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At least 19 recordsLinked to original sources
PubMed1992

The Mac-1 and p150,95 beta 2 integrins bind denatured proteins to mediate leukocyte cell-substrate adhesion.

Activated monocytic cells and neutrophils adhere to substrates coated with a wide variety of proteins including albumins, catalase, casein, and various extracellular matrix proteins. This adhesion can be specifically inhibited by antibodies directed to the beta 2 integrin subunit. This adhesion to protein substrates shares some similarities with two known protein-protein recognition systems with little apparent binding specificity, namely, the interactions of heat shock proteins and histocompatibility antigens with denatured proteins or peptides. Cell adhesion and affinity chromatography experiments were performed to test the hypothesis that monocytes and neutrophils adhere to and migrate on protein substrates due to the presence of cell surface receptors that recognize common protein structures such as denatured protein epitopes. Adhesion experiments revealed that activated monocytic cells adhere more rapidly and extensively on substrates coated with denatured protein versus native protein. Both adhesion and migration on such substrates in vitro was dependent on beta 2 integrins since blocking antibodies completely interfered with these cellular responses. Affinity chromatography experiments revealed that the Mac-1 and p150,95 integrins could be isolated from monocyte-differentiated HL-60 cells or neutrophils on a denatured protein-Sepharose column. Much greater yields of the receptors were obtained on a denatured versus native protein Sepharose column. The binding of these receptors was specific in that the LFA-1 beta 2 integrin did not bind to the denatured protein column. These data provide evidence that the adhesion of activated monocytes and neutrophils to many protein substrates in vitro is due to the ability of Mac-1 and p150,95 to directly bind to denatured proteins. A model of leukocyte adhesion and invasion whereby activated leukocytes denature extracellular proteins during diapedesis, making them suitable for recognition by beta 2 integrins, is proposed.

Albumins↗
PubMed1990

Lipophosphoglycan from Leishmania mexicana promastigotes binds to members of the CR3, p150,95 and LFA-1 family of leukocyte integrins.

The abundant surface glycolipid, promastigote lipophosphoglycan (LPG), of Leishmania promastigotes was isolated and reconstituted onto the surface of hydrophobic silica beads. These beads bound to both macrophages and monocytes, suggesting that phagocytes possess a receptor(s) capable of recognizing LPG. LPG beads were unable to bind to macrophages isolated from individuals with a genetic deficiency in the CD18 complex of leukocyte integrins (CR3, p150,95, and LFA-1), suggesting that one or more of these receptors were required for binding of LPG. Individual members of the CD18 complex were depleted from macrophages by plating cells on surfaces coated with anti-receptor mAb. These experiments indicated that CR3 and p150,95 from the CD18 complex, were the predominant mediators of attachment of LPG. The phagocyte receptor CR3 expresses two distinct binding sites, one that binds peptide ligands, such as C3bi, and a second site, that recognizes bacterial LPS. Antibody inhibition experiments and competition binding studies with synthetic peptides and soluble LPG indicated that LPG is recognized by the nonpeptide, or "LPS" binding site on CR3.

Animals↗
PubMed1990

Integrin distribution and cytoskeleton organization in normal and malignant monocytes.

In this work we have mapped by double-label immunofluorescence the cellular distribution of integrins and their relationship with cytoskeletal proteins in normal and malignant monocytes. In normal monocytes, CD18 and CD11c are concentrated at specific adhesion sites, named podosomes, together with actin, vinculin, and talin, while CD11a, CD11b, CD29/beta 1, CDw49d/alpha 4 and CD54/ICAM-1 retain a diffuse distribution on the cell surface without a selective pattern of localization. U-937 and fresh leukemic monoblasts under standard culture conditions do not adhere and do not form podosomes, but, when treated with TPA, they promptly adhere to substrate, form podosomes and focal adhesions in different cells and display the same integrin/cytoskeleton relationship as normal mature monocytes. Further, in these cells CD18, CD11a, CD11c, ICAM-1, and talin, but not vinculin, co-localize in homotypic cell junctions, thus showing a close relationship between integrins and talin. These observations provide morphological evidence that, in cells of the monocytic lineage, podosome formation is acquired upon differentiation and different integrins are selectively localized at different adhesion sites.

