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PubMed2001

The complement receptor 3, CR3 (CD11b/CD18), on T lymphocytes: activation-dependent up-regulation and regulatory function.

The complement receptor 3 (CR3; CD11b/CD18) is present exclusively on leukocytes, particularly on NK cells, monocytes and polymorphonuclear neutrophils. Approximately 10% of peripheral T lymphocytes and, as we found now mainly CD8(+) cells, expressed CD11b. Upon stimulation, however, expression of CD11b was up-regulated also on CD4(+) cells. Stimulation of T cells either by cross-linked anti-CD3 and IL-2 or by mononuclear cells and mitogen yielded up to 28% CD11b(+) T cells. The majority of CD11b(+) T cells also expressed CD56. T cell lines established from healthy donors were also found to express CR3. When restimulated up to 90% of cells became positive for CD11b making those cells an ideal tool for studying the functional role of CD11b. Antibodies to CD11b and bona fide ligands for the complement receptor inhibited the anti-CD3-induced T cell proliferation and as well as IL-2 release. In contrast, proliferation of a CD11b(-) T cell line was not inhibited. Taken together, our data indicate an activation-dependent expression of the complement receptor on T cells and suggest a regulatory function.

Amino Acid Sequence↗
PubMed1998

X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2.

Activation and covalent attachment of complement component C3 to pathogens is the key step in complement-mediated host defense. Additionally, the antigen-bound C3d fragment interacts with complement receptor 2 (CR2; also known as CD21) on B cells and thereby contributes to the initiation of an acquired humoral response. The x-ray crystal structure of human C3d solved at 2.0 angstroms resolution reveals an alpha-alpha barrel with the residues responsible for thioester formation and covalent attachment at one end and an acidic pocket at the other. The structure supports a model whereby the transition of native C3 to its functionally active state involves the disruption of a complementary domain interface and provides insight into the basis for the interaction between C3d and CR2.

Amino Acid Sequence↗
PubMed1997

Bispecific monoclonal antibody complexes bound to primate erythrocyte complement receptor 1 facilitate virus clearance in a monkey model.

We investigated the feasibility of using bispecific mAb complexes to redirect and improve the efficiency of the primate E complement receptor 1-based clearance reaction to remove a virus from the circulation. As an initial approach, we used bacteriophage phiX174 as an immunologic model for mammalian viruses. Bispecific complexes were prepared by chemically cross-linking a mAb specific for complement receptor 1 with a mAb specific for the bacteriophage phiX174. In a monkey model these complexes facilitate rapid and quantitative binding of the target bacteriophage to E in vitro and in vivo. Moreover, after in vivo binding to E, the complexes containing mAb and prototype virus are rapidly cleared from the circulation of rhesus and cynomolgus monkeys without loss of E. Our findings suggest that bispecific mAb complexes, in concert with primate E complement receptor 1, may have therapeutic utility in the treatment of diseases associated with blood-borne pathogens.

Animals↗
PubMed2000

Structure-guided identification of C3d residues essential for its binding to complement receptor 2 (CD21).

A vital role for complement in adaptive humoral immunity is now beyond dispute. The crucial interaction is that between B cell and follicular dendritic cell-resident complement receptor 2 (CR2, CD21) and its Ag-associated ligands iC3b and C3dg, where the latter have been deposited as a result of classical pathway activation. Despite the obvious importance of this interaction, the location of a CR2 binding site within C3d, a proteolytic limit fragment of C3dg retaining CR2 binding activity, has not been firmly established. The recently determined x-ray structure of human C3d suggested a candidate site that was remote from the site of covalent attachment to Ag and consisted of an acidic residue-lined depression, which accordingly displays a significant electronegative surface potential. These attributes were consistent with the known ionic strength dependence of the CR2-C3d interaction and with the fact that a significant electropositive surface was apparent in a modeled structure of the C3d-binding domains of CR2. Therefore, we have performed an alanine scan of all of the residues within and immediately adjacent to the acidic pocket in C3d. By testing the mutant iC3b molecules for their ability to bind CR2, we have identified two separate clusters of residues on opposite sides of the acidic pocket, specifically E37/E39 and E160/D163/I164/E166, as being important CR2-contacting residues in C3d. Within the second cluster even single mutations cause near total loss of CR2 binding activity. Consistent with the proposed oppositely charged nature of the interface, we have also found that removal of a positive charge immediately adjacent to the acidic pocket (mutant K162A) results in a 2-fold enhancement in CR2 binding activity.

