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PubMed1995

Hind III genomic polymorphism of the C3b receptor (CR1) in patients with SLE: low erythrocyte CR1 expression is an acquired phenomenon.

Expression of the human erythrocyte C3b receptor (CR1-CD35) and its Hind III RFLP was studied in a group of 37 patients with SLE, 15 consanguineous relatives of the patients and 48 healthy normal subjects. The CR1 number on erythrocytes was quantitated by ELISA using a mAb to CR1. Serum levels of complement proteins (C3, C4, C3d) and circulating immune complexes (CIC) were estimated simultaneously in controls and relatives. The patients were followed up during the course of the treatment. The CR1/erythrocyte (CR1/E) in patients were found to be significantly low in comparison to controls. The gene frequencies for the alleles H and L (7.4 and 6.9 kb Hind III restriction fragments) in the patients were 0.75 and 0.25, respectively, which did not differ significantly from the controls (0.77 and 0.23 in normal subjects and 0.79 and 0.21 in consanguineous relatives of the patients). However, patients expressed fewer CR1/E within each genotype than their relatives and healthy subjects. CR/E was found to be stable in consecutive samples in controls. In patients, the numbers varied between low and high during the course of the treatment. The variation in the numbers was significantly correlated with C3d and CIC as well as with the severity of the disease. Our results suggest that low levels of CR1 on erythrocytes in SLE patients are required during the course of the disease and that the 6.9 kb restriction fragment does not play a role in causing susceptibility to the disease.

Adolescent↗
PubMed1993

Isolation and characterization of complement receptor type 1 from rat glomerular epithelial cells.

Complement receptor type 1 (C3b/C4b receptor, CR1) is known to be present in human glomerular epithelial cells (GEC) in vivo. The presence of CR1 has not been documented in rat glomeruli, although cultured rat GEC appear to express CR1 based upon their ability to rosette with complement-coated erythrocytes. In this study, we establish that CR1 is present in cultured rat GEC: (1) by isolating a 200 kDa protein from detergent-solubilized cultured rat GEC through the use of C3b affinity chromatography; (2) by Western blotting studies demonstrating reactivity of anti-human CR1 antibodies with this protein from cultured GEC; and (3) by demonstrating that C3b binding to GEC monolayers exhibits low affinity and that an estimate of the number of binding sites is 6700 per cell, both of which are comparable to that seen for CR1 in human blood cells. Furthermore, we show that CR1 is also present in rat glomeruli by Western blotting studies with anti-human CR1. Anti-human CR1 also identifies a 70 kDa protein from cultured GEC and isolated glomeruli. This 70 kDa protein is likely to be the CR1-like protein, designated Crry, which was initially identified in the mouse and has significant homology to human CR1. Crry may be present in rat GEC instead of decay accelerating factor, which is present in human GEC.

Animals↗
PubMed2006

Structure of C3b in complex with CRIg gives insights into regulation of complement activation.

The complement system is a key part of the innate immune system, and is required for clearance of pathogens from the bloodstream. After exposure to pathogens, the third component of the complement system, C3, is cleaved to C3b which, after recruitment of factor B, initiates formation of the alternative pathway convertases. CRIg, a complement receptor expressed on macrophages, binds to C3b and iC3b mediating phagocytosis of the particles, but it is unknown how CRIg selectively recognizes proteolytic C3-fragments and whether binding of CRIg to C3b inhibits convertase activation. Here we present the crystal structure of C3b in complex with CRIg and, using CRIg mutants, provide evidence that CRIg acts as an inhibitor of the alternative pathway of complement. The structure shows that activation of C3 induces major structural rearrangements, including a dramatic movement (>80 A) of the thioester-bond-containing domain through which C3b attaches to pathogen surfaces. We show that CRIg is not only a phagocytic receptor, but also a potent inhibitor of the alternative pathway convertases. The structure provides insights into the complex macromolecular structural rearrangements that occur during complement activation and inhibition. Moreover, our structure-function studies relating the structural basis of complement activation and the means by which CRIg inhibits the convertases provide important clues to the development of therapeutics that target complement.

Complement Activation↗
PubMed2000

Identification of complement receptor one (CR1) polymorphisms in west Africa.

