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PubMed1996

Complement receptor type 3 mediates phagocytosis and killing of Listeria monocytogenes by a TNF-alpha- and IFN-gamma-stimulated macrophage precursor hybrid.

Previous work demonstrated that engagement of complement receptor type 3 (CR3) was required for inflammatory peritoneal macrophages to phagocytose and kill the facultative intracellular bacterium Listeria monocytogenes. The experiments described here tested the role of CR3 in phagocytosis and killing of Listeria by a clonal population of TNF-alpha/IFN-gamma-stimulated macrophage precursor hybrids. Stimulation with TNF-alpha and IFN-gamma increased CR3 expression 20-fold and induced a big increase in phagocytic activity. Phagocytosis and killing of Listeria by these cells were inhibited when bacteria were opsonized with complement-depleted serum or by incubation of the macrophages with anti-CR3 mAb. Furthermore, cytokine-stimulated macrophages could not kill Listeria opsonized with heat-inactivated anti-Listeria antiserum, indicating that macrophage receptors which mediate phagocytosis do not necessarily promote bactericidal activity. These data suggest that upregulation of CR3 and CR3-mediated phagocytosis are mechanisms by which TNF-alpha and IFN-gamma stimulate nonphagocytic, nonbactericidal macrophage precursors to kill intracellular bacterial pathogens.

Animals↗
PubMed1987

A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32.

The alternative or classical pathways for complement system component C3 may be triggered by microorganisms and antigen-antibody complexes. In particular, an activated fragment of C3, C3b, covalently attaches to microorganisms or antigen-antibody complexes, which in turn bind to the C3b receptor, also known as complement receptor 1. The genes encoding the proteins that constitute the C3-activating enzymes have been cloned and mapped to a "complement activation" locus in the major histocompatibility complex, and we demonstrate in this study such a locus on the long arm of chromosome 1 at band 1q32.

Chromosome Mapping↗
PubMed1989

Complement receptors.

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Antigens, Differentiation, B-Lymphocyte↗
PubMed1996

Priming of neutrophils with tumor necrosis factor-alpha measured as Fc gamma receptor-mediated respiratory burst correlates with increased complement receptor 3 membrane density.

Hyperactive or primed neutrophils which damage tissue via cytokines and membrane receptors may be implicated in the pathogenesis of inflammatory conditions. The purpose of this study was to elucidate the priming mechanism in neutrophils by assessing changes in membrane receptors and the Fc gamma R-mediated respiratory burst, measured as chemiluminescence. Purified neutrophilic granulocytes from healthy volunteers were preincubated with recombinant human tumor necrosis factor-alpha. This had a priming effect, increasing both the Fc gamma receptor-mediated luminol-enhanced chemiluminescence and the membrane expression of the C3bi receptor (CRB) (r = 0.843). The membrane densities of Fc gamma RII, Fc gamma RIII, and CR1 were unaffected by tumor necrosis factor-alpha. The mechanism of increased chemiluminescence may involve redistribution of the Fc gamma receptors and cooperation with upregulated CR3, facilitating crosslinking of the receptors. The experiments were performed in a buffer without divalent cations, since these increased the background activity and abolished the priming effect of tumor necrosis factor-alpha. In conclusion, a simultaneous increase in the Fc gamma R-mediated respiratory burst and CR3 density after priming with tumor necrosis factor-alpha indicates a cooperation between Fc gamma R and CR3.

Acetylglucosamine↗
PubMed2005

Mutational analysis of the complement receptor type 2 (CR2/CD21)-C3d interaction reveals a putative charged SCR1 binding site for C3d.

