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PubMed1995

Mutation of residues in the C3dg region of human complement component C3 corresponding to a proposed binding site for complement receptor type 2 (CR2, CD21) does not abolish binding of iC3b or C3dg to CR2.

Most evidence points toward there being a shared binding site in complement receptor type 2 (CR2, CD21) for the complement ligand C3dg and the EBV surface envelope glycoprotein gp350/220. Indeed, synthetic peptide studies have suggested that the CR2-binding sites in human C3dg and EBV gp350/220 share a similar sequence motif. The proposed CR2-binding sequence in C3dg is EDPGKQLYNVEA (residues 1199-1210 of mature C3), whereas that in EBV gp350/220 is EDPGFFNVEI (residues identical to C3dg are underlined). To further examine the role of amino acids 1199-1210 in the binding of the C3 fragments iC3b and C3dg to CR2, the following alanine-substitution variants of human C3 were tested in two independent CR2-binding assays: ED1199,1200AA; KQ1203,1204AA; L1205A; Y1206A; NV1207,1208AA; E1209A; and ED-KQ-NV1199,1200-1203,1204-1207,1208AA-AA-AA. Also engineered and tested was a chimeric C3 molecule in which the 1199-1210 sequence (PVPGGYQLTLEA) from the non-CR2-binding trout C3 molecule was grafted onto a human C3 background. Recombinant C3 proteins were expressed transiently in COS-1 cells, deposited as C3b on C3 convertase-bearing sheep erythrocytes and finally converted to cell-bound iC3b or C3dg using factors H and I. Binding of EAC423bi and EAC423dg to CR2 on Raji cells or EAC423dg to soluble CR2 was assessed. In most cases, the substitutions had little effect on CR2-binding activity and even in the case of the most highly substituted variants, the decrease in CR2-binding activity was less than twofold. Thus, contrary to the results anticipated from synthetic peptide studies, the single and multiple substitutions to the C3 sequence tested failed to corroborate a role for the 1199-1210 sequence in the C3dg-CR2 interaction.

Amino Acid Sequence↗
PubMedDate not supplied

Targeting with scFv: immune modulation by complement receptor specific constructs.

The fate of a microbe in the host is determined by various molecules of the innate immune system, which recognize the microbe and enhance its interaction with antigen presenting cells. This 'natural targeting' phenomenon, however, does not function when antigens with limited immunogenicity enter the host. Peptide vaccines, for instance, require adjuvants to induce immune responses. As a surrogate for the natural targeting mechanisms, antibodies against selected receptors of antigen presenting cells, conjugated with the peptides, could be used as targeting devices. Here we review various antibody-mediated antigen-targeting strategies, paying special attention to complement receptor-mediated targeting. We also describe and summarize our method of single-chain antibody-mediated targeting of viral epitopes to complement receptor type two and discuss the perspectives of single-chain antibody-mediated antigen targeting.

Adjuvants, Immunologic↗
PubMed2005

Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: regulation by phosphatidylinositol 3-kinase and cytohesin-1.

The glycosylphosphatidyl anchored molecule CD14 to the monocyte membrane plays a prominent role in innate immunity, and the paradigms for CD14 selective signaling are beginning to be elucidated. In this study, transfected human monocytic cell line THP-1 and Chinese hamster ovary (CHO) fibroblastic cells were used to examine phagocytosis of Mycobacterium bovis bacillus Calmette-Guerin (BCG). Flow cytometry was combined with molecular and biochemical approaches to demonstrate a dual mechanism for BCG internalization involving either CD14 alone or a CD14-regulated complement receptor (CR)3-dependent pathway. Phagocytosis by CD14-positive THP-1 cells was attenuated by phosphatidylinositol-3 inhibitors LY294002 and wortmannin and experiments using transfected CHO cells showed substantial accumulation of phosphatidylinositol-3,4,5-trisphosphate at the BCG attachment site in CHO cells expressing CD14 and TLR2 suggesting that bacteria bind to CD14 and use TLR2 to initiate a PI3K signaling pathway. Additional experiments using blocking Abs showed that anti-TLR2 Abs inhibit phagocytosis of BCG by THP-1 cells. Furthermore, knockdown of cytohesin-1, a PI3K-regulated adaptor molecule for beta(2) integrin activation, specifically abrogated CD14-regulated CR3 ingestion of BCG consistent with the observation of physical association between CR3 and cytohesin-1 in cells stimulated with mycobacterial surface components. These findings reveal that mycobacteria promote their uptake through a process of "inside-out" signaling involving CD14, TLR2, PI3K, and cytohesin-1. This converts low avidity CR3 into an active receptor leading to increased bacterial internalization.

