Complement activation in plasma exchange.
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Complement Activation↗
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Characterization of a receptor for C5a anaphylatoxin on human eosinophils.
The complement anaphylatoxin peptide C5a is well known to activate human polymorphonuclear leukocytes through receptor-mediated processes. C5a has also been reported to activate eosinophils for both chemotaxis and hexose uptake. We characterized the receptor molecule for human C5a on human eosinophils and compared it with the receptor on human neutrophils. At 4 degrees C, uptake of 1 nM 125I-C5a reaches equilibrium within 10 min on both cell types. Binding of 125I-C5a occurs over a concentration range comparable to that which stimulates lysosomal enzyme release and hexose uptake in both cell types. Scatchard analyses of the data indicate the presence of two receptor populations on eosinophils; a high affinity receptor with 15,000-20,000 sites/cell and a Kd of 3.1 +/- 0.6 x 10(-11) M, and a low affinity receptor with approximately 375,000 sites/cell and a Kd of 1 x 10(-7) M. Parallel experiments with neutrophils indicate the presence of a single receptor population with approximately 90,000 sites/cell and a Kd of 4.8 +/- 0.1 x 10(-10)M. The eosinophil receptor molecule was further characterized by covalently cross-linking 125I-C5a to cells followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the solubilized material. Autoradiography indicates the presence of a dominant C5a-eosinophil receptor complex with an apparent mass of 60-65 kDa. The corresponding neutrophil-C5a receptor complex has an apparent mass of 50-52 kDa as observed by others. When the cross-linked 125I-C5a-receptor complex was treated with cyanogen bromide, different patterns were observed on sodium dodecyl sulfate-polyacrylamide gel electrophoresis for neutrophils and eosinophils. Thus, human eosinophils have a receptor for C5a anaphylatoxin which appears to be distinct from the C5a receptor present on human neutrophils.
Cold Temperature↗
The expression of Fc and complement receptors in young, adult and aged mice.
Age-dependent changes in the expression of Fc receptors (FcR) for different isotypes of immunoglobulins and receptors for C3b, C5b and C3bi fragments of complement on the membranes of peritoneal macrophages were studied with mice of different ages. An age-related increase in expression of Fc receptors for IgM, IgE, IgA, IgG2b and IgG3, and a decrease in the expression of Fc receptors for IgG1 was observed. The expression of FcR on macrophages of donors of different ages corresponded with Fc-receptor mediated phagocytosis. The highest number of C3b-binding macrophages was found in aged mice, in contrast to low numbers of C3bi-binding macrophages at this age. The percentage of C5b-binding macrophages was lowest in adult animals. We also observed effective inhibition of binding of the C3b component of complement by preincubation of macrophages with aggregated IgG and vice versa. These observations suggest that fluctuation in expression of Fc but not C receptors may be important to the generalized changes that occur in macrophage function during development and ageing.
Aging↗
The biology and pathophysiology of complement receptors.
Activation of the complement cascade leads to the generation of multiple breakdown products which bind on to specific cellular receptors and regulate their function. In this review, we describe the biochemical and physiological features of the 7 known complement receptors. Four of them (complement receptors 1, 2, and 3 and receptors for C3a) bind cleavage fragments of the third component of the complement and three have specificity for C1q, factor H and C5a. In patients with systemic lupus erythematosus, a unique human autoimmune disorder, the numbers of CR1 on the surface of the red blood cells are decreased; in this review we discuss the implications in the pathogenesis of SLE. A number of patients have now been reported whose cells lack CR3 from their surface; this deficiency is associated with a number of immune cell dysfunctions which are discussed in detail. Finally, we discuss aberrations in the expression of complement receptors in certain human leukemic cells.
Antigen-Antibody Complex↗
[A new and original therapy for seborrheic dermatitis].
The AA describe the results of an original therapy for seborrhoic dermatitis in both localized and spread forms (Leiner's Disease). Due to similarity of seborrhoic dermatitis in the two forms with acrodermatitis enterophatica and considering that this last disease reacts positively after Zinc administration, the AA stated the validity of such therapy also for seborrhoic dermatitis and discuss its possible mechanism of action.
Administration, Oral↗
Increased adhesion to fibronectin and Mo-1 expression by diabetic monocytes.