Complement receptor one (CR1) is a ligand for the rosetting of Plasmodium falciparum infected red cells with uninfected cells. Since CR1 exhibits three known polymorphisms, we studied European-Americans (n = 112) and African-Americans (n = 330) and Malians (n = 158) to determine if genetic differences existed in an area endemic for malaria that could offer a survival advantage. The frequencies of Knops blood group phenotypes McC(b+) and Sl(a-) were greatly increased in Africans vs Europeans. Although the frequency of McC(b+) was similar between Africans from the USA or Mali, the Sl(a-) phenotype was significantly higher in Mali (39% vs 65%, respectively). There was an increased frequency of the largest size (250 kD) of CR1 in Mali, but this did not differ significantly from the USA (P = 0.09). Both cohorts of Africans had higher expression of red cell CR1 than European-Americans but this showed little difference between the USA and Mali groups. Thus, the most important CR1 polymorphism relevant to rosetting of malaria infected cells appears to be the Knops blood group.

Blood Group Antigens↗
PubMed2002

Erythrocyte CR1 expression level does not correlate with a HindIII restriction fragment length polymorphism in Africans; implications for studies on malaria susceptibility.

Complement receptor 1 (CR1) expression level on erythrocytes is genetically determined, and in Caucasian populations is linked to high (H) and low (L) expression alleles identified by a HindIII restriction fragment length polymorphism (RFLP). Erythrocyte CR1 may be an important factor in determining malaria susceptibility, as low expression of CR1 reduces the rosetting of uninfected erythrocytes with Plasmodium falciparum-infected cells, a process that contributes to malaria pathogenesis. Prior to studying CR1 expression and malaria susceptibility, we have investigated whether the quantity of erythrocyte CR1 correlates with the H and L alleles in an African population. Mean erythrocyte CR1 in 149 Malian adults was 415 molecules per cell, which is comparable to Caucasian populations; however, there was no relationship between erythrocyte CR1 level and genotype for the HindIII RFLP (mean CR1 per erythrocyte HH = 414, HL = 419 and LL = 403, P > 0.1, Student's t-test). The conclusions of a previous study of erythrocyte CR1 expression level and malaria susceptibility in West Africa that was based on HindIII RFLP genotyping may therefore need to be re-evaluated.

Black or African American↗
PubMed2005

A complement receptor-1 polymorphism with high frequency in malaria endemic regions of Asia but not Africa.

Complement receptor-1 (CR1) is a ligand for rosette formation, a phenomenon associated with cerebral malaria (CM). Binding is dependent on erythrocyte CR1 copy number. In Caucasians, low CR1 expressors have two linked mutations. We determined the Q981H and HindIII RFLP distribution in differing population groups to ascertain a possible role in adaptive evolution. We examined 194 Caucasians, 180 Choctaw Indians, 93 Chinese-Taiwanese, 304 Cambodians, 89 Papua New Guineans (PNG) and 366 Africans. PCR/RFLP used HindIII for CR1 expression and BstNI for the Q981H mutation. DNA sequencing and pyrosequencing were performed to resolve inconclusive results. Gene frequencies for the L allele were 0.15 in Africans, 0.16 in Choctaws, 0.18 in Caucasians, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.58 in PNG. Allelic frequency for 981H were 0.07 in Africans, 0.15 in Caucasians, 0.18 in Choctaws, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.54 in PNG. The Q981H polymorphism correlates with the HindIII RFLP in most groups except West Africans and appears to be part of a low CR1 expression haplotype. The gene frequency for the haplotype is highest in the malaria-endemic areas of Asia, suggesting that this haplotype may have evolved because it protects from rosetting and CM.

Africa↗
PubMed1983

Enzymic assay of C3b receptor on intact cells and solubilized cells.

