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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↗
PubMed2002

Understanding the Knops blood group and its role in malaria.

The antibodies that once were referred to as "HTLAs" have now help to define an entire blood group system with a well characterized genetic basis. Although not "clinically significant" in transfusion medicine, the Knops blood group has gained importance in the field of infectious disease. Its further role in protein (CR1) function and autoimmune diseases remains unknown but may provide interesting work for years to come.

Blood Group Antigens↗
PubMed2004

Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.

BACKGROUND: Mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed cryoglobulinemia with renal disease closely resembling human cryoglobulin-associated membranoproliferative glomerulonephritis (MPGN), including glomerular deposits of immunoglobulins and complement. We assessed the effect of complement inhibition through overexpression of Crry (complement receptor-1 related gene/protein Y), which blocks the classic and alternative pathway of complement activation through inhibition of the C3 convertase, in cryoglobulinemia-associated immune complex glomerulonephritis. METHODS: TSLP transgenic mice were crossbred with animals overexpressing Crry. Mice were sacrificed after 50 days (females) or 120 days (males), and kidneys, blood, and urine were collected from seven mice of each experimental group (wild type, Crry transgenic, TSLP transgenic, and Crry/TSLP doubly transgenic). RESULTS: TSLP/Crry doubly transgenic animals demonstrated expected serum levels of Crry. Renal involvement, both in TSLP transgenic and TSLP/Crry doubly transgenic animals, was characterized by glomerular matrix expansion, macrophage influx, activation of mesangial cells, and deposition of immunoglobulins and complement. Overexpression of Crry did not result in significant improvement of renal pathology or laboratory findings. Expression of recombinant soluble Crry was confirmed by enzyme-linked immunosorbent assay (ELISA) in Crry transgenic animals. However, formation of the membrane attack complex C5b-9 as a marker of terminal active complement components and represented by glomerular C9 staining could not be inhibited in Crry transgenic TSLP mice. CONCLUSION: These results indicate that overexpression of Crry was not sufficient to prevent renal injury in TSLP transgenic mice. We suggest that the inhibitory capacity of Crry may be overwhelmed by chronic complement activation. Further studies need to address the role of complement in cryoglobulinemic glomerulonephritis before therapeutic complement inhibition can be attempted.

Animals↗
PubMed2004

Identification of the Kna/Knb polymorphism and a method for Knops genotyping.

BACKGROUND: DNA mutations resulting in the McCoy and Swain-Langley polymorphisms have been identified on complement receptor 1 (CR1)-a ligand for rosetting of Plasmodium falciparum-infected RBCs. The molecular identification of the Kna/Knb polymorphism was sought to develop a genotyping method for use in the study of the Knops blood group and malaria. STUDY DESIGN AND METHODS: CR1 deletion constructs were used in inhibition studies of anti-Kna. PCR amplification of Exon 29 was followed by DNA sequencing. A PCR-RFLP was developed with NdeI, BsmI, and MfeI for the detection of Kna/Knb, McCa/McCb, and Sl1/Sl2, respectively. Knops phenotypes were determined with standard serologic techniques. RESULTS: A total of 310 Malian persons were phenotyped for Kna with 200 (64%) Kn(a+) and 110 (36%) Kn(a-). Many of the Kn(a-) exhibited the Knops-null phenotype, that is, Helgeson. The Kna/b DNA polymorphism was identified as a V1561M mutation with allele frequencies of Kna (V1561) 0.9 and Knb (M1561) 0.1. CONCLUSION: The high frequency (18%) of Knb in West African persons suggests that it is not solely a Caucasian trait. Furthermore, because of the high incidence of heterozygosity as well as amorphs, accurate Knops typing of donors of African descent is best accomplished by a combination of molecular and serologic techniques.

Black or African American↗
PubMed2005

Characterization of complement receptor 1 domains for prevention of complement-mediated red cell destruction.

BACKGROUND: Complement activation resulting in intravascular hemolysis can cause transfusion-associated mortality. We recently showed that a recombinant soluble form of complement receptor 1 (CR1) effectively reduces complement-mediated red blood cell (RBC) destruction in vitro and more importantly prolongs the survival of transfused human RBCs in mice. To determine CR1-active sites that prevent RBC destruction, structure-function analysis of its extracellular 1930-amino-acid domain has been performed. STUDY DESIGN AND METHODS: Several CR1-truncated soluble proteins were prepared and tested for their ability to prevent complement-mediated RBC destruction in vitro and in mice. RESULTS: A 250-amino-acid region in CR1 that possesses antihemolytic activity and is effective in prolonging survival of transfused RBCs in vivo was identified. Mutation of two critical residues (D109N and E116K) in this 250-amino-acid domain, previously shown to improve complement-inhibitory functions of CR1 derivatives, resulted in a more potent inhibition of complement activation in vitro. In vivo, however, the activity of mutant proteins was comparable to the wild-type molecules. CONCLUSION: Our structure-function studies have characterized smaller CR1-based complement inhibitors for future development of structure-derived transfusion therapeutics. Our studies underscore the importance of testing CR1 inhibitors in vivo.