As excessive monocyte adhesion to blood vessel wall could produce endothelial cell injury, we undertook comparative studies on the monocyte adhesiveness in insulin-dependent diabetics with vascular complications (n = 26) and healthy, normal subjects (n = 36). In the diabetic group, the extent of monocyte adhesion on fibronectin- and autologous plasma-coated surfaces was significantly increased compared with that in the control group (p less than 0.01 on both types of surfaces). Monocytes adhesion to the plasma-coated surface, but not to the fibronectin-coated surface, could be inhibited by monoclonal anti-Mo-1 antibody in a dose-dependent manner. For diabetic monocyte adhesion, a higher amount of anti-Mo-1 antibody was required to produce a similar extent of inhibition as observed with control monocytes. This indication of increased Mo-1 expression on diabetic monocytes was further confirmed by analyzing the fluorescence intensity of monocytes labeled with the antibody anti-Mo-1. The results of the present study suggest that diabetic monocytes have increased adhesiveness as the result of increased expression of fibronectin and Mo-1 receptors.
Antibodies, Monoclonal↗
L-asparaginase-induced hypocomplementemia in acute lymphocytic leukemia (ALL) of childhood.
Serum complement studies were carried out in five children with acute lymphocytic leukemia. During therapy with L-asparaginase, prednisone and vincristine, hypocomplementemia developed in all patients, and disappeared within 2 weeks after the discontinuation of L-asparaginase. Complement breakdown products were not present in plasma. The changes of serum complement levels paralleled those of plasma fibrinogen. These findings suggest that the hypocomplementemia observed in these patients may be related to impaired protein synthesis induced by L-asparaginase.
Adolescent↗
Fast deactivation of guinea-pig isolated ileum to C5adesArg: a possible cyclic AMP-dependent mechanism.
The fast component of deactivation of guinea-pig isolated ileum to the spasmogenic action of the complement peptide C5adesArg was further differentiated from the slow component which had been previously analysed (Damerau et al., 1985a, b). Fast deactivation differs from the slow component in the following characteristics: (a) it is unspecific in that it is also induced by C3a, another complement peptide, (b) it depends on the spasmogenic effect of the peptides, and (c) it does not occur at 16 degrees C. In contrast to the slow component, in which the deactivation is thought to be caused by blockade of C5a receptors, fast deactivation seems to be due to a transient increase of intracellular cyclic AMP evoked by C5adesArg and C3a; it is prevented by GDP beta S (5 X 10(-4) M) which blocks activation of adenylate cyclase, and prolonged by agents which sustain cyclic AMP elevations, namely 5 X 10(-4) M theophylline and 5 X 10(-4) M) GTP gamma S.
Animals↗
Complement-mediated arachidonate metabolism.
The leukotrienes are important mediators of numerous responses in lung tissue. Both direct injury and immune injury result in the production of these arachidonate products. Several cellular components participate in the immune surveillance system including monocytes, mast cells and PMNs. Each cell type produces different quantities and types of leukotrienes in response to ionophore (A23187) activation. A common feature shared by each of these cells is control of arachidonic acid metabolism at the level of the 5-lipoxygenase. One provocative interpretation of our results is that the 5-lipoxygenase is activated by C5a and that concomitant modulation of 5-lipoxygenase activity provides a means whereby arachidonic acid metabolism is directed in these cells to either the cyclooxygenase or lipoxygenase pathway. Another common feature that these cells share is that they utilize arachidonic acid mobilized from other cells such as stimulated platelets, certain monocytes, or even damaged tissue. For example, free nonesterified arachidonic acid has been measured at 100 microM in inflamed tissue. Therefore, fluctuations in exogenous arachidonate levels may provide a significant modulation of the inflammatory response by controlling the levels of lipoxygenase products formed by leukocytes. In this scenario the humoral factor C5a is the initiator of the host's response to provide a variety of functional arachidonate products. Another feature that the cellular components of the immune system share is that they may utilize other exogenous lipid substrates. In this case, a lipid product of one cell type may serve as a signal or substrate for a second cell's lipoxygenase pathway. This hypothesis may explain the apparent synergy observed in this and other studies when mixed cell populations were activated. Several hydroperoxy lipids are proposed to be regulatory for the lipoxygenase pathway. Another valid interpretation could be that 5-hyperoxy-eicosatetraenoic acid and LTA4 produced in one cell may diffuse to another cell and be utilized by the lipoxygenase pathway of that cell type. From the results of this study we conclude that the secondary mediator profile obtained when cells are activated by arachidonic acid and C5a depends on the cell composition. We can extend this interpretation of our results to explain two seemingly opposite results obtained when C5a is administered to experimental animals either intrabronchially or intravenously. Future evaluations of the biological effects of C5a should therefore take into consideration the composition of the cells at the target tissue site.(ABSTRACT TRUNCATED AT 400 WORDS)
Arachidonic Acid↗
Regulation of the oxidative response of human granulocytes to chemoattractants. No evidence for stimulated traffic of redox enzymes between endo and plasma membranes.