Animals↗
PubMed1977

Association between HLA determinants and complement receptors on human lymphocytes.

The relationship between the major histocompatibility complex (MHC) and functional receptors on the surface of human lymphocytes was studied. HLA antisera were tested for their effect on the formation of E-, EA-, and EAC'-rosettes by human peripheral blood lymphocytes (PBL). Antisera to various HLA specificities inhibited the formation of EAC'-rosettes, but had no effect on the formation of E-rosettes. The formation of EA-rosettes was inhibited by HLA antisera only in part among the individuals tested. Anti beta2-microglobulin serum resembled HLA antisera in its effect on the formation of the various rosettes. HLA determinants and complement receptors are different entities on the cell surface since elimination of complement receptors by trypsin treatment does not seem to affect the expression of HLA antigens on the cell surface. It is suggested that EAC' receptors are located close to HLA determinants.

Binding Sites, Antibody↗
PubMed1997

The roles of complement receptors type 1 (CR1, CD35) and type 3 (CR3, CD11b/CD18) in the regulation of the immune complex-elicited respiratory burst of polymorphonuclear leukocytes in whole blood.

The binding of immune complexes (IC) to polymorphonuclear leukocytes (PMN) and the consequent respiratory burst (RB) were investigated in whole blood cell preparations suspended in 75% human serum, using flow cytometry. Blockade of the complement receptor (CR)1 receptor sites for C3b on whole blood cells using the monoclonal antibody (mAb) 3D9 resulted in a 1.9-fold increase in the IC-elicited PMN RB after 5 min of incubation, rising to 3.1-fold after 40 min. This enhancement was not due to increased IC deposition on PMN. Blockade of CR3 abrogated the mAb 3D9-induced rise in RB activity and inhibited the IC binding to PMN in a whole blood cell preparation, with or without mAb 3D9, by approximately 40% from 15-40 min while reducing their RB over 40 min to approximately one third. Blockade of CR1 on either erythrocytes (E) or leukocytes, before mixing the populations, revealed that the potentiation of the RB by mAb 3D9 was associated with abrogation of E-CR1 function, whereas blockade of leukocyte-CR1 had a diminishing effect. Exposure to IC at high concentrations induced release of both specific and azurophilic granule contents from PMN. The latter was CR3 dependent in that blockade of the receptor inhibited the lactoferrin release by one third during 40 min of incubation. In conclusion, CR3 plays a significant role in the IC-mediated generation of an RB and release of specific granules by PMN, while CR1 on whole blood cells, primarily E CR1, restricts the IC-elicited RB in PMN. We propose that CR1 in whole blood promotes the degradation of IC-bound iC3b to C3dg, thereby rendering the IC inaccessible for binding to CR3.

Antigen-Antibody Complex↗
PubMed2005

The polymorphism C5507G of complement receptor 1 does not explain idiopathic pulmonary fibrosis among the Finns.

Idiopathic pulmonary fibrosis is the most common of the idiopathic interstitial lung diseases referring to the histo-pathological entity of usual interstitial pneumonia. It has been hypothesized that inflammation may trigger the multiformic fibrotic lesions found in the affected lung, and defects in the innate immune defense, including the complement, can predispose to pulmonary fibrosis. The polymorphism C5507G in the Complement Receptor 1 gene has been recently associated with idiopathic pulmonary fibrosis. C5507G causes an amino acid change from proline to arginine, and opens a potential cleavage site for trypsin-like enzymes and, therefore, a potential mechanism for increased shedding of the molecule from the cell surface. We studied the polymorphism in 96 Finnish patients with idiopathic pulmonary fibrosis and 164 population based controls. All the patients and controls were C5507 homozygous suggesting that either the Finns do not carry the G5507 polymorphism or it is extremely rare. We conclude that G5507 is not a susceptibility allele for idiopathic pulmonary fibrosis among Finnish patients.

