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PubMed1994

Molecular cloning of the rat complement regulatory protein, 5I2 antigen.

We have cloned a cDNA which encoded for rat complement regulatory protein, 5I2 antigen. The deduced amino acid sequence of 497 residues predicted essentially the same domain structure as the mouse complement regulatory protein, Crry/p65, composed of five short consensus repeat (SCR) domains, a transmembrane domain and a cytoplasmic domain. 5I2 antigen, however, had an additional SCR which showed a close similarity to the sixth SCR of mouse complement receptor 1 (CR1) or to the sixth, thirteenth, twentieth and twenty seventh SCR of human CR1. Corresponding domains of 5I2 antigen and mouse Crry/p65 showed 70%-86% amino acid identity, indicating that 5I2 antigen is the rat counterpart of mouse Crry/p65.

Amino Acid Sequence↗
PubMed1983

Dynamics of cytochemically distinct subpopulations of macrophages in elicited rat peritoneal exudates.

Qualitative and quantitative changes in rat peritoneal macrophage (M phi) subpopulations, differing in their ultrastructural peroxidatic staining characteristics were followed over the course of a thioglycollate (TG) broth-induced inflammatory response. In addition, selected functional features of the normal steady-state and 4-day TG-induced populations of M phi were compared. The steady-state population consisted primarily of M phi with peroxidatic staining limited to the nuclear envelope (NE) and rough endoplasmic reticulum (RER); such cells are called resident M phi. Within hours of TG injection, there was an influx of monocyte-derived exudate M phi, the number of which reached a maximum, by 24 hr. During the next 24 hr, the proportion of exudate M phi decreased with a concomitant increase in peroxidatic activity (PA)-negative M phi. These two cell types continued to predominate for the next 48 hr during which there was a gradual increase in resident M phi and so-called "exudate-resident" M phi, the latter of which exhibits both exudate and resident PA patterns. Thus, the 4-day TG-induced population consisted of four cytochemically distinct M phi subpopulations: approximately 50% PA-negative M phi, approximately 25% exudate M phi, approximately 15% resident M phi, and approximately 10% exudate-resident M phi. Differences in Fc receptors and complement receptors 1 and 3 were noted between the two populations in the presence of progenitors that give rise to colonies of M phi in liquid culture in response to murine-derived colony-stimulating factor 1. The implications of these results in regard to the origin(s) of M phi diversity are discussed.

Animals↗
PubMed1990

Immune complexes bind preferentially to specific subpopulations of human erythrocytes.

Primate erythrocytes have complement receptors (CR1) that, both in vivo and in vitro, bind immune complexes (IC) opsonized with C3b. The present study was undertaken to determine whether the ability of human erythrocytes to bind IC is a characteristic shared by all erythrocytes. Binding of IC to erythrocytes probably involves the interaction of several C3b molecules with several CR1 clustered in small areas of the erythrocyte surface. To identify IC binding CR1 clusters, we first assessed the binding to erythrocytes of fluorescein-labeled polystyrene beads coated with monoclonal anti-CR1 antibodies (anti-CR1-beads) and second, performed IC. The binding of these ligands to erythrocytes was evaluated by immunofluorescence microscopy and flow cytometry. We found that only a fraction of erythrocytes from normal individuals bound anti-CR1-beads specifically and the percentage of erythrocytes able to bind beads increased with increasing numbers of CR1 per erythrocyte. However, the number of anti-CR1-beads bound per erythrocyte varied among cells from the same individual. We demonstrated further that the erythrocyte binding sites for anti-CR1-beads are also binding sites for opsonized IC. This was shown by demonstrating that anti-CR1-beads inhibited the binding of opsonized IC to erythrocytes and opsonized IC inhibited the binding of anti-CR1-beads to erythrocytes. Incubation of erythrocytes with opsonized IC, followed by FITC-labeled secondary antibodies, confirmed that indeed only a fraction of erythrocytes is capable of binding opsonized IC and that the binding sites for IC occupy small regions on the erythrocyte membrane. By contrast, we demonstrated that greater than 90% of erythrocytes express CR1. In conclusion, only some erythrocytes have the capacity to bind IC. Differences in the ability of erythrocytes to bind IC are probably related to differences in the clustering of CR1 in the erythrocyte membrane. Anti-CR1-beads identify erythrocyte binding sites for IC. These beads should prove useful to assess the changes that occur in the erythrocyte CR1 after exposure to IC in vivo.

