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PubMed1990

Roles of the complement receptor type 1 (CR1) and type 3 (CR3) on phagocytosis and subsequent phagosome-lysosome fusion in Salmonella-infected murine macrophages.

The receptors involved in the recognition of Salmonella typhimurium and S. typhi by murine macrophages were identified, and their relevance to phagosome-lysosome fusion was also investigated. Phagocytosis of S. typhimurium by murine macrophages was dependent on the opsonization with normal fresh serum, although the opsonin had no triggering activity in phagosome-lysosome fusion. In contrast, the opsonization of S. typhi with normal fresh serum efficiently triggered both phagocytosis and following phagosome-lysosome fusion. Anti-murine CR1 antibody suppressed phagocytosis of S. typhimurium by 36%, whereas anti-CR3 antibody, mannan, and advanced glycosylation endproducts (AGE)-BSA all failed to prevent phagocytosis of S. typhimurium, suggesting that CR1 may only contribute to the recognition of S. typhimurium and may possibly play a minor role. Other receptors involved may also influence the outcome of phagocytosis in terms of phagosome-lysosome fusion. In the case of S. typhi, only anti-CR3 antibody significantly inhibited not only phagocytosis of S. typhi but also following phagosome-lysosome fusion. Treatment with K76COONa, an inhibitor of C3bINA (I factor), resulted in a marked inhibition of phagosome-lysosome fusion in S. typhi-infected macrophages, although no significant inhibition was observed on phagocytosis of S. typhi. These results suggest that S. typhimurium and S. typhi may be recognized at least in part by CR1 and CR3, respectively, and that the recognition by CR3 but not CR1 is functionally associated with subsequent phagosome-lysosome fusion in murine macrophages.

Animals↗
PubMed1991

Complement receptor type 1 (CR1, CD35) expression on peripheral T lymphocytes: both CD4- and CD8-positive cells express CR1.

T lymphocytes from 42 healthy blood donors were examined for expression of CR1 on the cell surface using a fluorescence-activated cell sorter. The fraction of CR1-positive T lymphocytes varied in the range from 1 to 8% (median 2.4%). The CR1-positive T lymphocytes constituted a homogeneous group of cells regarding both size and granulation; they seemed to be larger and more granulated than the average T lymphocytes. The CR1-expressing T lymphocytes were found both in the CD4- and in the CD8-positive subpopulations of T lymphocytes, and although the CD4-positive cells expressed CR1 with a slightly higher percentage than did the CD8-positive cells, this difference was not significant. The number of CR1-positive T lymphocytes did not correlate with the level of CR1 on erythrocytes. The presence of CR1 on a small T lymphocyte population suggests that CR1 on T lymphocytes might play a role in the immune regulation.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

In vivo binding and clearance of circulating antigen by bispecific heteropolymer-mediated binding to primate erythrocyte complement receptor.

We have used the avidin/biotin system to construct soluble, cross-linked bispecific heteropolymers containing mAb to both the primate E C receptor and the DNP group. These heteropolymers facilitate in vitro binding of DNP-bovine gamma-globulin (DNP-BGG) to both human and squirrel monkey E. Intravenous injection in squirrel monkeys of DNP-BGG followed by heteropolymer leads to E binding and clearance from the circulation of a significant fraction of both heteropolymer and DNP-BGG, without lysis or clearance of the E. This methodology may potentially be used to treat a variety of infectious diseases and other syndromes associated with blood-borne pathogens.

Animals↗
PubMed1990

The murine complement receptor gene family. IV. Alternative splicing of Cr2 gene transcripts predicts two distinct gene products that share homologous domains with both human CR2 and CR1.

