaphylatoxin C5a by cleaving a heptapeptide from the carboxyl terminus of C5a. This enzyme, called GBS C5a-ase, has been purified to homogeneity and cleaves and inactivates C5a in physiologic buffer. The enzymatic activity of soluble C5a-ase is completely inhibited, however, in the presence of plasma or serum from normal human adults. The neutralization of soluble C5a-ase by plasma and serum results largely from naturally occurring IgG antibodies directed against C5a-ase. IgG does not neutralize C5a-ase present on intact encapsulated type III GBS but does neutralize the C5a-ase activity associated with a transposon-induced mutant strain of type III GBS that lacks capsule. The location of GBS C5a-ase on the surface of encapsulated type III GBS permits the C5a-ase to inactivate C5a while evading neutralization by IgG antibodies.

Adhesins, Bacterial↗
PubMed1972

The relationship of the chemotactic behavior of the complement-derived factors, C3a, C5a, and C567, and a bacterial chemotactic factor to their ability to activate the proesterase 1 of rabbit polymorphonuclear leukocytes.

The inhibition profiles obtained when a series of p-nitrophenyl ethyl alkylphosphonates and of p-nitrophenyl ethyl chloroalkylphosphonates were used to interfere with the chemotactic activity of polymorphonuclear leukocytes stimulated by C3a, C5a, and bacterial factor were the same as found previously when C567 was the chemotactic agent. This indicates that as in the chemotactic activity induced by C567, an obligatory step in the chemotaxis caused by C3a, C5a, and bacterial factor is the activation of proesterase 1 of the rabbit polymorphonuclear leukocyte. C5a and C3a activate proesterase 1 of peripheral blood polymophonuclear leukocytes as measured by the increase of acetyl DL-phenylalanine beta-naphthyl esterase activity. Attempts to detect in a like manner the proesterase 1 of the same leukocytes using bacterial factor under varying circumstances have consistently failed. It is concluded that bacterial factor, for unknown reasons, is unable to activate proesterase 1 to the same extent as the complement-derived chemotactic factors. The hypothesis of there being a quantitative difference in the ability of bacterial factor to activate proesterase 1 compared with the complement-derived factors explains the previous observations that bacterial factor can not deactivate to itself or to the complement-derived factors, although these latter factors can deactivate to themselves, to each other, and to the bacterial factor. The quantitative difference in the ability of bacterial factor to activate proesterase 1 compared to the complement-derived factors is also associated with and explains the finding that the maximal chemotactic activity attainable when bacterial factor is the chemotactic agent is distinctly less than that obtained using either C3a, C5a, or C567. These results indicate that the activation of proesterase 1 is a general requirement for the chemotactic activity of rabbit polymorphonuclear leukocytes with known macromolecular chemotactic agents and suggest that under several different circumstances the level of chemotactic activity attained is related to the degree of such activation.

Animals↗
PubMed1984

Regulation of neutrophil migratory function in burn injury by complement activation products.

Polymorphonuclear neutrophils were isolated from patients with burn injury and random mobility, chemotaxis in response to C5adesArg (as agarose-activated control serum) and to N-formyl-methionyl-leucyl-phenylalanine (F-Met-Leu-Phe) were assessed. For a group of eight patients identified as not experiencing systemic infection, all three neutrophil migratory functions were observed to fall below control levels, beginning 4 to 6 days following burn injury, and to return to control levels after 21 to 30 days of hospitalization. Over this time the chemotactic differential (distance chemotactic migration-distance random migration) for F-Met-Leu-Phe remained positive, while the chemotactic differential for activated serum became nil after postburn day 4. This temporal, specific loss of a chemotactic response to activated serum was associated with rises in immunoreactive plasma C3a and C5a. This pattern of loss of chemotactic function was associated with a selective loss of C5a but not F-Met-Leu-Phe binding activity. These results demonstrate that burn injury can alter neutrophil migratory functions generally, and specifically depress chemotactic responsiveness to activated serum. The mechanism of the latter phenomenon appears to be related to desensitization of circulating neutrophils to C5a due to complement activation.

Adolescent↗
PubMed1989

Decreased releasability of basophils from patients with cold urticaria after cold exposure.

