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PubMed1987

Competitive enzyme-linked immunoassay for the quantitation of platelet-associated immunoglobulins (IgG, IgM, IgA) and complement (C3c, C3d) with polyclonal and monoclonal reagents.

A competitive enzyme-linked immunoassay (CELIA) was developed for the quantitation of platelet-associated immunoglobulins and complement proteins. The use of unlabeled polyclonal rabbit or monoclonal antibodies to human immunoglobulins and enzyme-labeled anti-mouse or anti--rabbit IgG (double-step technique) resulted in a higher sensitivity compared to the single-step technique using only enzyme-labeled anti-human immunoglobulin antibody preparations. Sensitivity and results obtained by both techniques were compared. The range of normal values for platelet-associated IgG, IgM, IgA, C3c and C3d was assessed upon a large number of normal blood donors. When platelet-associated IgG was concomitantly assayed with polyclonal and monoclonal anti-IgG by the double-step technique on platelets obtained from normal donors and thrombocytopenic patients, identical results were obtained with both reagents. Problems related to the quantitation of immunoglobulins on platelets with different assays and antibody preparations are discussed.

Antibodies, Monoclonal↗
PubMed2003

[Enhancement of HBV gene-induced specific cell-mediated immunoresponse by C3d-P28].

AIM: To investigate whether P28 derived from complement C3d can enhance the cell-mediated immunoresponse to HBV-preS2/S induced by direct injection of naked plasmid DNA containing four tandem repeats of C3d-P28 gene and HBV-preS2/S gene existed in fusion form. METHODS: Four copies of gene coding for C3d-P28, amplified by PCR and cut by restriction endonucleases digestion, were subcloned into a eukaryotic expression vector pVAON33 to construct pVAON33-P28.4. HBV-preS2/S gene was then introduced into the pVAON33 and pVAON33-P28.4 respectively to form pVAON33-S2/S and pVAON33-S2/S-P28.4. The recombinant plasmids were identified by PCR and restriction endonucleases digestion as well as DNA sequencing. BALB/c mice were immunized i.m. three times at 3 weeks' intervals with 100 microg of pVAON33-S2/S DNA, pVAON33-S2/S-P28.4 and mock DNA, respectively. Splenocytes from immunized mice were stimulated by HBsAg and then harvested to analyze the specific lymphocytic proliferative response and CTL cytotoxic activity by (3)H-TdR incorporation assay and isotopic release analysis, respectively. RESULTS: Specific lymphocytic proliferation and CTL cytotoxic activity against HBV-preS2/S were observed in mice immunized by both pVAON33-S2/S and pVAON33-S2/S-P28.4 in dose-dependent form. Specific lymphocytic proliferation and CTL response in mice immunized by pVAON33-S2/S-P28.4 were markedly stronger than those in mice immunized by pVAON33-S2/S. CONCLUSION: A C3d-P28 can enhance the cell-mediated immunoresponse induced by HBV-preS2/S gene immunization.

Animals↗
PubMed1990

Reduction of complement activation during bypass by prime manipulation.

Complement activation is believed to be of importance in the development of complications arising after cardiopulmonary bypass. The effect on complement activation of priming the extracorporeal circuit with crystalloid alone, crystalloid plus albumin, or crystalloid plus the plasma expander polygeline was assessed in 36 patients undergoing coronary artery operations with cardiopulmonary bypass using a bubble oxygenator. Activation of the alternative and common complement pathways was monitored before, during, and after the bypass period by measuring concentrations of factor B and its fragment Ba and C3 and its fragment C3d. Complement activation occurred in all three groups of patients, with no difference between the crystalloid and crystalloid-albumin groups. In contrast, Ba fragment concentrations were persistently and significantly lower during and after bypass in the polygeline group, denoting reduced complement activation. C3d levels also showed a tendency to be lower in this group. Our results indicate that addition of polygeline to the priming solution reduces complement activation. Because complement activation is associated with morbidity after cardiopulmonary bypass, addition of polygeline to the priming solution may offer an inexpensive method of reducing morbidity after cardiopulmonary bypass.

Albumins↗
PubMed2002

Membrane attack complex contributes to destruction of vascular integrity in acute lung allograft rejection.