The murine Cr2 gene encodes at least two related proteins. The first of these is predicted to include 1408 amino acids from a transcript including 4224 coding nucleotides. This protein is predicted to contain 21 60-amino acid repeats plus those residues encoding transmembrane and cytoplasmic regions for a total peptide m.w. of 155,307. The first six of these repeats are similar to human CR1 in sequence and organization. The second protein is encoded by an alternatively spliced Cr2 transcript that is lacking those sequences which encode the first six 60-amino acid repeats of the larger protein. This second, smaller protein, encoded by a transcript of 3096 coding nucleotides, is predicted to include 15 60-amino acid repeats, plus the transmembrane and cytoplasmic regions. This smaller protein contains 1032 amino acids for a peptide m.w. of 113,328. This second protein is extremely homologous in size and sequence to human CR2. Both proteins share the same signal sequence for membrane insertion. DNA sequence analysis, RNA protection studies and genomic phage mapping indicate the transcripts which encode these proteins are derived from the Cr2 gene via alternative splicing.

Amino Acid Sequence↗
PubMed1989

Regulation of human neutrophil type 3 complement receptor (iC3b receptor) expression during phagocytosis of Staphylococcus aureus and Escherichia coli.

Human neutrophils (PMN) express a receptor for iC3b, a cleavage product of C3b. CR3 is an important receptor for phagocytosis of opsonized bacteria and its expression is enhanced by cell activation. We examined PMN CR3 expression during phagocytosis using flow cytometry and a CR3-specific monoclonal antibody. After 30 min phagocytosis of opsonized S. aureus and E. coli, CR3 expression increased to 151% and 221% of controls, respectively. Unopsonized S. aureus had no effect on CR3; however, unopsonized E. coli enhanced CR3 expression despite not being phagocytosed. Time-kinetic studies indicated a rapid initial fall in CR3 after addition of bacteria to PMN, followed by enhanced expression within 5-10 min. The initial fall in CR3 probably represented CR3 internalization rather than receptor destruction, as superoxide dismutase, catalase and protease inhibitors had no effect on this. Correlation of CR3 expression with the PMN oxidative response, measured with the intracellular fluorescent probe DCF-DA, demonstrated a dichotomy. Opsonized S. aureus and E. coli caused an oxidative response from PMN but unopsonized E. coli, which caused significant CR3 up-regulation, did not. CR3 up-regulation with unopsonized and opsonized E. coli was markedly inhibited by Polymyxin B, suggesting a role for endotoxin. These experiments indicate that CR3 expression can be regulated during phagocytosis, and the mechanisms responsible are distinct from those involved in the oxidative burst. CR3 up-regulation following exposure to bacteria in vivo may enhance neutrophil function at sites of infection.

Escherichia coli↗
PubMed1989

Murine complement receptor gene family. II. Identification and characterization of the murine homolog (Cr2) to human CR2 and its molecular linkage to Crry.

CR2, a 145,000 to 150,000 Mr protein which binds specific breakdown products of C3, has been identified on the surface of both human and murine B cells. In order to understand the evolutionary relatedness of the human and murine proteins, we have used the coding sequences from the human CR2 gene to investigate those homologous sequences of murine Cr2. Human CR2 cDNA sequences were used as probes on a cDNA library derived from BALB/c spleen mRNA to identify cross-reacting cDNA sequences. A number of putative cDNA clones encoding murine Cr2 have been isolated and examined. DNA sequence analysis of these Cr2 cDNA clones indicates that they represent the murine homolog to human CR2. mRNA analysis with these Cr2 cDNA clones has revealed a transcription pattern similar to, but distinct from that seen for CR2. Whereas human CR2 coding sequences identify a single mRNA species of approximately 5 kb from human tonsillar mRNA, the murine counterpart identifies four transcripts from murine spleen of approximately 3, 5, 9 and 11 kb in size. The Cr2 cDNA clones which detect the four forms of spleen mRNA overlap in coding sequences and contain exons mapping to three colinear fragments as defined by EcoRI digestion. This suggests that the 3- 5-, 9-, and 11-kb mRNA forms arise by alternative splicing from a single gene. Use of these murine Cr2-specific cDNA clones to isolate their respective genomic sequences has allowed for the linkage of the 3' end of the Cr2 gene to the 5' end of the Crry gene, the evolutionary homolog to human CR1.