We have characterized the interaction between the first two short consensus repeats (SCR1-2) of complement receptor type 2 (CR2, CD21) and C3d in solution, by utilising the available crystal structures of free and C3d-bound forms of CR2 to create a series of informative mutations targeting specific areas of the CR2-C3d complex. Wild-type and mutant forms of CR2 were expressed on the surface of K562 erythroleukemia cells and their binding ability assessed using C3dg-biotin tetramers complexed to fluorochrome conjugated streptavidin and measured by flow cytometry. Mutations directed at the SCR2-C3d interface (R83A, R83E, G84Y) were found to strongly disrupt C3dg binding, supporting the conclusion that the SCR2 interface reflected in the crystal structure is correct. Previous epitope and peptide mapping studies have also indicated that the PILN11GR13IS sequence of the first inter-cysteine region of SCR1 is essential for the binding of iC3b. Mutations targeting residues within or in close spatial proximity to this area (N11A, N11E, R13A, R13E, Y16A, S32A, S32E), and a number of other positively charged residues located primarily on a contiguous face of SCR1 (R28A, R28E, R36A, R36E, K41A, K41E, K50A, K50E, K57A, K57E, K67A, K67E), have allowed us to reassess those regions on SCR1 that are essential for CR2-C3d binding. The nature of this interaction and the possibility of a direct SCR1-C3d association are discussed extensively. Finally, a D52N mutant was constructed introducing an N-glycosylation sequence at an area central to the CR2 dimer interface. This mutation was designed to disrupt the CR2-C3d interaction, either directly through steric inhibition, or indirectly through disruption of a physiological dimer. However, no difference in C3dg binding relative to wild-type CR2 could be observed for this mutant, suggesting that the dimer may only be found in the crystal form of CR2.

Amino Acid Substitution↗
PubMed1992

Loss of erythrocyte complement receptors (CR1; CD35) in patients with acute episodes of septicaemia or bacterial meningitis.

14 patients with septicaemia or bacterial meningitis were examined for serum levels of erythrocyte complement receptors CR1 (C3b/C4b; CD35) by an enzyme-linked immunosorbent assay and levels of circulating immune complexes (IC) by a polyethylene glycol precipitation complement consumption method, and concentrations of complement C3d split products in plasma by intermediate gel rocket immunoelectrophoresis. The CR1 receptor levels were significantly lower on day 7-8 after admission than on day 1-2 (p = 0.01), and than the levels 3-4 months later (p = 0.002). Both the levels of IC in serum and the C3d concentrations were significantly higher on day 7-8 than 3-4 months later (p = 0.02 and p = 0.004). The mechanism behind a temporary decreased expression of CR1 in patients with acute episodes of septicaemia or purulent meningitis is not fully known, and further investigations are needed to clarify whether this reduction in erythrocyte CR1 causes an impaired disposal of IC in patients with infections.

Acute Disease↗
PubMed1975

Complement receptor lymphocytes. Analysis of immunoglobin on their surface and further evidence of heterogeneity.

Mouse complement receptor lymphocytes (CRL) were detected by a rosetting method. The existence of an immunoglobulin class or subclass on the central rosetting cell wasstudied by immunofluorescence using rabbit antisera specific for mouse IgM, IgG1, IgG2a, IgG2b and IgA. Combining immunofluorescence for each immunoglobulin and for T cells with cytoxic removal of T cells, CRL were demonstrated to include immunoglobulin-bearing cells of all the classes and subclasses tested (IgM being the main one), a 'null' cell subpopulation, and some T cells. A scheme describingthe various nature of CRL is discussed and correlated with possible functions.

Animals↗
PubMed2004

Reduced complement receptor 1 (CR1, CD35) transcription in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of a broad spectrum of autoantibodies against nuclear, cytoplasmic and cell surface antigens and immune complex overload. Complement receptor 1 (CR1, CD 35), a transmembrane glycoprotein found on the surface of erythrocytes, leukocytes and glomerular podocytes plays a key role in the clearance of immune complexes and regulation of complement cascade. A drastic decline in the level of cell surface CR1 appears to be an important event in pathology of SLE. However, the etiology of lower than normal expression of cell surface CR1 in this disease is poorly understood. We studied the level of leukocyte CR1 transcription in 30 patients with active SLE and 30 controls by reverse transcriptase-polymerase chain reaction (RT-PCR) and related the same with the level of CR1 protein expression monitored by Western blotting. For RT-PCR, ratio of CR1/beta-actin was considered for semiquantitation of the level of CR1 transcription. Despite individual variation at the level of transcription, 70% (21 out of 30) of the patients expressed CR1 transcript at the lowest range of 0-15% as compared to the controls wherein only 30% (9 out of 30 individuals) demonstrated CR1 transcript in this range. Majority of the controls (70%) expressed CR1 transcript at the level above 15%. Mean level of CR1 transcript in patients (mean +/- S.D. = 21.09 +/- 14.3) was significantly lower than the controls (mean +/- S.D. = 48.91 +/- 26.34) (P < 0.001). The level of CR1 transcription correlated inversely with circulating immune complexes (CIC) (r = 0.52, P < 0.01). This may suggest that although erythrocyte CR1 is the chief vehicle for CIC clearance, drastic decline in leukocyte CR1 expression may impair the phagocyte mediated immune complex clearance and contribute to increased complement consumption in SLE. Total leukocyte CR1 protein expression was also significantly reduced in patients (P < 0.001) as compared to controls. This decline at the protein level gave a very significant positive correlation with CR1 transcript (r = 0.67, P < 0.01). A marginal increase in soluble CR1 (sCR1) was observed in the plasma (ELISA) of SLE patients compared to the controls but was insignificant. This paper for the first time brings evidence to suggest that reduced synthesis of CR1 contributes substantially to the low cell surface CR1 expression in SLE. Our findings also suggest increased proteolytic cleavage of leukocyte cell surface CR1 in these patients. However, evidence for the latter is indirect.