Experiments were performed to probe the role of exocytotic and endocytotic processes in the regulation of the human granulocyte O-2-generating system. Analytical subcellular fractionation studies indicated that 25-30% of the total cellular b-cytochrome and 8-10% of the flavin co-sedimented with plasma membrane markers, irrespective of stimulation of the cells by the chemoattractants N-formyl-Met-Leu-Phe (FMLP) or C5a. Phorbol myristate acetate stimulation resulted in significant translocation of b-cytochrome but not flavin from the specific granule/Golgi to the plasma membrane-enriched fractions. These results indicated that approximately 3.1 X 10(5) flavin and 0.8-1 X 10(6) b-cytochrome molecules are present in the plasma membrane of an isolated unstimulated human granulocyte and that these levels are invariant upon stimulation with chemoattractants. Maximal instantaneous rates of O-2 generation by cells in these preparations, however, were equivalent for all the stimuli. Since stimulation of granulocytes by phorbol myristate acetate, FMLP, or C5a results in exocytosis and/or endocytosis, then the role of these processes in regulating stimulated O-2 production by controlling the content of plasma membrane redox enzymes is questionable. This conclusion was supported by observations made with cytoplasts, which do not have an intracellular reserve of granules. Cytoplasts prepared from granulocytes produced O-2 at equivalent rates as their parent cells on a per unit surface area basis. These results suggest: 1) that stimulation of granulocytes with chemotactic peptides leads to full generation of O-2 at the cell surface without exocytotic recruitment of additional b-cytochrome and flavoprotein from the cytoplasmic compartment; 2) that these redox enzymes are not internalized along with chemoattractant receptors; and 3) that traffic of these redox enzymes between endo- and plasma membranes is not involved in the regulation of O-2 production in suspensions of human granulocytes stimulated by chemoattractants.
Cell Fractionation↗
The role of the polymorphonuclear leukocyte in hyperalgesia.
The results of recent studies of the mechanism of leukotriene B4-induced hyperalgesia suggest a dependence on polymorphonuclear leukocytes (PMNLs). In this study, we addressed the contribution of PMNLs to hyperalgesia evoked by the peptide chemotactic factors N-formyl-methionyl-leucyl-phenylalanine (fMLP) and the anaphylatoxin fragment of the fifth component of the complement pathway (C5a). Local injection of glycogen, which attracts but does not activate PMNLs, produced a marked shift to the left (toward lower concentrations) in the concentration dependence curve of fMLP-induced hyperalgesia. In addition, PMNL repletion by transfusion with syngeneic PMNLs reestablished fMLP-induced hyperalgesia in PMNL-depleted rats. Finally, supernatants from rat and human PMNLs, that had been stimulated with fMLP in vitro, produced hyperalgesia in PMNL-depleted rats. Preliminary characterization of the hyperalgesia-inducing activity released by stimulated PMNLs indicated that it is lipid in nature. The nonsteroidal anti-inflammatory indomethacin did not attenuate C5a and fMLP-induced hyperalgesia. Thus, the hyperalgesia produced by fMLP and C5a is similar to that produced by leukotriene B4 in that it is dependent on PMNLs and independent of the cyclo-oxygenation of arachidonic acid. Taken together, these data suggest that structurally diverse PMNL-chemotactic factors produce hyperalgesia by a novel mechanism, involving PMNL-derived factors.
Animals↗
Role of complement anaphylatoxins in neutrophil arachidonic acid metabolism.
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Anaphylaxis↗
Functional changes of neutrophil responses in relapsing acne fulminans.
A patient suffering from an acute episode of acne conglobata demonstrated a transient decrease in several C5a induced polymorphonuclear cell functions, whereas the response to N-formylmethionyl peptides (FMLP) was normal.
Abscess↗
Different complement and granulocyte activation in patients dialyzed with PMMA dialyzers.