Amino Acid Sequence↗
PubMed1987

Erythrocyte complement receptor type 1 (CR1) expression and circulating immune complex (CIC) levels in hydralazine-induced SLE.

Family studies were carried out to look at CR1 expression in 24 hydralazine-induced SLE patients (Hz Reactors), who had been off the drug for at least 1 year and were clinically well at the time of the study. Mean expression of CR1 was reduced by 27% in the group of hypertensives who had developed Hz-induced SLE compared with a group of 35 normal individuals. CR1 expression was also slightly reduced in the relatives of the Hz Reactors compared to the normal group. Using a solid-phase Clq binding assay, CIC levels were found to be elevated in the plasma of the Hz reactors and an inverse relationship was found between CR1 levels and CIC levels in this patient group. Both CR1 levels and CIC levels in Hz Reactors and normal individuals were constant over the 36 weeks studied. This study suggests that there is an association between an inability to deal efficiently with CIC and susceptibility to developing Hz-induced SLE.

Antigen-Antibody Complex↗
PubMed1988

Tumor necrosis factor is the major monocyte product that increases complement receptor expression on mature human neutrophils.

Interleukin-1 (IL-1) and other monocyte products have several important effects on the systemic response to infection in addition to their roles in lymphocyte stimulation. The present studies were carried out to determine whether products of stimulated monocytes activated circulating neutrophils (PMN) to increase expression of receptors for C3b (CR1) and C3bi (CR3), which are necessary for optimal margination, migration, and phagocytosis. Supernatants of human mononuclear cells that had been stimulated with lipopolysaccharide (LPS) or purified protein derivative (PPD) contained both tumor necrosis factor (TNF) and IL-1 and increased CR1 and CR3 expression on isolated PMNs. Supernatants of unstimulated cultures, media alone, or LPS or PPD alone had little or no effect. Supernatant effects were detectable at 1:3,000 final dilution and appeared to have a characteristic slow time course. These supernatants also caused dose- and time-dependent secretion of PMN granular constituents, but maximal receptor expression was accompanied by secretion of less than 10% of the cells' content of lysozyme and less than 16% of the B12 binding protein. Immunoadsorption studies showed that the supernatant's activity could be removed by anti-TNF but not by anti-IL-1. Recombinant IL-1 had no effect on receptor expression, but recombinant TNF increased CR1 and CR3 expression with kinetics similar to the supernatants. These results thus indicate that TNF is the major monocyte product that increases CR1 and CR3 expression on mature blood neutrophils. This would result in increased margination and phagocytic activity and may be an important systemic effect that would help the host eradicate infection.

Calcium↗
PubMed1988

Structural characterization of the human B lymphocyte-restricted differentiation antigen CD22. Comparison with CD21 (complement receptor type 2/Epstein-Barr virus receptor).

CD22 and CD21 are glycoproteins primarily expressed on normal and neoplastic human B cells. The surface expression of these two molecules parallel each other during normal B cell differentiation, and the reported relative mobilities for CD22 and CD21 are 130/140 kDa and 140 kDa, respectively. Herein we present a detailed analysis of the biosynthesis and structure of CD22 and also compare it directly to CD21. Electrophoresis under reducing and nonreducing conditions suggested that CD22 and CD21 may have similarities in intra-chain disulfide bond formation. Biosynthesis and processing of CD22 and CD21 were very similar with respect to kinetics and post-translational modification, and both could be phosphorylated. However, endoglycosidase digestion (using N-glycanase and endoglycosidase H) and peptide mapping (using V8 protease and N-chlorosuccinimide) strongly suggested that CD22 and CD21 are distinct gene products.

