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PubMed1986

Monoclonal antibodies binding to the human neutrophil C3bi receptor have disparate functional effects.

Three monoclonal antibodies (MAb)--OKMI, 7C3, and 60.3--immunoprecipitated a common 170-kd neutrophil membrane antigen closely associated with, or identical to, the C3bi receptor (CR3). Despite binding to a common receptor, these antibodies displayed marked differences in their effects on C3bi-mediated neutrophil function as assessed by the binding and ingestion of opsonized zymosan and the subsequent triggering of the respiratory burst. Antibody 7C3 caused a time-dependent, irreversible inhibition of the neutrophil oxidative response to opsonized zymosan that correlated with capping of the bound antibody. In contrast, antibody 60.3 caused an immediate inhibition of the neutrophil oxidative response to opsonized zymosan that required the continuous presence of exogenous antibody to achieve the maximal inhibitory effect. Antibody OKMI demonstrated minimal inhibition of O2- release. Despite their functional differences, binding of either 7C3 or 60.3 led to up-regulation of new antigen, presumably from intracellular sites as previously described using OKMI. Crossed immunoprecipitations of radiolabeled neutrophil lysates indicated that each MAb bound to different antigens near or within the CR3 complex. Thus three MAb binding to the neutrophil CR3 receptor each caused receptor up-regulation but had markedly different functional effects on the cell.

Antibodies, Monoclonal↗
PubMed1986

Aberrant activation and regulation of the oxidative burst in neutrophils with Mol glycoprotein deficiency.

Patients whose cells are deficient in the glycoproteins LFA-1, Mol, and p150,95 have recurrent infections and pronounced abnormalities in neutrophil adherence, aggregation, chemotaxis, and phagocytosis. We characterized activation and regulation of oxidative metabolism of Mol-deficient neutrophils. These cells failed to depolarize or to produce O2- or H2O2 normally when stimulated by opsonized zymosan. The chemotactic peptide formyl methionyl-leucyl-phenylalanine depolarized Mol-deficient neutrophils normally but caused supernormal production of O2- and H2O2, a result of a prolonged burst in oxidative metabolism. Phorbol myristate acetate depolarized Mol-deficient neutrophils at a nearly normal rate but evoked release of significantly less O2- and H2O2 than from normal PMN. The aberrant activation and regulation of the oxidative burst in Mol-deficient neutrophils are considered in light of recently emerging concepts in the cell biology of this process, and the possibility that these abnormalities reflect a defect in the cytoskeleton-membrane interaction is discussed.

Cell Adhesion↗
PubMed1985

Polymorphism of the C3b/C4b receptor (CR1): characterization of a fourth allele.

The receptor for C3b/C4b (C3bR or CR1) has an unusual polymorphism in which three codominant alleles determine variants with a large difference in Mr (160,000, 190,000, or 220,000). We found an individual who has, in addition to the common 190,000 Mr molecule, a C3bR whose Mr is 250,000. In this proband and in some members of his family, this novel heterozygous phenotype can be isolated from 125I surface-labeled cells by iC3 or iC4 affinity chromatography or by immunoprecipitation with the use of polyclonal or monoclonal anti-C3bR. Relative to the 190,000 Mr C3bR, E from individuals in this family have 20 to 30% of the total receptor counts in the 250,000 Mr C3bR. However, on C3bR-bearing leukocytes there is a much larger amount of the 250,000 Mr C3bR (approximately 60%) relative to the 190,000 Mr C3bR. Similar to the other three C3bR variants, the Mr is 5,000 greater on polymorphonuclear cells than on E, and treatment of this new C3bR with endoglycosidase F decreases its Mr by approximately 10,000. Therefore, because this variant is inherited and has structural and functional similarities to the other three C3bR, we conclude that this 250,000 Mr CR1 probably represents a fourth allele.

Alleles↗
PubMed1985

PMA induces the ligand-independent internalization of CR1 on human neutrophils.

