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PubMedDate not supplied

Modulation of IgG and complement receptor expression of phagocytes in kidney cancer patients during treatment with interferon-alpha.

BACKGROUND: The mode of action of interferon involves both direct cytotoxic and antiproliferative effects on the tumour cell and indirect effects that facilitate immune detection by the host. Among the immunological effects of interferon-alpha is the activation of monocytes. As opsonin receptors are crucial in the function of phagocytes, e.g. monocytes and neutrophils, their modulation by interferon-alpha (INF-alpha) merit to be further clarified. We hypothesised that the role of phagocytes in defence against cancer is reflected in the expression of opsonin receptors for IgG and complement, which further could be modified by INF-alpha. PATIENTS AND METHODS: The expression of the receptors for IgG and complement was studied in neutrophils and monocytes from blood samples of 18 kidney cancer patients treated with INF-alpha and from 39 healthy individuals. Blood samples were collected prior/to and during treatment with INF-alpha, 4.5 to 13.5 MU t.d.w., subcutaneously. After lysing the red blood cells, the samples were incubated with fluorochrome conjugated monoclonal antibodies specific for IgG (Fc gammaRI, -RII and -RIII) and complement (CR1, CR3) receptors and then analysed in flow cytometry. The results were given as the mean log fluorescence intensity (a measure of receptor number) and as the proportion of receptor-positive cells. In the in vitro experiments, the direct effect of interferon-alpha on the receptors of neutrophils and monocytes was studied. RESULTS: In patients before any treatment, the expression of CR3 and Fc gammaRI receptors in neutrophils and all receptors except Fc gammaRIII in monocytes was significantly raised when compared to the controls. Treatment with INF-alpha, induced statistically significant; transient changes in CR1-receptor expression in neutrophils and Fc gammaRI expression in monocytes. Incubation of blood cells with INF-alpha in vitro confirmed the induction of CR1 receptors in neutrophils. CONCLUSION: Changes in receptor expression reflect the inflammatory activation of phagocytes in metastatic kidney cancer. The pattern of receptor expression differs from that observed in infectious diseases. Interferon-alpha both in vivo and in vitro modulates the expression of phagocytic receptors.

Aged↗
PubMed2006

Acquired loss of erythrocyte complement receptor type 1 in patients with diabetic nephropathy undergoing hemodialysis.

BACKGROUND: Complement receptor type 1 on erythrocytes (E-CR1) plays important roles not only in the regulation of complement activation, but also the clearance of immune complexes. Reduced E-CR1 was previously found in patients undergoing hemodialysis (HD). We investigated whether the E-CR1level in HD patients with diabetic nephropathy (DMN) is decreased. The levels of decay accelerating factor (DAF) and CD59 on erythrocytes (E) were also determined to ascertain whether the loss of CR1 is a specific phenomenon or other complement regulatory proteins are also affected. METHODS: The levels of CR1, DAF, and CD59 on E were analyzed in 176 HD patients with DMN, 101 HD patients with non-diabetes mellitus renal diseases (non-DMN), and 108 healthy individuals. Hind III restriction fragment length polymorphism of intron 27 of the CR1 gene was analyzed. The serum-soluble CR1 levelwas measured by ELISA. RESULTS: The E-CR1 level was significantly lower in the DMN group than the non-DMN group (p < 0.0001) and healthy individuals (p < 0.05). The E-CR1 level was significantly higher in the non-DMN group than in healthy individuals (p < 0.01). The levels of E-DAF and E-CD59 were significantly lower in the DMN group than non-DMN group (DAF, p < 0.01; CD59, p < 0.0001). Within each genotype of the CR1 gene, the E-CR1 level was significantly lower in the DMN group than in the non-DMN group and healthy individuals (non-DMN, p < 0.01; healthy individuals, p < 0.05). The serum-soluble CR1 level was significantly higher in the DMN group than non-DMN group and control group (p < 0.01 each). However, soluble CR1 did not correlate with E-CR1. CONCLUSION: Acquired loss of E-CR1 was found among HD patients with DMN. From the viewpoint of host defense, it may be a prognostic factor.