Antigens, CD↗
PubMed1988

Monoclonal antibodies to mouse complement receptor type 1 (CR1). Their use in a distribution study showing that mouse erythrocytes and platelets are CR1-negative.

mAb to murine C receptor type 1 (CR1) were produced and three of them were characterized. One antibody, designated as 8C12, immunoprecipitated a protein of 190,000 Mr from a detergent extract of surface-labeled spleen cells and stained spleen B but not T lymphocytes in fluorescent flow cytometry. It inhibited both CR1-mediated rosette formation and the cofactor activity of CR1 for factor I-mediated cleavage of C3b, suggesting that it recognizes the ligand-binding site of CR1. The two other antibodies, designated as 7G6 and 7E9, recognized different epitopes from that recognized by 8C12, and they cross-reacted with a protein of 150,000 Mr that is present in a spleen extract. The distribution of CR1 in murine hemopoietic cells was studied by binding experiments with radiolabeled 8C12 and fluorescent flow cytometry. When CR1 was not detected by 8C12 alone, the two other antibodies were used in combination with 8C12 to confirm the negative results. Almost all B lymphocytes from the spleen, lymph nodes, and peripheral blood were CR1 positive. Most of the Thy-1-positive lymphocytes from these tissues were CR1 negative. Thymus lymphocytes were also CR1 negative. Peritoneal macrophages and chemotactic factor stimulated but not unstimulated peripheral blood granulocytes were CR1 positive. In contrast to human E, mouse E were CR1 negative. This pattern of distribution was consistent with previous results obtained by rosette assays. Although mouse platelets cause immune adherence hemagglutination with C3b-bearing SRBC, they are CR1 negative. Three other lines of evidence also indicated that platelets are CR1 negative. First, no band of CR1 was demonstrated by immunoprecipitation with 8C12 of an extract of surface-labeled platelets. Second, 8C12, which inhibited rosette formation by lymphocytes, alone or in combination with 7G6 and 7E9, did not inhibit immune adherence between platelets and C3b-bearing SRBC. Third, polyclonal rabbit IgG prepared from anti-mouse CR1 antiserum did not inhibit immune adherence by platelets. These results strongly suggest that the C3b-binding factor(s) on mouse platelets is different from CR1 and that processing of C3b-bearing immune complexes in mouse blood may be mediated by a new and as yet unidentified C3b-binding factor(s).

Animals↗
PubMed1988

Presence of the C3b complement receptor (CR1) antigen in the glomerular basement membrane of human fetal kidneys.

The distribution pattern of the C3b receptor (CR1) antigen, one of the earliest differentiation markers of the podocyte plasma membrane, has been studied during human renal ontogenesis by indirect immunofluorescence and immunoelectronmicroscopy using Fab'2 fragments of anti-CR1 antibodies. CR1 antigen has been detected at the open-stage glomerulus, which precedes constriction of the vascular pole, along the capillary wall, in a thick and homogeneous pattern of staining. By immunoelectronmicroscopy, CR1 antigen was present on the porocyte plasma membrane towards the glomerular basement membrane (GBM), and diffusely distributed within the GBM according to a decreasing intensity gradient from podocytes to endothelial cells. At a later stage of differentiation ('closed' glomerulus stage) when constriction of the vascular pole has occurred, the podocyte plasma membrane appeared diffusely labelled for CR1; the GBM was also stained with a decreasing intensity gradient from podocytes to endothelial cells. This result indicates that a plasma membrane receptor belonging to the cell coat of podocytes can be found in the extracellular space within the GBM. Thus the antigenic repertoire of the GBM of human fetal kidney comprises antigens of constituent molecules of the extracellular matrix and planted antigens originating from adjacent cells.

Basement Membrane↗
PubMed1993

Murine complement receptor gene expression: Cr2 gene transcripts are depressed during a high dose microbial challenge.