Animals↗
PubMed2005

Development of complement therapeutics for inhibition of immune-mediated red cell destruction.

A major objective of my National Blood Foundation (NBF)-funded proposal was to produce recombinant soluble forms of a complement regulatory protein called complement receptor 1 (CR1) that carries the Knops blood group system antigens to perform antibody neutralization studies. By generating these recombinant proteins, we were able to inhibit several Knops antibodies in patient serum samples, thereby demonstrating their usefulness for clinical use. Interestingly, the recombinant CR1 proteins generated through NBF funding were also found to strongly reduce complement-mediated red cell destruction in a mouse hemolytic transfusion model. In this review, I will outline our NBF-funded studies, give an overview of recent advances from our group and others in the development of complement therapeutics, and highlight their potential use in the transfusion medicine setting.

Animals↗
PubMed1997

Expression and quantification of the iC3b-binding protein in different Candida albicans strains and their morphological stages.

Expression and quantification of the iC3b-binding protein in yeast, germ-tube, and mycelial forms of several Candida albicans strains were studied. Ten isolates were obtained from patients with recurrent vaginal candidosis. The germ-tubes generated at 37 degrees C and the mycelial forms of all strains grown at 30 degrees C, as well as most of the mycelial forms grown at 37 degrees C, were able to bind complement-coated sheep erythrocytes (EAiC3b). ELISA results revealed that a decrease in the binding of EAiC3b by the mycelial form of strains CBS 5982 and K10 correlated with a decrease of the expression of the iC3b-binding protein, detected by cross-reaction with the monoclonal antibody OKM1, recognising the alpha chain of human CR3. Expression of the iC3b-binding protein in other strains, binding EAiC3b, was higher in the mycelial form or very similar to that of germ-tubes. The dependence of the expression of the iC3b-binding protein on the morphological stages of individual C. albicans isolates suggests a possible association with the virulence of these strains.

Candida albicans↗
PubMed1999

The influence of subinhibitory concentrations of conventional and experimental antifungal drugs on the expression of the iC3b binding protein in Candida albicans strains during filamentation.

The influence of six antifungal agents on the expression of the fungal iC3b binding protein was studied in germ-tubes and the mycelial form of several Candida albicans strains. All antifungal agents inhibited not only the yeast-mycelial transformation, but also the formation of rosettes consisting of complement-coated sheep erythrocytes (EAiC3b) bound to the mycelial form of C. albicans. Immunofluorescence as well as ELISA, employing the monoclonal antibody OKM-1 which recognizes the alpha chain of human CR3 and which cross-reacts with the fungal iC3b binding protein, revealed that subinhibitory concentrations of 0.1 mg l(-1) (which did not affect the growth of either germ-tubes or the mycelial form of C. albicans) inhibited the expression of the iC3b binding protein, while lower concentrations (0.01 mg l(-1)) allowed a comparable and sometimes even slightly higher expression of this protein, in comparison with the untreated control. However, treatment with antifungal agents apparently did not lead to a major cleavage of the protein. The dependence of the amount of the iC3b binding protein expressed on the concentration of added antifungal drugs and on the morphological forms of individual C. albicans isolates suggests a drug dependent influence on the expression of this protein and a possible association with the changing virulence of C. albicans strains during antifungal therapy.

Amphotericin B↗
PubMed2006

Importance of complement 3 and mannose receptors in phagocytosis of Paracoccidioides brasiliensis conidia by Nramp1 congenic macrophages lines.

Genetic factors influence susceptibility to Paracoccidioidomycosis, a Latin American endemic mycosis. The pattern of susceptibility of congenic mouse strains infected with Paracoccidioides brasiliensis resembles the pattern of the Nramp1 gene. Thus, congenic murine bone-marrow-derived macrophage lines B10R (Nramp1rGly169) and B10S (null Nramp1 protein expression, Nramp1sAsp169) were infected with P. brasiliensis conidia and compared, under opsonic and nonopsonic conditions. Opsonization increased the percentage of phagocytosis by both cell lines. B10R macrophages exhibited a higher percentage of cells with associated conidia and higher number of conidia per macrophage than B10S. Heat-inactivation and EDTA treatment of serum used for opsonization, and treatment of macrophages with anti-complement receptor 3 (CR3) decreased phagocytosis by both cell lines. alpha-methyl-d-mannoside reduced phagocytosis by B10R macrophages, suggesting that the mannose receptor participates in phagocytosis by these cells. The CR3 expression was similar on both cell lines and B10R expressed more mannose receptors, but neither cell line expressed CR1. IFNgamma decreased the conversion of conidia to the yeast form of P. brasiliensis in B10R, but not in B10S macrophages.

