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PubMed1985

Generation of C3d,g and C3d by urokinase-treated plasma in association with fibrinolysis.

In the breakdown of fluid phase C3 in plasma, the process of conversion of iC3b to C3c and 'C3d' has not been elucidated. Using fluorescent labeled iC3b as a substrate, urokinase (UK) treated but not normal plasma was found to exhibit effective 'C3d' production. To address the relationship between the fibrinolytic activity specific for UK-activated plasma and this 'C3d' production, an assay system was developed that permitted the simultaneous determination of both activities. This method indicated that 'C3d' generation paralleled that of plasmin-dependent fibrinogen degradation. A Km of iC3b for plasmin was 3.0 X 10(-6) mol/l which is similar to the Km of fibrinogen. Plasmin cleavage of iC3b gave rise to C3d1 (Mr 42,000) and C3d2 (Mr 28,000). Purified plasmin C3d1 showed the same Mr and pI as C3d,g prepared from iC3b, by H and I. C3d2 was derived from C3d1. From these in vitro experiments with urokinase-treated plasma, we conclude that in parallel with fibrinolysis efficient cleavage of fluid phase iC3b to C3c + C3d,g and C3d occurs and we hypothesize that this is one mechanism for the generation of C3d in vivo.

Complement C3↗
PubMed1985

Mixed-pattern immune deposit glomerulonephritis in a child with inherited deficiency of the third component of complement.

The renal histopathology of a 7-year-old Laotian male with inherited deficiency of the third component of complement, recurrent infections, and persistent hematuria and proteinuria is described. The histologic changes are predominantly those of mesangiopathic disease with isolated changes resembling type I membranoproliferative glomerulonephritis and transmembranous glomerulonephritis. IgG, IgA, IgM, C4, and fibrinogen, but not C3, were detected by immunofluorescence in mesangial zones and in segments of capillary walls. A normal distribution of C3b receptors was present along all capillary walls. This report provides additional support for the association of congenital C3 deficiency and immune deposit glomerulonephritis.

Child↗
PubMed2004

DNA vaccines expressing soluble CD4-envelope proteins fused to C3d elicit cross-reactive neutralizing antibodies to HIV-1.

DNA vaccines expressing the envelope (Env) of the human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, DNA vaccines were constructed to express a fusion protein of the soluble human CD4 (sCD4) and the gp120 subunit of the HIV-1 envelope. To enhance the immunogenicity of the expressed fusion protein, three copies of the murine C3d (mC3d3) were added to the carboxyl terminus of the complex. Monoclonal antibodies that recognize CD4-induced epitopes on gp120 efficiently bound to sCD4-gp120 or sCD4-gp120-mC3d3. In addition, both sCD4-gp120 and sCD4-gp120-mC3d3 bound to cells expressing appropriate coreceptors in the absence of cell surface hCD4. Mice (BALB/c) vaccinated with DNA vaccines expressing either gp120-mC3d3 or sCD4-gp120-mC3d3 elicited antibodies that neutralized homologous virus infection. However, the use of sCD4-gp120-mC3d3-DNA elicited the highest titers of neutralizing antibodies that persisted after depletion of anti-hCD4 antibodies. Interestingly, only mice vaccinated with DNA expressing sCD4-gp120-mC3d3 had antibodies that elicited cross-protective neutralizing antibodies. The fusion of sCD4 to the HIV-1 envelope exposes neutralizing epitopes that elicit broad protective immunity when the fusion complex is coupled with the molecular adjuvant, C3d.

AIDS Vaccines↗
PubMed1985

Adult respiratory distress-like syndrome during hemodialysis: relationship between activation of complement, leukopenia, and release of granulocyte elastase.

Twelve patients with terminal uremia (8 females and 4 males) treated with chronic maintenance hemodialysis, were extensively studied during two successive dialyses with alternate use of either a Cuprophan (CP) based membrane, or a Polycarbonate (PC) membrane. Arterial plasma levels of total hemolytic complement, complement factors C3d and C5a, and granulocyte derived elastase were determined immediately before dialysis and sequentially during the entire procedure. Effluent line from the hemodialyzer was similarly sampled. Collected samples were centrifuged immediately at the bedside and instantly frozen in liquid nitrogen in order to preserve labile plasma components of complement. Analysis of the overall results shows that initial arterial leukopenia and generation of C5a in the hemodialyzer, as well as maximal values of hemodialysis-induced free plasma C3d and granulocyte elastase are related. Reflecting differences in biocompatibility, CP membranes were shown to induce significantly more leukopenia, increase in plasma free C3d, generation of C5a, and release of granulocyte-derived elastase. These results indicate that activation of complement, leukopenia, and release of granulocyte derived elastase are interlinked pathophysiological mechanisms of importance for acute deterioration of pulmonary function during hemodialysis, and that this condition is closely related to adult respiratory distress syndrome (ARDS).