Animals↗
PubMed1998

Ubiquitination and dimerization of complement receptor type 2 on sheep B cells.

Complement receptor type 2 (CR2) is a membrane-anchored glycoprotein that specifically binds C3d, as well as other ligands, and plays diverse roles in regulating immunity. Here we show that two distinct isoforms of CR2 are expressed on the surface of sheep B lymphocytes. One (CR2no 150 kDa) is structurally similar to known mammalian homologues while the other (CR2ub 190 kDa) has been modified by the covalent attachment of ubiquitin to the cytoplasmic domain and is identified for the first time. CR2no and CR2ub are expressed on the surface of sheep B cells as noncovalently associated dimers and the external topography of the two isoforms differs in some respect. The basis for these unusual higher-order structural properties may lie in the primary sequence of sheep CR2, since the transmembrane domain contains a region resembling a rare 7-amino acid dimerization motif, and two lysine residues in the cytoplasmic domain provide potential sites for posttranslational ubiquitination. The primary structures of sheep ubiquitin and C3d ligand are extensively conserved. In conjunction with the results of separate in vivo studies, these findings suggest that selective ubiquitination plays a role in modulating the higher-order structure and/or expression of CR2 during B cell development.

Amino Acid Sequence↗
PubMed1988

Enhancement of the function of neutrophil type-1 and type-3 complement receptors by human leukocyte inhibitory factor (LIF).

The lymphokine leukocyte inhibitory factor (LIF) has previously been documented to enhance several neutrophil (PMN) functions, including stimulated chemotaxis and superoxide generation, phagocytosis and adherence of opsonized targets, and antibody-dependent cellular cytotoxicity. The present studies were designed to investigate the effects of LIF on PMN function mediated by the complement components C3b and C3bi. LIF induced a dose-dependent increase in superoxide production generated by opsonized zymosan (up to 97.1 +/- 31.4% at 16 U LIF/ml; P less than 0.01). While neither control nor LIF-treated PMN were capable of inducing phagocytosis of either C3b- or C3bi-opsonized sheep erythrocytes (E) directly, exposure to LIF caused a significant (P less than 0.05) increase in their adherence to E (137.4 and 59.4%, respectively). Specificity for complement receptor function was confirmed by the ability of anti-CR1 antibody to block adherence of LIF-treated PMN to EAC3b (77.0% inhibition) and anti-CR3 antibody to block adherence to EAC3bi (70.2% inhibition). Increased C3b and C3bi function may have been due, at least in part, to increased expression of their respective surface membrane receptors. Thus, using indirect immunofluorescence, LIF induced a 38.2% increase in fluorescence of the anti-CR1 antibody and a 96.1% increase in anti-CR3 binding. These studies describe an additional mechanism through which LIF may have an important pro-inflammatory role in vivo.

Antibodies, Monoclonal↗
PubMed1989

Expression of complement receptors type 1 (CR1) and type 3 (CR3) on circulating granulocytes in experimentally provoked asthma.