Animals↗
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↗
PubMed1990

Expression of complement C3b/C4b receptors (CR1) on erythrocytes from patients with myasthenia gravis.

The complement C3b/C4b receptor (CR1) expression on erythrocytes (E) (ECR1) from patients with myasthenia gravis (MG) and from blood donors was measured using haemadsorption and indirect hemagglutination techniques. The ECR1 expression in patients with MG appeared to be normal. This was also true for the subgroup of MG patients with additional autoimmune diseases. No correlation between ECR1 expression and severity of myasthenic symptoms was demonstrated.

Adolescent↗
PubMed1994

Reduced expression of erythrocyte complement receptor (C3bR) in MS.

The study was carried out in patients with MS (n-121) and in control group (n-519). On the basis of haemagglutination intensity and results of radioimmunoassay three phenotypes of complement receptor were classified: high HH, medium HL, and low LL. Considerable differences were observed in the distribution of these phenotypes between controls and MS in whom the low phenotype was more frequent. Family studies suggest that reduced expression of the complement receptor on the erythrocytes depends in MS on the disease process in the first place, and not on genetic factors.

Erythrocytes↗
PubMed1992

Neutrophil kinetics shortly after initial administration of recombinant human granulocyte colony-stimulating factor: neutrophil alkaline phosphatase activity as an endogenous marker.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered (1.5 micrograms/kg body weight) subcutaneously once daily for 5 to 9 days to 5 patients with malignant lymphoma. In all patients, initial administration of rhG-CSF induced a rapid fall in the neutrophil count within 30 minutes, followed by a recovery and an increase in the neutrophil count within 150 min. A rapid fall in the neutrophil count was accompanied by increased expression of neutrophil C3bi-receptors, and neutrophils left in the circulation had lower activity of neutrophil alkaline phosphatase (NAP) and phagocytosis. A decrease in the NAP scores observed at 30 min reflected a preferential decrease of neutrophils with high NAP activity. A recovery and an increase in the neutrophil count were accompanied by a further decrease of NAP scores, which was caused by a preferential increase of neutrophils with lower NAP activity. The NAP scores of mature neutrophils from peripheral blood were not affected by in vitro treatment of cells with rhG-CSF for up to 150 min at 37 degrees C. These findings and the previous observations that neutrophils in the circulating and marginal pools have high NAP activity and neutrophils in the bone marrow pool have low NAP activity taken together suggest that, following initial administration of rhG-CSF, functionally active neutrophils leave the bloodstream preferentially, which is primarily followed by an influx of neutrophils from the bone marrow, but not by demargination of sequestered neutrophils.

Adolescent↗
PubMed1995

Expression of complement regulatory proteins on human eggs and preimplantation embryos.

PROBLEM: To investigate the relation between the complement system and reproduction, expression of complement regulatory proteins (C3b receptors and inhibitor of the membrane attack complex) were screened on unfixed human eggs and preimplantation embryos. METHODS: Unfixed unfertilized oocytes and preimplantation embryos obtained from an in vitro fertilization program were stained by indirect immunofluorescence using monoclonal antibodies raised against membrane cofactor protein, (MCP or CD46), decay accelerating factor (DAF or CD55), protectin (CD59), human C3b/C4b receptor (CR1 or CD35), and major histocompatibility complex class I antigen (MHC class I). RESULTS: CD55 and CD59 were both expressed by the plasma membrane of unfertilized oocytes and pre-implantation embryos. CD46 was not expressed by unfertilized oocytes but appeared at the 6-to-8 cell stage embryo when human gene expression first occurs. CD35 and MHC class I antigens were not expressed at all on oocytes and preimplantation embryos. CONCLUSIONS: Selective expression of complement regulatory proteins (DAF and protectin) associated with the lack of MHC class I antigens may represent an immune protective mechanism by which human oocytes and preimplantation embryos escape complement-mediated damage during their travel through the female genital tract. Furthermore, participation of these complement regulatory proteins including MCP in cell to cell interaction during fertilization and/or implantation cannot be excluded.

Antibodies, Monoclonal↗
PubMed2005

Low erythrocyte complement receptor type 1 (CR1, CD35) expression in preeclamptic gestations.

