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PubMedDate not supplied

How are immune complexes bound to the primate erythrocyte complement receptor transferred to acceptor phagocytic cells?

Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor (CR1) are cleared from the circulation of primates and localized to phagocytic cells in the liver and spleen without E destruction. IC can be bound to E CRI either via C3b opsonization or with cross-linked mAb complexes (heteropolymers, HP) which contain a mAb specific for CRI and a mAb specific for an antigen. The long-term goal of our work is to apply the HP system to the treatment of human diseases associated with blood-borne pathogens. This review discusses the mechanism by which the E-bound IC are transferred to acceptor cells. Our studies in animal models as well as our in vitro investigations indicate that IC transfer is rapid (usually >90% in 10 min) and does not lead to lysis or phagocytosis of the E. Experiments with specific inhibitors and the use of IC prepared with Fab' fragments suggest that transfer depends mainly upon recognition by Fc receptors on the acceptor cell. Moreover, we find that IC release from the E is associated with a concerted loss of CR1, and is followed by uptake and internalization of the IC by the acceptor cell. We suggest that recognition and binding of the E-bound IC substrates by Fc receptors allows close contact between the E and acceptor cells, which in turn facilitates proteolysis of E CR1, presumably by a macrophage-associated protease. After proteolysis, the released IC are internalized by the macrophages.

Animals↗
PubMed1996

Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis.

The loss of muscle function seen in myasthenia gravis and in the animal model of the disease, experimental autoimmune myasthenia gravis (EAMG) is in part due to the activation of complement by anti-acetylcholine receptor (AChR) antibodies at the motor end-plate. In this study we describe the effects of a soluble recombinant form of human complement receptor 1 (sCR1) on the development of clinical disease and receptor loss in EAMG induced passively by administration of anti-AChR antibodies. Daily intraperitoneal injection of sCR1 significantly reduced the weight loss and severity of clinical symptoms seen and allowed treated animals to recover normal muscle function. These data suggest that sCR1 could provide a useful additional therapeutic agent in myasthenia.

Animals↗
PubMed1985

Influence of antibody and complement components on phagocytosis and chemiluminescence of macrophages.

Macrophages are known to release reactive oxygen species (O2-, 1O2, H2O2, OH.) in response to various membrane stimuli. However, our studies show that phagocytic stimulation of macrophages is not necessarily accompanied by a stimulation of the oxidative burst. Whereas IgG-opsonized erythrocytes were capable to induce phagocytosis and a chemiluminescence response, both being dependent on the number of IgG bound per erythrocyte, C3b-bearing erythrocytes were well ingested but failed to induce any chemiluminescence reaction. Furthermore, stimulation of macrophages, via the Fc-receptors, seems to alter their functional state in regard to the activation of a receptor, which enables them to recognize membrane lesions on the target erythrocyte. The presence of IgG and membrane lesions, e.g. the C5b-9-complex of complement, induced a marked increase in chemiluminescence compared with stimulation by IgG-bearing particles alone. The augmented response of macrophages was at least in part due to an additional release of H2O2, which was not liberated in response to IgG-bearing erythrocytes. This "lesion recognizing receptor" in the macrophage membrane could not be activated by stimulation of C3b-receptors, indicating its functional linkage to the Fc-receptors.

Animals↗
PubMed1985

Fc and C3b receptor changes on mouse peritoneal leucocytes following stimulation with an extract of Ascaris suum.

Changes in IgG-Fc and IgM-C3b receptors of mouse peritoneal leucocytes after in vivo stimulation with Ascaris suum adult extract were studied. Erythrocyte IgG-Fc rosettes were found to initially be decreased with A. suum stimulated neutrophils, eosinophils and macrophages in comparison with nonstimulated cells. IgG-Fc rosettes then increased with time and remained high for a 60 min exposure time. IgM-C3b rosette formation was lower with A. suum stimulated leucocytes throughout 60 min of exposure and dropped off dramatically after 30 min. Unstimulated leucocytes formed IgM-C3b rosettes sooner and maintained them at higher levels for a longer period of time than stimulated cells.