Phorbol myristate acetate (PMA) has been reported to confer on the C3b receptor (CR1) of neutrophils a capacity for phagocytosis of particles bearing C3b without the involvement of other membrane receptors. In the present study, we employed a monoclonal antibody, YZ-1, that is specific for CR1 to assess the effect of PMA on plasma membrane expression of CR1, total cellular CR1, and internalization of CR1 by neutrophils. PMA had a biphasic effect on the membrane expression of CR1 by purified neutrophils, with 4 ng/ml inducing a 60% increment in receptor expression, and higher concentrations causing up to a 70% decrement. PMA-dependent increases in CR1 expression were not accompanied by corresponding changes in total cellular CR1 and were preempted by treatment of cells with formyl-methionyl-leucyl-phenylalanine (FMLP). PMA-induced decreases in CR1 expression by neutrophils, as measured by binding of indirectly fluoresceinated or radiolabeled YZ-1, or of 125I-labeled dimeric C3b, were maximal with 20 to 30 ng/ml PMA, and occurred within 30 min of incubation at 37 degrees C. The PMA-dependent down-regulation of CR1 by neutrophils was not associated with a comparable decrease in total cellular CR1, and this response was observed to occur also with monocytes but not with peripheral blood lymphocytes. By tagging neutrophil CR1 with 125I-YZ-1 Fab and monitoring accessibility to Protease, intracellular CR1 (inaccessible) was discriminated from receptor on plasma membrane (accessible). Internalization of CR1 occurred within 5 min after addition of PMA to neutrophils, was dose dependent, and involved up to two-thirds of the tagged receptors. Therefore, PMA caused internalization of CR1 by neutrophils in the absence of ligand, indicating that this response was independent of a transmembrane signal generated by a C3b-CR1 interaction.

Animals↗
PubMed1985

Regulatory proteins for the activated third and fourth components of complement (C3b and C4b) in mice. II. Identification and properties of complement receptor type 1 (CR1).

We identified on the membrane of mouse spleen cells a polypeptide of Mr 190,000 (S190), with binding affinity for the mouse third component of the complement system (C3). S190, purified by affinity chromatography on C3-Sepharose, has properties resembling those of the human C3 receptor type 1 (CR1). Thus, S190, like CR1, served as a cofactor for the C3b inactivator (I)-mediated cleavage of fluid-phase C3b into iC3b, and had cofactor activity comparable to that of serum factor H (H). S190 also acted as a cofactor for the cleavages of membrane-bound C3b or membrane-bound iC3b into C3c (Mr 140,000) and C3dg (Mr 40,000) by serum factor I. As is the case with CR1, the specific activity of S190 for the cleavages leading to C3c-C3dg formation was approximately 100-fold greater than that of H. We therefore conclude that S190 and CR1 are analogous proteins.

Animals↗
PubMed1985

Evidence for distinct intracellular pools of receptors for C3b and C3bi in human neutrophils.

