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At least 883 records · Page 49Linked to original sources
PubMed1995

Characterization of a complement receptor 2 (CR2, CD21) ligand binding site for C3. An initial model of ligand interaction with two linked short consensus repeat modules.

Human CR2 (CD21, EBV receptor) is an approximately 145-kDa receptor and a member of the regulators of complement activation gene family. Regulators of complement activation proteins are characterized by the presence of repeating motifs of 60 to 70 amino acids that are designated short consensus repeats (SCR). CR2 serves as a receptor for four distinct ligands. Three of these ligands (complement C3, gp350/220 of EBV, and CD23) interact with the amino terminal 2 of 16 SCR (SCR 1 and 2). Previous studies have determined that at least four sites are important in allowing CR2 to efficiently bind EBV. Two of these sites are also important for binding mAb OKB7, a reagent that blocks both EBV and iC3b/C3dg binding to CR2. We have identified and characterized important sites of iC3b ligand binding by utilizing human-mouse CR2 chimeras, a rat anti-mouse CR2 mAb designated 4E3 that blocks receptor binding to C3, and human CR2-derived peptides. In addition to demonstrating an important role for the same sequence in SCR 1 that is part of the mAb OKB7 and EBV binding site, we have identified a new region within SCR 2 that interacts with C3. These results, when compared with a model of a dual SCR solution structure derived from human factor H SCR, predict that two distinct largely surface-exposed sites on CR2 interact with iC3b. A relative twist of 130 degrees about the long axis of the second SCR in this model would be necessary for these sites to form a single patch for iC3b binding on CR2.

Amino Acid Sequence↗
PubMed1991

Anti-inflammatory and immunosuppressive effects of recombinant soluble complement receptors.

CR1 and CR2 have served as unusual probes for the analysis of the two major functions of the immune system involving inflammation and the immune response, respectively. CR1, or some construct containing its active site SCRs, may find a role in the therapy of complement-dependent tissue injury, and may be used to define which diseases are caused by the inappropriate or excessive activation of this system. Although soluble forms of CR2 may be shown to have potential clinical utility when foreign antigen is given prospectively, as in monoclonal antibody therapy, perhaps the most important finding emanating from the analysis of this receptor is the recognition of a previously unrecognized membrane protein complex whose role in B cell development is yet to be determined. It is reasonable to predict that the function of the CD19 complex will be significant as it serves as the link between two evolutionarily distinct systems that share a common purpose of anti-microbial host defense.

Animals↗
PubMed2002

Fcgamma and complement receptors: expression, role and co-operation in mediating the oxidative burst and degranulation of neutrophils of Brazilian systemic lupus erythematosus patients.

We have investigated the individual role of FcgammaR and CR, as well as their cooperation, in mediating the oxidative burst and degranulation of neutrophils of Brazilian systemic lupus erythematosus (SLE) patients. Neutrophils were stimulated with the immune complexes (IC)-IgG or -F(ab')2, opsonized or not with normal or SLE human serum. The oxidative burst was decreased in neutrophils of active SLE patients compared to healthy controls when this response was mediated by FcgammaR and/or CR, while the degranulation was unaffected. The SLE hypocomplementemia did not affect the oxidative burst mediated only by CR. FcgammaRII and CR1 expression on neutrophils of active SLE patients was reduced, while the expression of FcgammaRIII and CR3 was unaffected. These results suggest that the different FcgammaR and CR may be involved or cooperate in different ways in the mediation of the oxidative burst and the degranulation. Moreover, the decreased oxidative burst of neutrophils of active SLE patients may not depend only on SLE hypocomplementemia for IC opsonization. These observations are directed at the understanding of how each of these immune system components (FcgammaR, CR and complement) influences the precise biological neutrophil responses both in physiological and pathological conditions. Since the Brazilian population comprises many races, these results are important because they are directed at a specific population of SLE patients.

Brazil↗
PubMed2004

Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass.

BACKGROUND: Increase in vascular permeability and multiorgan dysfunction after cardiopulmonary bypass (CPB) are barriers to successful cardiac surgery in infants. Complement inhibition with TP10, a C3/C5 convertase inhibitor (AVANT Immunotherapeutics, Needham, Mass), blunts post-CPB organ dysfunction in the neonatal pig. Methods and results The pharmacokinetics and safety of TP10 in infants (age <1 year, n = 15) undergoing CPB were examined in a phase I/II open-label prospective trial. TP10 (10 mg/kg) was given intravenously before CPB and also added (10 mg/100 mL prime volume) to the CPB circuit. TP10 plasma levels correlated with C3a levels and measures of clinical course. All infants survived. No adverse events were attributed to TP10. TP10 plasma concentration fell to < or =60 microg/mL 12 hours after CPB. A 2-compartment model was fit to the TP10 blood levels as a function of time. Based on this model, an initial dose of 10 mg/kg over 0.5 hours followed by 10 mg/kg over 23.5 hours is the most appropriate for maintaining TP10 concentration between 100 microg/mL and 160 microg/mL for 24 hours after CPB. C3a was lower 12 hours after CPB than before CPB and still lower 24 hours after CPB. TP10 concentration was inversely correlated with the 12-hour post-CPB to pre-CPB ratio of C3a (Spearman rho -0.76, P = -.016), and with total (rho -0.56, P =.047) and net (rho -0.85, P =.0016) fluid and blood product administration/kg >24 hours after CPB. CONCLUSIONS: TP10 administration to infants appears safe. Pharmacokinetic analysis generated an optimal dosing strategy to achieve effective TP10 levels for 24 hours after CPB. In the infant, TP10 appears to decrease CPB-induced complement activation and protect vascular function. These results support a phase III trial of TP10 in infants requiring CPB.