Animals↗
PubMed1996

Monocyte function associated with intermittent lentinan therapy after resection of gastric cancer.

The effect of lentinan administration on monocyte function in the peripheral blood were examined in 33 patients who underwent resection of gastric cancer. As parameters of monocyte function, IL-1 production, C3b receptor, Fc gamma receptor and monocyte ratio were determined every 4 weeks for a maximum of 24 weeks. Among patients who were taking combined therapy with lentinan, an increase in IL-1 beta production of more than 50% was found 8 weeks (2 months) after the initiation of therapy in 8 of 12 patients given 2 mg at 2-week intervals, and in 11 of 16 patients given the same dose at 4-week intervals. This increase was particularly clear in stage II or more advanced cases. There were no significant changes in the other parameters studied. It has been considered that lentinen is effective when administered once a week. The results of the present study, however, suggest that lentinan given every 4 weeks also stimulates monocyte function enough to maintain immunological activity.

Adjuvants, Immunologic↗
PubMed2001

Influence of colloid fluids on polymorphonuclear granulocyte function in vivo.

BACKGROUND: Granulocytes have a role in the immediate immune response. In a previous investigation we could demonstrate in vitro a moderate increase of the complement receptors CR1 (CD35) and CR3 (CD11b/CD18) on the surface of polymorphonuclear neutrophils (PMN) after incubation of whole blood with colloids. To elucidate the clinical significance, we investigated if these changes were also present in vivo. METHODS: The study was performed prior to anaesthesia for orthopaedic surgery. A total of 60 ASA-I patients was evaluated. Patients received in a randomised manner 7 mL/kg of the following solutions: human albumin 5% (HA), gelatine 4% (GEL), hydroxyethylstarch solution 6% with MW 200,000 Da, degree of substitution 0.5 (HES), or Ringer's solution. Prior to the infusion, at the end (30 min) and again 30 min later, blood samples were taken. Blood was incubated with fluorescein-conjugated monoclonal antibodies (CD11b, CD16, CD35, CD62L) and analysed with flow cytometry. RESULTS: HA, GEL, HES, and Ringer's solution failed to induce significant differences in the expression of complement receptors CR1 (CD35) and CR3 (CD11b/CD18), Fc gamma receptor IIIb (CD16), and of L-selectin (CD62L) receptor on the surface of PMN. CONCLUSIONS: Application of colloids like HA, GEL, or HES in moderate amounts shows no short-term effect on adhesion or activation molecules on granulocytes. However, in high doses, infused in situations such as multiple trauma and sepsis, the consequences on the function of PMN may be speculative and require further investigations.

Adult↗
PubMedDate not supplied

Ca2+-dependent and Ca2+-independent phagocytosis in human neutrophils.

The phagocytic function of neutrophils is a crucial element in host defence against invading microorganisms. Two main specific receptor-mediated mechanisms operate in the phagocyte plasma membrane, one recognizing the C3b/bi fragment of complement and the other the Fc domain of immunoglobulin G (ref. 1). There is evidence that phagocytosis mediated by these receptors differs in the number and nature of the intracellular signals generated. However, the mechanisms by which receptor binding is transduced into a signal that generates the formation of the phagocyte pseudopod is not known, although extensive biochemical evidence has allowed the postulate that calcium ion gradients in the peripheral cytoplasm, by interacting with calcium-sensitive contractile proteins, initiate the process of engulfment. Using the high-affinity fluorescent calcium indicator quin2 both to measure and to buffer intracellular calcium ([Ca2+]i), we show here that in human neutrophils two mechanisms of phagocytosis coexist: a [Ca2+]i-dependent and modulated phagocytosis, triggered by activation of the Fc receptor, and a [Ca2+]i-independent mechanism triggered by the activation of the C3b/bl receptors.

