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PubMed1973

Combined studies of complement receptor and surface immunoglobulin-bearing cells and sheep erythrocyte rosette-forming cells in normal and leukemic human lymphocytes.

Human lymphocytes from normal peripheral blood, thymus, spleen, thoracic duct, and peripheral lymphocytes from patients with chronic lymphatic leukemia were studied for complement receptor sites (CRL), surface immunoglobulin (SIg), and for the ability to form rosettes with sheep erythrocytes (TRFC). The two B cell markers (CRL and SIg) were found to be in overlapping, but not totally identical populations, whereas cells that were able to form rosettes were found in a totally unrelated population of lymphocytes; TRFC is therefore probably a reliable marker for T cells. In peripheral blood 24% of lymphocytes had SIg, but only half of these were also CRL. Almost all of the non-SIg peripheral blood lymphocytes were TRFC. In the spleen and thoracic duct only a few lymphocytes were observed that had SIg and were not CRL. On the other hand, in two of three spleens studied 10-20% of cells were CRL that did not have SIg. In the thoracic duct all non-CRL that did not have SIg. In the thoracic duct all non-CRL, non-SIg cells were TRFC. In chronic lymphatic leukemia three findings were made: (a) The presence or absence of CRL was independent of the presence or absence of SIg so that in individuals whose cells were non-SIg. CRL were usually plentiful. (b) Leukemic cells were essentially negative for TRFC. (c) Leukemic cells reacted poorly with human C3 compared to mouse C3, EACmo detecting up to 20-fold more CRL than EAChu. This latter finding was in sharp contrast to normal CRL that reacted somewhat preferentially with EAChu. These data suggest that altered surface Ig receptors and complement receptors are present in chronic lymphatic leukemic cells. Since the cells obtained from all leukemic patients tested in this study had either the complement receptor or surface immunoglobulin in a high percentage of their cells and were essentially negative for TRFC, it is strongly suggested that leukemic lymphocytes are of B cell origin. The finding of lymphocytes with only one of the two B cell markers suggests that these markers are not uniformly present on all B cells and that depending on the source, one or the other may be deficient.

Animals↗

PubMed1999

Role of complement receptors CD21/CD35 in B lymphocyte activation and survival.

In summary, the complement system has evolved an important function in regulation of humoral immunity to T-dependent antigens. Covalent attachment of activated C3 to antigen alters its fate by enhancing uptake on the surface of FDC via CD21/CD35; and by enhancing signal transduction via the B cell coreceptor CD21/CD19/Tapa-1. In the absence of complement receptors CD21/CD35 or C3 ligand, naive B cells bearing low affinity BCR fail to effectively survive within the lymphoid follicle following contact with antigen and death is mediated by a Fas-dependent mechanism. Alternatively, B cells sufficiently activated to initiate a GC reaction fail to survive in the absence of CD21-CD21L interaction.