Antibodies, Monoclonal↗
PubMed2000

Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice.

The anaphylatoxin C5a is a potent mediator of inflammation in the CNS. We analyzed the intracerebral expression of the C5a receptor (C5aR) in a model of closed head injury (CHI) in mice. Up-regulation of C5aR mRNA and protein expression was observed mainly on neurons in sham-operated and head-injured wild-type mice at 24 h. In contrast, in TNF/lymphotoxin-alpha knockout mice, the intracerebral C5aR expression remained at low constitutive levels after sham operation, whereas it strongly increased in response to trauma between 24 and 72 h. Interestingly, by 7 days after CHI, the intrathecal C5aR expression was clearly attenuated in the knockout animals. These data show that the posttraumatic neuronal expression of the C5aR is, at least in part, regulated by TNF and lymphotoxin-alpha at 7 days after trauma.

Animals↗
PubMed1990

Comparison of peritoneal white blood cell parameters from continuous ambulatory peritoneal dialysis patients with a high or low incidence of peritonitis.

The purpose of this study was to determine if there were differences in selected dialysate white blood cells (WBC) parameters between continuous ambulatory peritoneal dialysis (CAPD) patient groups identified as having a high or low incidence of peritonitis. Parameters studied were total peritoneal WBC yield, percentage and absolute number of various WBC types, and expression of WBC receptors known to be involved in normal host defense mechanisms. WBCs were obtained from peritoneal dialysis effluents (overnight dwell), which were collected at monthly intervals for 6 to 8 months from eight CAPD patients--four with a history of high peritonitis incidence (HPI) (more than two episodes in 12 months) and four with a history of low peritonitis incidence (LPI) (no episodes in more than 24 months). Our results demonstrated that there was no significant difference in the overall mean total cell yields or absolute cell counts between the two patient groups. WBC differentials, although differing somewhat among patients, stayed quite stable over time for an individual patient and there was no significant difference between the two patient groups. Analysis of receptors on the peritoneal WBC was performed using flow cytometry and fluorescein-conjugated chemotactic factors (C5a and fMet-Leu-Phe-Lys), as well as monoclonal antibodies specific for Fc receptors and complement receptors, CR1 (CD35) and CR3 (CD11b). Although there was a trend toward increased expression of all these receptors in the HPI patients, there was no significant difference in the fluorescence intensity of peritoneal neutrophils or macrophages that expressed these receptors between the two patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Enhanced expression of complement C5a receptor mRNA in human diseased kidney assessed by in situ hybridization.

BACKGROUND: Anaphylatoxin C5a mediates inflammatory responses through interaction with a specific C5a receptor (C5aR), the expression of which is thought to be restricted to peripheral blood leukocytes. Although the presence of C5aR on cultured mesangial cells and tubular epithelial cells has recently been documented, the tissue distribution of C5aR in diseased kidney has not yet been determined. METHODS: Immunohistochemistry and nonradioactive in situ hybridization for C5aR were performed in 34 tissue samples of kidneys from patients with various renal diseases, including 4 with minimal change nephrotic syndrome (MCNS), 5 with membranous nephropathy (MN), and 25 with mesangial proliferative glomerulonephritis (mesGN; 15 patients with IgA nephropathy, 5 with non-IgA mesGN, and 5 with lupus nephritis). Normal portions of surgically resected kidney served as the control. RESULTS: In normal kidneys, C5aR protein was detected in tubular epithelial cells, while C5aR mRNA was detected in a few glomerular cells, tubular epithelial cells, and vascular endothelial and smooth muscle cells. In MCNS, the distribution of C5aR protein and mRNA was similar to that in normal kidneys. In MN and mesGN, C5aR protein and mRNA were detected in mesangial cells, glomerular epithelial and endothelial cells, Bowman's capsule cells, tubular cells, infiltrating cells, and vascular endothelial and smooth muscle cells. The glomerular expression of C5aR mRNA and protein correlated positively with the degree of mesangial hypercellularity and mesangial matrix expansion in mesGN. In the tubulointerstitium, interstitial expression of C5aR mRNA correlated positively with the degree of tubular atrophy and interstitial broadening in mesGN. Furthermore, the interstitial expression of C5aR mRNA correlated positively with the level of serum creatinine. CONCLUSIONS: Our results indicate that renal cells produce C5aR and that activation of C5a/C5aR pathway on renal cells may be involved in tissue injury in mesGN.

