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PubMed1982

Complement: activation, consequences, and control.

The activation of complement provides the humoral (fluid-phase) effector mechanism most responsible for immune-mediated injury. The classical pathway is activated by an antigen-antibody reaction. The binding of C1q initiates the sequential activation of the eleven proteins. The classical pathway has a calcium-dependent step (C1q, C1r, C1s) and a magnesium-dependent reaction (the enzymatic action of C1s on C4 and C2). The alternative pathway appears to be spontaneously activated, but the perpetuation of that activation is dependent upon the availability of an activating (or protective) surface which interferes with the inactivation of C3b by control proteins. The alternative pathway has a magnesium-dependent step, the binding of B to C3b to form the C3 convertase. Once initiated, the alternative pathway activation results in the sequential activation of nine proteins, six of which are common to both pathways. The activation of complement results in a variety of biologic consequences which can result in injury to the host. The potential destructiveness of the effects of complement activation is modulated by a series of control proteins.

Carrier Proteins↗
PubMed1982

Modulation of the immune response by anaphylatoxin in the microenvironment of the interacting cells.

It was shown that the anaphylatoxins C3a and C5a can modulate in vitro immunological reactivities. C3a suppresses both the in vitro polyclonal antibody response and the specific antibody response to sheep red blood cells (SRBC) of both mouse spleen cells and human peripheral blood cells. The target cell in the mouse for C3a appears to be an Lyt-1+2- suppressor-inducer cell and macrophages appear not to be required. In contrast to C3a, C5a enhances in vitro responses of mice. Both the response to SRBC and the mixed lymphocyte reaction are enhanced by C5a. This enhancement appears to be through an Ia- macrophage that contains receptors for C5a. It appears that enhancement may be brought about by interleukin 1, which is released when Ia- macrophages are pulsed with C5a. It is suggested that these anaphylatoxins, when present in high concentrations in the microenvironment of the interacting cells of the immune system, play a dynamic role in the regulation of the immune response. Peptide fragments cleaved from the Fc portion of antibody, complexed with antigen in this microenvironment, may have a similar regulating role.

Animals↗
PubMed1984

Increased expression of the C3b receptor by neutrophils and complement activation during haemodialysis.

Activation of complement and the relative number of C3b receptors expressed by neutrophils was assessed in patients undergoing haemodialysis with new and reused cellulosic membranes, and with polymethylmethacrylate (PMMA) membranes. Activation of complement was assessed by radioimmunoassay of plasma C3adesArg, and neutrophil C3b receptors were measured by fluorescent flow cytometry of cells indirectly stained with F(ab')2 anti-C3b receptor. During first use of cellulosic dialysis membranes by four patients, the mean expression of C3b receptors by neutrophils in blood taken from the afferent line of the extra-corporeal system after 10, 20, 60 and 120 min of dialysis increased to 127, 189, 255 and 296%, respectively. The mean plasma C3adesArg concentrations in the corresponding samples of blood were 225, 320, 236 and 160% of the pre-dialysis levels. During third and fifth use of the same membranes by these patients, the mean C3b receptor expression by neutrophils did not exceed 150% of the predialysis determination, and correspondingly minimal increases in plasma C3adesArg were observed. Analysis of blood taken simultaneously from the afferent and efferent lines of the first use cellulosic dialysis system indicated that the increase in C3b receptor expression by neutrophils and generation of C3adesArg occurred when blood came in contact with the dialysis membrane. Haemodialysis of four additional patients with the non-complement activating PMMA membrane caused only modest or no increases in neutrophil C3b receptors. Thus, complement activation in vivo is associated with up-regulation of neutrophilic C3b receptors, indicating that this cellular response previously described only in model, in vitro systems, is a physiological mechanism by which this cell can augment its capacity for responding to C3b opsonized material.

Biocompatible Materials↗
PubMed1984

Structure and function of the human C3b receptor.

The human C3b receptor (C3bR) is a glycoprotein that exists in two allotypic forms having Mr values of approximately 250,000 (F) and 260,000 (S). The number of receptors present on erythrocytes varies by eightfold among normal individuals and is genetically regulated by two codominant alleles that are distinct from the alleles determining the structural polymorphism. C5a and C5ades Arg induce rapid increases in the number of receptors expressed by neutrophils in vitro, and probably account for the increased receptor expression on neutrophils in patients undergoing hemodialysis. Cytoskeletal association of the C3bR on monocytes and neutrophils is suggested by experiments demonstrating receptor-mediated phagocytosis and adsorptive endocytosis through coated pits, and by the reciprocal coredistribution of cross-linked C3b and Fc receptors and the detergent insolubility of cross-linked C3bR. The factor H-like cofactor activity of the C3bR promotes the cleavage of bound C3b to iC3b, C3c, and C3d,g, which may enhance the clearance of circulating immune complexes and the generation of ligands for CR2 and CR3. The inherited partial deficiency of the erythrocyte C3bR in patients with systemic lupus erythematosus and the absence of glomerular C3bR in these patients with proliferative glomerulonephritis may contribute to systemic and organ-specific abnormalities in the clearance of immune complexes in this disease.