Histamine release from peripheral blood basophils challenged with C5a, f-met-peptides and calcium ionophore was studied in patients with cold urticaria before and after exposure to low environmental temperatures. Compared to healthy controls, stimulated mediator release before cold exposure was increased in 7 of 11 patients. When challenged by cold exposure mediator release from in vitro-stimulated basophils was decreased. This decrease was more pronounced after stimulation with receptor-mediated stimuli (e.g. C5a) as compared to receptor-unrelated stimuli, e.g. calcium ionophore. In 4 of 11 patients stimulated mediator release before cold exposure was moderately increased. Also after cold exposure only a weak decrease of stimulated histamine release was seen. Levels of activated complement components (C3a) before and after cold exposure failed to provide evidence for complement activation in vivo. Also the number of circulating basophils as well as their cellular histamine content remained normal after cold exposure. The results show that in these patients release of histamine is altered before and after cold exposure. These changes in basophil responsiveness are not due to complement activation in vivo.

Basophils↗
PubMed1984

Selective inhibition by phenytoin of chemotactic factor - stimulated neutrophil functions.

We have found that pretreatment of human neutrophils with phenytoin (0.05 to 0.8 mM) results in concentration-dependent, reversible inhibition of both superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme, beta-glucuronidase) provoked by either the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP) or the complement fragment C5a. In contrast, phenytoin did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate or serum-opsonized zymosan particles. Phenytoin did not provoke leakage from neutrophils of the cytoplasmic enzyme, lactate dehydrogenase, and did not inhibit directed migration (chemotaxis) of neutrophils toward either FMLP or C5a. Specific binding of 3H-FMLP to neutrophil membrane receptors was not altered significantly by pretreatment of the cells with a wide range of concentrations of phenytoin. With flow microfluorometry and the fluorochrome, 3,3'-dipentyloxacarbocyanine, phenytoin was shown to prevent FMLP-induced changes in fluorescence intensity (i.e., apparent neutrophil membrane depolarization). These data indicate that various neutrophil functions may be regulated independently at other than the receptor level and that neutrophil chemotactic responses to FMLP and C5a do not appear to be dependent on membrane events registered by 3,3'-dipentyloxacarbocyanine.

Animals↗
PubMed1988

C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism.

Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

In vitro cleavage by asbestos fibers of the fifth component of human complement through free-radical generation and kallikrein activation.

Chrysotile and crocidolite fibers incubated in normal human plasma (NHP) generated from the C5 component of complement C5a-type fragments that stimulated polymorphonuclear leukocyte (PMN) chemotaxis. Absorption of NHP with antiserum against C5a totally abolished neutrophil chemotactic activity. Asbestos fibers also produced C5a small peptides in the presence of ethylene glycol bis(beta-aminoethyl ether) N,N,N'N'-tetraacetic acid (EGTA) but not ethylene diamine tetraacetic acid (EDTA). Activation of C5 was significantly inhibited when asbestos fibers were pretreated with iron chelators such as sodium dithionite (DTN), deferoxamine (DFX), or ascorbate (AA). Concentration-related inhibition of C5 activation was also observed when asbestos fibers were added concurrently to plasma in the presence of DFX, 1,3-dimethyl-2-thiourea (DMTU), a strong hydroxyl scavenger, or aprotinin (APR), a specific protease inhibitor. Further, chrysotile and crocidolite significantly increased plasma kallikrein activity. Data demonstrate that asbestos-induced C5 activation plays a role in inflammatory reactions characteristic of asbestosis through mechanisms involving iron ions, hydroxyl radicals, and oxidized C5-ike fragments. The ferrous ions present at the asbestos fiber surface trigger this activation and catalyze, via Fenton reaction, the production of hydroxyl radicals, which in turn convert native C5 to an oxidized C5-like form. This product is then cleaved by kallikrein, activated by the same asbestos fibers, yielding an oxidized C5a with the same functional properties as C5a.

Adult↗
PubMed2000

[From gene to disease; marenostrine and familial Mediterranean fever].

Familial mediterranean fever (FMF) is an autosomal recessive hereditary disorder associated with mutations in the gene on chromosome 16 encoding the protein pyrine (marenostrine). Marenostrine is thought to stimulate the production of an inactivator of a chemotactic factor (possibly C5a). The mutations result in ongoing inflammation, a hallmark of FMF. DNA diagnosis of FMF is operational in Leiden University, the Netherlands, for one year now.

Complement C5a↗
PubMed1987

Induction of chemotaxis in mouse peritoneal macrophages by activators of protein kinase C.