In this report, the modulation and localization of complement receptors CR1 and CR3 in neutrophils were examined with the use of monoclonal antibodies (mab) directed against these membrane proteins. We first studied complement receptor modulation in a patient with neutrophil-specific granule deficiency. With flow cytometric analysis, we determined that, while N-formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe) (10(-6) M) caused an increase in the binding of both anti-CR1 and anti-CR3 mab to normal neutrophils, the fmet-leu-phe-stimulated neutrophils from our patient increased anti-CR1 binding but decreased anti-CR3 binding. This suggested that CR3, but not CR1, might be associated with specific granules. We next studied receptor modulation in organelle-depleted neutrophil cytoplasts obtained from normal donors. Unlike the specific granule-deficient neutrophils, the normal cytoplasts failed to augment expression of either receptor after stimulation. Immunofluorescence studies of permeabilized polymorphonuclear leukocytes (PMN) revealed considerable internal binding of both anti-CR1 and anti-CR3. In additional studies, phorbol myristate acetate (PMA) was used as a stimulus for receptor modulation in normal neutrophils. Unlike fmet-leu-phe and C5a, PMA elicited a biphasic dose-response curve. High doses of PMA (greater than 0.5 ng/ml) caused a reduction in the magnitude of membrane expression of both CR1 and CR3. In studies designed to localize the internal pool of receptors, we evaluated the binding of 125I-anti-receptor mab to plasma membrane-, specific granule, and azurophilic granule-enriched fractions obtained from sucrose gradient fractionation of disrupted neutrophils. 125I-anti-CR1 mab bound to the membrane-enriched fraction but bound little to either granule-enriched fraction. In contrast, 125I-anti-CR3 mab bound more to the specific granule-enriched fraction than to the plasma membrane-enriched fraction. Azurophilic granules showed no increased anti-CR3 binding. Immunoprecipitation of radiolabeled solubilized subcellular fractions with anti-receptor mab confirmed these findings. CR3 was present in the plasma membrane-, and specific granule-enriched fraction but not in the azurophilic granule-enriched fraction. CR1, however, was present only in the plasma membrane-enriched fraction. These data indicate that there are intracellular pools for both the CR1 and CR3, but the intracellular locations for these pools are distinct. The pool for CR3 co-sediments with specific granules, while the pool for CR1 does not. Nonetheless, a variety of stimulatory agents increase and decrease the membrane expression of both receptors in parallel.

Acetone↗
PubMed1985

Chronic myelocytic leukaemia: HLA association and decreased erythrocyte C3b receptor expression.

A series of 27 adult patients with chronic myelocytic leukaemia (CML) were examined for erythrocyte C3b receptor (EC3bR) expression. Twenty-five patients were successfully HLA typed and there was a positive association of CML with HLA-B40 (P less than 0.01). Only 10 (37%) of the patients were EC3bR positive (P less than 0.00001) compared to 223 healthy controls of whom 198 (89%) were EC3bR positive. The positivity of EC3bR and HLA-B40 occurred simultaneously in six patients (P less than 0.05). HLA-B40 positivity and EC3bR expression were correlated with the following variables: age at the time of CML diagnoses, duration of CML (until death or the end of follow-up period 1 July 1983), the stage of CML and simultaneous medication. EC3bR positive patients were significantly more often in remission (P less than 0.05) and also had shorter duration of the disease (P less than 0.005) then did EC3bR negative ones. No significant correlation existed between EC3bR status and the other parameters. The presence of HLA-B40 did not associate with any of the listed variables. These findings may indicate the loss of the receptor in the course of CML with increasing immaturity of cells released from bone marrow.

Adult↗
PubMed1985

Characterization of a soluble form of the C3b/C4b receptor (CR1) in human plasma.

A radioimmunoassay with the use of soluble 125I-Fab monoclonal anti-CR1 and rabbit IgG anti-CR1 bound to Staphylococcus aureus particles was employed to detect and quantitate CR1 antigen in human plasma. Among 16 normal individuals the concentration of soluble CR1 in plasma ranged from 13 to 81 ng/ml, and a similar range of concentration was found in plasma from 15 patients having systemic lupus erythematosus (SLE). The amount of plasma CR1 in normal donors, but not in SLE patients, significantly correlated with the number of CR1 sites on erythrocytes (r = 0.90, p less than 0.001), and was 7.1% of the amount of receptor that was present on erythrocytes in blood. The concentration of soluble CR1 was not diminished by ultracentrifugation or ultrafiltration of plasma, was not affected by various modes of anti-coagulation or even by clotting of blood, and did not change during incubation of blood at 4 degrees C for up to 4 hr. On sucrose density gradient ultracentrifugation of plasma the CR1 was distributed as a broad peak that overlapped the plasma protein profile. The Mr of plasma CR1 was identical to that of erythrocyte CR1 when assessed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and immunoblotting. In addition, the plasma form of CR1 exhibited the same structural phenotype as did receptor from erythrocytes of the same individual. CR1 antigen purified from plasma was as active as CR1 from erythrocytes in promoting the cleavage by factor I of C3b to iC3b, C3c, and C3dg. Therefore, a functionally and structurally intact form of soluble CR1 resides in plasma.

