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At least 1,027 records · Page 57Linked to original sources
PubMed1981

A monoclonal antibody-inhibiting FMLP-induced chemotaxis of human neutrophils.

A monoclonal IgG1 antibody, termed NCD3, was raised against human neutrophils and has been shown to inhibit neutrophil chemotaxis. NCD3 displayed a considerable degree of stimulus specificity in that it inhibited N-formyl-methionyl-leucyl-phenylalanine- (FMLP) induced chemotaxis up to 80%, C5a and zymosan-activated plasma induced chemotaxis by only 20% and had no effect on leukotriene B4- (LTB4) or casein-mediated chemotaxis. NCD3 did not inhibit granule enzyme release from neutrophils in response to stimulation by various secretagogues, including FMLP, in the presence or absence of cytochalasin B (CB). Neutrophil phagocytosis of 51Cr-labeled opsonized sheep erythrocytes (51Cr-EAC) and superoxide anion (O2-) production in response to FMLP or phorbol myristate acetate (PMA) stimulation were not affected by pretreating cells with NCD3. Divalency of NCD3 was necessary for inhibition of chemotaxis, suggesting a requirement for cross-linking of the antigenic determinants on the neutrophil membrane surface.

Anaphylatoxins↗
PubMed1982

Cardiopulmonary bypass-induced complement activation. Evidence for C5a participation.

Plasma activity inducing polymorphonuclear neutrophils (PMN) aggregation, augmenting PMN adherence, plasma chemotactic activity as well as peripheral PMN count were estimated in patients during cardiopulmonary bypass. In the course of the surgical procedure the chemotactic activity and the activity inducing PMN aggregation were detected in plasma. The top of these two activities was always followed by the significant fall of the peripheral PMN count. The increase of the activity augmenting PMN adherence was observed in a part of cases, but when noticed, always preceded the maximum of the remaining evaluated activities.

Adult↗
PubMed1981

Diverging effects of chemotactic serum peptides and synthetic f-Met-Leu-Phe on neutrophil locomotion and adhesion.

The chemotactic serum peptide preparations CAT 1.6.1. and C5adesArg induced marked directional locomotion over a wide concentration range without significant effects on random locomotion and adhesion of human neutrophils in Gey's solution containing 2% HSA. In contrast, f-Met-Leu-Phe produced marked negative chemokinetic effects and its capacity to induce directional locomotion was more limited with respect to magnitude and concentration range. The negative chemokinetic effect of f-Met-Leu-Phe correlated closely with increased spreading and cell adhesion.

Cell Adhesion↗
PubMed1981

The membrane attack mechanism of complement: photolabeling reveals insertion of terminal proteins into target membrane.

We have utilized a membrane-restricted, photoactivable glycolipid probe to investigate the protein-lipid interactions involved in complement (C) mediated lysis of a target membrane. The purified C proteins C5b-6, C7, C8, and C9 were added to artificial membrane vesicles containing the 14C-labeled photoreactive probe anchored in the outer monolayer of the membrane, and 6-carboxyfluorescein trapped in the lumen as an indicator for effective lysis. Irradiation of the membrane samples at different stages of functional complex assembly resulted in labeling of each of the 5 terminal C proteins, indicating that all 5 proteins become inserted into the hydrophobic milieu of the membrane during some stage of complex assembly. However, at the final stage of complex assembly, only C9 appeared to be labeled. Because we can demonstrate that the photoreactive probe has no strong affinity for C9 over the other terminal components (C5b-C8), the extensive change in labeling specificity during assembly is evidence for substantial changes in protein-lipid and possibly protein-protein interactions during formation of the C lesion.

Cell Membrane↗
PubMed1981

Rapid in vivo clearance of C5ades arg: a possible protective mechanism against complement-mediated tissue injury.