Animals↗

PubMed2004

Expression of Fcgamma and complement receptors on peripheral blood monocytes in systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVES: Fcagamma and complement receptors play an important role in the interaction between immune complexes (IC) and monocytes/macrophages. Recent work has demonstrated that their relative expression on these cells may be modified by cytokines, including TNF-alpha and IL-4. Furthermore, cytokines may alter the expression of adhesion molecules such as ICAM-1. However, little data exist on the in vivo expression of specific Fcgamma and complement receptors in systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), two diseases in which IC are important in pathogenesis. METHODS: Venous blood was obtained from 30 patients with SLE, 25 with RA and 25 healthy controls. Monocyte phenotype was determined by flow cytometric analysis of whole blood samples, with selective gating using forward and side scatter signals. Surface expression of Fcgamma receptors RI (CD64), RII (CD32) and RIII (CD16), complement receptors CR1 (CD35) and CR3 (CD11b/CD18), and adhesion molecules ICAM-1 (CD54) and CD11a (LFA-1) was determined. The effects of disease activity and corticosteroid therapy on the expression of these molecules were also examined. RESULTS: The expression of FcgammaRII was reduced on monocytes from patients with SLE compared with healthy controls and patients with RA (P = 0.002). This did not correlate with disease activity using conventional indices [SLEDAI (SLE disease activity index), C3/C4 levels and anti-double-stranded DNA antibody titres], and was independent of prednisolone therapy. There was no significant difference in FcgammaRI or RIII expression on SLE monocytes compared with healthy controls. In contrast, the expression of FcgammaRIII was increased on RA monocytes (P = 0.01), this being highest in patients with active disease. The proportion of FcgammaRIII-positive monocytes was also increased in RA, and prednisolone therapy was associated with a lower proportion of FcgammaRIII-positive cells. An increase in CR3 expression was seen on RA monocytes (P = 0.002), whilst CR1 was increased on monocytes from patients with active SLE or active RA. ICAM-1 expression was reduced on monocytes from patients with SLE (P = 0.002), although high-dose prednisolone therapy was associated with the lowest level of surface ICAM-1 on monocytes. CONCLUSIONS: Peripheral blood monocytes from patients with SLE or RA display significantly altered phenotypes compared with those from healthy controls. The observed reduction in SLE of FcgammaRII may represent a mechanism by which monocytes are protected from IC-mediated activation. Prednisolone therapy and disease activity had little effect on phagocytic receptor expression. The observed changes may reflect the different cytokine profiles seen in SLE and RA.

Adult↗

PubMed1999

The structural basis for complement receptor type 2 (CR2, CD21)-mediated alternative pathway activation of complement: studies with CR2 deletion mutants and vaccinia virus complement-control protein-CR2 chimeras.

The role of complement receptor 2 (CR2) short consensus repeats (SCR) in binding of hydrolyzed C3 (iC3) to form an alternative pathway (AP) convertase, and promoting C3 fragment deposition following AP activation, was examined. We used (1) K562 cells transfected with CR2 constructs, where the C3d-binding site of CR2 (SCR1+2) was replaced with the four-SCR vaccinia virus complement control protein (VCP), or truncation mutants thereof, and (2) COS cells transfected with wild-type (wt) CR2, or deletion mutants thereof. AP activation required iC3 binding in both systems. Thus, the VCP-CR2 chimera had an iC3 binding efficiency of 11.4 %, compared to wtCR2, and a relative AP activity of 5.5 %, the truncation mutants being inactive. Of the CR2 mutants, only EK (DeltaSCR10 - 11) had AP activity similar to wtCR2. NN (DeltaSCR6 - 8) and NOP (DeltaSCR6-mid14) had reduced AP activity, but near normal iC3 binding. XB (DeltaSCR3 - 6) and PP (DeltaSCR3-mid14) were inactive in both assays. We conclude that, whilst iC3 binding to CR2 via SCR1 - 4 is essential for AP activation, the efficiency of C3 deposition also depends on the midportion of CR2.

Animals↗

PubMed1987

Functional role of the alpha-chain of complement receptor type 3 in human eosinophil-dependent antibody-mediated cytotoxicity against schistosomes.

The participation of complement receptor type 3 (CR3) in antibody-dependent effector function of human eosinophils against parasites was studied by using monoclonal antibodies directed against various surface molecules. Both adherence and cytotoxicity of hypodense eosinophils to IgE-coated schistosomula of Schistosoma mansoni were strongly inhibited by anti-CR3 antibodies (OKM1 or Mo1). The specificity of the inhibitory effect for the alpha-chain of CR3 was shown by the lack of inhibition of anti-beta-chain or anti-LFA1 alpha-chain monoclonal antibodies, although these antigens were expressed on human eosinophils. These results associated to previous works on IgE receptors demonstrate that both receptor for Fc fragments of IgE and CR3 are essential in IgE-dependent cytotoxicity of human eosinophils. Flow microfluorometry analysis revealed that hypodense eosinophils were more intensively stained by OKM1 antibodies than the normodense populations. In the case of IgG-mediated cytotoxicity by normodense eosinophils, only the enhancement of cytotoxicity due to monokine activation was inhibited by anti-CR3 alpha-chain antibodies. These findings suggest an increased expression of CR3 on eosinophils after activation either in vivo or in vitro. The participation of CR3 in IgE-mediated cytotoxicity against schistosomes was also required in the case of blood monocytes but not for platelet-mediated killing, which does not require prior adherence. The biologic role of CR3 is therefore extended to effector mechanisms involving eosinophils and two different isotypes of antibodies and possibly implied in immunity against schistosomes.