The lung is known to be particularly susceptible to complement-mediated injury. Both C5a and the membrane attack complex (MAC), which is formed by the terminal components of complement (C5b-C9), can cause acute pulmonary distress in nontransplanted lungs. We used C6-deficient rats to investigate whether MAC causes injury to lung allografts. PVG.R8 lungs were transplanted orthotopically to MHC class I-incompatible PVG.1U recipients. Allografts from C6-sufficient (C6(+)) donors to C6(+) recipients were rejected with an intense vascular infiltration and diffuse alveolar hemorrhage 7 days after transplantation (n = 5). Ab and complement (C3d) deposition was accompanied by extensive vascular endothelial injury and intravascular release of von Willebrand factor. In contrast, lung allografts from C6-deficient (C6(-)) donors to C6(-) recipients survived 13-17 days (n = 5). In the absence of C6, perivascular mononuclear infiltrates of ED1(+) macrophages and CD8(+) T lymphocytes were present 7 days after transplantation, but vascular endothelial cells were quiescent, with minimal von Willebrand factor release and no evidence of alveolar hemorrhage or edema. Lung allografts were performed from C6(-) donors to C6(+) recipients (n = 5) and from C6(+) donors to C6(-) recipients (n = 5) to separate the effects of systemic and local C6 production. Lungs transplanted from C6(+) donors to C6(-) recipients had increased alveolar macrophages and capillary injury. C6 production by lung allografts was demonstrated at the mRNA and protein levels. These results demonstrate that MAC causes vascular injury in lung allografts and that the location of injury is dependent on the source of C6.

Acute Disease↗
PubMed2001

Systemic complement depletion diminishes perihematomal brain edema in rats.

BACKGROUND AND PURPOSE: The complement cascade is activated after experimental intracerebral hemorrhage (ICH). It remains unclear, however, whether depleting the complement system will improve injury resulting from ICH. This study investigated the effects of systemic complement depletion on brain edema formation after ICH. METHODS: Fifty-six pentobarbital-anesthetized Sprague-Dawley rats were used. Treatment animals were complement-depleted with cobra venom factor (CVF) (intraperitoneally). Control rats received an equal volume of saline injection (intraperitoneally). In both treatment and control rats, autologous blood (100 microL) was infused stereotaxically into the right basal ganglia. Rats were killed 2, 24, or 72 hours later for brain water, ion, and tumor necrosis factor-alpha (TNF-alpha) measurements, for Western blot analysis, and for immunohistochemical studies. Brain edema was quantitated by wet/dry weight. TNF-alpha levels were measured by enzyme-linked immunosorbent assay. Western blot analysis was applied for C9 semiquantification. Immunohistochemistry was used to detect complement C3d, C5a, C9, and myeloperoxidase. RESULTS: Perihematomal brain edema was reduced by systemic complement depletion at 24 hours (78.8+/-0.6% versus 81.5+/-0.8% in control, P:<0.01) and 72 hours (81.5+/-1.5% versus 83.6+/-0.9% in control, P:<0.05), while cerebellar water content was unaffected (78.2+/-0.3% versus 78.0+/-0. 1%). Complement depletion reduced TNF-alpha production 2 hours after ICH. Immunocytochemistry showed that complement depletion significantly reduced perihematomal C9 deposition, C3d production, and the number of C5a- and myeloperoxidase-positive cells. CONCLUSIONS: Complement depletion by CVF attenuates brain edema in ICH, indicating that complement activation plays an important role in ICH-induced brain edema. Preventing complement activation may be effective in the treatment of ICH.

Animals↗
PubMed1998

CD21/CD35 in B cell activation.

The stimulus induced via the B cell receptor is a major factor in determination of the fate of naive B cells resulting in activation, elimination or anergy. The strength of B cell signal transduction is dependent not only on the affinity of antigen binding, but by positive signals via the co-receptor CD21/CD19/Tapa-1. Absence of CD21 expression by B cells results in an impaired humoral response to T-dependent antigens which is characterized by a reduction in B cell follicular retention and germinal center survival. The ligand for CD21 is complement C3d which becomes attached to antigen on activation of the complement system. Thus, the complement system of innate immunity is an important regulator of B lymphocytes.

B-Lymphocytes↗
PubMed1990

Comparative study of assays detecting complement activation. Complement-split product C3d (rocket immuno-electrophoresis) and C3d neodeterminants (ELISA).