Animals↗
PubMed1985

Biochemical analysis and subcellular localization of a neutrophil-specific antigen, PMN-7, involved in the respiratory burst.

The adherence of serum-opsonized yeast to neutrophils results in phagocytosis of these particulate stimuli and activation of the respiratory burst. Both events are mediated or modulated in part by the surface receptors for IgG and complement. The link between the binding of complex particulate stimuli to the cell surface, and the triggering of these neutrophil functions, is not completely understood. We have previously described an anti-human neutrophil, murine monoclonal antibody PMN7C3, which specifically inhibits the respiratory burst of neutrophils stimulated with serum-opsonized yeast. In the present study, we show that the antigen recognized by PMN7C3 (PMN7 antigen) is present on a number of neutrophil proteins, including the recently described group of related leukocyte membrane glycoproteins CR3, LFA-1, and p150,95. The PMN-7 antigen differs from other antigens associated with the C3bi receptor complex (MAC 1, MO 1, OKM1, OKM10) in that it is present only on neutrophils among peripheral blood cells. Furthermore, the binding of PMN7C3 to the neutrophil surface inhibits the activation of the respiratory burst by serum opsonized zymosan without affecting phagocytosis of these particulate stimuli. The cross-linking of cell surface PMN7 antigen by multivalent antibody is associated with the capping and internalization of antigen-antibody complexes, and appears to be necessary for the expression of maximum inhibition of opsonized zymosan-triggered respiratory burst activity. PMN7C3 also binds to a group of granule-associated proteins biochemically distinct from CR3, LFA-1, and p150,95. These granule-associated proteins containing PMN7 antigen can be mobilized to the cell surface with secretion. PMN7 antigen-bearing proteins may play a role in modulating the activation of the respiratory burst associated with phagocytosis of serum-opsonize zymosan.

Antibodies, Monoclonal↗
PubMed1985

Glomerular C3b receptor loss in renal allografts.

There is almost no data from the glomeruli of allografted kidneys with respect to changes in the CR-1 (C3b) receptor expressed on glomerular podocytes. We studied 22 renal graft biopsies from rejecting and stable allografts, using a panel of monoclonal antibodies. We found that the CR-1 expression was decreased in a focal and segmental fashion in some biopsies, particularly in rejecting kidneys. These changes correlated with the intensity of glomerular mononuclear cell infiltration, but in contrast no correlation was seen with peripheral capillary wall deposition of complement (C3). Thus, some active process is occurring in the glomeruli of rejecting grafts which affects the expression of the CR-1 receptor.

Graft Rejection↗
PubMed1985

Erythrocyte enhancement of C3b-mediated phagocytosis by human neutrophils in vitro: a combined effect of the erythrocyte complement receptors CR1 and erythrocyte scavengers to reactive oxygen metabolites (ROM).

