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PubMed1985

Thymic reticulum in mice. IV. The rosette formation between phagocytic cells of the thymic reticulum and cortical type thymocytes is mediated by complement receptor type three.

A phagocytic cell of the thymic reticulum (P-TR) with dendritic shape recently has been isolated and characterized. We have previously shown that P-TR have an important role to play in the constitution of the thymic microenvironment. Indeed, P-TR are able to produce interleukin 1 and prostaglandin E2, both of which regulate thymocyte activation and proliferation. They are able also to stimulate the proliferation of syngeneic thymocytes enriched in the medullary type. In the present paper, we analyze a close relationship which exists between P-TR and thymocytes of the cortical type. About 25% of P-TR are able to bind to thymocytes and to form rosettes. Rosetting thymocytes represent about 5% of the total population and are PNA+, Lyt 1+2+, H-2-, and sensitive to in vivo steroid treatment. Pretreatment of P-TR with anti-Mac-1, a monoclonal rat IgG antibody against mouse macrophages and specific for complement receptor type three (CR3), abolished rosette formation. Rosette formation also was found to be inhibited by zymosan-treated serum containing the CR3 ligand, C3bi, and by certain sugars, in particular, N-acetyl-D-galactosamine and L-xylose. Our results suggest that rosetting thymocytes bind to CR3 on the P-TR membrane and that sugar constituents of the carbohydrate moieties on the thymocyte surface may serve as a recognition site during the binding process.

Animals↗
PubMed1994

Erythrocyte complement receptor type 1 and interactions between immune complexes, neutrophils, and endothelium.

The deposition of immune complexes (IC) may play an important part in the pathogenesis of vasculitis. An increase in permeability of the vascular endothelial lining is a prerequisite for IC deposition. We used an in vitro model to examine the effects of interactions between IC, neutrophils, and endothelium on the integrity of endothelial cell monolayers. Human umbilical vein endothelial cells were grown to confluence on an FITC-labeled matrix, and monolayer integrity was assessed by the exclusion of an 125I-anti-FITC Ab. Alteration in endothelial monolayer permeability was associated with increased uptake of 125I-anti-FITC Ab, expressed as a percentage of the maximal uptake of Ab onto the FITC-matrix from which endothelial cells had been stripped. Neither resting nor cytokine-stimulated endothelial cells bound hepatitis B surface Ag (HBsAg/anti-HBsAg) IC. Immune complexes were shown to activate neutrophils to induce a 9.5% increase in the permeability of IL-1 beta-stimulated endothelium. This increase in endothelial permeability was abrogated by the addition of RBC bearing normal complement receptor type 1 (CR1) numbers (3.2%). This protective effect was shown to be related to the binding of IC to erythrocyte CR1 and was reduced by CR1 blockade using polyclonal rabbit anti-CR1 Abs. These observations demonstrate that IC are capable of directly activating neutrophils to induce increases in endothelial permeability, which may facilitate the deposition of circulating IC. The results support the hypothesis that the binding of IC to erythrocyte CR1 may inhibit damaging interactions between IC, neutrophils, and endothelium.

Antigen-Antibody Complex↗
PubMed1982

Heterogeneity of complement receptor expression on surface immunoglobulin-bearing cells from neonatal and adult mice.

The ontogeny of acquisition of complement receptors (CR) on splenic B lymphocytes from mice of varying ages was examined. Reagents used for the identification of CR included antibody- and complement-coated erythrocytes (EAC), bacteria (BAC) and bacteria treated with complement alone (BC). When whole mouse serum used as the source of complement both EAC and BAC failed to bind to human erythrocytes (C3b receptor-negative), showed binding to Raji and Daudi cells (C3d receptor) and formed rosettes with human neutrophils (C3bi receptor). Therefore these reagents bore C3d and C3bi, but not intact C3b. Although EAc and BAC detected nearly equal percentages of CR lymphocytes in adult mice, BAC bound to a higher percentage of neonatal lymphocytes (8-12%) than did EAC (1-3%). The ability of BAC to detect EAC-negative lymphocytes among neonatal spleen lymphocytes appeared to be due to the increased sensitivity of this bacterial reagent for binding to CR. Further evidence of this enhanced sensitivity was that BAC were less inhibitable than EAC by soluble antigen-antibody-complement complexes.