The C3b receptor of human erythrocytes is known to act as a cofactor for the cleavage of the complement protein C3b by the serine proteinase C3b/C4b Ina. The same cofactor activity is shown to be present on human tonsil B-lymphocytes. The cofactor activity of the C3b receptor can be assayed, on intact cells or in solubilized extracts of cells, by determining the rate of C3b cleavage in the presence of fixed concentrations of C3b and of C3b/C4b Ina. This assay method was used to compare the characteristics and relative quantities of C3b receptors on erythrocytes and lymphocytes. The cofactor activities associated with these two cell types resemble each other, but are distinct from the serum cofactor proteins, C4bp and Factor H, in antigenicity and in pH- and ionic-strength-dependence, and are distinct from Factor H in substrate specificity. Assay of cofactor activity in intact cells indicates that there are about 80-fold more receptors per cell on the lymphocyte surface than on erythrocytes. Assays with cells made permeable by detergent show that, whereas essentially all of the receptors on erythrocytes are on the cell surface, B-lymphocytes contain a large internal receptor pool, which makes up more than 80% of the total cofactor activity of the cell.

B-Lymphocytes↗
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↗
PubMed1986

Loss of complement receptor type 1 (CR1) on ageing of erythrocytes. Studies of proteolytic release of the receptor.

Complement receptor type 1 (CR1) is a glycoprotein of Mr about 250 000 present on erythrocytes and other cell types. CR1 acts as a cofactor in the factor I-mediated breakdown of complement fragment C3b to form iC3b. Using an assay of cofactor activity, a wide variation in mean CR1 levels between erythrocytes from individual donors is observed. CR1 levels also decrease on ageing of erythrocytes in vivo, and again the rate of loss is widely variable between individuals. However, variable loss of CR1 during ageing of erythrocytes is likely to make only a minor contribution to the observed variation in mean CR1 levels. CR1 is very sensitive to proteolysis, and random proteolytic removal of CR1 from erythrocytes is likely to be an important factor in loss of CR1 on ageing of red cells in vivo. In vitro, mild trypsin treatment, plasmin or thrombin digestion of erythrocytes results in the loss of the factor I cofactor activity from the cell surface, and appearance of this activity in the supernatant. We conclude that an active fragment of CR1 is released from the cell surface on proteolysis. Subsequent prolonged trypsin treatment destroys most of the activity of this fragment. Proteolytic removal of CR1 from red cells may account not only for loss on ageing of cells, but also for the acquired CR1 deficiencies observed by others in systemic lupus erythematosus.

Erythrocyte Aging↗
PubMed1990

Expression of the CD15 differentiation antigen (3-fucosyl-N-acetyl-lactosamine, LeX) on putative neutrophil adhesion molecules CR3 and NCA-160.

The expression of the carbohydrate antigen 3-fucosyl-N-acetyl-lactosamine (CD15, LeX) on human neutrophil glycoproteins has been studied by immunoprecipitation and immunoblotting by using monoclonal antibody MC2. The antigen is expressed on membrane glycoproteins of approximate molecular mass 165 and 105 kDa. These glycoproteins include the complement receptor and adhesion molecule, CR3, in which the beta-chain (CD18, 105 kDa) shows much greater expression than the alpha-chain (CD11b, 165 kDa). Most of the 165 kDa CD15 antigen is accounted for by expression on the carcinoembryonic antigen (CEA)-related molecule NCA160. Other members of this family, NCA95, NCA90 and NCA55, which are also found in neutrophils, do not express the CD15 antigen. There is a marked increase in the surface expression of CD15, CR3 and the antigen recognized by anti-CEA antibodies upon activation of neutrophils by the chemotactic peptide N-formylmethionyl-leucylphenylalanine.

Animals↗
PubMed1994

Recombinant glycosyl-phosphatidylinositol-anchored proteins are not associated with protein kinases in transfected thymoma cells.

The cross-linking by antibody of some glycosyl-phosphatidyl-inositol (GPI)-anchored proteins on the plasma membrane of T cells leads to cell activation. Phosphorylation of proteins on tyrosine residues has a central role in the control of T cell activation, and non-receptor protein tyrosine kinases can be coprecipitated with immune complexes of GPI-anchored proteins in T cell lysates. In order to investigate the nature of this interaction, two recombinant GPI-anchored proteins were constructed (using the GPI signal sequence from Thy-1), and their associations with protein tyrosine kinases in stable transfectants of a mouse thymoma have been investigated. One recombinant GPI protein is the extracellular domain of the human complement receptor-1, normally an integral membrane protein, and the other is the secreted protein, human tissue inhibitor of metalloproteinases. The latter protein should be foreign to the cell surface and yet has been expressed as a GPI-anchored protein at levels equivalent to the highly expressed antigens Thy-1 and Ly6.A2 on mouse thymoma cells. Neither of the two recombinant proteins, when immunoprecipitated from NP40 lysates of transfected cells, was associated with protein tyrosine kinases in contrast with the natural endogenous GPI-anchored proteins Thy-1 and Ly6.A2 in non-transfected parental cells. Moreover, high expression of foreign recombinant GPI protein appears to interfere with the association of the natural GPI proteins with protein tyrosine kinases.