Complement C4↗
PubMed1984

Complement activation by synthetic vascular prostheses.

Morphologic evaluation of synthetic grafts (both seeded and unseeded) harvested within 2 weeks of implantation has revealed heavy infiltration with polymorphonuclear leukocytes (PMNs). Since complement-activated PMNs are known to damage endothelial cells, we hypothesized that complement activation might prove a barrier to optimal endothelial cell seeding of prosthetic grafts. To determine whether synthetic vascular prostheses activate complement and whether the type of graft material influences the degree of activation, we assayed the plasma of 10 healthy donors for complement activity following incubation with short segments of knitted Dacron and polytetrafluoroethylene (PTFE) graft material. C5a generation was measured by radioimmunoassay and granulocyte aggregometry. Standard hemolytic assays were used to determine depletion of functional classical pathway (CH50 and C4) alternative pathway (APH50) activity. Results indicated substantial complement activation by Dacron and virtually none by PTFE. Activation by Dacron appeared to occur via both complement pathways. Such complement "reactivity" may have important implications for the performance of prosthetic materials as small-caliber vascular grafts, whether seeded with endothelial cells or not.

Blood Vessel Prosthesis↗
PubMed1981

Chemotactic deactivation of human neutrophils: protective influence of phenylbutazone.

The antiinflammatory drug, phenylbutazone (PBZ), has been studied in terms of its influence on chemotactic deactivation of human neutrophils. When PBZ was present during the time of preincubation of cells with N-formyl-methionyl-phenylalanine (F-Met-Phe), loss of subsequent spontaneous mobility and chemotactic responsivity to F-Met-Phe did not occur. The action of PBZ to protect neutrophils from peptide-mediated chemotactic deactivation was found to involve in part its inhibitory influence on hexose monophosphate shunt activity and in part its antagonistic effect on interaction of peptide receptors with N-formyl peptide. Phenylbutazone interfered with binding of N-formyl-methionyl-leucyl-[3H]phenylalanine but not [125I]C5a to the neutrophil, displaced labeled tripeptide bound in the absence of PBZ, increased the dissociation constant (KD) for labeled tripeptide, and limited down regulation of peptide receptor function. These results provide an example of drug-mediated modulation of the interaction of neutrophils with N-formyl peptide and strongly support the possibility that PBZ interacts directly and specifically with the human neutrophil peptide receptor as a competitive antagonist. They also provide an additional example of a compound outside of th N-formyl peptide series that interacts with the peptide receptor.

Anaphylatoxins↗
PubMed1982

Chemotactic factor inactivation by stimulated human neutrophils mediated by myeloperoxidase-catalyzed methionine oxidation.

Leukocyte chemoattractants were inactivated when exposed to human neutrophils and either ingestible particles or phorbol esters. Loss of biologic activity was time- and temperature-dependent, required physiologic concentrations of viable neutrophils and a halide, and was inhibited by azide or catalase. Neutrophils from patients with either hereditary myeloperoxidase deficiency or chronic granulomatous disease failed to inactivate the chemoattractants unless purified myeloperoxidase or H2O2, respectively, was added. Susceptibility to inactivation by neutrophils correlated with the presence of methionine in the attractant. Loss of chemotactic activity was blocked by low concentrations of methionine and by higher concentrations of other reducing agents, but was unaffected by oxidized methionine. Paper chromatography demonstrated that exposure of a formyl-methionyl peptide chemotactic factor to either the cellfree myeloperoxidase system or stimulated neutrophils resulted in its conversion to a molecular species whose location in the chromatographs was identical to that of the peptide containing oxidized methionine. Thus, stimulated human neutrophils inactivate peptide chemoattractants by secretion of myeloperoxidase and H2O2, which combine with halides to form oxidants that react with a critical methionine residue. We suggest that myeloperoxidase-catalyzed oxidation of thioethers may constitute an inflammatory control mechanism as well as a general means of modifying the functional properties of biologic mediators.