Animals↗
PubMed2001

Epitope mapping using the X-ray crystallographic structure of complement receptor type 2 (CR2)/CD21: identification of a highly inhibitory monoclonal antibody that directly recognizes the CR2-C3d interface.

Complement receptor type 2 (CR2)/CD21 is a B lymphocyte cell membrane C3d/iC3b receptor that plays a central role in the immune response. Human CR2 is also the receptor for the EBV viral membrane glycoprotein gp350/220. Both C3d and gp350/220 bind CR2 within the first two of 15-16 repetitive domains that have been designated short consensus/complement repeats. Many mAbs react with human CR2; however, only one currently available mAb is known to block both C3d/iC3b and gp350/220 binding. We have used a recombinant form of human CR2 containing the short consensus/complement repeat 1-2 ligand-binding fragment to immunize Cr2(-/-) mice. Following fusion, we identified and further characterized four new anti-CR2 mAbs that recognize this fragment. Three of these inhibited binding of CR2 to C3d and gp350/220 in different forms. We have determined the relative inhibitory ability of the four mAbs to block ligand binding, and we have used overlapping peptide-based approaches to identify linear epitopes recognized by the inhibitory mAbs. Placement of these epitopes on the recently solved crystal structure of the CR2-C3d complex reveals that each inhibitory mAb recognizes a site either within or adjacent to the CR2-C3d contact site. One new mAb, designated 171, blocks CR2 receptor-ligand interactions with the greatest efficiency and recognizes a portion of the C3d contact site on CR2. Thus, we have created an anti-human CR2 mAb that blocks the C3d ligand by direct contact with its interaction site, and we have provided confirmatory evidence that the C3d binding site seen in its crystal structure exists in solution.

Animals↗
PubMed1996

Complement inhibition by soluble complement receptor type 1 fails to moderate cerulein-induced pancreatitis in the rat.

CONCLUSION: Cerulein-induced pancreatitis in rats associated with remote liver and lung dysfunction. Soluble complement receptor 1 (sCR1) does not reduce the local or remote injury. Thus complement activation does not moderate cerulein-induced pancreatitis or the associated liver and injury. BACKGROUND: The local and remote injury of pancreatitis resembles other inflammatory events that are mediated by complement. This study examines the effect of complement inhibition with sCR1 in cerulein-induced pancreatitis in rats. METHODS: Thirteen Sprague-Dawley rats received five hourly subcutaneous doses of cerulein (100 micrograms initially, then 50 micrograms/kg). Six of these animals received hourly i.v. sCR1 (15 mg/kg, a proven complement-inhibiting dose in rats) and the other seven received i.v. saline. In parallel, 12 additional rats received hourly s.c. and i.v. saline. RESULTS: Compared to saline controls, rats receiving cerulein showed increased pancreatic wet-to-dry ratio (3.25:8.52), hematocrit (40 to 47%), ascites volume (2.1 to 6.1 mL), serum amylase (1680 to 10,700 U/L), and ascites amylase (32,200 to 167,000 U/L) (all p < 0.05). None of these parameters were modified by treatment with sCR1. Serum SGPT, which increased from 33.4 to 46.6 U/L in cerulein-infused rats, showed a trend toward reduction to 38.8 U/L in rats treated with sCR1. Cerulein-treated rats also had increased lung myeloperoxidase (0.069 to 0.097 U/g) and lung permeability, as assessed by a alveolar lavage to serum ratio of labeled albumen (0.041:0.121) both p < 0.05). Neither were changed by sCR1 treatment.

Acute Disease↗
PubMed2002

Modulation of murine liver macrophage clearance of liposomes by diethylstilbestrol. The effect of vesicle surface charge and a role for the complement receptor Mac-1 (CD11b/CD18) of newly recruited macrophages in liposome recognition.

