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PubMed1998

Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules.

Macrophages become activated by bacterial endotoxin (lipopolysaccharide) and other stimuli to release proinflammatory cytokines and NO. To prevent release of toxic or potentially lethal quantities of these factors, the state of macrophage activation is counter-regulated by anti-inflammatory mediators (e.g., glucocorticoid hormones, interleukin 10, and transforming growth factor type beta). Fetuin, a negative acute-phase protein, recently was implicated as an anti-inflammatory mediator, because it is required for macrophage deactivation by spermine. In the present studies, we found that fetuin is necessary for macrophages to respond to CNI-1493, a tetravalent guanylhydrazone inhibitor of p38 mitogen-activated protein kinase phosphorylation. Fetuin dose-dependently increases macrophage uptake of CNI-1493, which can be specifically inhibited by anti-human fetuin antibodies. Anti-human fetuin antibodies render primary human peripheral blood mononuclear cells insensitive to deactivation by CNI-1493. Thus, macrophages use fetuin as an opsonin for cationic-deactivating molecules, both endogenous (e.g., spermine) and pharmacologic (e.g., CNI-1493). This role of fetuin as an opsonic participant in macrophage-deactivating mechanisms has implications for understanding and manipulating the innate immune response.

Amino Acid Sequence↗

PubMed1998

Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family.

The Hakata antigen is a novel, thermolabile beta2-macroglycoprotein that reacts with sera from patients suffering from systemic lupus erythematosus. In this study we present the structure and the function of the Hakata antigen. We have identified cDNA clones encoding the Hakata antigen and analyzed its function. The cDNA included a possible open reading frame of 897 nucleotides, encoding 299 amino acids. The Hakata antigen consisted of a collagen-like domain in the middle section and a fibrinogen-like domain in the COOH terminus, both of which are homologous to human ficolin-1 and opsonin P35, indicating that these three molecules form a distinct family. The molecular mass of the Hakata antigen expressed in transfected cells was 35 kDa under reduced conditions, and it formed ladder bands under nonreducing conditions compatible with the previous result that the Hakata antigen exists in serum as homopolymers. Purified Hakata antigen sustained lectin activity, showing affinity with GalNAc, GlcNAc, D-fucose as mono/oligosaccharide, and lipopolysaccharides from Salmonella typhimurium and Salmonella minnesota. These results suggest that the Hakata antigen, a new member of the ficolin/opsonin P35 family, plays a role in the serum exerting lectin activity under physiological conditions.

Amino Acid Sequence↗

PubMed2004

Cellular membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves C3b, an essential component of the complement system.

Neoplasms have developed numerous strategies to protect themselves against the host immune system. Membrane type-1 matrix metalloproteinase (MT1-MMP) is strongly associated with many cancer types and is up-regulated in the aggressive, metastatic neoplasms. During the past few years, there has been an increasing appreciation of the important, albeit incompletely understood, role of MT1-MMP in cancer. We have discovered, using cell-free and cell-based assays in vitro, that MT1-MMP proteolysis specifically targets C3b, an essential component of the complement propagation pathway. MT1-MMP proteolysis liberates the deposited C3 activation fragments from the cell surface. The shedding of these cell-deposited opsonins by MT1-MMP inhibits the complement cascade and protects breast carcinoma MCF7 cells from direct complement-mediated injury in the in vitro tests. The functional link associating MT1-MMP with the host immune system, heretofore unrecognized, may empower tumors with an escape mechanism that contributes to the protection against the host anti-tumor immunity as well as to the survival of invading and metastatic malignant cells in the bloodstream.

Blotting, Western↗

PubMed2005

Liposome opsonization.

Adsorption of serum proteins to the liposomal surface plays a critical role in the clearance of liposomes from the blood circulation. In this review, we will discuss the role of the liposomal opsonins proposed so far in liposome clearance. Additional, related topics that will be addressed are the cell-surface receptors that might be involved in liposome elimination from the blood compartment and the effect of poly(ethylene glycol) (PEG) modification on prevention of liposome opsonization.