Plasma C3a and C5a levels as well as plasma levels of granulocyte lactoferrin, granulocyte myeloperoxidase and granulocyte elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) were investigated in 10 patients (52.7 +/- 5.9 years) undergoing maintenance hemodialysis (39.4 +/- 12.4 months) with hollow fiber dialyzers made from polymethylmethacrylate. Plasma levels of lactoferrin increased from 166.5 +/- 28.5 to 712.5 +/- 165.9 ng/ml, myeloperoxidase from 59.0 +/- 15.3 to 210.5 +/- 33.9 ng/ml and E-alpha 1PI from 114.2 +/- 18.1 to 681.8 +/- 102.6 ng/ml during dialysis. In contrast, plasma C3a levels rose from 179.8 +/- 33.6 to maximal 276.2 +/- 45.4 ng/ml and C5a from 55.7 +/- 8.1 to maximal 101.1 +/- 14.8 ng/ml. Our data indicate that degranulation of granulocytes occurs during dialysis despite only little complement activation and mild initial granulocytopenia.
Biocompatible Materials↗
Characterization of the plasma membrane bound GTPase from rabbit neutrophils. I. Evidence for an Ni-like protein coupled to the formyl peptide, C5a, and leukotriene B4 chemotaxis receptors.
We have characterized the GTPase activity of the Ni-like guanine-nucleotide-binding regulatory protein in rabbit neutrophil plasma membranes. The low Km (3.64 +/- 0.87 X 10(-7) M) GTPase copurified with the formyl peptide receptor in the plasma membrane fraction obtained by discontinuous sucrose density gradient centrifugation. The Vmax (23.9 +/- 2.91 pmol/mg/min) and Km of the unstimulated enzyme were similar to those reported for Ni in other cell types. The activity of the unstimulated enzyme was both magnesium and sodium dependent and linear over the first 4 min of the assay. The chemoattractants, formyl-methionyl-leucyl-phenylalanine (fMLP), C5a, and leukotriene B4 (LTB4) stimulated the GTPase in purified neutrophil plasma membrane preparations, whereas other secretagogues, such as A23187 and PMA, were without effect. Lineweaver-Burk analysis showed an fMLP-induced increase in Vmax (31.94 +/- 4.80 pmol/mg/min) (33.1 +/- 9.5%) but not in Km. The dose-response curve for fMLP stimulation showed an ED50 of 4.1 +/- 1.0 X 10(-8) M and an overall 22.2 +/- 3.1% maximal stimulation. C5a (30 micrograms/ml) increased the activity of the GTPase 21.3 +/- 5.7% and 10(-7) M LTB4 produced a 32.2 +/- 5.4% increase. Activated pertussis toxin treatment of neutrophil plasma membranes inhibited by 72.5 +/- 14.3% the stimulation of GTPase activity induced by fMLP; however, activated cholera toxin had no effect on the inhibition of fMLP stimulation, suggesting a direct role for an Ni-like protein in the coupling process. In contrast to the lack of inhibition of fMLP stimulation by activated cholera toxin treatment of plasma membranes, both pertussis toxin and to a lesser extent cholera toxin treatment reduced fMLP, C5a, and LTB4 stimulation of the GTPase in sonicates prepared from pretreated whole cells. Pertussis toxin inhibited fMLP stimulation of the GTPase by 75 +/- 7%, C5a stimulation was inhibited by 83 +/- 13%, and LTB4 stimulation was inhibited completely. Sonicates prepared from neutrophils treated similarly with cholera toxin showed a smaller inhibition of GTPase activity (50 +/- 4% and 14 +/- 9% for fMLP and LTB4, respectively) with the exception of C5a, where CT inhibition (81 +/- 32%) equaled pertussis toxin inhibition. Similarly, pertussis toxin completely inhibited the release of the granule enzyme N-acetyl-glucosaminidase by all three chemoattractants, whereas cholera toxin, except with C5a stimulation, had little or no effect.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Lipopolysaccharide modulates receptors for leukotriene B4, C5a, and formyl-methionyl-leucyl-phenylalanine on rabbit polymorphonuclear leukocytes.