Adult↗
PubMed1995

Binding to erythrocyte complement receptor type 1 of BSA/anti-BSA complexes opsonized by C4A3 or C4B1 in the presence of serum.

An in vitro model with human serum and human 0 Rh-negative erythrocytes was used for studies on preformed BSA/anti-BSA complex binding to complement receptor type 1 (CR1). The serum used was first depleted of Clq, factor D and properdin, then of C3, C4 or both and finally reconstituted with the desired proteins (serum reagent). With varying C4 concentrations and 100% C3 present, binding curves obtained for the two C4 isotypes were similar. When the serum reagent was not reconstituted with factor D and properdin there was no difference between the CR1 binding of normal serum and the partially reconstituted serum reagent, nor between the two C4 isotypes in this serum reagent. When C3 at 50% or 100% of normal concentrations was added to the serum reagent together with 100% C4A3 or C4B1, the C4B1-opsonized complexes showed more binding than the C4A3-opsonized complexes. At very low levels of C3 (< 25%) the binding could not be distinguished from the background. The results suggest that the binding of complement opsonized antigen/antibody complexes to erythrocyte CR1 is mediated mainly by C3, originating from activation of the classical pathway, and that the difference in properties between C4A and C4B does not have a major influence.

Animals↗
PubMed2000

Soluble complement receptor-1 protects heart, lung, and cardiac myofilament function from cardiopulmonary bypass damage.

BACKGROUND: Host defense system activation occurs with cardiopulmonary bypass (CPB) and is thought to contribute to the pathophysiological consequences of CPB. Complement inhibition effects on the post-CPB syndrome were tested with soluble complement receptor-1 (sCR1). METHODS AND RESULTS: Twenty neonatal pigs (weight 1.8 to 2.8 kg) were randomized to control and sCR1-treated groups. LV pressure and volume, left atrial pressure, pulmonary artery pressure and flow, and respiratory system compliance and resistance were measured. Preload recruitable stroke work, isovolumic diastolic relaxation time constant (tau), and pulmonary vascular resistance were determined. Pre-CPB measures were not statistically significantly different between the 2 groups. After CPB, preload recruitable stroke work was significantly higher in the sCR1 group (n=5, 46.8+/-3.2x10(3) vs n=6, 34.3+/-3.7x10(3) erg/cm(3), P=0.042); tau was significantly lower in the sCR1 group (26.4+/-1.5, 42.4+/-6. 6 ms, P=0.003); pulmonary vascular resistance was significantly lower in the sCR1 group (5860+/-1360 vs 12 170+/-1200 dyn. s/cm(5), P=0.009); arterial PO(2) in 100% FIO(2) was significantly higher in the sCR1 group (406+/-63 vs 148+/-33 mm Hg, P=0.01); lung compliance and airway resistance did not differ significantly. The post-CPB Hill coefficient of atrial myocardium was higher in the sCR1 group (2.88+/-0.29 vs 1.88+/-0.16, P=0.023). CONCLUSIONS: sCR1 meaningfully moderates the post-CPB syndrome, supporting the hypothesis that complement activation contributes to this syndrome.

Actin Cytoskeleton↗
PubMed2005

Processing of C3b-opsonized immune complexes bound to non-complement receptor 1 (CR1) sites on red cells: phagocytosis, transfer, and associations with CR1.