CD18 Antigens↗
PubMed1992

Coagulation inhibition and activation in pancreatic cancer. Changes during progress of disease.

BACKGROUND: To elucidate the disturbed hemostatic balance in patients with pancreatic cancer, the levels of plasma coagulation inhibition and coagulation activation were determined. METHODS: Twenty-one patients with adenocarcinoma of the pancreas were followed from time of diagnosis until death, using plasma analyses of coagulation inhibitors and a molecular marker of coagulation activation (thrombin-antithrombin complex, TAT). RESULTS: TAT was increased significantly at the time of diagnosis of pancreatic cancer compared with age-adjusted healthy control subjects (mean, 6.2 +/- 4.6 micrograms/l [standard deviation] versus 2.0 +/- 0.7 micrograms/l). It increased with disease progression (mean in the terminal phase, 14.1 micrograms/l; P < 0.05). Plasma levels of tissue factor pathway inhibitor (TFPI) also were increased significantly at the time of diagnosis compared with the control group (mean, 176 +/- 80% versus 127 +/- 29%; P < 0.05). The TFPI decreased to normal levels (121 +/- 40%) after surgical removal of the pancreatic tumor (n = 4) or relief of the cholestasis using a bypass procedure (n = 6). The TFPI levels increased significantly as the malignant disease progressed (from 1-3 months postoperatively to the terminal phase of disease; mean, 114 +/- 52% versus 154 +/- 60%). There was a significant positive correlation between TFPI levels and bilirubin levels; the correlation coefficient at diagnosis was 0.70 (P < 0.001). The levels of the coagulation inhibitors antithrombin, heparin cofactor II, protein C, and free protein S decreased significantly with disease progression compared with the normal values found at diagnosis. CONCLUSIONS: The mechanism for TFPI increase in cancer is not known. It may be related to the preoperative cholestasis seen in this study, but the increased degree of coagulation activation also may contribute.

Adenocarcinoma↗
PubMed1989

Increased expression of p150,95 and CR3 leukocyte adhesion molecules by mononuclear phagocytes in rheumatoid synovial membranes. Comparison with osteoarthritic and normal synovial membranes.

The expression of leukocyte adhesion molecules CR3 (CD11b) and p150,95 (CD11c) in synovial tissue was evaluated immunohistochemically. Although a significant proportion of synoviocytes in normal and osteoarthritic synovial membranes expressed the leukocyte common antigen and CR3, very few expressed the p150,95 molecule. In contrast, p150,95 was more evident in rheumatoid synovial membranes. Expression of this molecule was strongest in synovial membranes with a prominent macrophage infiltrate and accumulation of mononuclear phagocytes at the joint surface; p150,95 was also present on interdigitating cells in lymphoid collections. The patterns of expression suggest that these leukocyte adhesion molecules may be important in the diapedesis of mononuclear phagocytes into and through inflamed synovial membranes, as well as in cellular interactions within rheumatoid synovial membranes.

Adolescent↗
PubMed1984

Mechanism of activation of the classical pathway of complement by monoclonal IgE (DES). Restricted regulation of C4b by C4b-binding protein.

A human monoclonal IgE from patient DES, IgE (DES), has been shown to activate the classical pathway of complement. The mechanism of this activation has been investigated and can be summarized as follows: (a) IgE (DES) is able to bind and activate C1 in a dose-dependent fashion. This activation increases with the size of the aggregates used, but the affinity of C1 for IgE (DES) is weaker than for IgG. (b) A classical pathway C3 convertase can be assembled on IgE (DES) using purified C1, C4 and C2. The formation decay of this convertase is similar to that formed on IgG with an half-life of 9 min at 37 degrees C. (c) The extrinsic regulation of the C3 convertase by C4bp is restricted on IgE (DES) as compared to IgG. This restriction is shown on both the formation and the decay of the convertase. The mechanism of activation of the classical pathway of complement by IgE (DES) thus present some similarities with the assembly of the C3 convertase by the alternative pathway.

Antibodies, Monoclonal↗
PubMed1985

Ultrastructure of human C4-binding protein: proposition for a new model.