Adult↗
PubMed2006

T cell-independent and T cell-dependent immunoglobulin G responses to polyomavirus infection are impaired in complement receptor 2-deficient mice.

Polyomavirus (PyV) infection induces protective T cell-independent (TI) IgM and IgG antibody responses in T cell-deficient mice, but these responses are not generated by immunization with viral proteins or virus like particles. We hypothesized that innate signals contribute to the generation of isotype-switched antiviral antibody responses. We studied the role of complement receptor (CR2) engagement in TI and T cell-dependent (TD) antibody responses to PyV using CR2-deficient mice. Antiviral IgG responses were reduced by 80-40% in CR2-/- mice compared to wild type. Adoptive transfer experiments demonstrated the need for CR2 not only in TD, but also in TI IgG responses to PyV. Transfer of CR2-/- B lymphocytes to SCID mice resulted in TI antiviral IgG responses that corresponded to 10% of that seen in wild-type B cell-reconstituted mice. Thus, our studies revealed a profound dependence of TI and TD antiviral antibody responses on CR2-mediated signals in PyV-infected mice, where the viral antigen is abundant and persistent.

Adoptive Transfer↗
PubMed1983

Generation of three different fragments of bound C3 with purified factor I or serum. II. Location of binding sites in the C3 fragments for factors B and H, complement receptors, and bovine conglutinin.

The many different recognized functions of C3 are dependent upon the ability of the activated C3 molecule both to bind covalently to protein and carbohydrate surfaces and to provide binding sites for as many as eleven different proteins. The location of the binding sites for six of these different proteins (factors B and H, complement receptors CR(1), CR(2) and CR(3) and conglutinin) was examined in the naturally occurring C3-fragments generated by C3 activation (C3b) and degradation by Factor I (iC3b, C3c, C3d,g) and trypsin (C3d). Evidence was obtained for at least four distinct binding sites in C3 for these six different C3 ligands. One binding site for B was detectable only in C3b, whereas a second binding site for H and CR(1) was detectable in both C3b and iC3b. The affinity of the binding site for H and CR(1) was charge dependent and considerably reduced in iC3b as compared to C3b. H binding to iC3b-coated sheep erythrocytes (EC3bi) was measurable only in low ionic strength buffer (4 mS). The finding that C3c-coated microspheres bound to CR(1), indicated that this second binding site was still intact in the C3c fragment. However, H binding to C3c was not examined. A third binding site in C3 for CR(2) was exposed in the d region by factor I cleavage of C3b into iC3b, and the activity of this site was unaffected by the further I cleavage of iC3b into C3d,g. Removal of the 8,000-dalton C3g fragment from C3d,g with trypsin forming C3d, resulted in reduced CR2 activity. However, because saturating amounts of monoclonal anti-C3g did not block the CR(2)-binding activity of EC3d,g, it appears unlikely that the g region of C3d,g or iC3b forms a part of the CR(2)-binding site. In addition, detergent-solubilized EC3d (C3d-OR) inhibited the CR(2)-binding activity of EC3d,g. Monocytes and neutrophils, that had been previously thought to lack CR(2) because of their inability to form EC3d rosettes, did bind EC3d,g containing greater than 5 x 10(4) C3d,g molecules per E. The finding that monocyte and neutrophil rosettes with EC3d,g were inhibited by C3d-OR, suggested that these phagocytic cells might indeed express very low numbers of CR(2), and that these CR(2) were detectable with EC3d,g and not with EC3d because C3d,g had a higher affinity for CR2 than did C3d. A fourth C3 binding site for CR(3) and conglutinin (K) was restricted to the iC3b fragment. Because of simultaneous attachment of iC3b to phagocyte CR3 and CR(3), the characteristics of iC3b binding to CR3 could only be examined with phagocytes on which the CR(1) had been blocked with anti-CR(1). Inhibition studies with EDTA and N-acetyl-D-glucosamine demonstrated a requirement for both calcium cations and carbohydrate in the binding of EC3bi to CR3 and to K. However, CR(3) differed from K in that magnesium cations were required in addition to calcium for maximum CR(3) binding activity, and NADG produced less inhibition of CR(3) activity than of K activity.