Neutrophils demonstrate increased complement receptor activity, measured by rosetting of C3b-coated erythrocytes, after asthma that was provoked experimentally. However, it is not clear whether the increased rosetting is due simply to increase in receptor numbers or whether other factors, such as cell adhesiveness, are involved. We have therefore enumerated granulocyte complement receptors, after asthma provoked experimentally, with monoclonal antibodies against the receptors and flow cytometry. There was a maximal 28.2 +/- 7.5% and 33.4 +/- 9.5% (mean +/- SEM; n = 15) increase in granulocyte CR1 and CR3, respectively, at 3 hours after asthma induced by antigen. There was a maximal 32.0 +/- 7.3% (mean +/- SEM; n = 7) increase in granulocyte CR1, but no change in granulocyte CR3, at 1 hour after exercise-induced asthma. No significant changes in granulocyte CR1 or CR3 were observed up to 6 hours after methacholine challenge, or after exercise in subjects who did not develop exercise-induced asthma. There was a maximal 33 +/- 9% (mean +/- SEM; n = 8) increase in granulocyte CR1 at 30 minutes, but no increase in granulocyte CR3, after histamine challenge of subjects with asthma. Incubation of whole blood with histamine in vitro did not lead to any enhancement in expression of granulocyte CR1. This suggests that antigen- and exercise-induced release of histamine may augment granulocyte CR1 expression through an indirect mechanism. These data indicate that there is increase in the numerical expression of CR1 on granulocytes, after asthma provoked experimentally, which is accompanied by increases in granulocyte CR3 after bronchoprovocation with antigen, but not histamine or exercise.

Adolescent↗
PubMed2005

Investigation of the role of complement and complement receptors in the modulation of B cell activation by a Paracoccidioides brasiliensis cell wall fraction.

F1 fraction from Paracoccidioides brasiliensis is a potent activator of the complement system. Considering that complement receptors CR1 and CR2 are involved in the regulation of B cell response, we evaluated the in vitro effect of the F1 in the activation of B lymphocytes, as well as the participation of complement receptors in this process. Murine splenocytes were cultured in order to evaluate the expression of CD40, CD45RB and CD69 on B lymphocyte, and IgG and IgM were quantified in the culture supernatant. F1 participated in the activation of B cells, showing a positive modulation effect on all markers analyzed. An increase in the production of IgG was detected in the supernatants when the opsonized F1 fraction was present. Complement receptor blockade with monoclonal antibodies led to a partial reduction in immunoglobulin secretion, suggesting that these receptors, especially CR2, play a role in modulating the function of B lymphocyte stimulated with the opsonized F1 fraction. These results may contribute for a better understanding of the B cell activation and differentiation processes in response to the F1 fraction from P. brasiliensis.

Animals↗
PubMed1987

Enumeration of CR1 complement receptors on erythrocytes using a new method for detecting low density cell surface antigens by flow cytometry.

A sensitive enhancing system was developed for detecting low density cell surface antigen by flow cytometry. The system termed the 'super avidin-biotin system' (SABS) uses biotinylated antibody, phycoerythrin-streptavidin (StreptA-PE), biotinylated goat anti-streptavidin antibody, and StreptA-PE. CR1 complement receptor antigenic sites were quantified on erythrocytes from healthy individuals and patients with antibodies against human immunodeficiency virus (HIV) using SABS and a conventional radioimmunoassay (RIA) with monoclonal anti-CR1 antibody. As little as 50 sites/cell were detected using either SABS or RIA. Accurate quantification of CR1 antigenic sites was achieved within the range of 100-1300 sites/cell. Similar results were obtained using either of the two methods. Intra-assay and day-to-day reproducibilities using SABS were 2% and 12% respectively, comparable to those of conventional RIA measurements. In addition to enumeration of CR1 on erythrocytes for clinical purposes, the use of SABS may probably be extended to a wide number of situations where a sensitive detection of low density cell surface antigen is needed.

Acquired Immunodeficiency Syndrome↗
PubMed1979

Effects of immobilized immune complexes on Fc- and complement-receptor function in resident and thioglycollate-elicited mouse peritoneal macrophages.