Aminopeptidases↗
PubMed1982

Human neutrophil peptide receptors: mobilization mediated by phospholipase C.

Incubation of human neutrophils with phospholipase C from Clostridium perfringens caused an increase in the ability of the treated cells to bind the chemotactic peptide, F-Met-Leu-Phe. The increase in binding was related to an increase in specific binding of the ligand. The increase in specific binding was, in turn, related to an increased number of peptide receptors. The dissociation constant (KD) for the tripeptide was not altered, on the average, by enzyme treatment. The increase in peptide receptor number was related temporally, and possibly mechanistically, to enzyme-stimulated secretory function involving the secondary granules. Phospholipase C treatment did not similarly augment binding of the complement-derived attractant, C5a. Receptor numbers for different chemotactic ligands may therefore be controlled by different mechanisms. Supplementary experiments provided evidence that this phenomenon was attributable to phospholipase C activity and not to contaminating protease(s).

Complement C5↗
PubMed1982

Size of the transmembrane channels produced by complement proteins C5b-8.

It has been shown previously that erythrocytes can be lysed by complement proteins C5b-8, albeit at a much lower rate than C5b-9. We have now performed kinetic sieving experiments with resealed erythrocyte ghosts using sucrose (0.9 nm molecular diameter) and inulin (3.0 nm molecular diameter) as markers. We found that treatment of the ghosts with C5b-8 released sucrose, but not inulin. Addition of C9 to ghosts carrying C5b-8 dramatically increased the rate of sucrose flux and, in addition, caused release of inulin. Hence, unlike C5b-9 channels, those formed by C5b-8 measure less than 3 nm in diameter. Formation of C5b-8 channels was very slow compared with that of C5b-9 channels. Also, we found that about two-thirds of the C5b-8 ghosts did not have sucrose-releasing channels, but such channels were formed on reaction with C9.

Cell Membrane Permeability↗
PubMed1983

Direct effect of complement factor C5a on the contractile state of isolated smooth muscle cells.

The complement-(C) derived factor C5a has long been recognized as a potent contractile agonist in smooth muscle (1,2); however, controversy remains as to whether the effects of this anaphylatoxin are direct or secondary to the release of histamine (3) and/or other mediators (4-8) from nonmuscle cells within the tissue. To resolve this controversy, we have assessed the contractile effects of purified human C5a and C5a des Arg in a homogeneous preparation of enzymatically dispersed smooth muscle cells derived from the stomach of the toad, Bufo marinus. This preparation, which is insensitive to histamine at concentrations as high as 10(-4) M, responds normally to a variety of electrical (9), mechanical (10), and pharmacologic (11, 12) stimuli. These smooth muscle cells also respond to purified human anaphylatoxin; exposure to the cells to purified human C5a or C5a des Arg produce contractions of the smooth muscle cells that are accompanied by increased Ca2+ influx. The contractile response was unaffected by antagonists to histamine or acetylcholine but was reduced by 30% by pretreatment with the leukotriene antagonist FPL55712. A direct contractile effect of C5a on amphibian smooth muscle cells is suggested.

Animals↗
PubMed1983

Exposure of human neutrophils to chemotactic factors potentiates activation of the respiratory burst enzyme.

NADPH oxidase activity in particulate fractions from human neutrophils stimulated with phorbol myristate acetate (PMA) or opsonized zymosan was enhanced by prior exposure of the neutrophils to chemotactic factors. Enhanced activity was seen measuring both NADPH-dependent chemiluminescence and superoxide anion production. Enhancement was observed to be both time and dose dependent with several chemotactic stimuli, including casein, N-formyl-methionyl-leucyl-phenylalanine (f-MLP), and C5a. F-MLP and C5a showed similar patterns, with peak enhancement occurring within 2 to 15 min of preincubation and lasting up to 1 hr. In contrast, enhancement of PMA-stimulated oxidase activity by casein was more gradual and sustained, lasting up to 2 hr. Fractions from cells treated only with chemotactic factors and not stimulated with PMA showed no oxidase activity. Kinetic studies of this enhanced activity show that chemotactic factors induce increases in Vmax values but do not significantly alter Km values for the oxidase. Further experiments using agents that modulate degranulation suggest that enzyme release is not involved in this enhancement. These data suggest that pretreatment with chemotactic factors results in an increase in the amount of activated oxidase in membrane fractions obtained from PMA-stimulated neutrophils. This alteration of NADPH oxidase activity provides a subcellular basis for the enhanced bactericidal activity and increased oxidative metabolism seen in neutrophils treated with chemotactic factors.

Chemotactic Factors↗