We have studied the blood clearance and reticuloendothelial organ distribution of intravenously injected neutral (egg phosphatidylcholine, egg PC/cholesterol, mol ratio 7:2), anionic (egg PC/cholesterol/dicetylphosphate, mol ratio 7:2:1), and cationic (egg PC/cholesterol/stearylamine, mol ratio 7:2:1) liposomes of approximately the same size distribution in mice 3 days after treatment with the synthetic oestrogen diethylstilbestrol (DES). Male mice administered DES intraperitoneally at a dose of 1 mg per mouse (body weight 22-25 g) manifested an increase in the vascular clearance rate of liposomes irrespective of the initial vesicle surface charge. The enhancement in the vascular clearance of liposomes in DES-treated animals was associated with a concomitant increase in liver weight as well as hepatic phagocytosis. However, DES treatment significantly enhanced the hepatic sequestration (on the basis of % of injected dose of liposomes per g of liver tissue) of positively charged liposomes when compared to both neutral and negatively charged vesicles of similar size distribution. This observation was also confirmed by the 'hepatic-blockade' experiments where blockade was induced by prior intravenous injection of liposomes of the same size distribution and charge to that of test vesicles. The in vitro cell suspension studies suggested that the enhanced liposome uptake (irrespective of the initial vesicle surface charge) by Kupffer cells of DES-treated mice was independent of changes in the blood opsonization processes. Furthermore, in vitro studies also showed the operation of multiple mechanisms and involvement of different populations of liver macrophages (resident and recruited cells) in liposome recognition following DES treatment. For example, in DES-treated animals, the newly recruited liver macrophages were found to play a major role in the clearance of stearylamine incorporated liposomes via complement receptors (Mac-1). The resident Kupffer cells seem to recognize cationic vesicles via other receptors as the expression of Mac-1 is virtually absent in these cells. On the other hand, complement receptors seem to play a minor role in the uptake of anionic DCP vesicles by hepatic macrophages of DES-treated mice. DES appears to offer a new approach in dissecting the mechanisms of liposome-macrophage interaction.

Animals↗
PubMed1987

Functional and antigenic properties of complement receptor type 2, CR2.

This is the first report demonstrating that C3d receptor (CR2) has functional activity in regulating complement cascade. Purified CR2 was examined for its cofactor activity in factor I-mediated cleavage of membrane-bound iC3b. CR2 plus C3b inactivator (I) released C3c from EA 125I-iC3b, and the release was inhibited when CR2 was preincubated with OKB7 monoclonal anti-CR2. Furthermore, immunoelectroblotting analysis showed crossreactivity of CR2 with 57H anti-CR1. These results indicate that CR2 has functional and antigenic similarity to CR1, thus providing a supporting evidence for placement of CR2 as a member of the recently defined gene family of C3- and C4-regulatory proteins composed of CR1, C4-binding protein, and factor H.

Collodion↗
PubMed1989

Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis.

Activation of human neutrophils (PMN) is accompanied by rapid upregulation of CR1, the C3b receptor, and CR3, the iC3b receptor, which also serves as the PMN's major adherence protein. This is necessary for migration and phagocytosis, but the extent of expression of these proteins on PMN at inflammatory sites has not been determined. We used monoclonal antibodies and flow cytometry to assess CR1 and CR3 expression on PMN in bronchoalveolar lavage (BAL) fluid of cystic fibrosis (CF) patients chronically infected with pseudomonas and in sterile joint fluid of arthritis patients. Resting peripheral blood PMN from these patients and normals expressed similar low levels of CR1 and CR3, and the patients' PMN increased CR1 and CR3 expression normally when stimulated in vitro. CR3 expression on CF BAL PMN was 90 +/- 12% of that on the same patient's blood cells stimulated in vitro with FMLP. In contrast, CR1 expression on BAL PMN was only 27 +/- 8% of that on stimulated blood cells. Similar results were obtained for joint PMN. This pattern could be reproduced in vitro by treating FMLP-stimulated blood cells with BAL supernatants or with pseudomonas or PMN elastase. The serine protease inhibitors, PMSF and alpha 1-antitrypsin prevented the lavage supernatant from reducing CR1 expression, while metalloprotease inhibitors had no effect. Treatment of PMN with elastase in vitro decrease their ability to kill opsonized Pseudomonas aeruginosa. These results suggest that PMN at inflammatory sites have maximally upregulated expression of their complement receptors, but that CR1 is then cleaved by proteolysis in situ. Although not related to the basic defect in CF, this may interfere with efficient phagocytosis and contribute to the CF patient's inability to eradicate chronic lung infection.