Animals↗

PubMed1960

Further observations on the behavior of staphylococci within human leukocytes.

A specific serum factor was required for rapid phagocytosis of pathogenic staphylococci by human polymorphonuclear leukocytes when the ingestion process was studied in siliconed glass systems and the concentrations of staphylococci were maintained at low levels. In contrast to certain other microbes, the resistance to phagocytosis which characterized pathogenic staphylococci was relative, and phagocytosis was readily accomplished when large populations of staphylococci were present in the test system. A factor promoting phagocytosis was present in eight of eight normal adult sera. In contrast, the sera of twenty-eight of thirty normal rabbits did not promote phagocytosis. Serum obtained from 2 rabbits maintained in the rabbit colony for several months acquired the ability to opsonize pathogenic staphylococci. The phagocytosis-promoting factor was almost completely removed by prior absorption of test sera with the homologous strain. The factor was incompletely removed by absorption with heterologous strains of pathogenic staphylococci and was not significantly reduced by absorption with coagulase-negative staphylococci or unrelated microorganisms. Present evidence suggests that the factor promoting phagocytosis is a thermostable opsonin. While the activity of heated serum could not be restored by the addition of small amounts of fresh serum or complement, the addition of large amounts of complement partially restored opsonic activity. Incubation of staphylococci in fresh serum prior to heat inactivation did not reduce subsequent phagocytosis, further suggesting the heat stability of the phagocytosis-promoting factor. Preliminary studies correlating the presence of antistaphylococcal hemagglutinins and phagocytosis-promoting factor in certain sera suggest that the two factors were not necessarily related. The phagocytosis of staphylococci in fresh human serum was inhibited by the addition of fresh or inactivated rabbit serum. Further studies on the nature of such inhibition are in progress. Once ingestion was accomplished, coagulase-positive staphylococci consistently survived in significant numbers within the cytoplasm of human granulocytes. Coagulase-negative staphylococci appeared to be destroyed within the leukocyte and could not be recultured from the cytoplasm following 3 to 4 hours of intracellular residence.

Adult↗

PubMed1967

Further observations on the mechanism of reticuloendothelial blockade.

The mechanism of the reticuloendothelial "blockade" which followed injection of large quantities of chromic phosphate without exogenous stabilizing material was investigated in Wistar rats. The RE blockade observed for several hours after induction appeared related to the continuing circulation of the chromic phosphate-blockading dose, and a reduction in the size of the particles used enhanced blockade. RE blockade appeared to be particles specific and was not related to a generalized depression of RE-phagocytic cell function. Studies in isolated perfused rat livers appeared to eliminate saturation of particle-specific macrophage clones as a likely explanation of blockade, and blockade could not be explained on the basis of depletion of serum opsonins. In the system employed, it is postulated that blockade occurs when large numbers of circulating particles saturate specific macrophage cell membrane-binding sites rather than from physical stuffing of RE-phagocytic cells.

Animals↗

PubMed1976

2-Deoxyglucose selectively inhibits Fc and complement receptor-mediated phagocytosis in mouse peritoneal macrophages. I. Description of the inhibitory effect.

Incubation of normal or thioglycollate-elicited mouse peritoneal macrophages with 2-deoxy-D-glucose (2-dG) inhibits the capacity of these macrophages to phagocytize IgG- or complement-coated particles via their Fc and C3 receptors. 2-dG has no inhibitory effect on the capacity of these macrophages to phagocytize latex or zymosan particles, which are ingested in the absence of specific opsonins, and it does not inhibit binding of IgG- or C3-coated particles to their respective receptors on the macrophage's plasma membrane. 2-dG exerts its inhibitory effect on the macrophage and not on the opsonized particle. The inhibition is independent of particle size, occurs within 15-30 min of addition of this glucose analogue to the medium at 37 degrees C, cannot be overcome by supra-agglutinating amounts of opsonizing antibody, and is completely reversible by substitution of 5.5 mM glucose for 50 mM 2-dG in the medium. Addition of equimolar amounts of glucose or mannose, but not of fructose, galactose, fucose, or glucosamine, to medium containing 50 mM 2-dG results in substantial reversal of the inhibitory effect of 2-dG on Fc and C3 receptor mediated phagocytosis.