Two activators of calcium and phospholipid dependent protein kinase (protein kinase C), the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and the synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG), were compared as chemotactic agents for mouse peritoneal macrophages. Both of these compounds were found to induce chemotaxis in the macrophages to a similar extent in a time and dose dependent manner. Induction of chemotaxis was observed in the concentration range of 10-100 nM for TPA and 25-250 microM for OAG. Two structurally related synthetic sn 1,2-diacylglycerols, 1,2-dioctanoylglycerol (diC8) and 1,2-didecanoylglycerol (diC10), were also found to be chemotactic for macrophages, while monoacylglycerol (2-monoolein) was inactive. Of the diacylglycerols, OAG was found to be the most active followed by diC8 and diC10. In contrast to TPA, the synthetic diacylglycerols had no effect on superoxide anion release by the cells, suggesting that the mechanism of superoxide anion release by TPA in macrophages is distinct from chemotaxis. Phorbol-12,13-diacetate, a biologically inactive phorbol ester analog that inhibits the binding of TPA to its cellular receptors, inhibited macrophage chemotaxis induced by TPA, the synthetic diacylglycerols, and the complement fragment, C5a. Taken together, our results suggest that chemotaxis in macrophages may be mediated by activation of protein kinase C.

Animals↗
PubMed1993

Complement fragment C3a stimulates Ca2+ influx in neutrophils via a pertussis-toxin-sensitive G protein.

The signal pathways of neutrophils following stimulation with the complement fragment C3a (C3a) were studied in neutrophils and compared to the pathways activated by complement fragment C5a (C5a). Analysis of polyphosphoinositol lipid turnover showed that C5a, but not C3a, activated phosphatidylinositol-bisphosphate-3-kinase (PtdInsP2 3-kinase) indicating that different signal pathways are activated by the two anaphylatoxins. To examine whether C3a stimulated Ca2+ transients, cytosolic free Ca2+ levels were analyzed in Fluo-3-labelled neutrophils by flow cytometry. C3a stimulated a fast and concentration-dependent increase of cytosolic free Ca2+. Comparison of the C3a response with that of C5a revealed a more pronounced C5a-triggered Ca2+ rise. Addition of EGTA to the extracellular buffer prior to stimulation did not significantly alter the initial Ca2+ rise at low C5a concentrations, but reduced the time course of the Ca2+ transients at high concentrations. In marked contrast, EGTA completely blocked the Ca2+ response stimulated by C3a in neutrophils labeled with either Indo-1/AM or Fluo-3. Preincubation of neutrophils with pertussis toxin inhibited both C3a- and C5a-stimulated Ca2+ transients, indicating the involvement of guanine-nucleotide-binding proteins (G proteins) in these processes. In order to examine whether the C3a receptor is coupled to G proteins, binding of guanosine 5'-O-(3-[35S]thiotriphosphate) ([35S]GTP[S]) to purified neutrophil plasma membranes was studied. Both C3a and C5a stimulated high-affinity binding of [35S]GTP[S] up to 1.5-fold and 3-fold, respectively. These data suggest that the two anaphylatoxins activate pertussis-toxin-sensitive G proteins, which then trigger different signal transduction pathways. C3a specifically stimulated Ca2+ influx from the extracellular medium, whereas C5a additionally activated the PtdInsP2 3-kinase and stimulated Ca2+ mobilization from intracellular stores.

Calcium↗
PubMed1982

Serum stimulatory activity and polymorphonuclear leucocyte movement in patients with fulminant hepatic failure.

Serum from 27 patients with fulminant hepatic failure and grade IV encephalopathy had reduced ability to stimulate the movement in vitro of normal polymorphonuclear leucocytes. All patients had a deficiency of serum complement factors C3 and C5 and there was a significant positive correlation between C5 and serum stimulatory activity. However, in addition to this complement defect, serum from 22% of patients contained an antagonist to normal serum stimulatory factors. This antagonism was attributed to at least two different substances in the serum on the basis of differences in heat lability, dialysability and action on complement factor C5a. Polymorphonuclear leucocytes from eight of 13 patients had reduced movement toward serum, but serum from only one patient contained an antagonist acting on the cells; this was probably related to an underlying carcinoma of the breast. During the early stages of clinical recovery, serum stimulatory and complement activity returned to normal. These serum and cellular defects have not been reported previously in patients with fulminant hepatic failure and represent major defects in the body's defenses against bacterial infection.

Adolescent↗
PubMed1997

Anaphylatoxins in fresh-frozen plasma.