Adult↗
PubMed1989

The frequency of complement receptor type 1 (CR1) gene polymorphisms in nine families with multiple cases of systemic lupus erythematosus.

Low levels of complement receptor type 1 (CR1) on the erythrocytes of patients with systemic lupus erythematosus (SLE) may be acquired or genetically determined. Nine families with multiple cases of SLE were studied using a CR1 probe and restriction fragment length polymorphism analysis, to address this question. The absence of a significant increase in the frequency of a 6.9-kb band (previously shown to be associated with low-level CR1 on erythrocytes) suggests that this genetic marker does not play a major role in determining SLE, either in these families or in SLE patients in general.

DNA Probes↗
PubMed1998

Complement receptor 2 in the regulation of the immune response.

Antigens coated with split products of C3, the result of complement activation, are capable of crosslinking the complement receptor 2 (CR2, CD21) and the antigen receptor on the surface of B cells simultaneously. This dual recognition leads to increased cell proliferation and differentiation and enhanced antibody production. CR2 is also considered to be a regulator of the B cell response to antigen. In this review we summarize the biology of the CR2 and focus on its essential role in generating an effective B cell response to antigenic stimuli. The involvement of CR2 in the pathophysiology of infectious and autoimmune diseases is also discussed.

Antibody Formation↗
PubMed1990

Erythrocyte complement receptor type 1 in non-SLE rheumatic diseases.

An investigation was conducted to measure the levels of erythrocyte complement receptor type 1 (CR1) in patients with various rheumatic diseases other than systemic lupus erythematosus, and to evaluate the clinical significance of this receptor in patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Erythrocyte CR1 was measured in 37 normal controls and 106 patients with various rheumatic diseases. The levels of erythrocyte CR1 decreased significantly in patients with AS, juvenile rheumatoid arthritis, Sjögren's syndrome, and RA, while there was no statistical difference in levels of erythrocyte CR1 between normal controls and patients with gouty arthritis. This suggests that erythrocyte CR1 deficiency may occur in immune-mediated rheumatic diseases such as crystal-induced arthritis. In this study, we noted that the levels of erythrocyte CR1 were not related to the disease activity and severity of AS. The levels of erythrocyte CR1 were also not correlated with the clinical and laboratory parameters of disease activity in RA patients. However, there was a negative association between the levels of erythrocyte CR1 and titer of rheumatoid factor in RA patients. Further study is needed to determine whether or not the level of erythrocyte CR1 is related to prognosis in patients with RA.

Erythrocytes↗
PubMed2004

Reduction of soluble complement receptor 2/CD21 in systemic lupus erythomatosus and Sjogren's syndrome but not juvenile arthritis.

A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The amount of sCD21 in serum may modulate immunity as sCD21 levels are correlated with several clinical conditions. We report here the serum levels of sCD21 in juvenile arthritis (JA), systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). Using enzyme-linked immunosorbent assay, we determined sCD21 levels in SLE, SS and JA patients. Mann-Whitney test for nonparametric two-tail P value was performed to obtain statistical significance. Cytometrical analysis of synovial fluid leucocytes of JA patients was done on a FACSsort. While sCD21 levels in SLE and SS are reduced to levels previously found in rheumatoid arthritis (RA), JA sCD21 levels were normal. sCD21 levels did not correlate with clinical parameters and immunophenotype of synovial cells. CD4 T cells in the synovium were almost all of the CD45RO memory type and 13 of 40 patients displayed synovial expansion of gammadeltaT cells. CD21 shedding in JA differs from RA/SS/SLE. JA sCD21 levels in synovial fluid are always lower compared to blood levels of the same patients. Analysis of JA synovial T cells indicates a T-cell driven response.

Arthritis, Juvenile↗
PubMed1990

Immune complex erythrocyte complement receptor interactions in vivo during induction of glomerulonephritis in nonhuman primates.

