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PubMed2005

Band 3/complement-mediated recognition and removal of normally senescent and pathological human erythrocytes.

Band 3 modifications that normally occur during physiological red blood cell (RBC) senescence in humans, and occasionally in pathological conditions are described in the context of their role in enhancing RBC recognition and phagocytic removal. Band 3 modifications are mostly due to oxidative insults that gradually accumulate during the RBC lifespan or impact massively in a shorter time period in pathological conditions. The oxidative insults that impact on the RBC, the protective mechanisms that counteract those damages and the phenotypic modifications that accumulate during the RBC lifespan are described. It is shown how specific oxidative as well as non-oxidative band 3 modifications enhance RBC membrane affinity for normally circulating anti-band 3 antibodies, and how membrane-bound anti-band 3 antibodies bring about a limited complement activation and membrane deposition of complement C3 fragments. The partially covalent complexes between anti-band 3 antibodies and complement C3 fragments are very powerful opsonins readily recognized by the CR1 complement receptor on the phagocyte. Band 3 modifications typically encountered in old RBCs have crystallized to a number of band 3-centered models of RBC senescence. One of those band 3-centered models, the so-called 'band 3/complement RBC removal model' first put up by Lutz et al. is discussed in more detail. Finally, it is shown how the genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD) plus fava bean consumption, and a widespread RBC parasitic disease, P. falciparum malaria, may lead to massive and rapid destruction of RBCs by a mechanism comparable to a dramatic, time-compressed enhancement of normal RBC senescence.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1976

The role of complement in the clearance of cold agglutinin-sensitized erythrocytes in man.

To define the pathophysiologic mechanisms of cold agglutinin disease, we investigated a human model of this syndrome in normal volunteers and in patients with diminished levels of serum complement. Subjects received intravenous injections of autologous, chromated (51Cr) erythrocytes which had been exposed in vitro to purified cold agglutinin preparations and to fresh autologous serum (as a source of complement). In vitro tests confirmed that such cells were coated with activated complement components (C3b), but not with immunoglobulin. Studies of erythrocyte clearance and simultaneous organ scanning showed that erythrocytes sensitized with low levels of cold agglutinin primarily undergo reticuloendothelial sequestration by the liver rather than intravascular hemolysis. After the initial sequestration of C3b-coated erythrocytes, a fraction of the cells are released back into the circulation and survive normally thereafter. Both phenomena are dose dependent and closely follow the sequestration and release pattern observed with IgM isoagglutinin sensitization. Experiments that used heated autologous serum as a source of B3 inactivator demonstrated that functionally intact C3b is required for hepatic sequestration. Erythrocytes coated with C3d were not cleared from the circulation. In vitro assays that sued human macrophage monolayers suggested that the intrahepatic conversion of C3b to C3d is responsible for the release of sensitized erythrocytes back into the circulation. The clearance of cold agglutinin-sensititzed erythrocytes was compared to the clearance mediated by IgM isoagglutinin. We found that the rate of complement fixation by an IgM antibody proceeds rapidly in vivo that the time for complement activation is not a factor in limiting the rate of hepatic sequestration. The major limiting factor appears to be the rate of liver blood flow. Maximal in vitro coating of erythrocytes with C3d conferred protection from further cold agglutinin sensitization but not from IgM isoagglutinin-mediated clearance. This suggests a mechanism for the resistance to lysis observed in cells obtained from patients with the cold agglutinin syndrome and confirms the marked dependence of the site of C3 attachment on the site of membrane localization of the sensitizing antibody.

Agglutinins↗
PubMed1987

A dysfunctional Mo1 glycoprotein is present on a subline of the KG1 acute myelogenous leukemia cell line.