Animals↗
PubMed1998

Soluble form of complement C3b/C4b receptor (CR1) results from a proteolytic cleavage in the C-terminal region of CR1 transmembrane domain.

The complement C3b/C4b receptor (CR1) is an integral protein, anchored in the plasma membrane through a hydrophobic domain of 25 amino acids, but is also found in the plasma in soluble form (sCR1). A recombinant, soluble form of CR1 has been demonstrated to reduce complement-dependent tissue injury in animal models of ischaemia/reperfusion. In view of the important pathophysiological relevance of sCR1, we have investigated the mechanisms governing CR1 release by using various mutated and chimaeric receptors transiently expressed in COS cells. Pulse-chase experiments revealed that (1) sCR1 is produced by a proteolytic process, (2) the cleavage site lies within the C-terminus of CR1 transmembrane domain, (3) the proteolytic process involves a fully glycosylated CR1 form and (4) this process takes place in late secretory vesicles or at the plasma membrane.

Amino Acid Sequence↗
PubMed2002

Three-dimensional structure and flexibility of proteins of the RCA family - a progress report.

Members of the regulator of complement activation (RCA) protein family perform a vital role in health and disease. In this report we describe our efforts to solve the structures of human membrane cofactor protein (CD46), the vaccinia virus complement control protein, which mimics mammalian RCA proteins, and human complement receptor type 1 (CD35). These examples illustrate that, despite good progress over the last decade, the regulators of complement, as extracellular multiple domain glycoproteins, still pose formidable problems to structural biologists. Many important questions remain unanswered, in particular with regard to the flexibility of these proteins and the extent to which they undergo conformational rearrangements on engaging their binding partners.

Animals↗
PubMed2002

Structure-function studies of the receptors for complement C1q.

C1q is an essential component of the phylogenetically ancient innate complement (C) system and is crucial to our natural ability to ward off infection and clear toxic cell debris (e.g. amyloid fibrils, apoptotic cells). Several candidate C1q receptors [C1q receptor for phagocytosis enhancement (C1qRp), complement receptor (CR) 1, calreticulin (CRT), binding protein for the globular head of C1q (gC1qbp)] have been described, and the aim of this review is to shed light on their structure-function relationships. One cell-surface molecule, C1qRp, has emerged as a defence collagen receptor for C1q, as well as mannose-binding lectin (MBL) and surfactant protein A. C1qRp (also known as the AA4 antigen in rodents) is the antigen recognized by a pro-adhesive monoclonal antibody called mNI-11 and antibodies against CD93, but recent results failed to confirm C1q binding activity. CR1 (CD35), a multifunctional receptor both in its ligand specificity and in its C regulation activities, is found on circulating monocytes and neutrophils, but the major site of expression is B-lymphocytes. As a receptor, CR1 binds to C1q, other C opsonins (C4b, C3b, iC3b) and MBL, and as such, has been involved in promoting phagocytosis. Several studies support a role for the cell surface receptor for the collagenous domains of C1q (cC1qR; also known as CRT). CRT belongs to the family of heat-shock proteins, the most abundant and ubiquitous soluble intracellular proteins. Though CRT does not have a transmembrane domain, it seems to mediate phagocytosis of the apoptotic cells through association with CD91. A 33 kDa protein interacts with the globular head of C1q and, logically, has been termed gC1qbp. This protein is located in mitochondria, suggesting that gC1qbp is not a cell-surface receptor itself.

Animals↗
PubMed1996

The purification of CD34 cells from human cord blood: comparison of separation techniques and cytokine requirements for optimal growth of clonogenic progenitors.