C5ades arg is an important mediator of the tissue injury associated with intravascular complement activation and exerts its effects by causing granulocyte aggregation, leukoembolism, and oxidative damage to endothelial cells. We have now investigated some of the mechanisms responsible for deactivation of this potent complement fragment by studying the clearance of C5ades arg from the plasma of New Zealand white rabbits in vivo. Quantitative aggregation of human granulocytes was used as a bioassay for rabbit C5ades arg. After a bolus intravenous infusion of activated autologous plasma complement, athe plasma C5ades arg content peaked within 60 sec and was cleared rapidly and exponentially, with a mean half-life of 3.0 +/- 0.6 (S.E.M.) min. In neutropenic animals the half-life of C5ades arg was prolonged by 57% +/- 22 and splenectomy, but not hepatectomy, also significantly lengthened the half-life by 48% +/- 18. The most striking delay in C5ades arg clearance was induced by inhibition of endogenous proteases with EACA and aprotinin, which prolonged the half-life by 87% +/- 4 and 94% +/- 12, respectively. These data demonstrate that like other complement fragments such as C3a, C5ades arg has a very brief functional half-life in experimental animals and that although other mechanisms may be operative, endogenous proteases, circulating granulocytes, and the spleen may be important in deactivating this biologically important complement fragment. Impairment of these and other clearance mechanisms could lead to prolonged and excessive complement activation and subsequent exaggerated tissue injury.

Agranulocytosis↗
PubMedDate not supplied

Circadian and circannual aspects of the complement cascade - new and old results, differing in specificity.

Single cosinor analyses of several elements in the complement cascade suggest the occurrence of circadian rhythms in this immunochemical system. Some earlier results, obtained with less specific methods and reported as properdin, on reanalysis also reveal circadian and circannual rhythms in the aspects of immunology represented. The topic of the complement cascade as a whole is briefly reviewed in the content of modern knowledge.

Adult↗
PubMed1980

Mechanism of lethal effect of human serum upon Leishmania donovani.

In order to gain greater understanding of potential host defense mechanisms against Leishmania donovani, we examined the effect of nonimmune, human serum upon promastigotes and amastigotes. Fresh sera were found to be lethal for promastigotes, but had no detectable effect on amastigotes. Serum exposed promastigotes became immotile, did not take up neutral red dye, appeared to be disrupted, and failed to recover after further incubation in fresh media. Heat labile components were required for promastigote killing since heat-inactivated serum (56 degrees C, 30 min) agglutinated but did not kill them. Sera that lacked either the 5th or 6th complement (C) component had no effect when used alone, but when used together, were lethal, indicating that activation of the membrane attack complex (C5b-C9) ws necessary for the lethal effect. The mode of C activation was determined by using serum with complete, selective, deficiency of C2, and normal serum chelated with Mg-EGTA. The C2-deficient serum killed promastigotes only after the addition of purified C2, and Mg-EGTA chelated serum had no detectable lethal effect. Thus, promastigotes appeared to activate C through the classical pathway. Human IgG and IgM, detected with 125I-anti-human antibody, bound to promastigotes. Removal of antibody from serum by absorption with promastigotes eliminated the lethal effect. The effect was restored by addition of heat-inactivated serum to absorbed serum. We conclude that promastigotes bind antibody and are killed by activation of the membrane attack complex of C through the classical pathway.

Animals↗
PubMed1980

Analysis of solute diffusion across the C5b-9 membrane lesion of complement: evidence that individual C5b-9 complexes do not function as discrete, uniform pores.

We have investigated the diffusion of radiolabeled nonelectrolytes across the membranes of resealed erythrocyte ghosts that had been treated with the terminal complement components C5b-9 and incubated under nonlytic steady state conditions. For all solutes tested, we note that diffusion across the C5b-9 lesion is retarded to rates more than 2 orders of magnitude slower than can be anticipated for a transmembrane diffusional channel of the dimensions suggested by the ultrastructure of the C5b-9 membrane lesion. Furthermore, direct measurement of the relative selectivity of the C5b-9 membrane lesions to permeation by solutes of differing molecular radii suggests that individual membrane lesions are not of uniform functional size. Data are presented that suggest that the functional heterogeneity of the membrane lesion is due to the aggregation of individual membrane bound C5b-9 complexes into larger functional units and not due to variable stoichiometry of C9 within the individual C5b-9 complex.

Cell Membrane Permeability↗
PubMed1978

The structural events associated with the attachment of complement components to cell membranes in reactive lysis.