Adult↗
PubMed2002

Structure of complement receptor (CR) 2 and CR2-C3d complexes.

Using X-ray crystallography, we have determined the structure of the first two short consensus repeats (SCRs) of human complement receptor (CR) 2 in complex with C3d. These studies revealed: (i) a primary site of interaction for C3d within SCR2 of CR2, (ii) a hydrophobic patch holding SCR1 to SCR2 in a rigid V-shape, (iii) a dimer formed by interactions between SCR1 of each molecule, (iv) several non-linear sequences on C3d that interact with CR2 and (v) mutations of C3d amino acids within the co-crystal interface that resulted in decreased binding. In addition, a polymorphism that results in decreased C3d binding and introduces a new glycosylation site predicted to disrupt the dimer interface was found in the New Zealand White autoimmune mouse strain. Although the co-crystal complex results are in agreement with a subset of prior studies, our additional findings, which demonstrate an extended SCR1-SCR2 structure in solution and differences in the kinetics of ligand-receptor interactions with longer forms of CR2, have suggested a more complex receptor-ligand interaction. To characterize this interaction further, several approaches directed at the determination of solution phase interactions as well as the analysis of the three-dimensional structure of CR2 alone and key CR2 mutants will be necessary.

Animals↗
PubMed1986

Abnormal expression of complement receptor (CR1) in IgA nephritis: increase in erythrocytes and loss on glomeruli in patients with impaired renal function.

The number of complement receptor for C3b (CR1) molecules in erythrocytes from patients with renal diseases was measured by an immunoradiometric assay using monoclonal antibodies against CR1. IgA nephritis patients with high serum creatinine value (Scr) showed markedly elevated levels of CR1, whereas patients with normal Scr had normal CR1 levels. A similar increase in CR1 number was observed in membranoproliferative glomerular nephritis with high Scr. CR1 of these patients functioned normally as a cofactor of C3b inactivator in cleaving immune complex-bound C3b. In contrast, a high frequency (5/6) of negative staining of glomerular CR1 was observed in IgA nephritis patients with high Scr by immunofluorescence study. We postulate that the disease-associated, acquired factors at least in part contribute to the abnormal expression of CR1: elevated levels in erythrocytes and defective expression on glomeruli.

Anticoagulants↗
PubMed1996

Ligation of the functional domain of complement receptor type 2 (CR2, CD21) is relevant for complex formation in T cell lines.

We investigated the potential of CD21, the complement receptor type 2, to form receptor complexes with other membrane molecules on T cell lines. CD21 from T cell lines transformed with human T cell leukemia virus type I (MT2, HUT-102, C5.MJ, Mondi, and C91.PL) and T cell lines that were not virus transformed was analyzed by coprecipitation following cell lysis with digitonin. mAbs binding to functional and nonfunctional epitopes of CD21 and a polyclonal antiserum against its intracellular portion precipitated CD21, which was indistinguishable from CD21 on B cell lines. In contrast to B cells, where CD21 is complexed with CD19 and CD81 (target of anti-proliferative Ab 1) or, alternatively, with CD35 (CR1), no surface molecules could be coprecipitated with three of four mAbs from these T cell lines. Therefore, we assume that CD21 is not part of a preformed complex in T cell lines. OKB7, the only mAb directed against the functional C3d binding site, coprecipitated two proteins of 105 and 55 Mr with CD21 from MT2 and Mondi cells and from the T cell lines Jurkat E6-1 and SupT1. These bands were also recovered with CD21 precipitated from MT2 cells with C3d bound to Sepharose via the internal thioester, but were absent in CD21-expressing B cell lines. As C3d and OKB7 are functional ligands for B cells, we propose that upon ligation on T cells, CD21 associates with molecules of 105/55 Mr in the plasma membrane. Whether this is the first event of a signal delivered to the T cell is under current investigation.