Adult↗
PubMed1983

Use of monoclonal anti-C3 antibodies to characterise the fragments of C3 that are found on erythrocytes.

Using monoclonal antibodies to C3 it has been shown that the red blood cells of patients with cold haemagglutinin disease carry on their cells C3d,g (alpha-2D-globulin) rather than C3d. C3d,g seems to be the final product of in vivo C3 activation in fluid phase and on red cells. The cleavage of C3dg to C3d and C3g does not appear to occur in vivo either in the fluid phase or on red cell bound C3bi. In vitro C3-coated red cells prepared by antibody or low ionic strength techniques produce cells with C3d and C3bi as the predominant C3 fragment, whereas the Fruitstone technique in which coating occurs by the alternative pathway has principally C3b. The activity of C3 cleaving enzymes in whole serum is strongly influenced by the ionic conditions of the serum.

Anemia, Hemolytic, Autoimmune↗
PubMed1994

Synergy test for recognition of epitopes on soluble proteins; its application in the study of CD21 and CD23 antigens and their respective antibodies.

Antigens such as CD21 and CD23, which express only one copy of an epitope require two monoclonal antibodies (mAbs) for their detection and estimation. This requirement is exploited in two ways in a technique based on the chromic chloride haemagglutination test. For simple titration of antigen two portions of red cells each coated with one of a pair of synergising mAbs are used in a 1:1 combination. For testing the antigenic specificity of a mAb and assessing its region of epitope binding, the mAb under test is serially diluted in fluid containing a standard amount of antigen and red cells are added to which have been attached a different mAb. If the red cell-bound mAb recognises a determinant topographically distinct from that of the soluble mAb, red cell agglutination to high titre occurs. In titrations of ascitic fluid containing approximately 1 mg/ml mAb, titres of log2(9) to log2(16) were recorded from a starting dilution of 1 in 200. Hence the test is very sensitive and only minute amounts of a mAb are required for testing. The same test system can be used for assessing the relative display of epitopes on antigen obtained from different sources, e.g., culture supernates and body fluids. The method is of general applicability to monomeric antigens and its use is illustrated by analysis of CD21 and CD23 antigens and antibodies.

Animals↗
PubMed1997

Does heparin coating improve biocompatibility? A study on complement, blood cells and postoperative morbidity during cardiac surgery.

To evaluate whether the effect of heparin coating the extracorporeal circuit resulted in differences in patient outcome and haemostatic alteration, 24 patients undergoing elective, isolated coronary artery bypass were randomized prospectively to cardiopulmonary bypass (CPB) with heparin-coated circuits (group H, n = 12) or uncoated circuits (group C, n = 12). The technique of CPB, heparinization and its reversal were the same in both groups. We studied complement status (C3d, C3, C3d/C3, C4 and C-function), white blood cell counts with differentiation and the postoperative morbidity. The results confirmed that CPB activates complement and increases neutrophils in both the H and C groups. A significantly lower level of leucocytosis was seen in group H compared to the C group (p < 0.05). The complement function via the classical pathway (C-function), expressed as a percentage of the function of a reference serum pool (the values of normal sera were 75-125%), was significantly reduced in both heparin-coated and uncoated circuits (p < 0.05). There was no significant intergroup difference regarding C3, C3d/C3, C4 and C-function during the study period. A lower frequency of postoperative morbidity was present in the H group. We conclude that heparin-coated surfaces elicit less leucocytosis and decrease postoperative morbidity in patients undergoing cardiac surgery but do not cause a significant difference regarding activation of the complement system as reported by many other investigators.

Anticoagulants↗
PubMed2005

CD21/CD19 coreceptor signaling promotes B cell survival during primary immune responses.