We have examined the Fc- and complement-receptor function of resident and thioglycollate-elicited mouse peritoneal macrophages plated on surfaces coated with rabbit antibody-antigen complexes and with complement. We derive four major conclusions from these studies. (a) The trypsin-resistant Fc receptors of resident and thioglycollate-elicited macrophages are completely modulated when these cells are plated on rabbit antibody-antigen complexes. Residual Fc receptor activity is a result of the incomplete modulation of trypsin-sensitive IgG2a receptors. (b) The complement receptors of thioglycollate-elicited macrophages, but not of resident macrophages, are modulated when these cells are plated on complement-coated surfaces. The capacity of the two cell types to modulate their complement receptors is correlated with their ability to ingest complement-coated erythrocytes. (c) The complement and Fc receptors of both types of macrophages move independently of one another. (d) Complement masks the Fc segments of IgG in immune complexes thereby rendering them ineffective as ligands for macrophage Fc receptors.

Animals↗
PubMed1978

Complement receptor subtypes C3b and C3d in lymphatic tissue and follicular lymphoma.

To substantiate the origin of follicular (nodular) lymphoma cells from germinal-centre cells, the lymphoma cells from 7 patients with follicular lymphoma and from 9 tonsils and 2 lymph nodes were studied for the presence and distribution of complement-receptor subtypes (i.e., the receptors for C3b and C3d). It was found that erythrocytes coated with antibodies and C3d (EAC3d) adhered exclusively to germinal centres, whereas erythrocytes coated with antibodies and C3b (EAC3b) adhered to germinal centres and in many instances to the regions between them. These findings indicate that germinal-centre cells bear both complement-receptor subtypes and that the B cells of the interfollicular area, which belong at least in part to the precursors of plasma cells, bear only a receptor for C3b. In frozen sections of follicular lymphomas, a similar distribution of complement-receptor subtypes was observed; EAC3d was bound exclusively to the neoplastic nodules, and EAC3b adhered to the neoplastic nodules and adjacent paranodular tissue. Receptor studies on suspended cells of both normal tonsils and follicular lymphomas revealed a slight predominance of EAC3d(+) cells or equal numbers of EAC3b(+) and EAC3d(+) cells. The complete congruence in the expression and distribution of complement-receptor subtypes between tissues from follicular lymphomas and those from normal and hyperplastic tonsils or lymph nodes suggests that follicular lymphoma represents the neoplastic counterpart of the reactive germinal centre.

Binding Sites↗
PubMed2002

The role of complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) in promoting C3 fragment deposition and membrane attack complex formation on normal peripheral human B cells.

Normal human B lymphocytes are known to activate the alternative pathway (AP) of complement, leading to C3-fragment deposition and membrane attack complex (MAC) formation. The process is mediated via complement receptor type 2 (CR2, CD21), with complement receptor type 1 (CR1, CD35) playing a subsidiary role. In this study, we examine the relative contributions of CR1 and CR2 to the deposition of C3 fragments and MAC on B lymphocytes under circumstances where all complement pathways are operational. C3-fragment deposition and MAC formation were assessed on human peripheral B lymphocytes in the presence of 30% autologous serum. Blocking the CR2 ligand-binding site with monoclonal antibody (mAb) FE8 resulted in significant reduction (37.9+/-11.9%) in C3-fragment deposition, whereas MAC formation was only marginally affected (12.1+/-22.2% reduction). Blocking the CR1 binding-site resulted in significant reduction of both C3-fragment deposition (22.0+/-14.5%) and MAC formation (47.4+/-13.8%). Both the lack of CR2 influence on MAC formation and the promotion of C3-fragment deposition by CR1 are in striking contrast to the situation where only the AP is operational. The presence of erythrocytes (E) bearing CR1, however, markedly reduced both C3-fragment deposition and MAC formation. Our data suggest that C3-fragment deposition and MAC formation on B lymphocytes in vivo may involve both AP and classical pathway activation, with CR1 contributing significantly to the latter. On the other hand, the presence of extrinsic CR1, on E, may serve to limit spontaneous MAC formation and thereby ensure cell survival in the circulation.

B-Lymphocytes↗
PubMed1981

Complement receptor is an inhibitor of the complement cascade.