Mo1 is a glycoprotein heterodimer found on the surface of phagocytic cells. By use of monoclonal antibodies directed against various epitopes of the 155 kd alpha-chain of Mo1, two distinct functions of this glycoprotein have been identified. Mo1 serves as the receptor (CR3) for iC3b, one of the breakdown products of the third component of complement, and in addition appears to be involved in promoting cell-cell adhesion of granulocytes. In studies performed with a subline of the acute myelogenous leukemia tumor cell line KG1, we found cells from this subline (KG1m) incapable of iC3b-mediated binding despite these cells having surface Mo1. Five distinct epitopes on Mo1 identifiable on normal cells by a panel of anti-Mo1 alpha-chain monoclonal antibodies (including OKM10, thought to be identical to or close to the iC3b binding site) were equally present on KG1m by indirect immunofluorescence. The electrophoretic mobilities of both the alpha- and beta-chains of Mo1 derived from KG1m were identical to those isolated from normal granulocytes. To determine whether altered receptor mobility or decreased surface density of Mo1 was responsible for the lack of Mo1-related functions, binding to EiC3b of isolated Mo1 derived from KG1m lysate was measured. KG1m-derived Mo1 did not bind to EiC3b when compared with normal granulocyte-derived Mo1, suggesting that the lack of iC3b binding is not secondary to decreased surface receptor number or mobility. This subline of KG1 provides an excellent model for the study of the relationship between surface receptor structure and function.

Antibodies, Monoclonal↗
PubMed1982

Enumeration of lymphocyte populations in whole peripheral blood of patients with antibody-mediated nephritis during treatment with cyclosporin A.

Lymphocyte populations identified by surface markers were enumerated in whole peripheral blood of 3 patients with Goodpasture's syndrome (mediated by anti-glomerular basement membrane antibody) whilst on treatment with cyclosporin A (CSA). The whole blood method, using alkaline phosphatase-labelled reagents, permits precise enumeration of the relative and absolute numbers of lymphocyte subsets in the circulation. Using conventional rabbit and monoclonal mouse anti-human T-cell antibodies, a small decrease in the percentage of T-lymphocytes was noted following the start of CSA treatment. The absolute T-cell count fell, but only to just below normal. There was no marked or consistent effect on the percentages or absolute numbers of B-cells, C3b-receptor or Fc(gamma)-receptor bearing lymphocytes. These results are compatible with a mechanism of immunosuppression by CSA in which there is selective inhibition of a relatively minor subset of T-lymphocytes.

Adolescent↗
PubMed1999

The influence of subinhibitory concentrations of conventional and experimental antifungal drugs on the expression of the iC3b binding protein in Candida albicans strains during filamentation.

The influence of six antifungal agents on the expression of the fungal iC3b binding protein was studied in germ-tubes and the mycelial form of several Candida albicans strains. All antifungal agents inhibited not only the yeast-mycelial transformation, but also the formation of rosettes consisting of complement-coated sheep erythrocytes (EAiC3b) bound to the mycelial form of C. albicans. Immunofluorescence as well as ELISA, employing the monoclonal antibody OKM-1 which recognizes the alpha chain of human CR3 and which cross-reacts with the fungal iC3b binding protein, revealed that subinhibitory concentrations of 0.1 mg l(-1) (which did not affect the growth of either germ-tubes or the mycelial form of C. albicans) inhibited the expression of the iC3b binding protein, while lower concentrations (0.01 mg l(-1)) allowed a comparable and sometimes even slightly higher expression of this protein, in comparison with the untreated control. However, treatment with antifungal agents apparently did not lead to a major cleavage of the protein. The dependence of the amount of the iC3b binding protein expressed on the concentration of added antifungal drugs and on the morphological forms of individual C. albicans isolates suggests a drug dependent influence on the expression of this protein and a possible association with the changing virulence of C. albicans strains during antifungal therapy.

Amphotericin B↗
PubMed1978

C3b and c3d receptor sites on human fibroblasts derived from several human tissues.

The C3b and C3d receptor sites on one cell line of human diploid fibroblasts (WI-38) were reported in previous papers [3, 4]. In this paper we describe that C3b and C3d receptor sites can also be detected in fibroblast cell lines derived from other human tissues. We consider that C3b and C3d receptors are normally found on the cell surfaces of all human fibroblasts.

Binding Sites↗
PubMed1984

The effect of reactive oxygen metabolites (ROM) on the attachment and ingestion phases of C3b- and IgG-mediated phagocytosis by macrophages.