The structure of human C4-binding protein (C4bp), a regulatory factor of the classical C3 convertase of complement, has been under investigation for several years, but remains poorly understood. For example, the number of subunits in the C4bp molecule has not been established. In this report, we use two different techniques (partial reduction and electron microscopy) to clarify the structure of the C4bp. Our results lead us to propose a structural model which is quite different to that suggested before, i.e. the C4bp molecule appears to be a decamer. In addition to the disulfide bonds which link each subunit to another, a second disulfide interaction leads to the association of the subunits in pairs. Each pair of subunits appears as a filament ending in a globular head at the N-terminal extremity. The pairs of subunits join to form a conical central domain (at the C-terminal extremity) linked by disulfide bonds. The proposed pentameric shape of the C4bp is consistent with the stoichiometry of the C4b-C4bp interactions. The proposed model indicates an overall structural homology between C4bp and other binding proteins.

Carrier Proteins↗
PubMed1986

A model system for the study of the assembly and regulation of human complement C3 convertase (classical pathway).

The formation of classical C3 convertase of complement and its regulation by C4b-binding protein (C4bp) were studied using two different approaches: (a) the analysis was first carried out in fluid phase; a soluble stabilized C3 proconvertase could be assembled from C4b (or C4b-like C4) and iodine-treated C2 in the presence of Ni2+ ions. Upon activation of this complex by C1s, a C3 convertase C4b(C4b-like C4)-C2a was generated which was able to cleave purified C3. C4bp dissociated both C3 proconvertase and C3 convertase, but its effect was more important on C3 convertase. (b) A model system of phospholipid vesicles has been developed to study the assembly of the C3 convertase on a membrane. Among different phospholipid mixtures tested, P-glycerol/P-choline vesicles were found most effective for C4b binding. Optimal conditions were determined for C4b fixation on these vesicles; bound C4b participated in the formation of a functional membrane-associated C3 convertase. C4bp was found to bind to phospholipid vesicles with a higher affinity than C4b; it was able to dissociate the vesicle-associated C3 convertase.

Buffers↗
PubMed1988

Co-expression of Mac-1 and p150,95 on CD5+ B cells. Structural and functional characterization in a human chronic lymphocytic leukemia.

The leukocyte adhesion receptors (LAR) Mac-1 and p150,95 were thought to occur only on myeloid cells, but recently, mouse Ly-1+ (CD5+) B and pro-B cells were shown to bind M1/70 monoclonal antibody, an anti-Mac-1 antibody. Using immunoprecipitation, sodium dodecyl sulfate gel electrophoresis, immunofluorescence and flow cytometry, we have studied the expression of LAR in human CD5+ B cells from chronic lymphocytic leukemia (B-CLL) patients. 170,95 kDa Mac-1 and p150,95, as well as 180,95 kDa LFA-1 heterodimers are shown to be co-expressed on CD5+ mu + kappa + B cells from a patient where they retain their known function in homotypic cell-cell adhesion. Therefore, functional Mac-1 and p150,95 LAR are not restricted to myeloid cells.

Antibodies, Monoclonal↗
PubMedDate not supplied

Immunophenotype of blast cells in acute myeloid leukemia may be a useful predictive factor for outcome.

The immunophenotype of peripheral blood blast cells was tested in 92 patients with acute myeloid leukemia (AML), who were diagnosed and treated at single centre, St Bartholomew's Hospital, from 1978-1987 with a standard adriamycin, cytosine arabinoside and 6-thioguanine regimen. Immunological analysis involved standard fluorescence flow cytometry and utilized 31 monoclonal antibodies to known myeloid antigens (of CD groups 11b, 11c, 13, 14, 15, 16, w17, 31, w32, 33, 34, 35 and 36), a number of relatively less well studied antibodies with potential specificity for AML, and a series of control antibodies to T and B lymphocytes, platelets, erythrocytes and of widespread distribution (CD45, leucocyte common; HLA-DR). The results highlighted a number of antibodies with wide myeloid reactivity, in addition to CD13 and 33 (present in 66 per cent and 76 per cent of cases, respectively), which may be of immunodiagnostic use. A number of correlations between AML cell immunophenotype and FAB morphology subtype were found; in particular five antibodies (CD11c, 10.1, Tu3, CD15 and CD16), of both predominant granulocytic and monocytic reactivity, reacted with cells of AML-M5 subtype (p less than 0.05). There was no significant correlation between immunophenotype and clinical and pathological features at presentation. Correlation with clinical outcome was not a prominent feature, in contrast to some reports based on multicentre data. However, of particular note was the strong association between early death (at less than 2 months) and the coexpression of Leucocyte Function Associated (LFA) antigens, CD11b and 11c, on patient's blast cells (p = 0.003). The relationship was independent of clinical features and persisted even if AML-M5 cases were excluded. The significance of this latter finding is unclear, but may be related to the known role of CD11b and 11c LFA antigens in the cellular response to infection.