Animals↗
PubMed1977

Human lymphocyte complement receptors. Quantitative requirements for C3 of normal and chronic lymphocyte leukemia lymphocytes.

Erythrocytes coated with varying amounts of human complement were used to detect lymphocytes with complement receptors from normal subjects and patients with chronic lymphocytic leukemia. The relationship between the percentage of lymphocytes rosetting and the quantity of C3 present on complement-coated erythrocytes were studied. Small quantities of C3 (less than 5 fg/erythrocyte) caused maximal rosetting of normal lymphocytes. Maximal rosetting with chronic lymphocytic leukemia lymphocytes was not reached until much greater amounts of C3 were used to coat the erythrocytes. This difference in sensitivity to erythrocyte-bound complement was not due to an increased fraction of complement receptor-bearing cells in the leukemic patients. This loss of sensitivity of the chronic lymphocytic leukemia lymphocyte for complement may play a role in the immune deficiency present in this disease.

Cell Membrane↗
PubMed1998

Effect of soluble complement receptor type 1 on porphyrin-induced phototoxicity in guinea pigs.

The effect of recombinant human soluble complement receptor type 1 (sCR1) on the porphyrin-mediated phototoxic reaction was evaluated in guinea pigs. Phototoxicity was induced in the animals by intraperitoneal injection of hematoporphyrin derivative (HpD), followed by irradiation at a wavelength range of 320-450 nm. sCR1 administration decreased CH50 titers in a dose-dependent fashion, while it only moderately suppressed HpD/radiation-induced ear swelling at a high dose. These findings suggest that phototoxic dermatological changes in cutaneous porphyrias are not solely due to complement activation.

Animals↗
PubMed2006

Involvement of complement receptor 3 (CR3) and scavenger receptor in macrophage responses to wear debris.

The ability of prosthetic wear debris to induce pro-inflammatory responses in macrophages is widely appreciated, but little is known about the molecular mechanisms involved in particle recognition. Specifically, the nature of the cell surface receptors that interact with wear debris is poorly understood. Elucidating the identities of these receptors and how they interact with different types of wear debris are critical to understanding how wear debris initiates periprosthetic osteolysis. We examined the involvement of opsonization, complement receptor 3 (CR3), and scavenger receptor A (SRA), in responses to polymethylmethacrylate (PMMA) and titanium wear particles. Serum dependence of pro-inflammatory responses to PMMA and titanium was tested, and serum proteins that adhered to these two types of particles were identified. Several serum proteins, including known opsonins such as C3bi and fibronectin, adhered to PMMA but not titanium, and serum was required for pro-inflammatory signaling induced by PMMA, but not by titanium. Phagocytosis of PMMA and titanium by macrophages was demonstrated by flow cytometry. Blocking CR3 specifically inhibited phagocytosis of PMMA by macrophages, whereas blocking SRA specifically inhibited titanium uptake. Direct involvement of CR3 and SRA in cell-particle interaction was assessed by expression of these receptors in nonphagocytic HEK293 cells. CR3 specifically induced cell binding to PMMA particles and adhesion to PMMA-coated plates, while SRA specifically induced binding to titanium particles and adhesion to titanium-coated plates. Taken together, these results suggest involvement of opsonization, complement, and integrin receptors, including CR3 and fibronectin receptors, in PMMA action, and an involvement of scavenger receptors in responses to titanium.

Fibronectins↗
PubMed2004

Soluble human complement receptor 1 limits ischemic damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass.