Antibodies, Monoclonal↗

PubMed1989

Fc and complement receptor (CR1 and CR3) expression on neonatal human polymorphonuclear leukocytes.

Fc gamma receptor III (Fc gamma RIII) and complement receptors (CR1 and CR3) were examined on polymorphonuclear leukocytes (PMN) from neonatal cord blood and adult blood using monoclonal antibodies directed against these receptors. Receptor expression was determined by flow cytometry. Fc gamma RIII, CR1 and CR3 expression was examined in whole blood at 4 degrees C, at 37 degrees C with or without stimulation with the chemotactic peptide f-met-leu-phe, and on PMN isolated by Ficoll-Hypaque centrifugation and dextran sedimentation. There was no significant difference between adult and cord PMN in the percent of cells which expressed Fc gamma RIII, CR1 and CR3 when examined in whole blood at 4 or 37 degrees C, or following stimulation with f-met-leu-phe. The percentage of PMN expressing CR1 and CR3 was lower on cord PMN compared to adult PMN when these cells were examined following Ficoll-Hypaque centrifugation and dextran sedimentation. The mean peak fluorescence of PMN which stained positively for CR1 and CR3 increased following f-met-leu-phe treatment of whole blood from adults and neonates. Since neonatal cord PMN were capable of upregulating complement receptors in response to chemotactic factors these results do not explain the increased susceptibility to infection exhibited by neonates.

Adult↗

PubMed1981

Augmentation of macrophage complement receptor function in vitro. III. C3b receptors that promote phagocytosis migrate within the plane of the macrophage plasma membrane.

We have previously reported that treatment with a unique lymphokine enables resident mouse peritoneal macrophages to phagocytize via their complement receptors and we have presented evidence that the lymphokine act by enabling complement receptor engagement by C3b ligands to generate a phagocytic signal, thereby linking the cell surface binding event with the intracellular phagocytic machinery. In the present experiments, we used immobilized immune complexes to study the topography of C3b receptors of resident mouse peritoneal macrophages treated with the lymphokine. Our results indicate that lymphokine treatment enables the macrophages' C3b receptors to migrate within the plane of the cells' plasma membrane and that manipulations of macrophages that abrogate one response to the lymphokine, complement receptor mobility, also abrogate the other response, complement receptor-mediated phagocytosis. These findings strongly suggest that lateral mobility of a ligand-bound receptor within the macrophage plasma membrane is an essential component of the phagocytic signal. Moreover, our results indicate that the difference in complement receptor function among various populations of macrophages is not due to the expression of different types of complement receptors by the different macrophage populations but rather to a difference in the relationship of the C3b receptor with other plasma membrane or intracellular components.

Antigen-Antibody Complex↗

PubMed1994

HIV-1 infection of monocyte-derived macrophages reduces Fc and complement receptor expression.

Fc receptor (FcR) and complement receptor (CR) expression on HIV-infected monocyte-derived macrophages may be an important determinant of immune function. We studied the effects of HIV-1 infection of macrophages in vitro on FcR and CR expression. Macrophages were infected with HIV-1DV 7 days following isolation, and the expression of Fc gamma RI-III and CR3 were measured at intervals thereafter by flow cytometry. We found a reduction in receptor expression with the percentage of cells expressing FcRI 14 days post infection declining from 77% to 13%, FcRII fell from 96% to 85%, FcRIII from 45% to 9%, and CR3 from 91% to 67% 14 days following infection. As these receptors are important for macrophage function, their down-modulation may contribute to the pathogenesis of HIV-related disease.