The aim of the study was to investigate the correlation between two types of assay measuring specific products of complement C3 activation and their clinical application. Complement C3d split product was estimated using double-decker rocket immunoelectrophoresis (DD-RIE) and measurements of C3d neodeterminants exposed after C3 activation was carried out with an enzyme-linked immunosorbent assay (ELISA). A total of 595 blood samples were measured in parallel in the DD-RIE and the ELISA test systems. The samples originated from blood donors (44), uraemic patients undergoing dialysis (135), serial samples from rheumatoid arthritis (RA) patients during steroid treatment (88) and 328 randomly collected patient samples. The mean values for DD-RIE and ELISA (+/- 1 SD) for the 595 samples were 48 (+/- 20) mU/l and 48 (+/- 28) mU/l respectively. The interassay coefficient of variation (CV) in the ELISA was 18%. The Spearman rho-correlation coefficient between the two assays was 0.63 for all 595 samples. The mean values using ELISA and DD-RIE were practically identical for the 328 successively incoming samples, the samples from the 135 dialysis patients and the 44 donors. In RA patients a higher mean value was found for the 88 samples using DD-RIE than ELISA. In the majority of patient samples there was a good correlation between the two assays. However, the ELISA appears to be more sensitive in detecting acute complement activation and to give lower levels in RA patients with chronic complement activation.

Anaphylaxis↗
PubMed1985

Mapping of the C3d receptor (CR2)-binding site and a neoantigenic site in the C3d domain of the third component of complement.

The C3d domain of C3 contains the site that binds to the C3d receptor (CR2) which is expressed on B lymphocytes. It also contains a neoantigenic determinant that is recognized by monoclonal antibody (mAb) 130 and is expressed when C3b is cleaved to iC3b and subsequently to C3dg or C3d. mAb 130 inhibits the binding of C3d to CR2. In this study, the locations of the CR2-binding site and of the neoantigen recognized by mAb 130 within the C3d domain were investigated. Treatment of human C3d with CNBr generated two major fragments with Mrs of 12,500 and 8600. Binding studies showed that only the Mr 8600 fragment was capable of binding to both CR2 and mAb 130. Amino-terminal sequence analysis of the Mr 8600 fragment and comparison with the amino acid sequence derived from human C3 cDNA [de Bruijn, M. H. L. & Fey, G. H. (1985) Proc. Natl. Acad. Sci. USA 82, 708-712] placed it between residues 1199 and 1274 of the C3 sequence. Several peptides were synthesized according to the derived C3 sequence of amino acid residues 1209-1236. Based on their differential binding to CR2 and mAb 130, we localized the CR2-binding site and mAb 130 neoantigenic site, respectively, to residues 1227-1232 and 1217-1232 of the C3 sequence.

Amino Acid Sequence↗
PubMedDate not supplied

The predictive value of peritubular capillaries C3d deposition in IgA glomerulonephritis.

The IgA glomerulonephritis (IgAGN) is one of the most common primary glomerulonephritis and has a variable and difficult to predict evolution toward the end-stage nephrosclerosis. The deposition of C3d complement component in peritubular capillaries (PTCs) indicates a variant type of acute rejection while C3d deposition in primary glomerulonephritis (GN) is poorly documented. The aim of this study is to examine C3d expression in peritubular capillaries (PTCs) as a predictive marker and its correlation with the severity of renal injury in IgA glomerulonephritis. Polyclonal FITC conjugated rabbit anti-human C3c and C3d antibodies were used for direct immunofluorescent evaluation of the C3c and C3d deposits in 24 kidney biopsies with IgA glomerulonephritis. The study revealed that the C3d deposits in peritubular capillaries were associated with known predictors for rapid progression of IgAGN: glomerular sclerosis (63.6%), atrophic tubules (90.9%) and interstitial sclerosis (81.8%). The intensity of the C3c glomerular immunofluorescent deposits was related with active lesions. Thus, the predictive value of C3d deposition on PTCs in IgAGN is worth to be taken into consideration as an unfavorable outcome of the disease and request further long run investigations.

Adolescent↗
PubMed2001

Fusion of C3d molecule with bovine rotavirus VP7 or bovine herpesvirus type 1 glycoprotein D inhibits immune responses following DNA immunization.