Adolescent↗
PubMed1989

High molecular weight kininogen inhibits fibrinogen binding to cytoadhesins of neutrophils and platelets.

Fibrinogen inhibited 125I-high molecular weight kininogen (HMWK) binding and displaced bound 125I-HMWK from neutrophils. Studies were performed to determine whether fibrinogen could bind to human neutrophils and to describe the HMWK-fibrinogen interaction on cellular surfaces. At 4 degrees C, the binding of 125I-fibrinogen to neutrophils reached a plateau by 30 min and did not decrease. At 23 and 37 degrees C, the amount of 125I-fibrinogen bound peaked by 4 min and then decreased over time because of proteolysis of fibrinogen by human neutrophil elastase (HNE). Zn++ (50 microM) was required for binding of 125I-fibrinogen to neutrophils at 4 degrees C and the addition of Ca++ (2 mM) increased the binding twofold. Excess unlabeled fibrinogen or HMWK completely inhibited binding of 125I-fibrinogen. Fibronectin degradation products (FNDP) partially inhibited binding, but prekallikrein and factor XII did not. The binding of 125I-fibrinogen at 4 degrees C was reversible with a 50-fold molar excess of fibrinogen or HMWK. Binding of 125I-fibrinogen, at a concentration range of 5-200 micrograms/ml of added radioligand, was saturable with an apparent Kd of 0.17 microM and 140,000 sites/cell. The binding of 125I-fibrinogen to neutrophils was not inhibited by the peptide RGDS derived from the alpha chain of fibrinogen or by the mAb 10E5 to the platelet glycoprotein IIb/IIIa heterodimer. Fibrinogen binding was inhibited by a gamma-chain peptide CYGHHLGGAKQAGDV and by mAb OKM1 but was not inhibited by OKM10, an mAb to a different domain of the adhesion glycoprotein Mac-1 (complement receptor type 3 [CR3]). HMWK binding to neutrophils was not inhibited by OKM1. These observations were consistent with a further finding that fibrinogen is a noncompetitive inhibitor of 125I-HMWK binding to neutrophils. Fibrinogen binding to ADP-stimulated platelets was increased twofold by Zn++ (50 microM) and was inhibited by HMWK. These studies indicate that fibrinogen specifically binds to the C3R receptor on the neutrophil surface through the carboxy terminal of the gamma-chain and that HMWK interferes with the binding of fibrinogen to integrins on both neutrophils and activated platelets.

Antibodies, Monoclonal↗
PubMed1987

Characteristics of human rheumatoid synovial and normal blood dendritic cells. Retention of class II major histocompatibility complex antigens and accessory function after short-term culture.

Dendritic cells (DC) were isolated from synovial tissue and synovial fluids of patients with rheumatoid arthritis and from peripheral blood of healthy donors. The cells were analysed for various surface antigens in indirect immunofluorescence by means of monoclonal antibodies. Surface antigen expression and accessory activity of the DC during short-term cultures were also investigated. Both the rheumatoid synovial and the normal blood DC were strongly positive for panleucocyte antigen and class II major histocompatibility complex (MHC) antigens (HLA-DP, HLA-DQ, and HLA-DR). The DC suspensions (purity approximately 80-85%) showed very low percentage of cells staining for various other cell membrane markers, including B cell, T cell, natural killer (NK) cell, and various monocyte/macrophage markers as well as markers specific for dendritic reticulum cells and Reed Sternberg cells. Moreover, neither rheumatoid nor normal DC reacted with the RFD1 monoclonal antibody, which is specific for interdigitating cells of human thymus. In contrast to Langerhans' cells, the DC lacked the thymocyte (T6) marker. The various DC expressed neither complement receptors (CR1, CR3), transferrin receptors, nor Fc receptors. They also lacked enzyme markers like peroxidase and nonspecific esterase. The DC formed clusters with autologous T cells. Cluster formation was readily inhibited by anti-HLA-DR and anti-CD2 (T11) monoclonal antibodies. After 3 to 5 days in culture the DC still expressed class II MHC antigens and were potent stimulators in allogeneic mixed lymphocyte reactions (MLR). Only a small number of cells in the DC suspensions from synovial tissue expressed fibroblast antigens before and after culture.