The adaptive immune response is tightly regulated to limit responding cells in an Ag-specific manner. On B cells, coreceptors CD21/CD19 modulate the strength of BCR signals, potentially influencing cell fate. The importance of the CD95 pathway was examined in response of B cells to moderate affinity Ag using an adoptive transfer model of lysozyme-specific Ig transgenic (HEL immunoglobulin transgene (MD4) strain) B cells. Although adoptively transferred Cr2+/+ MD4 B cells are activated and persist within splenic follicles of duck egg lysozyme-immunized mice, Cr2-/- MD4 B cells do not. In contrast, Cr2-/- MD4 lpr B cells persist after transfer, suggesting that lack of CD21/CD35 signaling results in CD95-mediated elimination. Cr2 deficiency did not affect CD95 levels, but cellular FLIP (c-FLIP) protein and mRNA levels were reduced 2-fold compared with levels in Cr2+/+ MD4 B cells. In vitro culture with Cr2+/+ MD4 B cells demonstrated that equimolar amounts of rHEL-C3d3 were more effective than hen egg lysozyme alone in up-regulating c-FLIP levels and for protection against CD95-mediated apoptosis. Collectively, this study implies a mechanism for regulating B cell survival in vivo whereby the strength of BCR signaling (including coreceptor) determines c-FLIP levels and protection from CD95-induced death.

Animals↗
PubMed1991

Identification of 5'-regions affecting the expression of the human CR2 gene.

Human CR2 has a restricted cellular distribution, being expressed on B lymphocytes, dendritic cells of the spleen, pharyngeal epithelial cells, and at low levels on some T lymphocytes. CR2 is expressed by mature B lymphocytes, but not by pre-B cells or by plasma cells, suggesting that mechanisms exist for positive and negative regulation of CR2 gene expression during B cell development. S1 nuclease digestion and primer extension analysis positioned the transcriptional start site between 92 and 94 bp upstream of the ATG codon. Nucleotide sequence analysis identified several sequences within the CR2 promoter region with homology to other known promoter sequences. These included a site similar to an AP-1 site, a sequence with 10 of 13 nucleotides identical to the X box of class II genes, and a TATA box. Genomic DNA starting immediately 5' of the sequence encoding the CR2 signal peptide was subcloned upstream of the bacterial chloramphenicol acetyltransferase gene for analysis of functional promoter and enhancer sites. The functional boundaries of the CR2 promoter were determined by deletion analysis, with both the X box-like sequences and the TATA box required for CR2 expression. This analysis revealed sequences with regulatory effects on CR2 gene expression, however, these transcriptional controlling sequences did not act in a tissue specific fashion.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Cellular origins of serum complement receptor type 2 in normal individuals and in hypogammaglobulinaemia.

A soluble form of complement receptor 2 (sCR2) is found in normal human serum. Amounts present are about 30-90 ng/ml, which is of the same order as reported for soluble CR1. Although B cells express surface CR2 and are the main peripheral blood source of sCR2 they do not appear to be the major tissue source of serum sCR2. Serum levels of sCR2 of patients with hypogammaglobulinaemia were not significantly different from those of normal individuals even in the case of two brothers with Bruton's X-linked agammaglobulinaemia (XLA) lacking (CD19+) B cells. On gel filtration through Sephacryl S-300 the sCR2 from XLA serum behaved exactly like sCR2 from normal serum or sCR2 affinity purified from cell supernates of a B lymphoblastoid line or from the T-ALL line MOLT-4. In all cases a single peak appeared at the same point in the chromatogram. Possible alternative sources of serum sCR2 are follicular dendritic cells (FDC) which are known to express CR2 strongly and T6+ lymphocytes within the thymus. Peripheral T cells from adults have not been reported to express CR2. However, investigation showed that cells from the Bruton's XLA cases produced small amounts of sCR2 in culture and although no CD21 was detected on the surface of the mononuclear cells by flow cytometry, the more sensitive direct antibody rosette test readily detected CD21. Further studies showed that non-B cells from control samples of cord blood or blood of young children also weakly expressed CD21.

Agammaglobulinemia↗
PubMed1985

Neutrophils express a receptor for iC3b, C3dg, and C3d that is distinct from CR1, CR2, and CR3.