Adult↗
PubMed1985

The origin of the very variable haemolytic activities of the common human complement component C4 allotypes including C4-A6.

The human complement component C4 occurs in many different forms which show big differences in their haemolytic activities. This phenomenon seems likely to be of considerable importance both physiologically and pathologically. C4 is coded by duplicated genes between HLA-D and HLA-B loci in the major histocompatibility complex in man. Several fold differences in haemolytic activity between products of the two loci C4-A and C4-B have been correlated with changes of six amino acid residues in this large protein of 1722 residues and with differences of several fold in the covalent binding of C4 to antibody-antigen aggregates. Some allotypes of one locus also differ markedly, notably C4-A6 which has 1/10th the haemolytic activity of other C4-A allotypes. A monoclonal antibody affinity column has been prepared which is able to separate C4-A from C4-B proteins and, using serum from an individual expressing only the C4-A6 allele at the C4-A locus, C4-A6 protein has been prepared. Investigation has shown C4-A6 to have the same reactivity as other C4-A allotypes except in the formation of the complex protease, C5 convertase. This protease is formed from C4, C2 and C3 and if C4-A6 is used it has approximately 1/5th the catalytic activity compared with other C4-A allotype. Allelic differences in sequence identified in C4 proteins so far are few and it is probable that the big difference in catalytic activity of C5 convertase is caused by very small changes in structure.

Alleles↗
PubMed1988

Relative contribution of the leukocyte molecules Mo1, LFA-1, and p150,95 (LeuM5) in adhesion of granulocytes and monocytes to vascular endothelium is tissue- and stimulus-specific.

Adhesion of human monocytes and granulocytes to vascular endothelium plays an important role in migration of these cells to inflammatory sites in tissues. A family of three human leukocyte heterodimeric surface molecules named Mo1, LFA-1, and p150,95 (LeuM5) has been shown to mediate leukocyte adhesion to confluent monolayers of human umbilical vein endothelial cells (HUVE). The relative contribution of each of the three molecules in leukocyte endothelial adhesion was studied using a variety of stimuli. Purified human granulocytes and monocytes were radiolabelled and incubated with HUVE for 45 minutes in a 37 degrees C humidified 5% CO2 incubator in the presence or absence of subunit-specific monoclonal antibodies (MAbs). Adhesion was assessed by quantitation of endothelial cell-associated radioactivity and confirmed by microscopic evaluation. MAbs directed against the alpha subunit of LFA-1 as well as to the beta subunit common to all three antigens significantly inhibited unstimulated monocyte adhesion to HUVE. Small but significant inhibiton was also observed using MAbs directed against Mo1a and p150. Phorbol myristate acetate (PMA)-induced grranulocyte adhesion to HUVE was significantly inhibited by anti-Mo1a and anti-beta, but not by anti-LFA-1a or anti-p150. When HUVE were prestimulated by recombinant IL-1, a different pattern of antigen utilization by granulocytes was observed. MAbs directed against each of the three alpha subunits as well as the common beta subunit all inhibited granulocyte adhesion to HUVE. Furthermore the effect of the three anti-alpha subunit MAbs on granulocyte-HUVE adhesion was additive. These studies show that relative contribution of Mo1, LFA-1, and p150,95 to leukocyte endothelial adhesion varies depending on the cell type and the stimulus used. These studies also reveal a novel role for p150,95 in promoting monocyte and granulocyte adhesion to HUVE.

Antibodies, Monoclonal↗
PubMed1989

Heterogeneity of macrophages in the rat evidenced by variability in determinants: two new anti-rat macrophage antibodies against a heterodimer of 160 and 95 kd (CD11/CD18).