Antigen-Presenting Cells↗
PubMed1988

The expression of CR1 and CR3 on non-modulated and modulated granulocytes of healthy blood donors as measured by flow cytofluorometry.

Complement receptors, CR1 and CR3, on neutrophils increase their cellular spontaneously at 37 degrees C or after mechanical stress during the cell preparation. We have established a cell preparation procedure and a cytofluorometric immunoassay method to evaluate the receptor expression in vivo in this study. The expression of CR1 and CR3 was studied after haemolysis in NH4Cl at different temperatures and incubation intervals. It was shown that cell preparation and receptor analysis must be performed at 15 degrees C or lower to avoid up-regulation of the receptor structures. Two minutes' incubation at 20 degrees C was sufficient to modulate the cells in this regard. Granulocytes from healthy blood donors were analysed and the mean fluorescence intensity (MFI), which reflects the number of receptors on the cell surface, showed a normal distribution for the CR1 (n = 158) and CR3 (n = 76) expression in the healthy population. The MFI of the two receptors showed a correlation (r = 0.71). Granulocytes from all donors could be modulated at 37 degrees C to a similar degree for both receptors (r = 0.76), despite the fact that they are supposed to be mobilized from different intracellular pools. A group of patients with localized inflammatory processes, such as sinusitis, differed from the healthy controls. In this group, the CR1 expression was not normally distributed, but 15 out of 26 patients (58%) had granulocytes with a CR1 expression exceeding the mean +/- SD of the normal population.

Adolescent↗
PubMed1992

Antiglobulin testing for CR1-related (Knops/McCoy/Swain-Langley/York) blood group antigens: negative and weak reactions are caused by variable expression of CR1.

The Knops, McCoy, Swain-Langley and York antigens have recently been identified as being on complement receptor type 1 (CR1, CD35, C3b/C4b receptor). We examined the relationship between CR1 expression and the reactivity of the CR1-related blood group antigens with their specific antibodies. RBC from donors of selected phenotypes were tested by hemagglutination using two monoclonal antibodies to CR1, as well as anti-Kna, -McCa, -S1a, -'Kn/McC' and -Yka. Monoclonal antibodies 3D9 and E11 required approximately 250 and approximately 400 CR1/RBC to obtain a positive reaction. Agglutination of antigen-positive cells by human polyclonal antisera was related to the CR1/RBC: thus, cells expressing 20-100 CR1/RBC were negative and included the previously designated null phenotypes for this collection, 100-150 were weak or negative, and greater than 200 were usually positive. One RBC sample carried Yka on the 190,000 dalton (A or F allele), but not the 220,000 dalton (B or S allele) variant of CR1, and gave inconsistent reactions with Yka antisera. These data provide an explanation for certain of the serologic characteristics of the CR1-related blood group antigen system.

Alleles↗
PubMed1993

Comparison of receptors required for entry of Leishmania major amastigotes into macrophages.

We investigated the mechanisms of entry of amastigotes of Leishmania major from two different sources into macrophages by comparing their use of the Fc receptor (FcR), complement receptor type 3 (CR3), and mannose-fucose receptor (MFR). Amastigotes were obtained from BALB/c mice and SCID mice. FcR involvement was examined by opsonizing L. major with parasite-specific immunoglobulin G (IgG). Antiparasite IgG did not alter the uptake of amastigotes from BALB/c mice since these amastigotes had antibody bound to their surface: IgG1 was the most predominant antibody, followed by IgG2b, IgM, and IgG2a. However, opsonization with antiparasite IgG enhanced the entry of amastigotes that lacked antibody on their surface, namely, amastigotes obtained from SCID mice or from macrophages infected in vitro. These results indicate that the FcR is important for amastigote entry into macrophages. Down-modulation of FcRs onto immune complexes, however, did not reduce the entry of amastigotes containing surface-bound IgG into macrophages. Monoclonal antibodies against the CR3 inhibited the entry of amastigotes from either BALB/c or SCID mice into J774A.1 macrophage-like cells. Simultaneous blocking of FcR and CR3 further increased the inhibition of phagocytosis. Treatment of macrophages with soluble mannan or down-modulating the MFR onto mannan-coated coverslips had no effect on the entry of amastigotes from BALB/c or SCID mice. Thus, the MFR does not appear to be used by amastigotes of L. major. We show that ingestion of amastigotes appears to occur primarily through the FcR and CR3; however, additional receptors may also participate in the uptake of amastigotes.