BACKGROUND: This study was undertaken to determine whether soluble human complement receptor type 1 (TP10), a potent inhibitor of complement activation, would reduce morbidity and mortality in high-risk patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). METHODS: This was a randomized multicenter, prospective, placebo-controlled, double-blind study in which 564 high-risk patients undergoing cardiac surgery on CPB received an intravenous bolus of TP10 (1, 3, 5, 10 mg/kg) or placebo immediately before CPB. The primary endpoint was the composite events of death, myocardial infarction (MI), prolonged (> or =24 hours) intra-aortic balloon pump support (IABP), and prolonged intubation. RESULTS: TP10 significantly inhibited complement activity after 10 to 15 minutes of CPB and this inhibition persisted for 3 days postoperatively. However, there was no difference in the primary endpoint between the 2 groups (33.7% placebo versus 31.4% TP10; P=0.31). The primary composite endpoint was, however, reduced in all male TP10 patients by 30% (P=0.025). TP10 reduced the incidence of death or MI in males by 36% (P=0.026), the incidence of death or MI in CABG males by 43% (P=0.043) and the need for prolonged IABP support in male CABG and valve patients by 100% (P=0.019). There was, however, no improvement seen in female TP10 patients. There were no significant differences in adverse events between the groups. CONCLUSIONS: TP10 effectively inhibits complement activation during CPB; however, this was not associated with an improvement in the primary endpoint of the study. Nevertheless, TP10 did significantly decrease the incidence of mortality and MI in male patients.

Aged↗
PubMed1981

Complement receptor positive spleen cells in microwave (2450-MHz)-irradiated mice.

Male CBA/J mice were exposed under far-field conditions in a temperature and humidity controlled environment to 2450-MHz (CW) microwaves. Mice were exposed once for 30 minutes at a power density of 15, 20, 30, or 40 mW/cm2. The whole-body-averaged dose rate was approximately 0.7 mW/g per mW/cm2. Six days after irradiation, the percentage of complement-receptor-positive (CR+) spleen cells was determined. No difference was observed in the percentage of CR+ spleen cells of young adult (10-12-week-old) mice exposed at any of the power densities as compared with sham-irradiated controls. However, a significant (P less than .05) increase was observed in the percentage of CR+ cells from 16-week old mice exposed at 40 mW/cm2. This increase in CR+ cells was accompanied by a significant (P less than .05) decrease in the number of nucleated cells in the spleens of these mice. This change in CR+ and nucleated spleen cells was not consistently produced. The available data indicate that the age and strain of the mouse, the microwave exposure characteristics, and the environmental conditions may all be sources of variation that affect the CR+ end point.

Animals↗
PubMed1994

The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts.

The use of xenografts (Xgs) from distantly related species to relieve the increasing shortage of organs for clinical transplantation is prevented by the occurrence of hyperacute rejection (HAR). This process, in which C activation plays a central role, cannot be inhibited with currently available immunosuppressants. In two clinically relevant xenotransplantation models, this study evaluated the effect of C inhibition using recombinant soluble complement receptor type 1 (sCR1) on HAR. In an ex vivo model in which porcine cardiac Xgs were perfused with human blood, cardiac function ceased within 34 min when the perfusate blood was untreated (n = 3). When the perfusate blood was treated with sCR1 (300 micrograms/ml), cardiac Xg function was maintained for up to 4 hr (n = 3). Immunohistologic examination of these Xgs demonstrated deposition of C3b/iC3b and C3d in Xgs perfused with untreated human blood but only C3d deposition in those Xgs perfused with sCR1-treated human blood. These findings are consistent with the cofactor activity of sCR1 for factor I-mediated degradation of deposited C3b/iC3b to C3d. Treatment with sCR1 also prevented the histopathologic changes of HAR observed when untreated blood was used as the perfusate. In an in vivo pig-to-primate heterotopic cardiac xenotransplantation model, in which porcine Xgs transplanted into untreated cynomolgus monkey recipients underwent HAR in 1 hr or less (n = 3), a single intravenous bolus of sCR1 (15 mg/kg) administered to the recipient immediately before Xg reperfusion markedly inhibited total and alternative pathway serum C activity and prolonged Xg survival to between 48 and 90 hr (n = 5). These studies confirm the important role of C activation in HAR of porcine cardiac Xgs by primates and indicate that sCR1 may be a useful agent for xenotransplantation.

Animals↗
PubMed1996

Folding and conformational studies on SCR1-3 domains of human complement receptor 1.