Cell Adhesion Molecules↗

PubMed1997

Evaluation of the role of Fc gamma and complement receptors in the decreased phagocytosis of hereditary haemochromatosis patients.

Hereditary haemochromatosis (HH) monocytes have a decreased antibody mediated phagocytosis of rabbit erythrocytes and Staphylococcus aureus compared to control monocytes. In order to investigate whether this decrease could be attributed to a different level of expression of Fc gamma receptors (Fc gamma R) or complement receptors (CR), which cooperate even in the absence of complement, the surface expression of these receptors was determined on monocyte-enriched suspensions. In contrast to what was expected, HH monocytes displayed a significantly higher level of Fc gamma RI and Fc gamma RIIa as compared to healthy donor monocytes, but these differences were very small. The expression of the other receptors studied were similar for both groups. The heat-inactivated mouse serum used for opsonizing the erythrocytes mainly contained mouse IgG1. Two genetically different forms of Fc gamma RIIa are known, each with a different affinity for mouse IgG1 antibodies. Therefore, the Fc gamma RIIa polymorphism in monocytes (MN) of both groups was also investigated. A similar distribution was found for patients and healthy donors. In addition, the extent of erythrophagocytosis of both donors and patients was independent of Fc gamma RIIa allotype. Our results indicate that the altered phagocytosis by HH monocytes cannot be attributed to a different level of expression of receptors involved in phagocytosis or to Fc gamma RIIa polymorphism.

Adult↗

PubMed1996

Increased levels of soluble complement receptor 1 in serum patients with liver diseases.

Complement receptor type 1 (CR1) is an integral membrane protein of many hematopoietic cells and is found in a soluble form in plasma. Preliminary data have indicated that soluble complement receptor 1 (sCR1) levels in serum were increased in patients with cirrhosis. In this study, sCR1 was measured in patients with various liver diseases with a newly established enzyme-linked immunosorbent assay (ELISA). sCR1 level was elevated in chronic active hepatitis C (24 patients, 62.6 +/- 31 ng/ML; 31 normal controls, 31.4 +/- 7.8 ng/mL, P < .001), and in cirrhosis (35 patients, 143.7 +/- 61 ng/mL, P < .001). The levels increased transiently in 3 patients who had amanita phalloides intoxication. In 25 patients with advanced cirrhosis (pretransplantation screening), there were significant inverse correlations between sCR1 and both the prothrombin index (rs = -.60, P < .002) and the aminopyrine breath test (rs = -.51, P < .01). Following liver transplantation, the levels dropped from 166 +/- 70 to 49 +/- 24 ng/mL (P < .0001), and serial measurements in the posttransplantation period showed a correlation with liver dysfunction, regardless of etiology. Since CR1 is not produced by hepatocytes, the most likely explanation for the increased level of sCR1 is reduced is reduced catabolism. Thus, sCR1 may be added to the short list of large glycoproteins that accumulate in liver disease.

Amanita↗

PubMed1997

Neutrophil Fc gamma and complement receptors involved in binding soluble IgG immune complexes and in specific granule release induced by soluble IgG immune complexes.