PROBLEM: Erythrocyte complement receptor type 1 (E-CR1) is the main immune complex clearance mechanism in humans. Decreased E-CR1 expression is noted in certain inflammatory disorders. Recent evidence implicates inflammation in the pathogenesis of preeclampsia. We investigated whether E-CR1 is decreased in preeclampsia. METHOD OF STUDY: E-CR1 protein expression was quantified by radioimmunoassay. Plasma concentration of soluble CR1 was quantified using a specific enzyme linked immunosorbent assay. Quantitative genotypes were evaluated by HindIII restriction fragment length polymorphism analysis. RESULTS: E-CR1 expression was reduced in patients with preeclampsia. Lack of neoantigen expression (indicative of enzymatic cleavage of CR1) or elevated plasma-soluble CR1 was evidence against an acquired loss of E-CR1. Genotype analysis revealed a higher frequency of a CR1 allele associated with low E-CR1 expression in preeclampsia when compared with normal pregnant controls. CONCLUSIONS: E-CR1 expression is decreased in preeclamptic patients and levels correlate with severity of disease. This condition may have a genetic basis in some patients.

Erythrocytes↗
PubMed1987

Effects of endotoxins from Bacteroides intermedius and Escherichia coli on human monocytes in vitro.

Endotoxins (lipopolysaccharides, LPSs) from the strictly anaerobic bacterium Bacteroides intermedius and from Escherichia coli were compared with respect to effects on human monocytes. Exposure of monocyte monolayer cultures to the structurally different endotoxins caused morphological changes, demonstrated by large rounded cells containing cytoplasmic granules with the B. intermedius LPS, and smaller cells with several cytoplasmic protrusions with the E. coli LPS after 10 days of culture. The B. intermedius LPS was, at some doses, able to induce an increased level of the lysosomal enzyme acid phosphatase and increased C3b-receptor-mediated phagocytosis, while other doses gave no effect or weak suppression compared to control cultures. The stimulatory effects were donor-dependent. The E. coli LPS had predominantly suppressive effects on acid phosphatase level and C3b phagocytosis. Both endotoxins resulted in enhanced expression of the activation related cell surface antigen, characterized by the mononuclear phagocyte specific monoclonal antibody 1D5. Biphasic dose-response relationships were observed, particularly pronounced with B. intermedius LPS, giving stimulation of enzyme activity with low (1 ng/ml) and high (0.5 microgram/ml) doses, and suppressed enzyme activity with intermediate doses (0.01-0.10 microgram/ml). The results imply that the effects of endotoxins on different aspects of human monocytes vary considerably; they also suggest that the balance between stimulatory and suppressive properties of a particular endotoxin may influence its net effect on mononuclear phagocyte functions.

Acid Phosphatase↗
PubMed1990

Different cell surface and phagocytic properties in mononuclear phagocytes from blood and alveoli. A comparative study of blood monocytes and alveolar macrophages from human nonsmokers using flow cytofluorometry.

Flow cytofluorometry was used to compare blood monocytes (BMs) and alveolar macrophages (AMs) from the same nonsmoking subject (n = 13). Autofluorescence was quantified, cell surface markers (HLA-DR, CR3) were detected by monoclonal antibodies, and phagocytic ability was determined using C3b-coated yeast particles. AMs expressed more HLA-DR (p less than 0.001) and CR3 (p less than 0.01) on their surfaces than did BMs. The phagocytic capacity was enhanced in AMs compared to BMs (p less than 0.001) and the cells showed an increased autofluorescence (p less than 0.001) in the alveoli compared to blood. The findings suggest that the mononuclear phagocyte is activated when it migrates from blood to alveoli in order to adapt to the milieu in the alveolar space.

Adult↗
PubMed1990

Discrepancy between transcriptional products and cell surface expression of MHC class I antigens in metastatic and non-metastatic Lewis lung tumor cells.

Major histocompatibility complex class I transcriptional products and cell surface expression of their corresponding proteins were measured in tumorigenic Lewis lung carcinoma cells with either high metastatic activity (G4 cells) or with no metastatic activity (G2 cells). The transcriptional products were measured by hybridization to gene-specific oligonucleotide probes for H-2Kb and H-2Db respectively. The cell surface density of the corresponding H-2 glycoproteins was determined by FACS cell sorter analysis and by radioimmunoassay using anti-H-2Kb and anti-H-2Db specific monoclonal antibodies. The analyses revealed that the cell surface density of both Kb and Db was reduced 4-9 fold in G4 cells compared to G2 cells. However, this reduction of G4 cell surface expression of MHC class I molecules was not reflected at the mRNA level since both subclones had similar low levels of detectable Kb and Db specific mRNA. beta 2-microglobulin was analysed at the mRNA and protein level and found not to be the rate-limiting factor in the MHC class I expression of the metastatic G4 cells. Thus, the cell surface expression of H-2Kb and H-2Db by the two Lewis lung carcinoma subclones did not correlate with the amount of specific mRNA. Other regulatory mechanisms of gene expression acting at the levels between transcription and the appearance of the gene product at the cell surface must therefore account for the observed difference in the cell surface expression of MHC class I molecules of the two Lewis lung carcinoma cells. The potential importance of MHC class I expression in the metastatic capacity of the tumor cells is discussed.

Animals↗