Animals↗
PubMed2005

Identification of novel vascular endothelial-specific genes by the microarray analysis of the zebrafish cloche mutants.

The zebrafish cloche (clo) mutation affects the earliest known step in differentiation of blood and endothelial cells in vertebrates. We established clo/gata1-GFP transgenic line with erythroid-specific green fluorescent protein (GFP) expression, which allowed differentiation of clo and wild-type siblings at the midsomitogenesis stages before morphologically visible phenotypes appeared. To discover novel genes potentially involved in hematopoietic and vascular development, we performed microarray analysis of more than 15,000 zebrafish genes or expressed sequence tags (ESTs) in clo mutant embryos. We isolated the full-length sequences and determined the expression patterns for 8 novel cDNAs that were significantly down-regulated in clo-/- embryos. Dual specificity phosphatase 5 (dusp5), cadherin 5 (cdh5; VE-cadherin), aquaporin 8 (aqp8), adrenomedullin receptor (admr), complement receptor C1qR-like (crl), scavenger receptor class F, member 1 (scarf1), and ETS1-like protein (etsrp) were specifically expressed in the vascular endothelial cells, while retinol binding protein 4 (rbp4) was expressed in the yolk syncytial layer and the hypochord. Further functional studies of these novel genes should help to elucidate critical early steps leading to the formation of vertebrate blood vessels.

Amino Acid Sequence↗
PubMed1987

LTB4 production and lysosomal enzyme release by rat alveolar macrophages: effects of phagocytosis, receptor binding, and ionophore stimulation.

We have previously shown that the predominant lipoxygenase product of arachidonic acid metabolism in rabbit alveolar macrophages is leukotriene (LT) B4. LTB4 was not detectable in normal unstimulated rabbit macrophages, but its production was increased following calcium ionophore A23187 stimulation, especially after in vivo activation of the immune system. In the present study, we describe that (a) rat alveolar macrophages produced LTB4 in response to natural, biological stimuli such as binding of Fc receptors and complement receptors, as well as zymosan phagocytosis and ionophore stimulation. In contrast, binding of lectin receptors such as concanavalin A and phytohemagglutinin failed to elicit significant increase of LTB4. (b) The predominant LT that was produced was LTB4 regardless of the type of stimulus. This pattern is similar to that of rabbit lung macrophages, but rat alveolar macrophages released higher quantities of LTB4, which can be easily quantitated by high-performance liquid chromatography (HPLC). (c) Phorbol myristate acetate by itself was a weak agonist for LTB4 release. Yet, in combination with a low dose of calcium ionophore A23187 it resulted in LTB4 production. (d) There was a general correlation between release of LTB4 and lysosomal enzymes. In other words, the stimulus that is effective for eliciting enzyme release was usually also effective in causing LTB4 production. (e) A considerable proportion of the LTB4 produced was retained intracellularly. This phenomenon was especially pronounced when zymosan was used as stimulus. (f) Despite the parallelism between LTB4 production and lysosomal enzyme release, the former probably does not regulate the latter. The time courses of their release are dissimilar, and nordihydroguaiaretic acid fails to inhibit lysosomal enzyme release by a dose markedly inhibiting LTB release. (g) Contrary to rabbit lung macrophages rat lung macrophages showed a predominance of lipoxygenase pathway over cyclooxygenase pathway following zymosan ingestion. However, macrophages from both species produced mainly cyclooxygenase products in response to exogenous arachidonic acid.