Human erythrocyte CR1 receptors have been shown to bind complement-fixing immune complexes and, thus, facilitate their elimination from the circulation. The autotoxic effect of free radicals released from phagocytes during phagocytosis can be alleviated by scavengers like catalase and superoxide dismutase. Erythrocytes are known to contain these antioxidants. This study showed that 74% of opsonized yeast particles adhered to human erythrocytes. No difference was seen between yeast opsonized with C3b and yeast opsonized with both IgG and C3b. This adherence was due to the C3b receptor (CR1), as monoclonal antibodies against the CR1 receptor could abrogate the adherence. The yeast phagocytosis by neutrophils was increased by 15% when yeast-C3b was used, and by 34% when yeast-IgG/C3b was used in the presence of human red blood cells. The increase of phagocytosis was not seen when rat erythrocytes (lacking CR1) were present. The cytochrome c reduction decreased with the presence of human erythrocytes during phagocytosis, indicating a scavenging effect on the superoxide anions. The addition of scavengers or erythrocyte lysate, instead of erythrocytes, enhanced phagocytosis of yeast-IgG/C3b to at least the same extent as the erythrocytes. These observations suggest that human erythrocytes primarily enhance phagocytosis through the scavenging effect of those erythrocytes which are concurrently attached with the prey through its CR1 receptor, and then attached to the PMN.

Complement C3b↗
PubMed1985

Neutrophil phagocytosis in sarcoidosis. Reduced C3b receptor-mediated phagocytosis in active and silent sarcoidosis.

The phagocytic and complement receptor function of polymorphonuclear neutrophils (PMN) from patients with sarcoidosis was studied using a kinetic assay which allows the distinction to be made between Fc receptor-mediated and C3b receptor-mediated particle uptake. The study included one group (A) of patients with active disease (n = 20), and one group (B) with silent or inactive disease who since 10 years had no symptoms or radiological signs of sarcoidosis (n = 11). Abnormal C3b receptor function was observed in both groups but the impairment was most pronounced in the A group. The presence of C3b receptor dysfunction in both groups with a quantitative difference between the groups, is compatible with C3b receptor dysfunction being a primary causal factor of sarcoidosis.

Adult↗
PubMed1985

Tumor-promoting phorbol esters induce rapid internalization of the C3b receptor via a cytoskeleton-dependent mechanism.

Plasma membrane expression as well as phagocytic capability of the C3b receptor (CR1) are under regulatory control. Phorbol esters are one class of agents which have been shown to influence both of these events. In this study, by using radiolabeled Fab fragments of a monoclonal anti-CR1 antibody to tag the receptor and acid elution of surface-bound Fab, we showed that both phorbol myristate acetate and phorbol dibutyrate induced internalization of the C3b receptor; this occurred in a dose- and time-dependent manner in the absence of occupancy of the receptor by ligand. This was shown to occur in neutrophils, monocytes, and macrophages. We also showed that phorbol esters enhanced CR1-dependent phagocytosis despite the presence of two-thirds fewer receptors present on the plasma membrane. However, fibronectin, another agent that influences phagocytosis, had no effect on receptor internalization. Phorbol ester internalization was temperature-dependent and was inhibitable by cytochalasins B and D. Inhibition of internalization was reversible when cytochalasin B was removed. Phorbol esters also induced increased detergent insolubility of CR1 with kinetics similar to those of receptor internalization. It is possible that association of CR1 with the cytoskeleton is important to the process of "activation" of CR1 in phagocytosis.

Antibodies, Monoclonal↗
PubMed1985

Calcium requirements for increased complement receptor expression during neutrophil activation.