In the present study we examined human neutrophils for the expression of a receptor capable of binding C3dg and defined the relationship of this receptor to those that have been previously described, namely CR1, CR2, and CR3. C3dg was isolated from serum depleted of plasminogen, supplemented with 20 mM Mg++, and incubated at 37 degrees C for 6 to 8 days. The purified protein was homogeneous when analyzed by polyacrylamide gel electrophoresis and exhibited an apparent m.w. of 41,000. C3dg was polymerized by treatment with dimethyl suberimidate, and the dimer was isolated by gel filtration. Binding of both monomeric and dimeric 125I-labeled C3dg to neutrophils was saturable, and the latter ligand bound to an average of 12,400 sites/cell among nine normal individuals. At 4 degrees C, bound monomeric C3dg dissociated from neutrophils with an average t1/2 of 30 min, whereas dimeric C3dg dissociated with a t1/2 in excess of 120 min. Specific binding of multimeric C3dg was cation independent and was competitively inhibited by molar concentrations of iC3b and C3d that were equivalent to the inhibitory concentrations of unlabeled C3dg; C3b was less able to compete with C3dg for binding to these sites. The capacity of this neutrophil receptor to bind iC3b, C3dg, and C3d suggested its possible identity as CR2 or CR3. However, no specific binding to neutrophils of 125I-labeled HB-5 monoclonal anti-CR2 was detected. Furthermore, uptake of 125I-labeled C3dg was not inhibited by saturating concentrations of rabbit anti-CR1, anti-Mac-1, or OKM10. Thus, a receptor resides on neutrophils that binds the C3d region of iC3b and C3dg and is distinct from CR1, CR2, and CR3.

Animals↗
PubMed1986

Influence of C3 level on the determination of C3d in plasma and synovial fluid by radial immunodiffusion.

The influence of C3 levels on the determination of C3d in plasma and synovial fluid by radial immunodiffusion was investigated. In the method used, C3 is precipitated by 11% polyethylene glycol (PEG), and C3d is measured in the supernatant. In 51 healthy donors, a weak though significant correlation between C3 and C3d levels was found. The mean concentration of C3d was 1.6% of that in aged serum from healthy donors. So, small amounts of C3 (i.e., 1-2% of the normal plasma level) in the 11% PEG supernatants may contribute significantly to the C3d levels measured. A radioimmunoassay that detects C3, C3b, iC3b and C3c was used to measure C3 levels in the PEG supernatants. In PEG supernatants of 4 plasma samples, 0.3-0.6% of the C3 level in normal plasma was found, whereas in those of 2 synovial fluids much higher levels were found (4-10% of the normal plasma level). When purified 125I-labeled antibodies against C3c were added to the gel of the radial immunodiffusion, C3c antigen was detected in the precipitation rings obtained with all PEG supernatants of plasma samples from patients. Therefore, the quantitative contribution of C3 to the precipitation rings in the C3d radial immunodiffusion was analyzed after the addition of an excess of anti-C3c antibodies to the gel. No effect on the size of the C3d-precipitation rings obtained with plasma samples from patients was observed. However, the C3d precipitation rings obtained with synovial fluids were significantly smaller when the gel used in the radial immunodiffusion contained an excess of anti-C3c antibodies together with the anti-C3d serum. We conclude that it is necessary to add an excess of anti-C3c antibodies to the gel used for the radial immunodiffusion, for the determination of C3d levels in synovial fluid. An antiserum against human C3b, which contains both anti-C3c and anti-C3d antibodies, can be used for this purpose.

Blood Donors↗
PubMed1993

Evidence for three binding sites for C3 (hemolytically inactive), C3b and C3d on a CR2-positive Burkitt lymphoma-derived cell line (Raji).

The present investigation shows that C3 (hemolytic inactive) as well as C3b and C3d bind Raji, a CR2-positive Burkitt lymphoma-derived cell line. Pretreatment of the cells with OKB-7 inhibited the binding of C3, whereas pretreatment with HB-5 inhibited the binding of C3b. Furthermore, the cells coated either with OKB-7 or HB-5 bound high amounts of C3d. TPA-treated cells showed binding for C3b and weak binding for C3 and C3d. Taken together, the data suggest that Raji cells may express three binding sites for C3, C3b and C3d which can be differently modulated by anti-CR2 MoAbs and TPA.

Antibodies, Monoclonal↗