Antibodies, Monoclonal↗
PubMed1997

The primate erythrocyte complement receptor (CR1) as a privileged site: binding of immunoglobulin G to erythrocyte CR1 does not target erythrocytes for phagocytosis.

The primate erythrocyte (E) complement receptor, CR1, is a transmembrane glycoprotein located in clusters on the surface of E. In vivo studies have demonstrated that during processing and clearance of complement-opsonized immune complexes, large amounts of immunoglobulin G (IgG) can be bound to primate E via CR1 with no E loss or lysis. However, when comparable amounts of IgG are bound to other sites on E, in many cases the E are cleared from the circulation by the mononuclear phagocytic system. Therefore, due to its role in immune complex processing, CR1 may represent a privileged site on the primate E. To delineate further this property of E CR1, we performed in vitro phagocytosis assays in the absence of complement and examined the ingestion of E, opsonized at various sites with IgG, by peripheral blood monocytes. When either human or rhesus monkey E were opsonized at sites other than CR1, with between 1,000 and 15,000 IgG per E, substantial phagocytosis of E was evident. However, when comparable amounts of IgG were bound exclusively via CR1, little, if any, phagocytosis was observed. The key to the low phagocytic level of E opsonized via CR1 may be related to the requirements of a "zipper mechanism" for phagocytosis first annunciated by Griffin et al. Based on their findings, we suggest that due to the presence of preexisting clusters of CR1 on the E membrane, large amounts of IgG can be bound to E under conditions that preclude circumferential engagement (and phagocytosis) of the entire E by Fc receptors on the monocyte.

Animals↗
PubMed1988

Effect of antigen site and complement receptor status on the rate of cleavage of C3c antigen from red cell bound C3b.

C3b was bound to human red cells when serum complement was activated by addition of antibodies directed against different red cell antigens, and the rate of cleavage to C3dg was determined by assay for loss of bound C3c antigens using radiolabeled monoclonal anti-C3c. When C3b was bound by antibodies to antigens on branched-chain glycoproteins, cleavage to C3dg occurred more rapidly than when C3b was bound by antibodies to antigens closer to the red cell lipid bilayer. The rate of cleavage to C3dg also correlated directly with the number of complement receptors (CR1) per red cell, reflecting their role as cofactors in the cleavage of iC3b by factor I. Thus, the life span of C3b/iC3b on human red cells, which may be important for determining the rate and mechanism of clearance of C3-coated red cells, appears to depend on the CR1 status of the red cells and the characteristics of the antigen sites around which complement is bound.

Antigens↗
PubMed1983

Complement receptor distinguishes between two subsets of large granular lymphocytes with different natural killer activity and cytochemical and ultrastructural features.

Human peripheral blood large granular lymphocytes (LGL)--that is, cells with intracytoplasmic azurophilic (electron-dense) granules, with a positivity for the cytochemical localization of certain acid hydrolases, and with avid surface receptors for the Fc portion of IgG--have been purified on Percoll density gradients. Approximately 30% of these cells expressed receptors for the third complement component (C3R). They were separated into C3R-positive and C3R-negative cells. C3R+ cells had a significantly greater natural killer (NK) activity against K562 target cells than C3R+ cells. This difference was unrelated to the presence in the C3R+ cells of a contaminant cell type incapable of NK activity, since cytochemical and ultrastructural analysis revealed that C3R+ and C3R- fractions contained comparable LGL numbers. Agarose cytotoxicity assays at the single-cell level demonstrated that C3R+ LGL contained a large number of cells that bound to but did not lyse the target. The remaining fully cytotoxic C3R+ LGL had, however, the same killing and recycling properties as the cells from the C3R fraction. Electron microscopy and cytochemical studies showed that C3R+ cells had fewer electron-dense granules than C3R cells and stained more faintly for the localization of alpha-naphtyl acetate esterase. In contrast to C3R cells, C3R+ LGL displayed morphological features suggesting that an active process of granule formation was taking place. Taken together, the data indicate that C3R+ cells represent a discrete subset or a maturational stage of LGL.