Multiple lines of evidence indicate that the erythrocyte complement receptor (E-CR) system, which is unique to the primate, may play an important role in the clearing of immune complexes (ICs) from the circulation. However, all previous investigations of IC/E-CR interactions in vivo have involved the study of small amounts of preformed or passively formed ICs interacting with E-CR that were numerically in vast excess. The present study was undertaken to assess IC/E-CR interactions under conditions in which large amounts of ICs were formed in the circulation, amounts that when sustained for several weeks by daily intravenous administration of antigen resulted in the development of active glomerulonephritis. Twelve cynomolgus monkeys with E-CR levels ranging from 25 to 5000 mean CRs per erythrocyte (CR/E) were actively immunized to BGG, and 6 to 12 weeks later they were studied first at low levels of IC formation in vivo (L-Protocol experiments, mean 125I-labeled BGG dose of 0.04 mg/kg given over 1 minute, a marked antibody excess state) and then at high levels of IC formation in vivo (H-Protocol experiments, mean 125I-labeled BGG dose 4.9 mg/kg given over 10 minutes, a state approximating antigen-antibody equivalence). Cynomolgus monkeys with fewer than 100 CR/E showed no evidence of binding of ICs to erythrocytes with either low-dose or high-dose 125I-labeled BGG. However, cynomolgus monkeys with greater than 450 CR/E showed significant binding of ICs to erythrocytes: mean peak binding of 125I-labeled BGG to erythrocytes was 22.1% +/- 1.1% in the L-Protocol experiments and 33.4% +/- 8.0% in the H-Protocol experiments. During H-Protocol experiments, mean CR/E, measured by using a monoclonal anti-human CR1 antibody, decreased acutely (mean decrease 36.2% +/- 14.1%, p less than 0.05), with recovery of E-CR levels within the next 24 to 72 hours. The acute decrease in E-CR levels could not be accounted for by occupancy of E-CR by ICs or by change in hematocrit. In summary, the present study demonstrates that during the development of glomerulonephritis, IC/E-CR interactions occur and the E-CR system is altered by these interactions. The present observations are consistent with the hypothesis that the E-CR system may play a role in the pathogenesis of IC-mediated disease in the primate.

Animals↗
PubMed1985

Large-scale isolation of complement receptor type 1 (CR1) from human erythrocytes. Proteolytic fragmentation studies.

A large-scale procedure for the isolation of complement receptor type 1 (CR1, the C3b receptor) from human erythrocytes is described. Two of the four known phenotypes of CR1 are detectable in the isolated material. Amino acid and hexosamine analysis of the A phenotype (Mr 240 000) indicates a polypeptide chain length of about 2030 amino acids and a carbohydrate content of 8%. Both N- and O-linked sugars appear to be present. Trypsin digestion of isolated CR1 shows that it is degraded rapidly and extensively, and no stable products of Mr greater than 25000 are found. The ability of the receptor to bind to solid-phase ligand is destroyed after a single cleavage by trypsin. The capacity of the receptor to act as a cofactor for Factor I-mediated cleavage of soluble C3b is, however, only gradually decreased by proteolysis, and 30% of this activity remains after extensive degradation. The same pattern of loss of binding to solid-phase ligand, with partial retention of interaction with soluble ligand, is also characteristic of the complement proteins Factor H and C4bp, which are functionally related to CR1.

Amino Acids↗
PubMed1991

The effect of soluble complement receptor type 1 on hyperacute allograft rejection.

A major obstacle to successful organ transplantation in sensitized recipients is antibody-mediated hyperacute rejection. We hypothesized that human recombinant soluble complement receptor type 1 (sCR1), which inhibits activation of the complement cascade at multiple stages, would delay this process. Using a well-established model of hyperacute rejection, 21 Lewis rats each received three successive ACI rat skin grafts which resulted in high serum titers of ACI-specific antibodies. These hypersensitized Lewis rats then received heterotopic ACI cardiac allografts. Immediately prior to allograft reperfusion, sCR1 at 3 mg/kg (n = 11) or an equivalent volume of phosphate-buffered saline (PBS) (n = 10) was administered intravenously. Five minutes following allograft reperfusion, hemolytic complement activity was reduced by 63 +/- 2% (SEM) in the sCR1 group vs 25 +/- 3% in the PBS group (P less than 0.0001, Wilcoxon rank sum test (WRST)). Graft survival in the sCR1 group was prolonged to 32.0 +/- 4.47 hr vs 3.25 +/- 0.81 hr in the PBS group (P less than 0.0001, WRST). Serial histologic examination of allografts showed that sCR1 therapy prevented the early development of luminal platelet thrombi in the allograft coronary vessels. This study demonstrates that a single 3 mg/kg dose of sCR1 significantly prolongs ACI cardiac allograft survival in the hypersensitized Lewis rat recipient. Complement inactivation, mediated by sCR1, may prove useful for transplantation in sensitized recipients.