BACKGROUND: Fresh-frozen plasma (FFP) is widely used in patients with coagulation disorders and simultaneous complement activation. Complement activation in FFP itself is poorly investigated. STUDY DESIGN AND METHODS: The concentration of anaphylatoxins C3a and C5a, the complement precursors C1q and factor B, and complement function were measured in 40 consecutively administered FFP units in two pediatric neonatal intensive care units. In 12 samples, the measurements were also performed after incubation with inulin. RESULTS: In 15 of 40 FFP units, both anaphylatoxin concentrations were below the upper cutoff levels reported for healthy humans (C3a, 500 microg/L; C5a, 5 microg/L). Anaphylatoxin levels were higher in FFP units produced by apheresis than in those from blood donation. Complement activation of FFP by inulin increased anaphylatoxin concentration, whereas C1q and factor B levels, and complement function remained unchanged. CONCLUSION: Elevated concentrations of anaphylatoxin are frequently found in FFP units produced by apheresis. Studies are necessary to investigate the reasons for complement activation and the possibilities of prevention during apheresis. As the concentrations of complement precursors and complement function did not change with activation in FFP, these studies should include measurement of the anaphylatoxins C3a and C5a.

Anaphylatoxins↗
PubMed2002

M(+) group a streptococci are phagocytized and killed in whole blood by C5a-activated polymorphonuclear leukocytes.

Historically, resistance to phagocytosis has been determined by incubating group A streptococci in human blood and comparing the numbers of CFU before and after incubation. Utilizing a flow cytometry-based technique, we have investigated the phagocytosis of M(+) group A streptococci by polymorphonuclear leukocytes (PMNs) in heparinized human peripheral whole blood. Intracellular labeling of streptococci with a nontoxic fluorescent dye allowed us to quantify the association and phagocytosis of M(+) streptococci by PMNs in whole blood in the presence or absence of C5a, a physiologically important chemotactic activator of PMNs. We found that wild-type strains of group A streptococci that are resistant to phagocytosis (determined by the classical Lancefield method) readily associate with C5a-activated whole-blood PMNs. In the absence of opsonizing M-type-specific antibodies, the M(+) streptococci associated with PMNs are phagocytized and killed. In addition, blockade of the beta(2) integrin, CD11b/CD18, with anti-human CD11b monoclonal antibody inhibited association between M(+) streptococci and C5a-activated PMNs. These findings establish a new relationship between M(+) streptococci and PMNs, in which C5a-activated PMNs have the capacity to kill M(+) streptococci in whole blood through a receptor-mediated phagocytic mechanism.

Antibodies, Monoclonal↗
PubMed1993

Complement 5a induces in vivo synthesis of cysteinyl leukotrienes in rats.

The complement derived anaphylatoxin complement 5a (C5a) is suggested to be involved in the pathogenesis of various types of diseases including endotoxic or anaphylactic shock. Studies in our laboratory demonstrated a marked and sustained reduction in renal blood flow and glomerular filtration rate after infusion of a low dose of recombinant C5a (rC5a). Renal rC5a effects were inhibited by leukotriene (LT) and thromboxane antagonists suggesting that the effects were mediated by LT. To elucidate the mechanisms of C5a effects, we monitored the biliary excretion rate of the stable metabolite, N-acetyl-LTE4, by reversed phase high performance liquid chromatography (HPLC). Rats in the experimental group were administered rC5a intravenously at 0.5 micrograms/min for 10 min. Biliary N-acetyl-LTE4 excretion was significantly increased following rC5a infusion, 0.03 ng/microliters bile to 0.129 ng/microliters. The bile flow in the experimental group was reduced about 39% by rC5a, while bile flow of the control group increased by 20% during the observation period. Infusion of rC5a resulted in an increase of arterial hematocrit from 44.7% to 48.7%, whereas blood pressure was not significantly altered in experimental and control groups. Our results suggest the in vivo effects of C5a to be mediated by cysteinyl leukotrienes, which may be important in the pathogenesis of septic, anaphylactic or traumatic shock.

Animals↗
PubMed1989

Histamine and sulfidoleukotriene release from human basophils: different effects of antigen, anti-IgE, C5a, f-Met-Leu-Phe and the novel neutrophil-activating peptide NAF.

Human blood leukocytes were challenged by IgE-dependent stimuli (antigens or anti-IgE antibodies) and the chemotactic agonists C5a, N-formyl-Met-Leu-Phe (fMLP) or NAF, a novel neutrophil-activating peptide produced by stimulated human monocytes. IgE-dependent stimuli induced abundant release of histamine and sulfidoleukotrienes (LTC, LTD and LTE). The effects of the chemotactic peptides differed considerably: C5a induced high percentages of histamine release already at concentrations as low as 10(-9) M, but no leukotriene formation: NAF was completely inactive up to 10(-6)M, and fMLP induced moderate release of both products at relatively high concentration only (1-2.5 x 10(-6) M). All three chemotactic peptides, however, induced a concentration-dependent release of elastase from cytochalasin-B-treated human neutrophils. The EC50 was approximately 0.3, 2 and 5 x 10(-9) M for C5a, NAF and fMLP, respectively. NAF showed activity over a wider concentration range and its dose-response curve was less steep than that of the two other agonists. Our results suggest that NAF, that may be generated at the sites of hypersensitivity reactions, is likely to induced the immigration of neutrophils, but not the direct activation of basophils and mast cells. In this respect, NAF differs from less selective chemotactic peptides like the complement product C5a or the N-formyl-methionyl peptides.