It has recently been shown that human neutrophils rapidly increase surface expression of membrane receptors for C3b (CR1) and C3bi (CR3) in response to chemoattractants and other stimuli. In the present studies, we used monoclonal antibodies and flow cytometry to assess the role of Ca2+ in this process. Stimulation with ionophore A23187 in the presence of 1.2 mM Ca2+ increased CR1 330% and CR3 650% compared with unstimulated cells at 37 degrees C. Because this indicated that increasing the cytosolic free Ca2+ caused increased receptor expression, we examined the role of Ca2+ in the response to other stimuli as well. Adding 1.2 mM Ca2+ or 5 mM EDTA to the media in which the polymorphonuclear leukocytes were suspended had no effect on the CR1 response to f-MLP or LTB4, whereas Ca2+ slightly enhanced and EDTA markedly inhibited the CR3 response to these stimuli. The effects of Mg2+-EGTA and EDTA were identical. TMB-8 (200 microM), which inhibits the release of Ca2+ from intracellular stores, completely blocked the increased expression of both receptors induced by fMLP or LTB4. Increased expression of both receptors was also prevented by the calmodulin antagonists chlorpromazine (50 microM) and trifluoperazine (10 microM), but not by chlorpromazine sulfoxide. Phorbol myristate acetate (0.1 ng/ml) increased CR1 230% and CR3 265%. Again Ca2+ and EDTA did not alter the CR1 response, whereas Ca2+ increased CR3 to 287% and EDTA reduced CR3 to 187% of control. TMB-8 (250 microM) completely blocked both CR1 and CR3 responses to this stimulus as well. Thus, release of intracellular Ca2+ is necessary and sufficient for increased CR1 expression in response to diverse stimuli, but maximal increases in CR3 expression require an additional influx of extracellular Ca2+. These results indicate that the mechanisms by which the surface expression of the two different complement receptors increase are different in their requirements for extracellular Ca2+. In comparison with the work of others, we suggest that the processes of increased complement receptor expression and secretion of granular enzymes may also differ.

Calcimycin↗
PubMed1985

The change in C3b receptors on erythrocytes from patients with systemic lupus erythematosus.

A deficiency of C3b receptors (CR1) on erythrocytes from patients with systemic lupus erythematosus (SLE) has already been reported and assumed to be one of the causes of the impaired immune complex clearing function found in these patients. In the present study, we developed a functional assay to quantify the amount of CR1 on human erythrocytes. Sample erythrocytes were reacted with tetanus toxoid-anti-tetanus toxoid immune complexes (IC) in the presence of complement. The amount of CR1 was expressed as the amount of IC bound to sample erythrocytes. Determination of CR1 showed a decrease in erythrocytes from patients with SLE, rheumatoid arthritis and other connective tissue diseases. The activity of CR1 in erythrocytes from patients with SLE changed in parallel with complement activity and also reflected the clinical status of two of three patients. These results imply that the reduction of CR1 found in SLE patients might be cause not only by hereditary factors but by unknown factors that influence the amount or function of CR1.

Adult↗
PubMed1985

Purification and functional analysis of the polymorphic variants of the C3b/C4b receptor (CR1) and comparison with H, C4b-binding protein (C4bp), and decay accelerating factor (DAF).

Four CR1 variants have been found in the normal population and are designated CR1-A (190,000 daltons), CR1-B (220,000 daltons), CR1-C (160,000 daltons), and CR1-D (250,000 daltons). In the present study, we first developed an improved chromatographic purification scheme for CR1 that does not employ a C3b affinity step. CR1 variants (A, B, and C) were then isolated, and their individual functional activity was assessed. Each possessed similar co-factor activity for I-mediated cleavage of C3(H2O), as well as for the inhibitory activity for fluid phase C3 convertases. These results indicate that, despite relatively large Mr differences, in the purified state these three CR1 variants have similar functional activities. The functional activity of CR1 was also compared with C4bp, H, and decay accelerating factor (DAF) in fluid phase assays designed to assess the inhibition of the C3 convertases and co-factor activity. On a molar basis, CR1 had approximately the same inhibitory activity as C4bp for the classical pathway convertase, and had the same as H for the alternative pathway convertase. These results indicate that CR1 encompasses the functional capabilities of both proteins. They also raise a number of interesting genetic and structural questions in regard to these complement regulatory proteins, because C4bp is thought to have multiple C4b binding domains, whereas H is reported to bind one C3b. DAF was an approximately fourfold better inhibitor of the alternative pathway convertase than CR1 or H, but was a fourfold less efficient inhibitor of the classical pathway convertase than CR1 or C4bp. The effective inhibitory capacity of DAF in these fluid phase assay systems suggests that the DAF substrate specificity is for the convertases. Fluid phase CR1 was twofold less efficient than H in serving as a co-factor for the first cleavage of fluid phase C3b, and hardly mediated the second cleavage. These data are in contrast to the co-factor activity of CR1 on a cell membrane, and provide additional evidence for the local environment being a critical modulator of the function of proteins that regulate the activation of C3.