Aminoquinolines↗
PubMed1997

Progression of HIV disease is associated with increased expression of Fc gammaRI and CR1 on alveolar macrophages.

The expression of receptors for complement and the Fc region of immunoglobulin by alveolar macrophages (AM) constitutes a valuable aid to effector function of these cells. However, during HIV infection such expression may also act to increase binding of immune complexes, thus facilitating viral infection of these cells. This study was designed to determine whether changes in the expression of these receptors occurs in situ during HIV infection. Lung macrophages were isolated by bronchoalveolar lavage in groups of HIV+ subjects segregated on the basis of peripheral CD4 count. A group of normal subjects was also investigated. Expression of CR1 and Fc gammaRI was quantified by measuring the optical density of reaction product following controlled immunoperoxidase staining with MoAbs CD35 and CD64. Both CR1 and Fc gammaRI were increased over normal in all HIV+ subjects. This increase was progressive with advancing disease as determined by correlation with declining peripheral CD4 count. Comparison of asymptomatic and symptomatic subjects with HIV infection showed no difference in CR1 expression but a rise in Fc gammaRI expression in the latter group. An overall inverse correlation was also found between peripheral CD4 count and Fc gammaRI expression, but not CR1 expression. These data demonstrate a significant increase in the expression of these receptors on AM from HIV+ subjects, and show that this increase may occur before any symptoms in these patients.

Adult↗
PubMed2003

The inducibility of TNF-alpha production is different in the granulocytic and monocytic differentiated forms of wild type and CGD-mutant PLB-985 cells.

Chronic granulomatous disease is an inherited disorder associated with a defect in phagocytic cell oxidative metabolism resulting in ineffective microbicidal activity. Consequently, patients with chronic granulomatous disease suffer from recurrent infections. Published data show that besides the failure to produce superoxide and its derivatives, other functional problems can also be found in chronic granulomatous disease-mutant cells. Since in innate immune responses other mediators, such as cytokines, also play an important role, we hypothesized that there may be a disturbance in cytokine production by chronic granulomatous disease-mutant cells as well. To prove this hypothesis, the production of tumour necrosis factor-alpha, an important proinflammatory cytokine, was determined by enzyme-linked immunosorbent assay in wild-type and chronic granulomatous disease-mutant myelomonoblastic PLB-985 cells in their immature, granulocytic and monocytic/macrophage differentiated forms. Tumour necrosis factor-alpha production was induced with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (100 nmol/L), lipopolysaccharide (10 micro g/mL), opsonized zymosan (100 micro g/mL) or phorbol 12-myristate 13-acetate (100 nmol/L) for 24 h. We could demonstrate that: (i) there were marked differences in tumour necrosis factor-alpha production only in the differentiated forms of both wild-type and chronic granulomatous disease-mutant cells, while there were no differences in the case of their immature counterparts; (ii) only chronic granulomatous disease-mutant cells retained sensitivity to phorbol 12-myristate 13-acetate both in their granulocytic and monocytic forms, although phorbol 12-myristate 13-acetate responsiveness was a characteristic of both types of immature cells; (iii) the granulocytic form of wild-type cells produced tumour necrosis factor-alpha after opsonized zymosan stimulation, but such a response was not observed in cells originating from the chronic granulomatous disease-mutant cell line; (iv) with the monocytic forms, significantly higher tumour necrosis factor-alpha production could be induced by lipopolysaccharide in the wild-type cells than in the chronic granulomatous disease-mutant cells, although there was no difference in their lipopolysaccharide receptor CD14 expression. In summary, these data show an altered inducibility of tumour necrosis factor-alpha production by chronic granulomatous disease-mutant cells. Our observations suggest a further defect in differentiated chronic granulomatous disease-mutant cells in addition to the known defect in reduced nicotinamide adenine dinucleotide phosphate oxidase, which may contribute to the development of susceptibility to infections in people with chronic granulomatous disease.