The effects of enzymatically produced reactive oxygen metabolites (ROM) on the attachment and ingestion phases of C3b- and IgG-mediated phagocytosis by cultured mouse peritoneal macrophages (MPM) was investigated using a hypoxanthine-xanthine oxidase ROM-generating system. ROM-exposure at a dose which did not affect cell viability caused a slight decrease in the percentage of phagocytosing cells. The total number of cell-associated (attached and ingested) C3b- and IgG-coated particles initially decreased in relation to controls. After 120 min the number of attached and ingested C3b-particles had returned to the level of controls, while the corresponding value for IgG-particles lagged behind. The number of ingested particles decreased in both C3b- and IgG-groups at each time-point studied (30-150 min). A linear increase in the formation of lipid peroxidation products was measured during the period of observation, while transmission electron microscopical studies showed largely intact morphology. These results indicate that ROM species may induce membrane-related changes in inflammatory cells such as macrophages, probably due to lipid peroxidation; affecting the binding functions of the C3b- and Fc-receptors, without any obvious alteration in cellular fine structure.

Animals↗
PubMed1983

Studies on the phagocytic activity of the granulocytes in psoriasis and palmoplantar pustulosis.

A kinetic method was used to determine the rates of phagocytosis of IgG-coated and C3b-IgG-coated latex particles by neutrophil granulocytes from twenty patients with psoriasis and twenty with palmoplantar pustulosis (PPP). Patients with psoriasis showed a highly increased rate of uptake of IgG-coated particles. An increased rate was also observed in patients with PPP. These results indicate enhanced Fc-receptor function. In healthy controls the uptake rate of C3b-IgG-coated particles was at least 30% higher than that of particles coated with IgG alone. In nearly half of the patients in the psoriasis and PPP groups the uptake rate failed to increase in the normal way, indicating that C3b dysfunction is common in both psoriasis and PPP. In neither group was there any relationship between the rate of phagocytosis and the clinical severity of the disease.

Adolescent↗
PubMed1987

Ixodes dammini: salivary anti-complement activity.

Saliva of the tick Ixodes dammini prevents hemolysis of rabbit erythrocytes by the human alternative pathway of complement. Deposition of C3b to activating surfaces and concomitant C3a release are inhibited. C3b deposition to activating surfaces is inhibited regardless the origin (humans, rat, mouse, guinea pig, and hamster) of the serum. The inhibitor elutes as a single peak upon gel filtration, with an apparent molecular weight of 49,000. Salivary anti-complement may contribute to successful feeding of I. dammini in their natural hosts.

Animals↗
PubMed1975

Immunologic cell features in lymphocytic leukemias: a review.

Since four years, it has been possible to classify most cases of Chronic Lymphocytic Leukemia (CLL) as given to the expansion of abnormal B-lymphocytes. On the contrary, the T-cell class is apparently normal and the T cell extent in CLL-peripheral blood can be even greater than normal when taken as absolute value. The clonal nature theory of B-lymphocytes in CLL is substantiated by the fact that, in general, in every patient only one Ig light chain determinant is present. Again, when serum Ig monoclonality is present in CLL, it appears idiotypically identical to the Ig shown by the lymphocytes of the same patient. Among the most important B-lymphocyte abnormalities in CLL, there are: (a) fluorescence of surface Ig is usually less intense than that in normal subjects, and fluorescence intensity may vary not only from patient to patient, but also from cell to cell in the same patient; (b) the Fc-receptor can be lacking; (c) the C3b-receptor is not always present, or it is from 2 to 20 folds less frequent than the C3d-receptor, whereas normal human lymphocytes do not show any outstanding differences between the number of EAC rosette-forming cells either when tested with mouse complement (C3d-receptor) or with human complement (C3b-receptor); (d) the traffic capacity of peripheral-blood B-lymphocytes in CLL is quite defective. All the above-mentioned data, taken as a whole, suggest that CLL is in general given by the expansion of an abnormal clone of cells of B origin, arrested in their maturative development, non-responsive to the mitogen stimulation, accumulating in the peripheral-blood for a traffic deficiency.

Animals↗
PubMed1983

C3b acceptors on human peripheral blood mononuclear cells; characterization and functional role.