Severe anemia is a lethal complication of Plasmodium falciparum malaria, particularly in children. Recent studies in children with severe P. falciparum anemia have demonstrated elevated levels of E-bound Abs, reduced E-associated complement receptor 1 (CR1) and decay-accelerating factor (DAF), and pronounced splenic enlargement, suggesting a mechanism for E loss involving Abs, complement, and phagocytosis. Motivated by these reports, we have developed an in vitro model in which human E with Abs and complement bound to CR1, DAF, or glycophorin A are incubated with model human macrophages (the THP-1 cell line). Previous work has demonstrated that immune complex (IC) substrates bound to E CR1, either by an Ab or via C3b, are transferred to macrophages with loss of CR1. In this study, we report that IC bound to DAF or glycophorin A by an Ab linkage are also transferred to macrophages. DAF is lost from the E during the transfer of DAF-bound IC, but the transfer of CR1-bound IC does not lead to a significant loss of DAF. Using glycophorin A-bound IC, we observe competition between transfer of IC and phagocytosis of the E: a fraction (</=15%) of the E was phagocytosed, while the remaining E were stripped of IC. We also examined the organization of CR1 and DAF in the presence of E-bound Ab/complement. We find that CR1, but not DAF, colocalizes with IgM mAb-C3b and IC-C3b substrates attached to glycophorin A. We observe that the binding of the IgM mAb-C3b to glycophorin A induces a novel unclustering of CR1.

Antibodies, Monoclonal↗
PubMed1986

Complement receptors (CR) and cytotoxic responses: monoclonal antibodies directed against CR1 and CR3 inhibit the generation of human allospecific and virus specific cytotoxic cells in vitro.

A variety of cellular immune responses involve complement factors which bind to specific receptors, and modulate or effect a specific reaction. Monoclonal antibodies (MAb) have been generated against complement receptors (CR) 1 and 3, which were utilized to investigate human allogeneic and Epstein-Barr virus specific cytotoxic cells in vitro. MAb OKM1, which binds to the C3bi CR (CR3), and MAb M710, which binds to the C3b/4b CR (CR1), inhibited the generation of both allogeneic and virus specific cytotoxic responses in vitro in a dose-dependent way; doses of 1 microgram/ml (or greater) completely abrogated the cytotoxic responses. Inhibition of these responses was observed when the MAb was added to the cultures at any time point except the last two days. In addition, treatment of the responder (but not the stimulator cells) with either MAb resulted in complete inhibition of cytotoxic responses. These experiment indicate that complement receptors participate in the generation of human cytotoxic responses in vitro.

Antibodies, Monoclonal↗
PubMed2003

Complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) cooperate in the binding of hydrolyzed complement factor 3 (C3i) to human B lymphocytes.

The C3b-binding receptor, CR1/CD35, supports CR2/CD21-mediated activation of complement by human B lymphocytes, possibly by associating with CR2 to promote or stabilize the binding of hydrolyzed C3 (C3i), the primary component of the AP convertase, C3i-Bb. To evaluate this hypothesis, we examined the uptake kinetics and binding equilibria for C3i dimer interaction with human blood cells in the absence and presence of CR1- and CR2-blocking mAb. C3i displayed dual uptake kinetics to B lymphocytes, comprising of rapid binding to CR1 and slower binding to CR2. The forward rate constants (k(1)) for CR1 and CR2, operating independently, differed ca. 9-fold (k(1)=193+/-9.4 and 22.2+/-6.0 x 10(3) M(-1)s(-1), respectively). Equilibrium binding of C3i to B lymphocytes was also complex, varying in strength by ca. 13-fold over the C3i concentration range examined. The maximum association constant (K(a, max)=109+/-27.2 x 10(7) l/mole) was ca. 9- and 6-fold greater, respectively, than those for CR1 or CR2 acting alone (K(a)=13.2+/-5.3 and 18.5+/-3.5 x 10(7) l/mole). The high avidity of the CR1-CR2 complex for C3i is consistent with its rates of C3i uptake and release being determined by CR1 and CR2, respectively.

B-Lymphocytes↗
PubMed2003

Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice.