Cell Differentiation↗
PubMed1983

Vitamin D metabolites change the phenotype of monoblastic U937 cells.

U937 is a human-derived lymphoma cell line that has monoblastic properties and high-affinity receptors for 1 alpha,-dihydroxyvitamin D3. Incubation of these cells with the vitamin D metabolite at 10 nM for 5 days produced marked stimulation in adherence and ingestion of Staphylococcus aureus (645% of control) and of C3b receptor (CR1) expression (292% of control) and a slight increase in hexose monophosphate shunt activity without changing cell growth rates or Fc fragment receptor expression. The changes in cellular association of S. aureus and the CR1 were detected as early as 48 hr of incubation and peaked between 3 and 5 days. Similar changes in the CR1 were induced by 25-hydroxy- and 24,25-dihydroxyvitamin D3 at micromolar concentrations. Dexamethasone, hydrocortisone, and progesterone had no effect on CR1 expression. U937 cells incubated in the presence of vitamin D metabolites exhibited a change in their phenotype. These results suggest that vitamin D metabolites may contribute to monocyte/macrophage differentiation.

Calcifediol↗
PubMed1988

Epstein-Barr virus (EBV) infection of murine L cells expressing recombinant human EBV/C3d receptor.

The normal host range of Epstein-Barr virus (EBV) is limited to primate B lymphocytes and certain epithelial cells that express the C3d/EBV receptor [complement receptor 2 (CR2, CD21)]. In the present study, expansion of the tissue tropism of EBV has been accomplished by stably transfecting the murine fibroblast L cell line with pMT.CR2. neo.1, a eukaryotic expression vector promoting the transcription of a complementary DNA insert encoding human CR2. High CR2-expressing transfected L cells were selected by fluorescence-activated cell sorting. The recombinant CR2 was shown to have the same molecular weight as wild-type CR2 from Raji cells and to mediate the binding by the transfectants of particles bearing the iC3b and C3d fragments of the third component of complement. All CR2-expressing L cells, but not nontransfected controls, also bound EBV, as assessed by indirect immunofluorescence. After a 60-hr culture, approximately 0.5% of the CR2-expressing cells preincubated with EBV demonstrated immunofluorescent staining of EBV nuclear antigen with serum from a patient with nasopharyngeal carcinoma. No fluorescent staining of cells was seen with monoclonal antibodies to the early antigen complex or to gp350/220, indicating that the infection was predominantly latent. Infected cells cultured for up to 4 weeks remained EBV nuclear antigen-positive. The capacity of recombinant human CR2 to confer on murine L cells susceptibility to stable latent infection by EBV indicates that this receptor is a primary determinant of the tissue tropism of EBV and may facilitate studies of cell-specific factors that regulate the viral growth cycle.

Animals↗
PubMed1989

Adhesomes: specific granules containing receptors for laminin, C3bi/fibrinogen, fibronectin, and vitronectin in human polymorphonuclear leukocytes and monocytes.

We have localized several major extracellular matrix protein receptors in the specific granules of human polymorphonuclear (PMN) and monocytic leukocytes using double label immunoelectron microscopy (IEM) with ultrathin frozen sections and colloidal-gold conjugates. Rabbit antibodies to 67-kD human laminin receptor (LNR) were located on the inner surface of the specific granule membrane and within its internal matrix. LNR antigens co-distributed with lactoferrin, a marker of specific granules, but did not co-localize with elastase in azurophilic granules of PMNs. Further, CD11b/CD18 (leukocyte receptor for C3bi, fibrinogen, endothelial cells, and endotoxin), mammalian fibronectin receptor (FNR), and vitronectin receptor (VNR) antigens were also co-localized with LNR in PMN specific granules. A similar type of granule was found in monocytes which stained for LNR, FNR, VNR, CD18, and lysozyme. Activation of PMNs with either PMA, f-met-leu-phe (fMLP), tumor necrosis factor (TNF), or monocytic leukocytes with lipopolysaccharide (LPS), induced fusion of specific granules with the cell membrane and expression of both LNR and CD18 antigens on the outer cell surface. Further, stimulation led to augmented PMN adhesion on LN substrata, and six- to eightfold increases in specific binding of soluble LN that was inhibited by LNR antibody. These results indicate that four types of extracellular matrix receptors are located in leukocyte specific granules, and suggest that up-regulation of these receptors during inflammation may mediate leukocyte adhesion and extravasation. We have thus termed leukocyte specific granules adhesomes.