C3b acceptors (C3bAs) of human peripheral blood mononuclear cells (PBMC) reacting with the labile binding site of nascent C3b(C3bx) have been investigated by the immune adherence (IA) test. In non-cellular systems some conventional chemical groups (OH-, NH-2) have been reported to be the target of the covalent binding of C3bx. Thus it should be assumed that every cell can fix C3bx via its labile binding site and C3bAs are barely saturable. Contrary to this expectation, however, normal human PBMC were found to be heterogeneous from this point of view, as 57 +/- 4% of B cells and 21 +/- 2% of Null cells possess C3bAs while T cells do not. C3bAs of human PBMC are saturable and trypsin-sensitive structures. The covalent nature of the C3bx-C3bA interaction has also been proved. Studying the effect of acceptor-bound C3b on the function of other cell-surface structures, the inhibition of the Fc gamma receptor function and the abolishment of the enhancement of pokeweed mitogen-stimulated blastogenesis by immune complexes were found.

Antigen-Antibody Complex↗
PubMed1989

Characterization of the baboon erythrocyte C3b-binding protein.

E from primates demonstrate type 1 CR (CR1) with binding specificities for C3b and C4b. In the present study we characterized the E C3b-binding protein of baboons. We showed that three out of four mouse mAb and one polyclonal antiserum, raised against human E CR1, cross-reacted with baboon E. In addition, one anti-human CR1 mAb (1B4) and a polyclonal anti-human CR1 inhibited the binding of C3b opsonized immune complexes to baboon E. Finally, a mAb to human CR1 (E11) recognized epitopes on E of a variety of nonhuman primates, including baboons. SDS-PAGE analysis of biochemically purified baboon E membrane fractions reactive with E11 demonstrated a 65-kDa protein as a major component. Affinity absorption and elution experiments verified this protein to be E11 reactive as well as a C3b binding protein. E surface radiolabeling, followed by C3i affinity purification, confirmed that this 65-kDa protein is the only C3b-binding protein present on the baboon E membrane. We postulate that the baboon E 65-kDa protein is the equivalent of the human E CR1. In addition, there appear to be antigenic similarities between the baboon E 65-kDa protein and the human E CR1.

Animals↗
PubMed1997

Defective elimination of C3b/iC3b-coated autologous erythrocytes in patients with primary biliary cirrhosis, alcoholic cirrhosis, and ulcerative colitis.

Delayed in vivo elimination of autologous erythrocytes coated with immunoglobulin G has been reported in autoimmune and inflammatory gastrointestinal diseases. Our aim was to elucidate whether impairment of the macrophages was restricted to the Fc receptors of the reticuloendothelial system or whether complement receptors were also affected. We studied elimination by complement receptors of autologous erythrocytes coated with fragments of C3 and C4 in patients with primary biliary cirrhosis, ulcerative colitis, and alcoholic cirrhosis. Impaired function was seen in all patient groups as compared with function in normal subjects, both concerning the mean half-life of the injected cells and the total number of eliminated erythrocytes. Neither of these parameters correlated with the levels of C3 fragments bound to the injected autologous erythrocytes. This is the first report of defective complement receptor function in ulcerative colitis and alcoholic cirrhosis. Immunoglobulin G-dependent elimination of erythrocytes was confirmed to be lowered in all patient groups. The results suggest severe macrophage functional aberrations involving both complement receptors and Fc receptors as the basis of phagocytic defects in autoimmune/inflammatory conditions. In contrast, a general loss of macrophages might cause the functional loss in alcoholic cirrhosis.

Adult↗
PubMed2001

Bactericidal/permeability-increasing protein promotes complement activation for neutrophil-mediated phagocytosis on bacterial surface.

The neutrophil bactericidal/permeability-increasing protein (BPI) has both bactericidal and lipopolysaccharide-neutralizing activities. The present study suggests that BPI also plays an important role in phagocytosis of Escherichia coli by neutrophils through promotion of complement activation on the bacterial surface. Flow cytometric analysis indicated that fluorescein-labelled E. coli treated with BPI were phagocytosed in the presence of serum at two- to five-fold higher levels than phagocytosis of the bacteria without the treatment. In contrast, phagocytosis of the fluoresceined bacteria with or without treatment by BPI did not occur at all in the absence of serum. The phagocytosis stimulated by BPI and serum was dose-dependent. The effect of BPI on phagocytosis in the presence of serum was not observed on Gram-positive bacteria (Staphylococcus aureus). Interestingly, the complement C3b/iC3b fragments were deposited onto the bacterial surface also as a function of the BPI concentration under conditions similar to those for phagocytosis. Furthermore, the BPI-promoted phagocytosis was blocked completely by anti-C3 F(ab')(2) and partially by anti-complement receptor (CR) type 1 and/or anti-CR type 3. These findings suggest that BPI accelerates complement activation to opsonize bacteria with complement-derived fragments, leading to stimulation of phagocytosis by neutrophils via CR(s).