The murine Cr2 gene encodes mRNA that produce two protein products predicted to be approximately 145,000 M(r) (Cr2-145) and 190,000 M(r) (Cr2-190). All cells examined which express the Cr2 gene produce transcripts encoding both the Cr2-145 and Cr2-190 proteins: both transcripts are constitutively expressed by mature B cells. To determine if Cr2 expression could be altered by activating splenic B cells, splenic cultures were incubated with lipopolysaccharide (LPS) and cell surface Ig chains were cross-linked with anti-mu. In the presence of LPS and anti-mu both Cr2 and Oct-2 transcripts were diminished while the control beta-actin transcript levels remained unchanged. However, when LPS alone was added, only the Cr2 transcript levels were diminished. To test if these findings could be reproduced in vivo, animals were provided with a peritoneal injection of either Escherichia coli or Listeria monocytogenes and transcript levels analysed. The quantities of both Cr2 transcripts, as well as those encoding Oct-2, were substantially reduced in splenocytes and peripheral lymphatic tissues obtained from these infected mice while those encoding the mouse Crry protein, the B-cell marker CD19 and beta-actin remained unchanged. These data suggest that when confronted with a major bacterial infection, murine B cells respond by shutting down synthesis of transcripts encoding the Cr2 and Oct-2 gene products.

Animals↗
PubMed2005

IgG and complement receptor expression in children treated by peritoneal dialysis.

Children treated by peritoneal dialysis (PD) are at increased risk of infections. IgG receptors (FcgammaRs) and complement receptors (CRs) on white blood cells (WBCs) are important for the phagocytic process. We have investigated FcgammaR and CR expression on monocytes, macrophages and neutrophils in blood and in peritoneal dialysis effluent (PDE) of 39 PD children. WBCs were isolated from blood and PDE, labelled with FITC-conjugated CD16 (FcgammaRIII), CD32 (FcgammaRII), CD64 (FcgammaRI), CD11b (CR3) and CD35 (CR1) monoclonal antibodies, and analysed by flow cytometry. Peritoneal cells had lower percentages of FcgammaR-positive or CR-positive cells than blood. On the other hand, the receptor number per cell [mean fluorescence intensity (MFI)] was higher on peritoneal macrophages and neutrophils than blood, except for CD16. The FcgammaR and CR expression in blood and dialysate did not change significantly during the first year of PD treatment. During a peritonitis episode the MFI of all receptors in blood increased only on monocytes, with the exception of CD32. The percentages of FcgammaR-positive and CR-positive macrophages and neutrophils in the PDE increased, whereas the MFI did not increase consistently. Peritoneal cells of PD children showed a lower percentage of FcgammaR-positive and CR-positive neutrophils and macrophages, combined with an increased MFI, indicating a state of activation. Blood and peritoneal cells are capable of up-regulating the receptor expression during peritonitis but probably not to a maximum level.

Adolescent↗
PubMed2003

B cell activation leads to shedding of complement receptor type II (CR2/CD21).

Complement receptor type II (CR2/CD21) is the major receptor for C3d fragments on immune complexes. CD21 also serves as the receptor for Epstein-Barr virus in humans. On mature B cells, CD21 reduces the threshold of BCR signaling together with CD81, Leu13 and CD19, but it also occurs on other cells of the immune system where it performs unknown functions. A soluble form of CD21 (sCD21) is shed from the cell surface and is found in human blood plasma. An as-yet-unknown protease is thought to be responsible for this shedding. Altered levels of sCD21 occur in plasma in certain clinical conditions. We show here by mass spectrometry that sCD21 in human plasma of healthy donors is predominantly a short form of CD21 without the exon-11-encoded sequences. Whereas the N terminus of sCD21 was found unmodified, the C terminus is truncated, implying that only the extracellular portion of CD21 is shed. Peripheral blood B cells, but not T cells, contribute to the plasma CD21-pool. CD21 shedding is induced by stimulation with PMA plus Ca(2+) ionophore, or by stimulation of the BCR with anti-IgM+anti-CD40.