We examined the effect of soluble IgG immune complex (IC) characteristics on the binding of IC to human neutrophils and IC-induced specific granule release of neutrophils via Fc gamma receptors (CD16 and CD32) and complement receptors (CR1 and CR3). A set of soluble IgG IC varying in size, IgG subclass, antigen epitope density and complement (C) incorporation were formed between 5-iodo-4-hydroxy-3-nitrophenacetyl (NIP) coupled to bovine serum albumin (BSA) and chimeric mouse-human anti-NIP monoclonal antibodies (mAb) of all four IgG subclasses. High and low epitope density IC of all four IgG subclasses induced specific granule release with C, but in the absence of C only IgG1 and IgG3 IC were functionally active. The Fc gamma and C receptors responsible for IgG IC-induced specific granule release and IC binding were determined using mAb specific for the ligand binding sites of CD16, CD32 and CR3, and recombinant soluble CR1. Each defined IC displayed a unique pattern of receptor preference, dependent upon subclass and antigenic epitope density. IC binding and IC-induced specific granule release was not mediated by the same receptor, or combination of receptors. High and low epitope density IgG3 IC binding and induction of specific granule release was mediated predominantly via CD16. Other IC subclasses bound differently, i.e. IgG1 IC used CD16 and CR3; IgG2 and IgG4 predominantly used complement receptors; but all three induced specific granule release via CD32. In vivo these results may translate into differential activation of neutrophils by soluble IC dependent upon their characteristics, leading to subtle nuances in the etiology, pathology and control of the immune response in IC-related diseases.

Animals↗

PubMed1985

Polymorphism of the complement receptor for C3bi.

RM2.184, a mouse IgG2a monoclonal antibody, recognizes a polymorphic determinant on the complement receptor for C3bi which is present on granulocytes and monocytes. The RM2.184 epitope is distinct from the monomorphic determinant recognized by the monoclonal antibody OKM1. The RM2.184 epitope is probably on the alpha subunit and dependent on the association of the alpha and beta subunits for its configuration, as it can not be detected after the subunits have been dissociated. The phenotypic frequency of the RM2.184 antigen is approximately 14%, and its segregation in families is independent of HLA and consistent with an autosomal co-dominant mode of inheritance.

Antibodies, Monoclonal↗

PubMed1986

Leukocyte complement receptors and adhesion proteins in the inflammatory response: insights from an experiment of nature.

The complement receptor type 3 (CR3) mediates phagocytosis and degradation of iC3b-opsonized particles by macrophages and granulocytes. The CR3 is identical to the Mac-1 molecule, which is composed of two non-covalently associated glycoprotein subunits, alpha M of Mr 170,000 and beta of Mr 95,000. Patients with recurring, life-threatening bacterial infections have been identified who have moderate (95%) or severe (greater than 99%) deficiency of Mac-1 and of the related LFA-1 and p150,95 molecules. The primary defect is in the shared beta subunit of these molecules. Patient leukocytes are not only deficient in CR3 but in a wide variety of adhesion-dependent functions, including granulocyte chemotaxis, adherence to surfaces, and aggregation. Monoclonal antibodies to the Mac-1 alpha subunit and to the beta subunit block these functions. The hypothesis will be advanced that Mac-1 functions dually as the CR3 and in 'nonspecific' adherence reactions. Adherence functions are stimulated in normal granulocytes by chemoattractants, which also induce a rapid 5-fold increase in Mac-1 and p150,95 on the cell surface. It is proposed that absence of Mac-1 and p150,95 expression and upregulation by patient granulocytes is causally related to their inability to extravasate and migrate into inflammatory sites.

Adult↗

PubMed2004

Complement receptors and the shaping of the natural antibody repertoire.

Complement and complement receptors have been known for several decades to play important roles in immune effector mechanisms related to pathogen elimination and tissue inflammation. In addition, studies over the last 10 years have clearly demonstrated a key role for the complement C3d activation fragment receptor designated CR2 (complement receptor type 2) in the switched-isotype, high-affinity and memory humoral immune responses to T-dependent foreign antigens. More recent studies have extended those observations to include a key role for CR2 and C3d in the humoral immune response to T-independent foreign antigens. Conversely, as these studies have proceeded, a parallel series of analyses have linked defects in expression or function of complement C4 and other classical pathway activation pathway proteins, as well as CR2 and the closely related CR1, to the loss of self tolerance to nuclear antigens such as double-stranded DNA and chromatin in systemic lupus erythematosus. With regard to the topic of this issue, it is now becoming increasingly clear that CR2 also plays a major role in the development of the natural antibody repertoire. Specifically, in the absence of this receptor natural IgM and IgG develop in the naïve animal that demonstrate clearly altered recognition patterns for specific natural antibody targets. This repertoire change is important physiologically in at least one setting because these CR2-dependent natural antibodies are necessary for the recognition of ischemic self tissues. In addition, it is possible that certain of the phenotypes manifest by CR2-deficient mice may be strongly influenced not only by effects on later stages of B cell activation and maturation, as commonly thought, but also by alterations in the pre-existing pool of natural antibodies that are influenced by this receptor. This review will examine the evidence that has accumulated over the last few years supporting these hypotheses.