A glycoprotein from the membrane of human erythrocytes has been identified as a receptor for C3b (CR1). It promotes the dissociation of the alternative pathway C3 convertase C3b,Bb and the cleavage of C3b by C3b/C4b inactivator. We find that CR1 also inactivates the C3 and C5 convertases of the classical pathway. CR1 inhibits the consumption of C3 by C3 convertase EAC142 and enhances the decay of C4b,2a sites. On a weight basis, CR1 is approximately 5-10 times more active than C4 binding protein, a serum inhibitor of C4b,2a. The binding of 125I-CR1 to EAC14 cells is inhibited by C2. Therefore, it is likely that CR1 and C2 compete for a site on C4b. CR1 inhibited C5 convertase even more effectively, but had no effect on the assembly of the late complement components. At high concentrations, CR1 alone has no irreversible effects on cell-bound C4b. In the fluid phase, CR1 can function as a cofactor for the cleavage of the alpha' chain of C4b by C3b/C4b inactivator. A well-known function of CR1 is to promote adherence of microbes or immune complexes bearing C3b and C4b to cells. This interaction could result in a microenvironment damaging to the plasma membrane of the responding cell because the extrinsic C3b and C4b fragments can serve as additional sites of assembly of enzymes of the cascade. We therefore wish to propose that CR1 on the surface of cells supplies an increased local concentration of a strong inhibitor of the amplifying enzymes of the complement system and provides cells with a mechanism for circumventing damage when they bind C3b- and C4b-bearing substrates.

Complement C3-C5 Convertases↗
PubMed2004

Association of complement receptor 1 (CR1, CD35, C3b/C4b receptor) density polymorphism with glomerulonephritis in Indian subjects.

Complement receptor 1 (CR1, CD35, C3b/C4b receptor), a polymorphic membrane bound glycoprotein is important both as a complement regulatory protein, and as a vehicle for immune complex clearance. It is differentially expressed on erythrocytes, eosinophils, monocytes, B and T-lymphocytes, dendritic cells and kidney podocytes. It also occurs in the plasma as soluble CR1 (sCR1) and in urine as urinary CR1 (uCR1). Different population studies have either suggested or refuted the functional and physiological significance of genomic (HH, high erythrocyte CR1 expression; HL, intermediate and LL, low expression) polymorphism of CR1 in health and disease. Prevalence of autoimmune disorders like RA, GN and SLE is higher in Asian-Indians compared to the western world. Although several studies from India emphasize the modulation of E-CR1 levels as a key factor in the pathophysiology of glomerulonephritis (GN), none of them, however, provide much information on the role of CR1 gene variance in this context. We, therefore, carried out the study of CR1 polymorphism in 117 normal Indian subjects and 65 patients suffering from glomerulonephritis in order to study its possible association with the disease and E-CR1 levels. This is the first study of its kind in the Indian population, in which, the direct effect of a particular genotype on the E-CR1 levels and its possible association with the disease has been studied simultaneously.

Adult↗
PubMedDate not supplied

Expression of complement receptors (CR1 and CR3) and Fc gamma RIII on polymorphonuclears from patients with spondylarthropathies.

We assessed the expression of complement receptors (CR1 and CR3) and Fc gamma RIII on unstimulated and FMLP activated polymorphonuclears (PMNs) by indirect immunofluorescence and flow cytometry using CD35 (CR1), CD11b (CR3) and CD16 (Fc gamma RIII) monoclonal antibodies in 24 patients with spondylarthropathies (SpA) and in 18 healthy subjects. SpA patients were classified into 3 groups according to the severity of the disease (severe = asymmetrical peripheral joint involvement and permanent limitation of spine motion; moderate = one of the two items, mild = none of the items). CR1 and Fc gamma RIII expression were significantly decreased in patients with mild SpA, whereas CR1 and CR3 expression were significantly increased in patients with severe disease as compared to control subjects. In patients with mild disease, CR1 expression increased after FMLP activation, but remained significantly lower than in control subjects. The results were confirmed by immunoelectroblotting. These findings suggest that membrane and intracellular pools of CR1 and CR3 may contribute to the clinical modulation of the spondylarthropathies.