B-Lymphocytes↗
PubMed2004

Activation of mitogen activated protein kinases via complement receptor type 2.

BACKGROUND: Complement receptor type 2 (CR2) is the receptor for C3d and C3dg and for Epstein-Barr virus. The aim of our study was to explore whether CR2 can independently mediate the activation of mitogen-activated protein kinases (MAPKs, including ERK, JNK, and p38MAPK), and to highlight the molecular mechanism of CD4+ cell deletion in AIDS. METHODS: HOS cells (HOS-CR2) and HOS-CD4 cells (HOS-CD4CR2) stably expressing CR2 were established and then identified by FACS and Western blotting. Activation and blocking tests of MAPKs were assessed by Western blot. Cell proliferation was determined using Cell Titer 96((R)) Aqueous One Solution Reagent. RESULTS: FACS results showed that the positive rates of HOS-CR2 and HOS-CD4CR2 cells were greater than 96%, and Western blot showed that the CR2 expression levels on HOS-CR2 and HOS-CD4CR2 cells were high. Activation and blocking tests of MAPKs (ERK, JNK, and p38MAPK) were carried out in HOS-CR2, HOS-CD4, and HOS-CD4CR2 cells. The activation of MAPKs in HOS-CR2 cells stimulated with PMA (100 ng/ml) and NHS (10%) was identical. The activation of MAPKs increased at 5 minutes, reached a peak at 10 minutes, and decreased to baseline within 30 minutes, all in a time-dependent manner; the activation of MAPKs was blocked by anti-CR2 McAb, PD98059 (inhibitor of ERK), and Wortmanin (inhibitor of PI-3K), respectively. In HOS-CD4 cells, MAPKs were activated by HIV-gp160. In HOS-CD4CR2 cells, MAPK activation was induced by HIV-gp160, 10% NHS, and HIV-gp160 + 10% NHS; phosphorylation of p38MAPK was dramatically induced by HIV-gp160 + NHS, and lasted for 1 hour. The cell proliferation results showed that HIV-gp160 inhibited the proliferation of HOS-CD4 and HOS-CD4CR2 cells (P < 0.01) and that NHS enhanced the effect of HIV-gp160 (P < 0.01). CONCLUSIONS: The activation of MAPKs is independently mediated by CR2 and that anti-CR2 McAb, PD98059, and Wortmanin block the activation of MAPKs, respectively. The results of the signal transduction and cell proliferation assays of HOS-CD4CR2 cells show that CR2 plays a role in the pathogenesis of HIV infection, especially in the inhibition of CD4+ cell proliferation.

Cell Division↗
PubMed1997

Regulation of interleukin-12 by complement receptor 3 signaling.

Complement receptor type 3 (CR3, CD11b/CD18) serves as a receptor for a number of endogenous ligands and infectious organisms, and is involved in adhesion and host defense functions. Here, we report that signaling via CR3 plays an important role in regulating production of interleukin-12 (IL-12), a key mediator of cell-mediated immunity (CMI). We demonstrate with a variety of stimuli a dose-dependent, specific downregulation of IL-12 secretion by human monocytes in vitro after exposure to antibodies to CR3 (anti-CD11b and anti-CD18), as well as to the natural CR3 ligands, iC3b, and Histoplasma capsulatum. CR3 antibodies also suppressed interferon-gamma (IFN-gamma) production in cultures of human peripheral blood mononuclear cells (PBMC). We determined that one mechanism by which CR3 antibodies may suppress IL-12 production is by the inhibition of IFN-gamma-induced tyrosine phosphorylation. Finally, in a murine model of IL-12-dependent septic shock, we provide evidence that administration of CR3 antibodies leads to suppression of IL-12 and IFN-gamma in vivo. Our studies thus define a novel role for CR3 in regulating CMI functions via IL-12.

Animals↗