Animals↗

PubMed1999

Structure and expression of ovine complement receptor type 2.

The structure of sheep complement receptor type 2 (CR2) was characterised by cDNA cloning, protein sequencing and immunoprecipitation. The primary structure of sheep CR2 is similar to known mammalian homologues but the higher-order structure is unusual. Two distinct CR2 isoforms occur, one of which is ubiquitinated in the cytoplasmic domain, and the two molecular forms are expressed at the cell surface as non-covalently associated dimers. The percentage of sheep B-cells that express CR2 changes during development and varies between different body compartments. CR2+ and CR2 B-cell subsets also differ in the expression of other surface markers and in functional properties. Differential expression of CR2 may, therefore, delineate B-cells that arose by alternative developmental pathways, or it could be a marker for B-cells at different phases of antigen exposure.

Animals↗

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↗

PubMed2000

Serum regulates the expression of complement receptor 2 on human B cell lines.

Complement receptor 2 (CR2) participates in the regulation of B cell responses to antigen. In this study we report that treatment of IM-9 B lymphoblastoid cells or Raji Burkitt's lymphoma cells with 10% heat-inactivated fetal bovine serum for 24 hr increased both the CR2 mRNA level and CR2 surface protein expression more than two-fold. No change in the CR2 expression level was observed if cells were cultured in serum-free medium. The CD19 mRNA level decreased after 24 hr independently of the presence of serum. The serum-stimulated increase in CR2 expression was not due to changes in the proliferative capacity of the cells and could not be mimicked by various cytokines. However, IFN-gamma as well as OKB7, a CR2-specific monoclonal antibody, blocked the serum-induced increase in CR2 expression at the mRNA level. Our data show for the first time that factors in serum induce the expression of the CR2 gene and that signals initiated by IFN-gamma and OKB7 interfere with the serum-induced changes. Because stimuli that alter CR2 expression can influence the extent of the B cell response to antigen-C3d complexes, serum factors may play a role in regulating the responsiveness of B cells.

Animals↗

PubMed1988

Complement receptor type three (CD11b/CD18) of human polymorphonuclear leukocytes recognizes fibrinogen.

Human polymorphonuclear leukocytes (PMN) have previously been shown to bind to aggregates of fibrin and to fibrinogen-coated surfaces. During their interactions with fibrinogen-coated surfaces, PMN make such close contact with the surface that a portion of the secreted elastase activity is protected from macromolecular protease inhibitors in the surrounding medium. Here we show that the receptor on PMN that mediates this interaction is complement receptor type 3 (CR3; CD11b/CD18), a molecule previously identified as a receptor for the complement protein fragment C3bi. Monoclonal antibodies against CR3 that block the binding of C3bi also block the binding of PMN to fibrinogen-coated surfaces and the formation of a protected compartment. The region of fibrinogen recognized by CR3 lies at the carboxyl terminus of the gamma chain, since peptides based on this sequence effectively inhibit the binding of PMN to fibrinogen-coated surfaces. These peptides also block the binding of C3bi-coated erythrocytes to CR3, thus indicating that a single binding site is used for binding both C3bi and fibrinogen. Sequence analysis shows strong structural similarity between this region of fibrinogen and other known ligands of CR3. These studies thus indicate that CR3 functions as a receptor not only for C3bi but also for fibrinogen.

Antibodies, Monoclonal↗