Adult↗
PubMed1989

Analysis of epitope expression and the functional repertoire of recombinant complement receptor 2 (CR2/CD21) in mouse and human cells.

We transfected human complement receptor 2 (CR2/CD21) cDNA containing eukaryotic expression constructs into CR2-negative mouse L cells and human K562 erythroleukemia cells. We subsequently selected stably transformed cells that expressed human CR2, as assessed by flow microfluorimetry analysis and immunoprecipitation of 125I-labeled surface membranes using the monoclonal anti-CR2 antibody, HB5. Utilizing flow microfluorimetry analysis, epitopes recognized by anti-CR2 mAb HB5, OKB7, B2, and four other anti-CR2 antibodies were detected on CR2 expressing transfectants but not parental cells. In addition, CR2 expressing transfected cells efficiently formed rosettes with sheep erythrocyte intermediates bearing human C3bi and C3d, but not C4b or C3b, consistent with the known ligand specificity of CR2. CR2 containing transfectants were also demonstrated to specifically bind EBV. Infection with EBV of CR2 expressing L cells and K562 cells resulted in mean expression of Epstein-Barr nuclear Ag (EBNA) at 48 h in 0.35% of CR2 expressing L cells and 3.7% of CR2 expressing K562 cells. Parental L cells and K562 cells did not express EBNA after EBV infection. These results indicate that CR2 alone is sufficient to transfer both C and EBV receptor functions to heterologous cells. In addition, expression of EBNA was found to be significantly higher in human K562 than mouse L cells, both expressing the same recombinant receptor. These results suggest that mechanisms other than CR2 binding lead to inefficient EBV infection and/or EBNA synthesis in mouse fibroblasts.

Animals↗
PubMed1982

Complement receptor phenotypes of culture-derived murine macrophages.

The distribution of complement receptors CR1 and CR3 among macrophages derived from cultures of bone marrow, blood, and elicited or normal peritoneal cell populations was studied. Cells and colonies from the first three sources had a common phenotype, CR1+3-, whereas those from the normal peritoneal populations had either CR1+3- or CR1+3+. The former phenotype characterized spindle-shaped as well as epithelial-like macrophages; the latter was essentially restricted to colonies made up of the epithelioid cells. Both morphologic features and the CR phenotypes remained stable throughout the culture period. These phenotypic differences might be explained by the presence of at least two clonally derived types of macrophages.

Animals↗
PubMed1990

Effect of local and systemic burn microenvironment on neutrophil activation as assessed by complement receptor expression and morphology.

Previously, we documented that humoral factors, especially complement products, contained in burn wound blister fluid (BF) modulate normal neutrophil (PMN) function and metabolism. The goal of the current study was to examine the effects of the local (BF) and systemic (burn serum or plasma) burn microenvironment on PMN activation as assessed by complement receptor expression and morphology. Induction of CR1 (C3b) and CR3 (iC3b) receptor expression of normal PMNs after incubation in medium, BF, or plasma (serum) from healthy volunteers or burned patients was measured using monoclonal antibodies and flow cytometry. BF (10% v/v, 37 degrees C) induced 25% more CR1 receptor expression than control or burn plasma (p less than 0.05), while the levels of CR3 expression of PMNs incubated in BF (10% or 80% v/v at 37 degrees C) was more than 300% that found when the PMNs were incubated in medium, burn, or patient plasma (p less than 0.05). The electron microscopic appearance of PMNs incubated in these fluids documented that degranulation was greater when cells were incubated in BF than medium, control, or patient plasma. These results indicate that PMN activation (CR1 and CR3 expression) is greater in cells exposed to the local (BF) than the systemic (plasma) humoral microenvironment shortly after thermal injury.

Blister↗