Electron microscopic study of the events occurring at the cell membrane during reactive lysis by complement, showed that a foliaceous particle was formed at the C5b-7 stage, that enlarged to a particle with a variable number of arms at the C5b-8 stage. Up to this point, no typical complement lesions were found. At the C5b-9 stages, the particles were completely converted to typical complement lesions, i.e. hollow cylinders projecting from the cell membrane and partly penetrating it. C5b-9 complexes assembled in the fluid phase did not show the typical structure of the lesions, but were amorphous masses of fibres.

Complement C5↗
PubMed1994

Defective regulation of complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation.

A prominent clinical manifestation of sickle cell disease (SCD) is hemolytic anemia. Although complement activation can lead to intravascular hemolysis, its role in the hemolysis of SCD is not known. Because normal red blood cells induced to vesiculate by treatment with calcium and ionophore become sensitive to damage by activated complement and because sickle cells release microvesicles as they circulate, we postulated that sickle cells might also be unusually sensitive to complement-dependent hemolysis. Complement activation is tightly regulated on the membrane of the normal erythrocyte; therefore, defective complement regulation by the sickle cell would be necessary for complement-dependent hemolysis to occur. These studies show a defect in the regulation of membrane attack complex (C5b-9) formation in sickle erythrocytes, particularly in the most dense cells. The defect is characterized by increased binding of C5b-7 and of C9 to denser sickle cells and results in increased susceptibility of sickle cells to C5b-9-mediated (reactive) lysis initiated by either C5b6 or activated cobra venom factor. Among the densest sickle cells, irreversibly sickled cells are especially sensitive to reactive lysis. The similarity of this defect to that previously described in a patient with paroxysmal nocturnal hemoglobinuria suggests that complement-mediated hemolysis could play a role in the anemia of SCD.

Adenosine Triphosphate↗
PubMed1995

Calcium-loaded erythrocytes have a defect in complement regulation distinct from that resulting from exposure to 2-aminoethylisothiouronium bromide.

Calcium-loaded red blood cells (RBCs) previously have been shown to have an increased sensitivity to complement-mediated hemolysis and particularly to lysis mediated by the C5b-9 membrane attack complex (MAC) of complement. Because RBCs exposed to 2-aminoethylisothiouronium bromide (AET) also have been shown to be particularly sensitive to the MAC, a direct comparison of calcium-loaded and AET-treated RBCs was performed. Calcium-loaded and AET-treated RBCs shared a marked increase in sensitivity to lysis by the MAC in two different assays. However, measurements of C5b-7 and C9 binding suggested that different mechanisms were responsible. AET-treated RBCs showed an increase in C9 binding and an increased C9/C7 ratio consistent with functional loss of CD59/membrane inhibitor of reactive lysis (MIRL). In contrast, calcium-loaded RBCs had minimally increased C9 binding that resulted in C9/C7 ratios that were less than those for untreated RBCs, suggesting that CD59/MIRL inactivation had not occurred. When RBCs were incubated in acidified serum, AET-treated cells demonstrated a marked increase in C3b binding and hemolysis that was observed in neither control nor calcium-loaded RBCs. These results suggest that the underlying lesions responsible for an increase in susceptibility to complement-mediated hemolysis are different for calcium-loaded and AET-treated RBCs.

Adult↗
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↗
PubMedDate not supplied

Expression of the complement regulator factor C8 binding protein on human glomerular cells protects them from complement-mediated killing.

The complement-regulatory factor C8 binding protein (C8bp) was first identified on human erythrocyte membranes by its affinity for the complement component C8 and its ability to inhibit lysis by homologous complement. Cultured human glomerular mesangial or epithelial cells (GEC) expressed C8bp on the cell surface and in the cytoplasm. Following stimulation of the glomerular cells with interleukin 1 beta, C5b-9 or with endotoxin, a transient, protein synthesis-independent increase in C8bp surface expression was seen. Blocking of C8bp function with F(ab)2 fragment of an antibody to C8bp rendered GEC susceptible to complement-mediated killing, indicating that C8bp contributes to the cellular defense against complement attack.

Blood Proteins↗