Acute Disease↗
PubMed2002

Human complement receptor type 1 (CR1) binds to a major malarial adhesin.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a major adhesin molecule expressed on Plasmodium-falciparum-infected erythrocytes, interacts with several receptors on endothelial cells and uninfected erythrocytes. This 'stickiness', known as rosetting, is a strategy used by the parasite to remain sequestered in the microvasculature to avoid destruction in the spleen and liver. Erythrocyte rosetting causes obstruction of the blood flow in microcapillaries. Recent data suggest a direct interaction between PfEMP1 and a functional site of complement receptor type 1 (CR1; CD35) on uninfected erythrocytes. Consistent with the hypothesis that CR1 is important in malaria pathogenesis is a 40-70-fold increase in the frequency of two CR1 blood-group antigens (at least one of which might rosette less efficiently) in malaria-exposed African populations. Furthermore, structural differences in erythrocyte CR1 between human and non-human primates are probably explained by the selective pressure of malaria.

Animals↗
PubMed2002

Concerted clearance of immune complexes bound to the human erythrocyte complement receptor: development of a heterologous mouse model.

Experiments in primates have demonstrated that immune complexes (IC) bound to erythrocytes (E) via complement receptor 1 (CR1) are cleared to the liver in a process which removes CR1, but otherwise spares the E. Human E are stabilized for >1 h in the circulation of the mouse if the terminal complement pathway is blocked, and we used this paradigm to examine clearance in a mouse model. Human E were opsonized with an anti-CR1 mAb cross-linked to dsDNA (antigen-based heteropolymer, AHP), and then incubated with systemic lupus erythematosus (SLE) plasmas containing IgG anti-dsDNA to form IC in situ. These IC stably bind to E CR1 in the complete absence of complement, thus allowing analysis in a model which does not require human C3b to facilitate E binding. Dual label experiments, based on RIA, flow cytometry and fluorescence microscopy, were employed to monitor separately E and IC. When opsonized E-IC were injected into A/J mice, >90% of the IC were rapidly removed from the E coincident with loss of CR1. The E remained in the circulation while IC were localized to the liver, mainly to Kupffer cells. Preliminary experiments in NZB/W mice, which spontaneously develop IgG anti-dsDNA, indicated that infusion of E-AHP led to rapid binding of murine IgG to the E-AHP, followed by removal of the nascent IC from E, and loss of CR1 in a concerted reaction. These studies provide additional evidence that E CR1 functions as a privileged site for IC clearance, and that the key step in clearance requires removal of CR1 from E to release bound IC for uptake by acceptor macrophages. This model can be extended to genetically altered mice to investigate the role of specific Fc gamma receptors as well as complement receptors in IC clearance.

Animals↗
PubMed2002

Soluble complement receptor type 1 protects rats from lethal shock induced by anti-Crry antibody following lipopolysaccharide priming.

BACKGROUND: In rats primed with a trace amount of lipopolysaccharide (LPS), acute lethal shock is induced following the injection of monoclonal antibody against a membrane inhibitor of complement (anti-Crry). Administration of cobra venom factor to exhaust complement before the LPS priming can prevent the lethal reaction. Therefore, we evaluated whether soluble complement receptor type 1 (sCR1), which inhibits complement reaction, can interfere with lethal shock when administered after LPS priming or even after anti-Crry injection. METHODS: sCR1 was administered intravenously before or after the administration of anti-Crry, and the effects on blood pressure and acute lethality were determined. RESULTS: Administration of sCR1 could rescue rats from lethal shock even when it was administered after anti-Crry injection, which immediately causes a blood pressure decrease leading to lethal shock. CONCLUSION: sCR1 may be an effective treatment for acute shock involving complement activation.