Capillary Permeability↗
PubMed1988

Role of platelet factors and serum complement in growth of fibroblasts with high-affinity Clq complement receptors.

Cultures of human diploid fibroblasts are heterogeneous in that a subpopulation interacts via high-affinity receptors with the globular head regions of the Clq complement protein. Growth and synthetic properties of these cells are characteristic of cells residing in healing wounds and inflammatory lesions. At these sites, fibroblasts are exposed to regulatory molecules such as complement components and factors released from blood platelets. We assessed the effects of native complement proteins and platelet-derived factors on proportions and phenotypic stability of high-affinity and low-affinity receptor cells generated from explants of adult and embryonic connective tissue, using radioligand binding assays and immunofluorescence analysis by flow cytometry. Fibroblasts expressing high-affinity Clq receptors could be generated from explants only when factors from platelets were present in the medium; native complement proteins were not essential. High-affinity receptor cells could be generated only from tissue; they could not be generated by incubating cultures of the low-affinity receptor phenotype in medium containing platelet-derived factors. High-affinity receptor cells, once established from explants in the presence of platelet-derived factors, persisted through many replications in the absence of platelets. We obtained the same fibroblast phenotypes from embryonic skin as from adult gingiva, but the proportion of high-affinity receptor cells from skin was much greater. We conclude that factors derived from platelets are essential for generating cultures containing fibroblasts expressing high-affinity Clq receptors, but not for their maintenance. High-affinity receptor cells may comprise a rapidly dividing subpopulation giving rise only to like progeny or to other, more differentiated cells.

Adult↗
PubMed1977

Complement receptors in human renal glomeruli. Further evidence by immunofluorescence.

A new method is described for demonstrating the presence of glomerular receptors for the third component of complement in human kidney. Frozen sections are incubated together with normal human serum and inulin. Activated C3 is detected by a fluoresceinated anti-C3 antiserum. Glomeruli are labelled by C3-coated inulin particles while there is no labelling in tubules and interstitium. This method is easy and rapid and it allows the exact localization of C3 glomerular receptors.

Animals↗
PubMed1985

Regulatory proteins for the activated third and fourth components of complement (C3b and C4b) in mice. II. Identification and properties of complement receptor type 1 (CR1).

We identified on the membrane of mouse spleen cells a polypeptide of Mr 190,000 (S190), with binding affinity for the mouse third component of the complement system (C3). S190, purified by affinity chromatography on C3-Sepharose, has properties resembling those of the human C3 receptor type 1 (CR1). Thus, S190, like CR1, served as a cofactor for the C3b inactivator (I)-mediated cleavage of fluid-phase C3b into iC3b, and had cofactor activity comparable to that of serum factor H (H). S190 also acted as a cofactor for the cleavages of membrane-bound C3b or membrane-bound iC3b into C3c (Mr 140,000) and C3dg (Mr 40,000) by serum factor I. As is the case with CR1, the specific activity of S190 for the cleavages leading to C3c-C3dg formation was approximately 100-fold greater than that of H. We therefore conclude that S190 and CR1 are analogous proteins.

Animals↗
PubMed1980

Complement receptors on Raji cells. The presence of a new type of C3 receptor.

Raji cells in our laboratory did not form rosettes with EAC43hu. When EAC43hu are treated with beta 1H, the treated EAC43hu forms heavy rosettes with Raji cells. Evidence is presented to show that these rosettes resulted from a new type of C3 receptor which is different from either CR1 (C3b receptor), CR2 (C3d receptor) or CR3 (C3bi receptor). Three lines of evidence clearly showed that C3 is implicated in the new rosette formation. C3 receptors isolated from human erythrocytes inhibited the new rosette formation, while they did not inhibit the rosette formation of Daudi cells via CR2, indicating that the new rosette-forming receptor is different from CR2. Anti-Raji cells antiserum inhibited the new rosette formation while it did not inhibit the reaction between human erythrocytes and EAC43 via CR1. This fact indicates that the new rosette-forming receptor is different from CR1 in accordance with the lack of rosette formation of Raji cells with EAC43. The evidence to differentiate the receptor from CR3 comes from no participation of C3b inactivator in the generation of rosette-forming activity of EAC43. Both the mode of action of anti-beta 1H and the effect of modification of bound C3b by N-bromosuccinimide suggest that EAC43 reacts with beta 1H, which in turn results in a conformational change of C3b. Raji cells might have receptors for the beta 1H altered C3b.

Blood Proteins↗
PubMed1999

Neutrophils from patients with advanced human immunodeficiency virus infection have impaired complement receptor function and preserved Fcgamma receptor function.

Interleukin (IL)-8 production by human polymorphonuclear leukocytes (PMNL) to Cryptococcus neoformans is related to complement activation. Generation of the bioactive fragments C3a and C5a is responsible for IL-8 release. IL-8 production was analyzed in response to C. neoformans by PMNL from persons with early- and late-stage (>400 and <200 CD4 cells/mm3, respectively) human immunodeficiency virus (HIV) infection who were at high risk for cryptococcosis. IL-8 release by PMNL from persons with early-stage infection and from healthy donors was similar; however, PMNL from persons with late-stage HIV infection had significantly impaired IL-8 production, which correlated with reduced IL-8 response to C3a and C5a proteins and decreased CD88 expression. Addition of murine monoclonal antibody (MAb) 18B7 promoted phagocytosis and restored IL-8 release consistent with integrity of FcgammaRIII. These results provide evidence for a selective defect in CD88 expression on PMNL from persons with late-stage HIV infection. However, Fcgamma receptor expression in PMNL appears to be intact and allows MAb to glucuronoxylomannan to positively influence PMNL function.

Adult↗