The binding of the complement C3d molecule with receptors on B cells and/or follicular dendritic cells (FDCs) influences the induction of humoral immune responses. For example, C3d fused to an antigen has been shown to have a strong adjuvant effect on antibody production. We investigated the possibility that co-expression of antigen and C3d as a fusion protein could enhance antigen-specific immune responses, following plasmid immunization. One or two copies of murine C3d-cDNA, C3d or (C3d)(2), respectively, were cloned together with bovine rotavirus (BRV) VP7 or bovine herpesvirus type 1 (BHV-1) glycoprotein D (gD) genes. All constructs contained a signal peptide that resulted in the secretion of the expressed proteins. In vitro, the characterization of the chimeric proteins indicated that both VP7 and gD retained their antigenicity and the C3d remained biologically active. However, immunization with plasmids encoding VP7-C3d chimeras did not enhance rotavirus-specific antibody responses and the frequency of BRV-specific IFN-gamma secreting cells in the spleens were significantly lower in mice immunized with pVP7-(C3d)(2) when compared with mice immunized with plasmid encoding VP7. The same pattern of immune responses was observed for plasmids encoding gD-C3d. Both gD-specific antibody responses and the frequency of gD-specific IFN-gamma secreting cells were significantly lower in mice immunized with plasmid expressing gD-C3d chimeras when compared with mice immunized with plasmid encoding gD alone. These results indicate that co-expression of C3d with an antigen actually inhibit both humoral and cell-mediated antigen-specific immune responses.

Animals↗
PubMed2004

Complement receptors and the shaping of the natural antibody repertoire.

Complement and complement receptors have been known for several decades to play important roles in immune effector mechanisms related to pathogen elimination and tissue inflammation. In addition, studies over the last 10 years have clearly demonstrated a key role for the complement C3d activation fragment receptor designated CR2 (complement receptor type 2) in the switched-isotype, high-affinity and memory humoral immune responses to T-dependent foreign antigens. More recent studies have extended those observations to include a key role for CR2 and C3d in the humoral immune response to T-independent foreign antigens. Conversely, as these studies have proceeded, a parallel series of analyses have linked defects in expression or function of complement C4 and other classical pathway activation pathway proteins, as well as CR2 and the closely related CR1, to the loss of self tolerance to nuclear antigens such as double-stranded DNA and chromatin in systemic lupus erythematosus. With regard to the topic of this issue, it is now becoming increasingly clear that CR2 also plays a major role in the development of the natural antibody repertoire. Specifically, in the absence of this receptor natural IgM and IgG develop in the naïve animal that demonstrate clearly altered recognition patterns for specific natural antibody targets. This repertoire change is important physiologically in at least one setting because these CR2-dependent natural antibodies are necessary for the recognition of ischemic self tissues. In addition, it is possible that certain of the phenotypes manifest by CR2-deficient mice may be strongly influenced not only by effects on later stages of B cell activation and maturation, as commonly thought, but also by alterations in the pre-existing pool of natural antibodies that are influenced by this receptor. This review will examine the evidence that has accumulated over the last few years supporting these hypotheses.

Animals↗
PubMed1994

Backdiffusion or bicarbonate may stimulate complement activation during haemodialysis with low-flux membranes.

Backdiffusion of dialysate during haemodialysis with low-flux membranes and the use of bicarbonate dialysatebase, may increase the risk for contamination. The influence on the complement system was studied by altering the flux of acetate or bicarbonate dialysate base across the membrane. Eight patients were dialysed with a transmembrane pressure of 100 mm Hg (group I) during the first 60 min to standardize the ultrafiltration (UF) and acetate as dialysate. In eight other patients (group II) the UF was "set at zero" ml during the first 60 min using an FCM 10-1 monitor (Gambro) and bicarbonate as base. The groups were dialysed three times on two hollow-fiber membranes made of Hemophan and cellulose acetate (CA). Blood samples were taken at 0, 15, 60 and 180 min, and analysed for plasma protein, haematocrit and complement C3d. In group II there was a reduction in plasma protein concentration at 15 and 60 min (p < 0.002) for Hemophan and at 60 min (p < 0.01) using CA. C3d was increased at 15 min for both filters (p < 0.03). The reduction of protein in group II was followed by changes in the haematocrit, indicating a backdiffusion of dialysate, which may contribute to the concomittant increase in C3d.