Antibodies↗
PubMed1990

Fc and C3bi receptors and the differentiation antigen BH2-Ag are randomly distributed in the plasma membrane of locomoting neutrophils.

Reports from several laboratories suggest that neutrophils arrested during locomotion preferentially bind immune complexes at the front of the cell. Such asymmetry of binding has been interpreted as indicating an active modulation of phagocytic receptors to the anterior of the cell. To investigate this further, we have used digital analysis of fluorescence images to determine the binding patterns of mAbs directed against the Fc receptors, the receptors for the C3bi fragment of C3, and a neutrophil-specific antigen. We found that all three proteins are distributed nearly identically along the length of migrating neutrophils, and their distribution very closely parallels the anterior to posterior distribution of the plasma membrane. The use of mAbs offered an important advantage in that the binding of antireceptor antibodies, unlike the binding of ligands, should be independent of potential changes in the affinity of the receptors. We conclude that the anterior distribution of the phagocytic receptors in the plasma membrane of locomoting neutrophils parallels the overall increase in membrane area at the front of a migrating cell and that specific translocation of phagocytic receptors does not occur.

Antigens, CD↗
PubMed1984

Regulation of elastase and plasminogen activator secretion in resident and inflammatory macrophages by receptors for the Fc domain of immunoglobulin G.

We have determined that the interaction of IgG-coated erythrocytes (EIgG) and complement-coated erythrocytes (EIgMC) with macrophage Fc and complement receptors, respectively, modulates the secretion of the neutral proteinases, elastase, and plasminogen activator. EIgG binding and ingestion stimulated secretion of elastase and plasminogen activator less than or equal to 6-fold and 20-fold, respectively, over the 3 d following treatment. Stimulation was dependent on the IgG titer bound to each erythrocyte and was detectable at greater than 6.2 X 10(3) molecules IgG/ erythrocyte (total 0.99 nM IgG in the culture). Cytochalasin B did not inhibit stimulation, indicating that the ingestion of ligands was not necessary. Binding of EIgG to the three subclass-specific Fc receptors (IgG2a, IgG2b/IgG1, IgG3) was effective. Stimulation of elastase secretion required continued exposure of ligands to cells for up to 24 h, whereas production of plasminogen activator, which has plasma membrane-bound forms as well as secreted forms, was stimulated by exposure for 2 h. The stimulated production of elastase and plasminogen activator by triggering Fc receptors was seen only when the initial secretion rates were low. Periodate- or thioglycollate-elicited macrophages, which have high rates of proteinase secretion, were not stimulated further. EIgMC, which are bound but not ingested by resident macrophages, stimulated elastase secretion transiently, and the rate of secretion returned to the control level by 24 h. Therefore, the mode of stimulation of neutral proteinase secretion by complement receptor differed from that of Fc receptor; stimulation by complement receptor possibly involves a limited release of enzyme from intracellular stores, rather than stimulating accelerated synthesis of enzyme. Erythrocytes coated with both complement and IgG showed both the transient increase in elastase typical of complement-mediated secretion and the sustained increase typical of Fc receptor-mediated secretion. These results suggest that macrophage Fc and complement receptors regulate secretion of proteinases by receptor-specific mechanisms.

Animals↗
PubMed1985

Ligated complement receptors do not activate the arachidonic acid cascade in resident peritoneal macrophages.