A set of three monoclonal antibodies (MoAbs), ED1, ED2, and ED3, has been shown to recognize in situ different subsets of macrophages in the rat. This macrophage diversity can be correlated with differences in stage of differentiation of cells belonging to one lineage. The present study quantifies this antigen distribution in the macrophage fractions of several lymphoid organs provided by Percoll centrifugation. Four new MoAbs (ED4, ED7, ED8, and ED9) raised against macrophages are included in this study. The tissue distribution of each of the four new MoAbs is determined by immuno- and enzyme-histochemistry on cryostat sections. The MoAbs recognize distinct subpopulations of macrophages. The new MoAbs ED4, ED7, ED8, and ED9 recognize granulocytes and other unrelated cell types, as well as cells of the mononuclear phagocyte system. ED7 and ED8 recognize a surface heterodimer of Mr 160,000 and 95,000.

Animals↗
PubMed1989

Diagnostic application of monoclonal antibody KB90 (CD11c) in acute myeloid leukaemia.

The expression of membrane CD11c by leukaemic blast cells was examined (indirect immunorosetting) in 75 cases of acute leukaemia (myeloid, n = 60; lymphoid, n = 15) and evaluated as a potential marker for the diagnostic discrimination between monocytic (AMML-M4 and AMoL-M5) and non-monocytic (M1, M2 and M3) AML subtypes. Preliminary studies of normal bone marrow cells indicated that CD11c expression was not restricted to cells of monocytic lineage but was also present, with apparent lower density, on significant proportions of mature and immature granulocytes. Examination of acute myeloid leukaemia (AML) subtypes revealed that the non-monocytic leukaemias (n = 33) were CD11c-, defined as less than 30% positive cells, whereas all but one of the AMML-M4 (n = 13) and AMoL-M5 (n = 14) cases were CD11c+. All 15 cases of lymphoblastic leukaemia (ALL) showed less than 5% CD11c+ blasts. Membrane CD11c expression was also compared to the more widely used markers of monocytic differentiation; cytoplasmic alpha-naphthyl acetate esterase (ANAE) and membrane CD14 expression. This analysis showed that all 13 AMML-M4 leukaemias studied, including seven cases that were CD14- and eight that were ANAE-, were CD11c+. In addition, the AMoL-M5 cases (all of which were ANAE+) could be phenotypically subdivided into CD11c+ CD14+ (n = 9), CD11c+ CD14- (n = 4) and CD11c- CD14- (n = 1) subgroups. The study also confirmed that the discriminitive ability and sensitivity of the immunorosetting procedure for the detection of membrane CD11c compared favourably to immunofluorescent staining intensities as measured by flow cytometry.

Antibodies, Monoclonal↗
PubMed1990

Nonsteroidal antiinflammatory agents inhibit upregulation of CD11b, CD11c, and CD35 in neutrophils stimulated by formyl-methionine-leucine-phenylalanine.

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit PMN aggregation, chemotaxis, degranulation, and superoxide anion production stimulated by synthetic formyl peptides. Many of these functions are dependent upon receptors for the complement components C3b and iC3b (CD35 and CD11b, respectively), or the adherence molecules CD11b and CD11c. Using flow cytometry and specific monoclonal antibodies, we studied the effects of the NSAID piroxicam and indomethacin on the upregulation of these cell surface proteins on PMNs stimulated with FMLP, C5a, or ionomycin. Incubation of PMNs at 37 degrees C increased the expression of all three of these surface proteins. A further increase was induced by stimulation with FMLP, C5a, or ionomycin. Both piroxicam and indomethacin inhibited FMLP-induced upregulation of CD11b, CD11c, and CD35, but neither drug affected the upregulation of these surface molecules induced by C5a or ionomycin. Furthermore, piroxicam had no effect on 37 degrees C-induced upregulation of any of the surface proteins, while indomethacin showed no effect on 37 degrees C-induced CD11b upregulation but suppressed CD11c and CD35 upregulation. Inhibition of surface protein upregulation by FMLP was not due to inhibition of FMLP binding to PMNs. We conclude that piroxicam and indomethacin inhibit FMLP receptor-mediated upregulation of CD11b, CD11c, and CD35 in PMNs, but have no effect on the upregulation of these molecules by ionomycin or C5a. These data suggest that piroxicam and indomethacin interfere with postreceptor signaling events specific to PMN stimulation by FMLP.

Adult↗