Antibodies, Anti-Idiotypic↗
PubMed1998

Eosinophil leukocyte degranulation in response to serum-opsonized beads: C5a and platelet-activating factor enhance ECP release, with roles for protein kinases A and C.

BACKGROUND: Eosinophils have a typical content of granule-bound, cytotoxic, cationic proteins which may, when released to the external milieu, play roles in diseases such as asthma and parasitic infestation. Therefore, we have investigated possible mechanisms by which their release is regulated in eosinophils. METHODS: The enzyme-linked immunosorbent assay (ELISA) was used to detect released eosinophil cationic protein (ECP). Release of ECP was induced by serum-opsonized, nonphagocytosable Sephadex beads (SOS). RESULTS: The complement fragment C5a and platelet-activating factor (PAF) were found to enhance ECP release in response to SOS in a dose-dependent fashion, and, contrary to previous reports, they were not found to act as secretagogues themselves on eosinophils in suspension. The role of protein kinase C (PKC) in eosinophil degranulation has been controversial. We found that ECP release induced by SOS was inhibited by the PKC inhibitors staurosporine and calphostin C. Activation of protein kinase A (PKA), by raising cAMP, also inhibited ECP release. Furthermore, pertussis toxin decreased ECP release on opsonized beads, indicating the involvement of pertussis-toxin-sensitive G proteins. CONCLUSIONS: C5a, and PAF enhance granule release, rather than acting as secretagogues themselves. PKC and PKA have opposing roles in the regulation of ECP release in response to SOS.

Blood Proteins↗
PubMed1989

Complement activation by the alternative pathway is modified in renal failure: the role of factor D.

Factor D, an essential enzyme of the alternative pathway (AP) of complement, is eliminated by the kidney, and its plasma concentration increases 10-fold in end-stage renal disease (ESRD). The purpose of this study was to analyze the consequences of factor D accumulation. A number of in vitro assays were used to analyze AP activation in normal human serum (NHS), in normal serum supplemented with purified factor D to 10-fold its normal concentration (10 x D), and in sera of patients with ESRD. When compared with NHS, in 10 x D: 1) Spontaneous fluid-phase activation of complement at 37 degrees C was greatly increased as measured by C3 cleavage, 2) The lysis of rabbit erythrocytes, a function of the AP, was accelerated, 3) More C3 fragments bound to cuprophane membranes and to immune precipitates; both reactions were accompanied by the formation of more C5a, 4) Complement mediated solubilization of antigen-antibody precipitates was enhanced. Sera of patients with ESRD behaved similarly to 10 x D in all assays used, i.e., enhanced AP function, although complement activation measured in these assays varied widely from one individual to another. Thus, the elevated factor D concentration observed in renal failure might have important pathophysiological consequences, some of which could be detrimental (e.g., C5a produced during hemodialysis), while others might be beneficial, e.g., solubilization of immune precipitates.

Aged↗
PubMed1986

Inhibition of immunological and non-immunological histamine release from human basophils and lung mast cells by formoterol.

3-Formylamino-4-hydroxy-alpha(N-1-methyl-2-p-methoxyphenethyl-a min omethyl)benzylalcohol hemifumarate (formoterol fumarate, BD40 A, CGP 25 827 A-E) inhibited both allergic (anti-IgE) and non-allergic histamine release (calcium ionophore and human complement component C5a) from human basophils. The degree and efficacy of inhibition was comparable to that of ketotifen, equal to or better than fenoterol and ten times more potent than isoprenaline (beta 2-stimulator). Salbutamol, another beta 2-stimulator was practically ineffective in these models. Similarly the anti-IgE, calcium ionophore and complement component C5a induced release of histamine from human lung mast cells could be blocked by formoterol, its potency being again comparable to that of ketotifen. The above degranulation inhibition effect taken together with the pronounced bronchodilator property would confirm formoterol as a drug of choice in asthma with more efficient action than the other beta 2-stimulators such as fenoterol, salbutamol or isoprenaline.

Albuterol↗