Complement Activating Enzymes↗
PubMed1985

Factor I co-factor activity of CR1 overcomes the protective effect of IgG on covalently bound C3b residues.

We have shown previously that C3b resides in a protected site when it is covalently bound to IgG (C3b-IgG). Such C3b displays a reduced affinity for factor H, with consequent enhanced survival in the presence of factors H and I and increased capacity for promoting alternative pathway consumption of C3. Because erythrocyte CR1 may be a major co-factor for factor I-mediated inactivation of immune complex-borne C3b in blood, we have examined the effect of covalently bound IgG on the C3b-CR1 interaction. Binding of monomeric C3b and C3b-IgG to human erythrocyte CR1 demonstrates identical ionic strength dependence for both species. Identical numbers of binding sites with indistinguishable affinities are detected by both ligands. Cleavage of the alpha'-chain of C3b and the alpha'-heavy chain of C3b-IgG proceeds at the same rate when erythrocyte CR1 serves as co-factor for factor I. Unlike factor H, CR1 supports a second cleavage of fluid-phase iC3b alpha'1 chain (free or bound to IgG) that generates C3c and a 33,000 m.w. fragment, which bears antigenic markers characteristic of C3g. Inactivation of C3b and C3b-IgG by CR1 and factor I also occurs at physiologic ionic strength, but proceeds very slowly relative to rates attainable with sub-physiologic inputs of factor H. CR1 does not recognize IgG-bound C3b as being in a protected site but, because of low binding affinity at physiologic ionic strength, is probably highly dependent on multivalent ligand-receptor interactions to efficiently exert its co-factor functions. Thus, inactivation of C3b-IgG heterodimers or small immune complexes bearing limited numbers of C3b residues may remain largely factor H-dependent in vivo, with resultant enhanced C3b survival.

Antigen-Antibody Complex↗
PubMed1985

Fibronectin-enhanced phagocytosis of an alternative pathway activator by human culture-derived macrophages is mediated by the C4b/C3b complement receptor (CR1).

We examined the ability of human monocytes and culture-derived macrophages under serum-free conditions to phagocytose desialated sheep erythrocytes (E), an activator of the alternative pathway of human complement. Freshly derived monocytes ingested desialated erythrocytes, but the degree of phagocytosis varied among individual donors. However, exposing the phagocyte to intact plasma fibronectin (Fn) had no effect on monocyte phagocytosis. Macrophages derived from monocytes in culture were far more efficient at ingesting desialated E, and the extent of phagocytosis was proportional to the degree of desialation. Although exposure of macrophages to substrate-bound Fn or fluid-phase Fn enhanced the phagocytosis of desialated E, pretreatment of desialated E with Fn did not enhance phagocytosis, demonstrating that Fn acted through an interaction with the macrophages. Fn-enhanced phagocytosis of desialated E was inhibited by treating macrophages with a monoclonal antibody to the C4b/C3b receptor (CR1), but not with a monoclonal antibody to the receptor for C3bi (CR3). Addition of cobra venom factor (CVF) to the macrophages also inhibited Fn-enhanced phagocytosis of desialated E. Phagocytosis of IgG-sensitized E, either in the absence or in the presence of Fn, was not significantly affected by anti-CR1 or CVF, demonstrating that these reagents did not lead to a general inhibition of phagocytosis. These experiments suggest that macrophages may deposit enough C3b onto desialated E to cause CR1-mediated phagocytosis in the presence of Fn. The ability of macrophages to opsonize and ingest foreign particles that activate complement may be critically important in areas of inflammation where concentrations of serum-derived specific opsonins may be inadequate.

Animals↗