Peripheral blood polymorphonuclear leukocytes (PMNL) isolated from rabbits after an i.v. injection of endotoxin exhibited decreased chemotactic migration in response to leukotriene B4 (LTB4) and C5a, but not N-formyl-methionyl-leucyl-phenylalanine (fMLP), after endotoxin treatment. The binding of radiolabeled LTB4, fMLP, and C5a to isolated PMNL was assessed in order to determine whether altered receptor expression could account for the observed functional changes. Control PMNL expressed binding sites for fMLP, LTB4, and C5a similar to those previously characterized from human PMNL. Control PMNL expressed a single class of 14,600 +/- 2700 receptors for fMLP with a mean dissociation constant (Kd) of 2.0 +/- 0.6 nM at 0 degrees C, whereas two subclasses of binding sites were expressed for LTB4: 10,300 +/- 6800 high-affinity and 85,600 +/- 53,000 low-affinity binding sites per PMNL with mean Kd for LTB4 of 0.75 +/- 0.43 nM and 70 +/- 58 nM (mean +/- SD, n = 5), respectively. Control PMNL bound [125I]-C5a in a dose-dependent and saturable manner at 24 degrees C. At saturating concentrations of C5a, PMNL obtained from control rabbits bound 270,000 +/- 50,000 molecules of [125I]-C5a with half-maximal binding occurring at [125I]-C5a concentrations of 5.5 +/- 1.9 nM. The binding of LTB4 and C5a to PMNL obtained 24 hr after an i.v. injection of endotoxin was markedly decreased compared with control PMNL. PMNL from endotoxin-treated rabbits exhibited 68% fewer high-affinity binding sites per PMNL for LTB4 and a 51% decrease in the amount of [125I]-C5a bound at saturating concentrations compared with control PMNL. There was no significant change in the Kd of the high-affinity binding sites for LTB4, no change in the Kd and number of the low-affinity binding sites for LTB4, and a small decrease in the apparent Kd for C5a to 3.3 +/- 1.1 nM. Even though the pretreatment with i.v. endotoxin did not alter chemotactic or degranulation responses elicited by fMLP, the endotoxin pretreatment induced an eightfold increase in the receptor density without altering the Kd for fMLP. Decreased receptor expression could account in large part for the decreased chemotactic responsiveness towards C5a and LTB4 induced by LPS. The finding that a substantial increase in receptors for fMLP need not be accompanied by a comparable functional change suggests that decreased efficiency in receptor coupling to intracellular biochemical events may also result from i.v. endotoxin.
Animals↗
Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to the major physiological chemoattractants.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a T cell-derived lymphokine which induces hematopoietic precursor cells to proliferate in vitro and differentiate to neutrophils and macrophages. GM-CSF also inhibits the motility of mature neutrophils (NIF-T activity), and primes neutrophils to enhance oxidative metabolism in response to the bacterial chemoattractant, N-formyl-methionyl-leucyl-phenylalanine (f-MLP). The present study was designed to determine whether this lymphokine also enhances neutrophil oxidative metabolism in response to the other major physiological chemoattractants which include complement-derived C5a, and the 5-lipoxygenation product of arachidonic acid, leukotriene B4 (LTB4). Superoxide anion production was measured as superoxide dismutase-inhibitable cytochrome C reduction. Purified biosynthetic GM-CSF enhanced superoxide anion production by neutrophils in response to f-MLP, C5a desArg, and LTB4. In contrast to several other factors which prime neutrophils, GM-CSF did not prime for an enhanced oxidative response to phorbol myristate acetate (PMA). These results suggest that GM-CSF may be an endogenous regulator of neutrophil inflammatory responses induced by the major physiological chemoattractants.
Chemotactic Factors↗
Effect of LTB4 and its isomers on human leucocyte migration into skin chambers.
The in vivo chemotactic effect of LTB4 and of its isomers, 6-trans-LTB4, 12 epi-6-trans-LTB4 and 5S, 12S-DHETE, was tested with a skin chamber technique in healthy volunteers and in parallel in vitro with an under-agarose technique. LTB4 had an in vivo chemotactic effect at 10(-7) mol/l in 24-hour experiments, while its isomers had no in vivo chemotactic effect at this concentration. LTB4 was also in vitro a more effective attractant than its isomers. In addition, C5ades Arg was tested using zymosan-activated serum, and was found to have an in vivo chemotactic effect at 1.5 X 10(-10) mol/l. However, when LTB4 and C5ades Arg were studied in 6-hour experiments in skin chambers there was an alteration in relative potency, LTB4 being relatively more potent at shorter test durations. This is most likely due to metabolisation of LTB4 in the presence of PMN:s and precludes a strict comparison of the in vivo chemotactic effects of LTB4 and C5ades Arg. When zymosan-activated serum or LTB4 was replaced by PBS after six hours in skin chamber experiments more leukocytes accumulated in the chambers at 24 hours than in chambers containing PBS for the whole 24 hour period. The reason for the increased migration even after the removal of the chemo-attractants as well as the relevance of LTB4 and C5a as chemo-attractants in the inflammatory process is discussed.
Chemotaxis, Leukocyte↗