Animals↗

PubMed1978

Synthesis of fibronectin by cultured human endothelial cells.

Plasma fibronectin is probably the major nonimmune particulate opsonin in blood and is cross-linked to fibrin during the final stage of blood coagulation. Fibronectin also occurs in an insoluble form in basement membranes especially those underlying endothelial cells and in loose connective tissue. Fibronectin was demonstrated in cultured human endothelial cells and in the surrounding extracellular matrix by immunofluorescence microscopy by using antibody to human plasma fibronectin. Cultured human endothelial cells released fibronectin into the culture medium which was immunologically identical to the fibronectin in human plasma. Cultured human endothelial cells were labeled with [3H] leucine. The radioactive fibronectin present in the endothelial postculture medium and in urea extracts of cellular monolayers was isolated with either anti-fibronectin coupled to Protein A-Sepharose or double antibody immunoprecipitation and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When reduced, the [3H] fibronectin synthesized by cultured endothelial cells had the same mol wt (approximately 200,000) as plasma fibronectin. Unreduced, the [3H] fibronectin synthesized by endothelial cells migrated as a dimer, as did plasma fibronectin. Fibronectin accounted for approximately 15% of the protein synthesized and released by endothelial cells into the culture medium. Thus, cultured endothelial cells synthesize fibronectin, secrete it into the culture medium, and incorporate it into extracellular matrix. The results suggest that the endothelial cell is potentially a major site of synthesis of circulating plasma fibronectin. In addition, fibronectin derived from endothelial cells may be an important structural component of the subendothelium.

Cells, Cultured↗

PubMed1979

Immunodeterminant specificity of human immunity to type III group B streptococcus.

The type III polysaccharides of group B Streptococcus in its native state chemically consists of glucose, galactose, glucosamine, and sialic acid. The core of this polysaccharide lacks sialic acid and precipitates with type III antiserum to give a partial identity with the precipitate between the native antigen and this serum. The core determinant is immunochemically similar to the capsular polysaccharide of type XIV Streptococcus pneumoniae, while the native type III group B streptococcal polysaccharide does not cross-react with type XIV pneumococcal antiserum. In human sera, it is antibody directed to the native antigen which correlates very highly with opsonic immunity (r = 0.94) while a poorer correlation exists between antibody to the core antigen and opsonins (r = 0.51 P less than 0.001). In natural infections, as association exists between low levels of maternal antibody to the native antigen and risk of disease in the infant. This association is not true for antibody to the core structure, where both infected infants and their mothers have much higher levels of antibody to the core than the native antigens. Infected infants are also more likely to respond to infection by developing antibody to the native antigen. Immunization of 12 adults with multivalent pneumococcal polysaccharide induced significantly better antibody response to the core antigen than to the native, and this vaccine induced opsonic activity in only one recipient. Immunization of adults with type III group B streptococcal antigens induced antibody to the native determinant which correlated with opsonic activity. Therefore, it would appear that native group B streptococcal polysaccharides will provide the best candidate antigens for immunization.

Antibodies, Bacterial↗

PubMed1983

Plasma fibronectin enhances phagocytosis of opsonized particles by human peripheral blood monocytes.

We have investigated the effect of plasma fibronectin (Fn) on binding and phagocytosis of sheep erythrocytes (E) by human peripheral blood monocytes. Unopsonized E were not phagocytosed in the absence or presence of Fn, but Fn enhanced the phagocytosis of E bearing IgG. Sheep erythrocytes sensitized with IgM and C3b were ingested only when monocytes were exposed to Fn. The Fn enhancement of phagocytosis occurred for both fluid-phase and glass-adherent monocytes. Experiments in which Fn was washed out before mixing monocytes with opsonized E demonstrated that the Fn effect occurred because of interaction with the monocytes and not the opsonized particles. Chromatography of the Fn on Biogel A 1.5m showed that the phagocytosis-enhancing activity exactly co-chromatographed with the Fn protein. Fn did not increase the number of monocyte membrane receptors for the Fc fragment of monomeric IgG. We conclude that Fn enhances monocyte phagocytosis, not by binding to particles as a conventional opsonin, but by stimulating monocytes to ingest already opsonized particles more avidly.