Antimicrobial Cationic Peptides↗
PubMedDate not supplied

Periodic elevation of complement activation products in peritoneal dialysis effluent.

Peripheral white blood cells (WBCs) of chronic ambulatory peritoneal dialysis (CAPD) patients show a reduced expression of chemotactic receptors and a desensitization to chemotactic factor induced events. Chronic complement activation has been suggested as a cause of such phenomena, resulting from either uremia, the indwelling peritoneal catheter, and/or dialysis fluid stimulation. The presence of complement activation products in peritoneal dialysis effluent was assessed by longitudinal measurement of C3bi in eight patients over a 6 to 8 month period, while peritoneal polymorphonuclear leukocyte (PMN) and monocyte CR3 and C5a receptor expression was quantitated by flow cytometry. In six of eight patients, C3bi levels were stable over time and usually measured less than 5 micrograms/ml. Two other patients showed periodic elevation of C3bi, which was not associated temporally with peritonitis. Further study is required to identify the origin of such activated complement components within the peritoneal cavity. However, no correlation was found between dialysate C3bi levels and peritoneal PMN or monocyte expression of CR3 or C5a receptors. Furthermore, the incidence of peritonitis for the two individuals with elevated C3bi was discordant (1 episode/8 patient months vs. 0 episodes/32 patient months), suggesting little or no relationship between these parameters.

Adult↗
PubMed1987

Characterization of the C3 receptor induced by herpes simplex virus type 1 infection of human epidermal, endothelial, and A431 cells.

Herpes simplex virus type 1 (HSV-1) infection induces the appearance of viral analogues of human Fc IgG and C3 receptors on the surface of human cells. The virally induced C3 receptor(s) has been broadly defined as a C3b receptor, but its ligand binding characteristics have not been rigorously defined. In this study, human epidermal cells, A431 cells, and human umbilical vein endothelial cells infected with HSV-1 demonstrated rosetting with sheep erythrocytes (E) coated with IgG (E-IgG) or the complement components C3b (EAC3b) or iC3b (EAC3bi), but not with E-IgM, C4 (EAC14), C3d (EAC3d), or E alone. Rosetting was markedly enhanced by pretreatment of HSV-1-infected cells with neuraminidase. Unlike human C3 receptors, the HSV-1-induced C3 receptor was found to be trypsin resistant. To determine whether HSV-1 induced CR1-like receptors or CR3-like receptors, infected cells were pretreated with EDTA, which is known to inhibit native CR3 function. EDTA failed to prevent rosetting with EAC3bi. Furthermore, blocking studies using monoclonal antibodies against CR1 and CR3 revealed that the anti-CR1 antibody 5C11 consistently blocked EAC3b and EAC3bi rosetting with HSV-1-infected cells in a dose dependent manner, but monoclonal antibodies against CR3 did not. This study indicates that the HSV-1-induced C3 receptor is an analogue of CR1.

Antibodies, Monoclonal↗
PubMed1988

Macrophage heterogeneity in prostaglandins and thromboxane synthesis: differential activation by Fc- and C3b-dependent bacterial phagocytosis.

Resident peritoneal macrophages, obtained from rats, were separated into subpopulations by centrifugation on a Percoll discontinuous density gradient. Nine fractions of pure macrophages were isolated. Each subpopulation was studied for Fc- and C3b-dependent bacterial phagocytosis and assayed for the related synthesis of PGE2, TxA2 and PGI2, measured by their stable metabolites TxB2 and 6-Keto-PGF1. The results show that with decreasing density, which corresponds to a greater maturity, the production of PGE2 increases and that of TxB2 and 6-Keto-PGF1 decreases. The cells of low density were mostly stimulated by IgG-opsonized bacteria, whereas those of high density responded preferentially to C3b- opsonized bacteria. This pattern is roughly similar to the one characterizing the phagocytosis via these two receptors although the correlation is not absolute. It can be concluded that enzymes involved in the metabolism of arachidonic acid, as well as receptors for C3b and IgG, are differentially expressed among resident macrophage subpopulations and thus during macrophage maturation.

Animals↗