Short consensus repeats SCR3 and SCR1-3 are soluble recombinant proteins, consisting of the third and first three N-terminal domains of complement receptor 1, respectively, which retain some anti-complement activity. The conformational stabilities and folding/unfolding of SCR3 and SCR1-3 have been studied using circular dichroism and equilibrium and pre-equilibrium fluorescence spectroscopy. Denaturation by guanidinium hydrochloride (GdnHCl) is rapid and completely reversible. Reduction of disulphide bridges in the folded proteins by beta-mercaptoethanol leads to an increase in fluorescence intensity. The fluorescence intensity of the folded proteins is approximately 7.5% of that of the respective unfolded proteins. The data can be approximated to a two-state transition between native and denatured forms of the proteins. SCR3 has a conformational stability in water of 12-13 kJ/mol whereas that of SCR1-3 is 19.5-19.9 kJ/mol depending upon the technique utilized. The heat capacity change associated with the unfolding of SCR1-3 was obtained by a series of GdnHCl unfolding experiments over a range of temperatures and was found to be 6.6 kJ/K.mol or 33.8 J/K.mol(residue). The refolding process of SCR3 was found to be simple, described by a single exponential equation, whereas that of SCR1-3 was found to be complex and could be fitted to a double exponential equation indicating the presence of folding intermediates.

Circular Dichroism↗
PubMed1993

Defect of a complement receptor 3 epitope in a patient with systemic lupus erythematosus.

Complement receptor 3 (CR3) is expressed on cells of the reticuloendothelial system and involved in the clearance of immune complexes. In this article a patient with a deficiency of the C3bi binding site of this receptor is described. Clinically this patient exhibited predominantly cutaneous manifestations of a systemic lupus erythematosus with an immune vasculitis and panniculitis. The deficiency of the CR3 epitope was demonstrated using flow cytometry. The functional relevance of this defect was demonstrated in a rosetting assay with C3bi-loaded erythrocytes. C3bi binding was found to be significantly decreased. Furthermore, there was an impairment of phagocytosis of opsonized Escherichia coli. The CR3 defect is not due to an autoantibody but is assumed to have a genetic basis. These data suggest that the defect of the CR3 may be involved in the pathogenesis of the immune vasculitis in this patient.

Adult↗
PubMed1987

A lysine-binding protein in SLE sera inhibits the binding of immune complexes to normal erythrocyte CR1 (complement receptor type 1).

The binding of 125I-labelled immune complexes (IC) to normal human erythrocyte CR1 (complement receptor type 1) by sera from patients with SLE was found to be significantly decreased compared to normal sera. In 13/29 patients, there was an inhibitor which decreased the binding of opsonized IC in normal sera to normal erythrocytes. It was found in each of the nine patients who had clinically active disease. The inhibitor was shown to be a globulin that was labile at 56 degrees C and bound to lysine; low concentrations of tranexamic acid and of lysine abolished the effects of the inhibitor which suggests that it possesses lysine-binding sites: these may block the CR1-binding site on IC opsonized with complement. This inhibitor may decrease the efficiency of IC carriage by erythrocyte CR1.

Antigen-Antibody Complex↗
PubMed2006

The use of TP10, soluble complement receptor 1, in cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) for cardiac surgery or lung transplantation initiates a systemic inflammatory response characterized by increased vascular permeability, generalized edema, abnormal lung function and oxygenation and impaired ventricular function. This post-CPB syndrome significantly contributes to postoperative morbidity and mortality. Activation of complement during CPB is a key component that initiates and augments this process. TP10, soluble complement receptor 1, is a novel complement inhibitor that is a potent inhibitor of C3 and C5 convertases, blocking activation of the complement cascade at the nexus of all three complement pathways. Recent controlled trials in humans have demonstrated that TP10 effectively inhibits complement activation during CPB. In high-risk adult patients, TP10 decreases the incidence of mortality and myocardial infarction in males but not in females following cardiac surgery. TP10 is also well tolerated and protects vascular function in infants undergoing CPB. In addition, TP10 leads to early extubation in adult lung transplant recipients. TP10 is currently positioned for clinical development in a male-only indication of cardiac surgery on CPB.

Cardiopulmonary Bypass↗