Animals↗
PubMedDate not supplied

Absence of an association between intercellular adhesion molecule 1, complement receptor 1 and interleukin 1 receptor antagonist gene polymorphisms and severe malaria in a West African population.

Many genes have been shown to be involved in host susceptibility to the severe forms of Plasmodium falciparum malaria but it is likely that a large number of malaria-susceptibility genes remain to be determined. We conducted a large case-control study of children with the severe forms of this disease-cerebral malaria and severe malarial anaemia--to attempt to identify these genes. Over 1200 children in The Gambia were typed for polymorphisms of the intercellular adhesion molecule 1 (ICAM-1), complement receptor 1 (CR-1) and interleukin 1 receptor antagonist (IL-IRA) genes. None of the polymorphisms typed was significantly associated with severe disease. These data differed significantly from the results of a previous study (Chi 2 = 8.81; P = 0.003) in which the ICAM-1 gene polymorphism was shown to be significantly associated with cerebral malaria in a case-control study of 547 subjects in Kenya. This suggests that there may be heterogeneity in genetic susceptibility to this condition between these 2 African populations.

Case-Control Studies↗
PubMed1991

Characterization of the human complement receptor 2 (CR2, CD21) promoter reveals sequences shared with regulatory regions of other developmentally restricted B cell proteins.

Expression of human complement receptor 2 (CR2, CD21, C3d,g/EBV receptor) is developmentally restricted on human B lymphocytes to cells of the late-pre and mature stages. CR2 is also a member of the genetically linked regulators of complement activation family found on human chromosome 1q32. Regulators of complement activation proteins are variably expressed in plasma, on cell membranes, and in nonvascular extracellular fluid sites. To begin to understand the mechanisms that control both tissue specific and B cell developmental restriction of CR2 expression, we have cloned and characterized the CR2 promoter upstream of a single apparent transcriptional initiation site. Within this region are sequences with significant similarity to previously characterized TATA, SP1, AP-2, AP-1-like, and Ig enhancer E motif DNA protein binding sites, in addition to direct and inverted repeats. Significant regions of identity are also found between CR2 promoter sequences and those of the CD23 promoter, another protein whose expression is developmentally restricted on B cells. The CR2 promoter will direct transcription of the reporter gene chloramphenicol acyltransferase when transiently transfected into the human Raji B cell line. Therefore, we have identified the promoter for a human B cell protein whose expression is developmentally restricted. Further analysis of this region and the transcriptional regulation of CR2 gene expression should lead to significant insights into the molecular mechanisms by which B cells mature and are activated.

Antigens, CD↗
PubMed1975

Effect of corticosteroids on the human monocyte IgG and complement receptors.

A quantitative in vitro assay was employed to directly assess the effect of corticosteroids on the IgG and complement receptor function of human mononuclear phagocytic cells. In this system corticosteroids were solubilized with cholesterol-phospholipid sonicated dispersions before exposure to mononuclear cells. Solubilized corticosteroids at concentrations between 10(-4) and 10(-3) M inhibited both IgG and complement receptor activity in a dose-response fashion. Inhibition was dependent upon the time of interaction of the mononuclear cells with corticosteroids and was half-maximal by 15 min. The inhibitory effect at all concentrations of hydrocortisone was partially overcome by increasing the number of IgG molecules per erythrocyte. Hydrocortisone also inhibited the binding of erythrocytes coated with both IgG and C3, despite the fact that when both were on the erythrocyte surface a synergistic effect on binding to mononuclear cells was observed. At the steroid concentrations employed, the capacity of mononuclear cells to exclude trypan blue and to take up latex particles and neutral red was unaffected. Mineralocorticoids also inhibited receptor activity, but the sex hormones were less effective. These studies demonstrate an effect of steroid hormones on cell membrane receptor function, and they suggest that an inhibition of the recognition system for IgG and C3 in vivo may explain, in part, the effect of corticosteroids in man.