Adult↗
PubMed1993

Local and systemic activation of the whole complement cascade in human leukocytoclastic cutaneous vasculitis; C3d,g and terminal complement complex as sensitive markers.

We have studied complement activation both in plasma samples and in lesional skin from patients with leukocytoclastic cutaneous vasculitis (LCV). Enzyme immunoassay (EIA) quantification of the complement activation markers, C3d,g and the terminal complement complex (TCC) in plasma, showed that their levels were significantly increased in 66% and 55% of the patients, respectively (n = 29) compared with healthy controls, whereas the standard measurements of C3, factor B, C1q, C4 and C2 were generally within normal range. Elevations of C3d,g and TCC levels in plasma were significantly correlated. Importantly, a significant correlation was found between the severity of the vasculitis and both C3d,g and TCC plasma levels. Immunofluorescence studies of skin biopsy specimens demonstrated simultaneous presence of perivascular dermal deposits of C3d,g and TCC in lesional skin from 96% and 80% respectively of the patients (n = 25). There was a significant correlation between the intensity of the deposits of both markers. Clusterin, a TCC inhibitory protein, was always found at the same sites of perivascular TCC deposits. Immunofluorescence studies at the epidermal basement membrane zone (BMZ) revealed in each case deposits of C3d,g which were accompanied by TCC deposits in 52% of the biopsy specimens. These data demonstrate that there is a local and systemic activation of the whole complement cascade in human LCV. The presence of both C3d,g and clusterin-associated TCC perivascular deposits suggests an intervention of a regulatory mechanism of local complement activation in LCV. Finally, measurement of plasma C3d,g and TCC appears to be a sensitive indicator of systemic complement activation and disease severity in LCV.

Aged↗
PubMed1986

Cell cycle control of activated, synchronized murine B lymphocytes--roles of macrophages and complement C3.

Three restriction points control the cell cycle of activated murine B lymphocytes in a synergistic way. The first is controlled by the occupancy of surface immunoglobulin either by antigen- or by immunoglobulin-specific antibodies. The second is controlled by the complement C3d receptor CR2 which can be occupied by cross-linked C3b or C3d to stimulate the entry into S phase, or by soluble C3d or a C3 alpha-chain peptide, binding to the CR2 receptor, which inhibit the entry into S phase. Macrophages produce so-called alpha factors which also control the B-cell cycle at the same point. Thus, it is suspected that macrophages produce components of the early pathway of complement activation which finally lead to cross-linking of CR2 receptors on B cells. The third restriction point is controlled by unknown receptors that recognize so-called beta factors produced by helper T lymphocytes.

Animals↗
PubMed1985

Early- and late-phase activation of complement evaluated by plasma levels of C3d,g and the terminal complement complex.

Activation of the initial part (early phase) and terminal part (late phase) of the complement cascade was examined. C3d,g and the fluid-phase terminal complement complex were quantified and compared after spontaneous in vitro activation and after acute in vivo activation caused by extracorporeal circulation during coronary artery surgery. The results suggest that there is a close but not complete correlation between early- and late-phase activation of complement, that C3d,g and the terminal complement complex have different elimination rates in vivo, and that these two indicators are valuable for evaluation of early- and late-phase activation, respectively.

Complement Activation↗
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↗
PubMed1988

Autorosette inhibition factor: a positive acute phase reactant in interstitial cystitis.

Autorosette inhibition factor (AIF), complement C3d and eosinophil cationic protein (ECP) in urine were determined in 28 patients with painful bladder disease. In patients with interstitial cystitis (IC), diagnosed by the demonstration of detrusor mastocytosis, a positive correlation (r = 0.73, p less than 0.01) between AIF and C3d was found, whereas no reliable correlation was found in the remaining patients. The median concentration of urinary ECP was significantly elevated in the group of patients with IC whereas the median concentration of C3d was significantly elevated in both groups. AIF seems to behave as a positive acute phase reactant in IC. It is hypothesized that AIF may play a role in the pathogenesis of IC by influencing the normal barrier function of the epithelium of the bladder.

Acute-Phase Proteins↗