Antibodies, Monoclonal↗
PubMed2001

Kinetic analysis of the interactions of complement receptor 2 (CR2, CD21) with its ligands C3d, iC3b, and the EBV glycoprotein gp350/220.

The molecular mechanisms involved in the interaction of complement receptor 2 (CR2) with its natural ligands iC3b and C3d are still not well understood. In addition, studies regarding the binding site(s) of the receptor on C3 as well as the affinities of the C3 fragments for CR2 have produced contradictory results. In the present study, we have used surface plasmon resonance technology to study the interaction of CR2 with its ligands C3d, iC3b, and the EBV surface glycoprotein gp350/220. We measured the kinetics of binding of the receptor to its ligands, examined the influence of ionic contacts on these interactions, and assessed whether immobilized and soluble iC3b bound with similar kinetics to CR2. Our results indicate that 1) gp350 binding to CR2 follows a simple 1:1 interaction, whereas that of the C3 fragments is more complex and involves more than one intramolecular component; 2) kinetic differences exist between the binding of C3d and iC3b to CR2, which may be due to an additional binding site found on the C3c region of iC3b; and 3) iC3b binds to CR2 with different kinetics, depending on whether the iC3b is in solution or immobilized on the surface. These findings suggest that binding of CR2 to iC3b and C3d is more complex than previously thought.

Alanine↗
PubMed2006

Optimal long-term humoral responses to replication-defective herpes simplex virus require CD21/CD35 complement receptor expression on stromal cells.

Replication-defective herpes simplex virus (HSV) strains elicit durable immune responses and protect against virulent HSV challenge in mice, despite being unable to establish latent infection in neuronal cells. Mechanisms for generating long-lived immunity in the absence of viral persistence remain uncertain. In animals immunized with replication-defective HSV, durable serum immunoglobulin G (IgG) responses were elicited. Surprisingly, Western blot analyses revealed that the specificities of antiviral IgG changed over time, and antibody reactivity to some viral proteins was detected only very late. Thus, some of the durable IgG activity appeared to be contributed by either new or significantly enhanced antibody responses at late times. Following immunization, radiation bone marrow-chimeric mice lacking complement receptors CD21 and CD35 on stromal cells elicited only short-lived serum IgG and failed to mount recall responses to subsequent HSV exposure. Our results suggest that complement-mediated retention of viral antigens by stromal cells, such as follicular dendritic cells, is critical for optimal maintenance of antibody responses and B-cell memory following vaccination with replication-defective HSV.

Animals↗
PubMed1994

Prolongation of discordant renal xenograft survival by depletion of complement. Comparative effects of systemically administered cobra venom factor and soluble complement receptor type 1 in a guinea-pig to rat model.

There is an increasing body of evidence to suggest that inhibition of complement activation may be a valuable approach to avert hyperacute rejection. In our study, the guinea-pig to rat discordant kidney xenograft model was adapted for the investigation of renal transplant function and an attempt was made to delay the hyperacute rejection using systemically administered cobra venom factor (CVF) and soluble complement receptor type 1 (sCR1). The saline-treated control recipients experienced a rapid transplant rejection with a xenograft survival averaging 10.5 +/- 2.1 min. Administration of a single 60 U/kg i.v. bolus of CVF significantly prolonged renal graft survival to 20.4 +/- 2.5 h, and by a single bolus of sCR1 (50 mg/kg) a prolongation of graft survival to 18.8 +/- 2.3 h was achieved. The grafts functioned only over periods of 2.5 +/- 0.3 and 2.3 +/- 0.2 h, respectively. No complications of sCR1 were noted. We concluded that complement inhibition by sCR1 may be an important component in the therapeutic approach aiming at the prevention of hyperacute rejection in human organ transplantation.

Animals↗