Adrenal Cortex Hormones↗
PubMed2001

Decay-accelerating factor (DAF), complement receptor 1 (CR1), and factor H dissociate the complement AP C3 convertase (C3bBb) via sites on the type A domain of Bb.

The AP C3 convertase, C3bBb(Mg(2+)), is subject to irreversible dissociation (decay acceleration) by three proteins: DAF, CR1, and factor H. We have begun to map the factor B (fB) sites critical to these interactions. We generated a panel of fB mutations, focusing on the type A domain because it carries divalent cation and C3b-binding elements. C3bBb complexes were assembled with the mutants and subjected to decay acceleration. Two critical fB sites were identified with a structural model. 1) Several mutations centered at adjacent alpha helices 4 and 5 (Gln-335, Tyr-338, Ser-339, Asp-382) caused substantial resistance to DAF and CR1-mediated decay acceleration but not factor H. 2) Several mutations centered at the alpha 1 helix and adjoining loops (especially D254G) caused resistance to decay acceleration mediated by all three regulators and also increased C3b-binding affinity and C3bBb stability. In the simplest interpretation of these results, DAF and CR1 directly interact with C3bBb at alpha 4/5; factor H likely interacts at some other location, possibly on the C3b subunit. Mutations at the C3b.Bb interface interfere with the normal dissociation of C3b from Bb, whether it is spontaneous or promoted by DAF, CR1, or factor H.

CD55 Antigens↗
PubMed2006

Erythrocyte complement receptor 1 (CR1) expression level is not associated with polymorphisms in the promoter or 3' untranslated regions of the CR1 gene.

Complement receptor 1 (CR1) expression level on erythrocytes is genetically determined and is associated with high (H) and low (L) expression alleles identified by a HindIII restriction fragment-length polymorphism (RFLP) in intron 27 of the CR1 gene. The L allele confers protection against severe malaria in Papua New Guinea, probably because erythrocytes with low CR1 expression, are less able to form pathogenic rosettes with Plasmodium falciparum-infected erythrocytes. Despite the biological importance of erythrocyte CR1, the genetic mutation controlling CR1 expression level remains unknown. We investigated the possibility that mutations in the upstream or 3' untranslated regions of the CR1 gene could control erythrocyte CR1 level. We identified several novel polymorphisms; however, the mutations did not segregate with erythrocyte CR1 expression level or the H and L alleles. Therefore, high and low erythrocyte CR1 levels cannot be explained by polymorphisms in transcriptional control elements in the upstream or 3' untranslated regions of the CR1 gene.

3' Untranslated Regions↗
PubMed2002

Expression of human complement receptor type 2 (CD21) in mice during early B cell development results in a reduction in mature B cells and hypogammaglobulinemia.

Complement receptor (CR) type 2 (CR2/CD21) is normally expressed only during the immature and mature stages of B cell development. In association with CD19, CR2 plays an important role in enhancing mature B cell responses to foreign Ag. We used a murine Vlambda2 promoter/Vlambda2-4 enhancer minigene to develop transgenic mice that initiate expression of human CR2 (hCR2) during the CD43(+)CD25(-) late pro-B cell stage of development. We found peripheral blood B cell numbers reduced by 60% in mice expressing high levels of hCR2 and by 15% in mice with intermediate receptor expression. Splenic B cell populations were altered with an expansion of marginal zone cells, and basal serum IgG levels as well as T-dependent immune responses were also significantly decreased in transgenic mice. Mice expressing the highest levels of hCR2 demonstrated in the bone marrow a slight increase in B220(int)CD43(+)CD25(-) B cells in association with a substantial decrease in immature and mature B cells, indicative of a developmental block in the pro-B cell stage. These data demonstrate that stage-specific expression of CR2 is necessary for normal B cell development, as premature receptor expression substantially alters this process. Alterations in B cell development are most likely due to engagement of pre-B cell receptor-mediated or other regulatory pathways by hCR2 in a CD19- and possibly C3 ligand-dependent manner.

Agammaglobulinemia↗