Animals↗
PubMed1992

Abnormal immune adherence and elimination of hepatitis B surface antigen/antibody complexes in patients with AIDS.

C3b-coated immune complexes (IC) adhere to complement receptor 1 (CR1) on human E in the circulation. E from AIDS patients have an acquired low CR1 number. To study immune adherence and IC elimination in AIDS, radiolabeled hepatitis B surface Ag/antibody complexes were injected i.v. in six AIDS patients and in 14 healthy controls. The binding of IC to E was reduced in AIDS patients (mean binding 2 min after injection: 24.9 +/- 13.3%) compared with healthy individuals (63 +/- 3.7%) (p = 0.0005). The low binding correlated directly with the number of CR1/E and to the capacity of these E to bind IC in vitro. During the first 15 min disappearance of IC was faster in AIDS patients than in normal subjects and correlated with CR1 number. Thereafter, elimination was very slow in AIDS patients, which suggested that a fraction of IC might be released back into the circulation similarly to what has been observed for C3b-coated E. When the data were analyzed with a mathematical model allowing for such release to occur, five of six AIDS patients had a high release rate compared with little or no release in normal individuals (p less than 0.001). Thus, low CR1 on E is responsible for defective immune adherence, and might determine abnormal disappearance of IC from the circulation as well.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Two functional domains in the phagocyte membrane glycoprotein Mo1 identified with monoclonal antibodies.

Granulocytes from patients genetically deficient in the leukocyte glycoprotein family, Mo1, LFA-1, and Leu-M5 (P150,94), have defective complement receptor type III (CR3) activity as well as abnormal adhesion-dependent functions such as spreading, chemotaxis, and phagocytosis. To determine the contribution of the Mo1 heterodimer deficiency to the various functional aberrations observed in deficient granulocytes, we mapped the functional domains of Mo1 using several monoclonal antibodies to this molecule. In addition to iC3b binding, two granulocyte adhesion functions were examined: Cell spreading on plastic coverslips and chemotaxis. One monoclonal antibody to Mo1, 44, inhibits all three functions. Other monoclonal antibodies (903, Leu-15, and OKM10) inhibit iC3b binding to granulocytes but have no effect on cell spreading and/or chemotaxis. Another antibody, 904, has no significant inhibition of iC3b binding but inhibits spreading on plastic and chemotaxis. These studies suggest the presence of two functional domains in Mo1: one involved in iC3b binding and the other in enhancing certain granulocyte adhesion-dependent functions.

Antibodies, Monoclonal↗
PubMed1989

Expression of complement 3 receptors (CR1 and CR3) on neutrophils and erythrocytes in patients with IgA nephropathy.

Expression of C3 receptors (CR1 and CR3) on neutrophils (PMN) was measured in 26 patients with IgA nephropathy (IgA N), 17 normal persons, and 8 patients with non-IgA glomerulonephritis (non-IgA GN) by fluorescence activated cell sorting after labeling with monoclonal antibodies. Mean channel fluorescence for both CR1 and CR3 on PMN was significantly higher in IgA N patients than in either control group (p less than 0.01). (CR1 mean +/- SD 42.5 +/- 10.4 in IgA N, 31.7 +/- 11.5 in normal controls, 27.8 +/- 9.0 in non-IgA GN; CR3 94.0 +/- 16.5, 75.0 +/- 16.6 and 76.7 +/- 15.6, respectively.) No differences were found between the two control groups or between IgA N patients with normal and impaired renal function. These results imply that PMN are activated in IgA N patients. The expression of CR1 and CR3 of PMN may be upregulated by immune complexes (ICs), enhancing both phagocytosis of C3b- or iC3b-coated particles, and absorptive pinocytosis of soluble ICs containing C3b or iC3b. Erythrocyte CR1 and CR3 expression was measured by ELISA and found to be slightly but significantly lower in IgA N patients than in the other 2 groups (CR1 85.3 +/- 28.4 in IgA N, 113.1 +/- 28.8 in normal controls, 109.4 +/- 28.2 in non-IgA GN, p less than 0.02; CR3 80.9 +/- 20.0, 100.4 +/- 19.9, 101.2 +/- 24.9, respectively, p less than 0.05).

Adult↗