Erythrocytes↗

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↗

PubMed1998

CD66-mediated phagocytosis of Opa52 Neisseria gonorrhoeae requires a Src-like tyrosine kinase- and Rac1-dependent signalling pathway.

The interaction of Neisseria gonorrhoeae with human phagocytes is a hallmark of gonococcal infections. Recently, CD66 molecules have been characterized as receptors for Opa52-expressing gonococci on human neutrophils. Here we show that Opa52-expressing gonococci or Escherichia coli or F(ab) fragments directed against CD66, respectively, activate a signalling cascade from CD66 via Src-like protein tyrosine kinases, Rac1 and PAK to Jun-N-terminal kinase. The induced signal is distinct from Fcgamma-receptor-mediated signalling and is specific for Opa52, since piliated Opa- gonococci, commensal Neisseria cinerea or E.coli do not stimulate this signalling pathway. Inhibition of Src-like kinases or Rac1 prevents the uptake of Opa52 bacteria, demonstrating the crucial role of this signalling cascade for the opsonin-independent, Opa52/CD66-mediated phagocytosis of pathogenic Neisseria.

Antigens, CD↗

PubMed1976

Specific and Nonspecific immunity to Serratia marcescens infection.

By specific active or passive immunization, mice were protected against lethal infection with Serratia marcescens. Animals that were immunized against organisms of the challenge strain O serotype survived, whereas animals that were immunized against other serratia O serotypes did not survive. Protective sera (from convalescent partients or immunized rabbits) contained a specific complement-independent opsonin. These sera also contained passive hemagglutinating and bacterial agglutinating antibodies in high titer. The protective and complement-independent opsonizing antibodies were associated with IgG fractions of the serum, while the agglutinating antibodies were primarily associated with the IgM. Mice also survived infection with Serratia after immunization against the Re595 Salmonella minnesota mutant. However, complement-independent opsonizing antibody was not demonstrated in these cross-protective sera.

Animals↗

PubMed1977

Kinetics of phagocytosis and bacterial killing by human polymorphonuclear leukocytes and monocytes.

The kinetics of phagocytosis and bacterial killing by normal human polymorphonuclear leukocytes (PMNLs) and by monocytes (MNs) were compared by use of [3H]thymidine-labeled Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes. The rate of phagocytosis by PMNLs was approximately twice that by MNs for all three bacterial species. Although a marked difference was found in opsonic requirements for phagocytosis of S. aureus, E. coli, and L. monocytogenes, phagocytosis by PMNLs and MNs was mediated via the same serum factors. All three species were killed rapidly once they were associated with leukocytes; however, the rate of killing by MNs was slower than that of PMNLs. The slower rate of killing appeared to be secondary to slower ingestion of attached bacteria by MNs. Thus, PMNLs and MNs appear to possess receptors with specificity for the same bacterial opsonins; however, PMNLs are capable of more efficienct bacterial phagocytosis (attachment and ingestion) than are MNs.

Escherichia coli↗

PubMed1978

Phagocytosis of Candida albicans by human leukocytes: opsonic requirements.