Receptors for IgG stimulate the release of approximately 20% of cellular arachidonic acid (20:4) from murine resident peritoneal macrophages. In contrast, C3 receptors do not trigger the secretion of any 20:4 in excess of that released constitutively from the cells. Since the ability of C3 receptors to promote phagocytosis is regulated, we compared resting macrophages, whose C3 receptors do not promote phagocytosis of C3-coated particles, and lymphokine-treated cells, whose receptors do promote ingestion. Despite their ability to promote phagocytosis, the C3 receptor of lymphokine-treated macrophages remain unable to initiate release of 20:4. We speculate that the intracellular signals that initiate phagocytosis are distinct from those that initiate release of 20:4.

Animals↗
PubMed1989

Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages.

Lipopolysaccharide binding protein (LBP) is an acute-phase reactant that binds bacterial LPS. We show that LBP binds to the surface of live Salmonella and to LPS coated erythrocytes (ELPS), and strongly enhances the attachment of these particles to macrophages. LBP bridges LPS-coated particles to macrophages (MO) by first binding to the LPS, then binding to MO. Pretreatment of ELPS with LBP enabled binding to MO, but pretreatment of MO had no effect. Moreover, MO did not recognize erythrocytes coated with LBP unless LPS was also added, thus suggesting that interaction of LBP with LPS results in a conformational change in LBP that allows recognition by MO. Binding of LBP-coated particles appears to be mediated by a receptor found on blood monocytes and MO but not on other leukocytes or umbilical vein endothelium. The receptor is mobile in the plane of the membrane since binding activity on MO was downmodulated upon spreading of cells on surfaces coated with LBP-LPS complexes. The receptor appears to be distinct from other opsonic receptors since downmodulation of CR1, CR3, Fc gamma RI, Fc gamma RII, and Fc gamma RIII with mAbs did not affect binding of LBP-coated particles, and leukocytes from CD18-deficient patients bound LBP-coated particles normally. Coating of erythrocytes with LBP-LPS complexes strongly enhanced phagocytosis observed in the presence of suboptimal amounts of anti-erythrocyte IgG. However, binding mediated by LBP-LPS complexes alone caused neither phagocytosis of the LBP-coated erythrocytes nor initiation of an oxidative burst. The results of our studies define LBP as an opsonin. During the acute phase, LBP can be expected to bind gram-negative bacteria and bacterial fragments and promote the interaction of coated bacteria with phagocytes.

Acute-Phase Proteins↗
PubMed1995

Functional analysis of complement receptor 1 using a new monoclonal antibody, KuN241.

A monoclonal antibody (MAb), KuN241, recognized an antigen present on all monocytes, polymorphonuclear leukocytes (PMNs), B cells, and a subpopulation of T cells. Cell surface expression pattern and immunoprecipitation studies indicated the molecule recognized by KuN241 to be complement receptor 1 (CR1). This was confirmed by sequential immunoprecipitation using E11, a CR1-specific monoclonal, and by immunoprecipitation analysis of a truncated transfection product of CR1. In vivo activation of PBLs for 7 days with pokeweed mitogen (PWM) abrogated surface expression of CR1 on B cells. Overnight culture with phorbol 12-myristate 13-acetate (PMA) downregulated the expression of CR1 detected by KuN241 both on PMNs and monocytes. Addition of MAb KuN241 to purified PMN and monocytes resulted in a transient increase in intracellular calcium ([Ca2+]i). This was blocked by the Fab fragment of MAb KuFc79 directed against the Fc gamma receptor. Further, Fab fragment of KuN241 cross-linked with F(ab')2 goat anti-mouse Ig failed to increase [Ca2+]i levels. Taken together, these results suggested a novel mechanism for transmembrane signaling events by dual binding of KuN241, the Fab region to CR1 and the Fc region of Fc gamma RII.

Animals↗