This study was performed to assess the methods which gave maximal recovery of purified CD34/45+ cells from a cord blood specimen and optimal growth of progenitors cultured from the purified cells. Cord blood samples were separated using Percoll gradients (either one (1.080) or two successive (1.080 and 1.068) gradient(s)) and commercially available devices for CD34+ cell isolation (affinity columns as manufactured by CellPro Inc. or immunomagnetic separation procedure as devised by Baxter Inc.). "CellPro' or "Baxter' techniques gave similar results in terms of nucleated, CD34/45+ and progenitor cell concentration; however, the yield of CD34/45+ cells in the CD34+ enriched fraction was significantly higher when using the "CellPro' technique. We also found significantly higher numbers of CD34/45+ cells in the CD34+ enriched final fraction when using only one, 1.080, Percoll density gradient in the first separation step. Using one density separation step followed by the "CellPro' technique, we obtained an average of 3 x 10(6) purified CD34/45+ cells from samples containing 8.5 x 10(8) nucleated cells. Granulomonocytic progenitors (CFU-GM) and mixed progenitors (CFU-GEMM) cells from light-density and purified CD34/45+ cell fractions were evaluated. We found that 20-30% of the light-density cells and the purified CD34/45+ cells, yielded a granulomonocytic colony in serum free medium in the presence of interleukins 3 and 6, erythropoietin, granulomonocytic and granulocytic colony-stimulating factors and stem cell factor. The addition of tumour-necrosis factor alpha to the cocktail significantly improved the growth of CFU-GEMM allowing 10% of the purified CD34/45+ cells to yield a mixed colony, which confirms the role of this cytokine on CD34+ cells from cord blood. This study provides an improved method for recovery of CD34/45+ purified cells and their colony formation. These methods may serve as a basis for studies on CD34/45+ cell amplification and gene transfer.

Antigens, CD34↗
PubMed1999

Complement sensitivity of erythrocytes in a patient with inherited complete deficiency of CD59 or with the Inab phenotype.

We investigated the complement sensitivity of erythrocytes from three patients, one with inherited complete deficiency of CD59, one with the Inab phenotype, and one with paroxysmal nocturnal haemoglobinuria (PNH). The complement lysis sensitivity units on the erythrocytes were 11.7, 4.6, and 47.6 for inherited CD59 deficiency, Inab phenotype, and PNH, respectively. Two-colour flow cytometric analysis showed that the erythrocytes from the three patients consisted of a single population negative for CD59, negative for decay accelerating factor (DAF), and negative for both proteins, respectively. In addition, only the Inab phenotype patient had no haemolysis in vivo. These facts suggest that CD59 deficiency plays a more important role than DAF deficiency in complement-mediated haemolysis in vitro and in vivo, and that deficiency of both proteins, but not CD59 or DAF alone, causes complement sensitivity corresponding to that of PNH III erythrocytes in vitro.

Adult↗
PubMed2003

Overexpression of complement receptors and related antigens on the surface of bone marrow mast cells in patients with systemic mastocytosis.

Depending on their stage of maturation and other factors, mast cell (MC) subsets differ from each other in terms of the expression of complement-associated antigens. This study analysed the expression of various complement-related cell surface antigens (CD11b/CR3, CD11c/CR4, CD35/CR1, CD55/DAF, CD59/MIRL, CD88/C5aR) on bone marrow mast cells (BMMC) in patients suffering from systemic mastocytosis (SM), other haematological diseases and non-haematological disorders (control groups). Expression of complement-associated cell surface antigens was analysed by flow cytometry. There were clear immunophenotypic differences between BMMC obtained from patients with SM and those from the control subjects: the percentage of patients expressing surface CD11c, CD35 and CD88 was significantly higher in patients with SM (76%, 100%, 54%) than in the control subjects (58%, 11%, 18%) (P < 0.05). In addition, the levels of CD11c, CD35 and CD88 expressed per MC (sites per cell) were significantly higher (P < 0.05) in SM than in the control group. Expression of the complement regulatory molecules CD55 and CD59 was detected in BMMC in all patients analysed. However, the levels of CD59 per BMMC were higher in patients with SM as compared with the control subjects, which could help to explain the formation of BMMC aggregates in the former group of individuals. Together, our results showed that BMMC in systemic mastocytosis overexpressed the cell surface membrane receptors involved in binding of complement components and complement-mediated cell activation. Whether this pathological expression of complement receptors is of pathophysiological significance remains to be determined.

Adult↗