The kinetics of phagocytosis of Candida albicans by human polymorphonuclear leukocytes was studied. The basis for these studies was a phagocytic assay with use of C. albicans radiolabeled with [3H]adenine. After incubation of leukocytes with C. albicans, extracellular C. albicans was separated from phagocytes by centrifugation through Ficoll-Hypaque suspensions (specific density, 1.175 g/cm3). Recovery of leukocytes by this technique was greater than or equal to 85%. The initial rate of phagocytosis was more rapid than that previously reported for bacteria. Ethylenediaminetetraacetate, vinblastine, ethylmaleimide, NaF, and ice bath temperature completely inhibited phagocytosis. Colchicine had no effect, and NaN3 was partially inhibitory. Pooled sera possessed low titers (greater than or equal to 1:40) of heat-stable opsonins. The opsonic activity of pooled sera was shown to depend primarily upon complement activated through both the alternative and classical pathways. Decomplemented hyperimmune sera were opsonic at high dilutions (greater than or equal to 1:160), and complement amplified the initial rate of ingestion seen with hyperimmune sera.

Candida albicans↗

PubMed1978

Antibacterial functions of macrophages in experimental protein-calorie malnutrition. II. Cellular and humoral factors for chemotaxis, phagocytosis, and intracellular bactericidal activity.

Cellular and humoral aspects of the antibacterial activity of macrophages during experimental protein-calorie malnutrition were studied. There were no defects in chemotaxis or bactericidal activity of cells from protein-deficient animals, although phagocytosis-associated oxygen consumption and hexose monophosphate shunt activity were depressed. However, marked impairment of humoral chemotactic factors generated in the peritoneal cavity by glycogen injection and of heatlabile serum opsonins for Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, and Salmonella enteritidis was found. The studies suggested that some macrophage antibacterial functions measured in vitro are not altered in experimental acute protein-calorie malnutrition, but that serum factors, presumably complement-derived, would limit their in vivo function. Thymic involution and lymphocyte depletion would further impair in vivo cellular immune reactions affected by macrophages. This model may therefore prove useful for the study of specific aspects of cellular immunity in malnourished hosts and of specific rehabilitation strategies.

Animals↗

PubMed1979

The role of antibody and complement in phagocytosis by rabbit alveolar macrophages.

The relative importance of antibody and complement in the phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa, two common bacterial pathogens, by alveolar macrophages from rabbits was studied. Normal rabbit serum was a satisfactory opsonin for the phagocytosis of S. aureus but not for P. aeruginosa. Normal rabbit serum opsonized S. aureus by both the classic and the alternative complement pathways; loss of both pathways destroyed opsonic activity. The presence of complement was not required for maximal phagocytosis when 10% staphylococcal immune serum was used. However, an intact alternative complement pathway enhanced phagocytosis when the concentration of staphlyococcal immune serum was lowered to 0.3%. Similarly, 10% pseudomonas immune serum opsonized P. aeruginosa without complement. When the concentration of pseudomonas immune serum was lowered to 1%, either the classic or the alternative complement pathway could significantly enhance phagocytosis of P. aeruginosa. Similar results were obtained with alveolar macrophages activated with bacille Calmette-Guérin. These studies demonstrate the importance of complement in enhancing phagocytosis by alveolar macrophages of bacterial pathogens when antibody concentration is the limiting factor.

Animals↗

PubMed1981

Phagocytosis, bacterial killing, and metabolism by purified human lung phagocytes.

Phagocytic and bactericidal activities of purified polymorphonuclear neutrophils (PMNs), monocytes (MNs), or alveolar macrophages (AMs) from the same individuals for Staphylococcus aureus strain 502A or Escherichia coli strain ON2 were compared in vitro. Factors that may influence these activities were evaluated. The bactericidal activity of S. aureus and E. coli of PMNs was greater than that of MNs or AMs. Two factors were identified that may account for this result. (1) The rate of phagocytosis of opsonized S. aureus and E. coli was greater by PMNs. (2) The nonmitochondrial oxygen burst after nonparticulate stimulation was much greater by PMNs. Qualitative differences in opsonic requirements for ingestion of S. aureus by PMNs, MNs, and AMs were also identified. In contrast to PMNs or MNs, phagocytosis of S. aureus by AMs was not opsonin-dependent. The results suggest that mononuclear phagocytes may adapt their opsonic requirements to facilitate uptake of S. aureus. Despite this adaptation, their bactericidal capability remains limited when compared with PMNs.

Escherichia coli↗