Group B Streptococcus (GBS) is the foremost bacterial cause of serious neonatal infections. Protective immunity to GBS is mediated by specific Abs to the organism's capsular polysaccharide Ags. To examine the role of complement in the humoral immune response to type III GBS capsular polysaccharide (III-PS), mice deficient in C3 or in CD21/CD35 (i.e., complement receptors 1 and 2; CR1/CR2) were immunized with III-PS. Mice deficient in C3 or Cr2 had an impaired primary immune response to III-PS. The defective response was characterized by low IgM levels and the lack of an isotype switch from IgM to IgG Ab production. Compared with wild-type mice, C3- and Cr2-deficient mice exhibited decreased uptake of III-PS by follicular dendritic cells within the germinal centers and impaired localization of III-PS to the marginal zone B cells. Complement-dependent uptake of capsular polysaccharide by marginal zone B cells appears necessary for an effective immune response to III-PS. The normal immune response in wild-type mice may require localization of polysaccharide to marginal zone B cells with subsequent transfer of the Ag to follicular dendritic cells.

Animals↗
PubMed1996

The effect of soluble complement receptor 1 (sCR1) and human thyroid antibodies on the course of experimental autoimmune thyroiditis in rats.

Experimental autoimmune thyroiditis (EAT), induced by immunisation of rats with thyroid extract and complete Freund's adjuvant, has been used as a model to study the effects of complement inhibition mediated by soluble complement receptor 1 (sCR1) administration during the initial phase of the disease. There was no effect of sCR1 on the severity of thyroiditis at day 28 after immunisation or on the levels of thyroid antibodies, whether sCR1 was given during the first or second week after immunisation. Human IgG containing high levels of thyroid peroxidase antibodies given to rats at the time of immunisation caused significant worsening of thyroiditis severity (P < 0.01 compared to animals receiving normal IgG) but sCR1 again had no effect in this variant of the EAT model. The results indicate that complement does not play a major role in the initial phase of tissue injury in EAT and complement inhibition does not impair the generation of an autoimmune response against the thyroid, although it remains possible that complement activation is important during the chronic phase of disease maintenance in human autoimmune thyroid disease.

Animals↗
PubMed2000

Effect of low-dose prednisone in vivo on the ability of complement receptor to mediate an oxidative burst in rat neutrophils.

Glucocorticoids have been used in the treatment of a variety of inflammatory processes including autoimmune diseases. However, the influence of low-dose glucocorticoids on the respiratory burst activity of neutrophils has not been studied. The aim of this work was to study the effect of treatment with low-dose prednisone on the oxidative burst of rat peripheral blood neutrophils. Wistar male rats were treated with prednisone by gavage (28, 87 or 257 microg/animal/day) for 7 or 15 days. These doses are equivalent to 10, 30 or 90 mg/adult human ( approximately 70 kg)/day, respectively. Sera from normal rats were used to opsonize zymosan (opZy). Neutrophils (1x10(5)) were stimulated by opZy and the oxidative burst of control or treated rat cells was measured by luminol-dependent chemiluminescence (CL). Prednisone did not affect the CL of rat neutrophils for either period of treatment, or any studied doses, when compared with controls. These results suggest that the low-dose prednisone has no effect on the oxidative burst mediated by complement receptors during the rat neutrophil phagocytosis of complement-opZy.

Animals↗
PubMed1995

Primate erythrocyte (E) complement receptor (CR1) as an anchor site for bispecific-based therapies to clear pathogens or autoantibodies safely from the circulation.

We have prepared cross-linked, bispecific complexes [heteropolymers (HP) and antigen-based heteropolymers (AHP)] that facilitate complement-independent binding of target model pathogens or autoantibodies to primate erythrocytes (E) via complement receptors (CR1). The method is based on using monoclonal antibodies (mAb) specific for CR1 that either are cross-linked to an mAb specific for a prototype pathogen (e.g., IgE) or are cross-linked to an autoantigen (e.g., dsDNA) that is recognized by circulating pathogenic autoantibodies in the autoimmune disease systemic lupus erythematosus (SLE). The underlying assumption in this research is that complexed ligands containing IgG bound to primate E CR1 should be recognized and processed via the same mechanism by which complement-opsonized immune complexes bound to E CR1 are cleared from the circulation and phagocytosed in the liver and spleen. Our work in experimental monkey models has demonstrated that binding of substrates to primate E via this method does indeed lead to the safe and rapid clearance of the target pathogens or autoantibodies from the circulation, without any lysis or loss of the E. Although a number of questions must still be resolved, it may be possible to generalize these findings and use this CR1-based approach to develop a simple noninvasive bispecific therapy that can be used to clear pathogens or autoantibodies from the circulation.

Animals↗