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PubMedDate not supplied

The estimation of circulating immune complexes, C3d, and anti-ds-DNA-antibody serum levels in the monitoring of therapeutic plasmapheresis in a patient with systemic lupus erythematosus. A case report.

A short-time monitoring of therapeutic plasmapheresis in a patient with systemic lupus erythematosus (SLE) by the estimation of circulating immune complexes, C3d serum levels and anti-ds-DNA-antibodies is described. It was found that serum immune complexes, C3d, and anti-DNA-antibodies decreased even further shortly after plasma exchange. The decrease found in C1q binding material in the patient's serum was paralleled by a decrease in serum immune complexes containing acridine orange binding material, possibly representing ds-DNA. A rapid increase of serum immune complexes, C3d, and anti-ds-DNA-antibodies after plasma exchange therapy indicated an antibody rebound phenomenon followed by a relapse of the disease.

Adult↗
PubMed2000

C3d enhancement of antibodies to hemagglutinin accelerates protection against influenza virus challenge.

The ability of the C3d component of complement to enhance antibody responses and protective immunity to influenza virus challenges was evaluated using a DNA vaccine encoding a C3d fusion of the hemagglutinin (HA) from influenza virus. Plasmids were generated that encoded a transmembrane HA (tmHA), a secreted form of HA (sHA), or a sHA fused to three tandem copies of the murine homologue of the C3d (sHA-3C3d). Analysis of the titers, avidity maturation, and hemagglutinin-inhibition activity of raised antibody revealed that immunizations with sHA-3C3d DNA accelerated both the avidity maturation of antibody to HA and the appearance of hemagglutinin-inhibition activity. These accelerated antibody responses correlated to a more rapid appearance of protective immunity. They also correlated to complete protection from live virus challenge by a single vaccination at a dose ten times lower than the protective dose for non-C3d forms of HA.

Animals↗
PubMed1997

Immunological adjuvants and their modes of action.

New adjuvant formulations contain a vehicle, which carries antigens to antigen-presenting cells. Examples of vehicles are liposomes, immune-stimulating complexes and microfluidized squalene-in-water emulsions. Adjuvant formulations may contain immunomodulators, which augment cytokine production, such as a synthetic muramyl dipeptide analog or monophosphoryl lipid A. In a primary cascade of cytokine production at the site of antigen + adjuvant injection, TNF-alpha promotes the migration of dendritic cells (DC) to lymphoid tissues while GM-CSF accelerates the differentiation of DC into efficient presenters of antigens to T cells. Adjuvants also up-regulate a secondary cascade of cytokines in lymphoid tissues responding to antigenic stimulation: IL-12 augments the production of IFN-gamma, which favors the production of antibodies of protective isotypes (IgG2a in the mouse). Thus adjuvants can regulate immune responses qualitatively as well as quantitatively. Adjuvant formulations can also activate complement, generating C3d, which binds CD21 on follicular dendritic cells (FDC) and B cells. FDC targeting favors the generation of B lymphocyte memory, which is important for vaccination.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

An immunoperoxidase study of immunological factors in high immune and low resistance granulomas in leprosy.

The epithelioid cell granuloma in high resistant tuberculoid (TT) leprosy was contrasted with the pure macrophage granuloma of anergic lepromatous leprosy (LL) by evaluating various immunological factors operating in these lesions. The immunoperoxidase technique using antisera to immunoglobulin IgG, IgM, complement C3, C3d and C1q and other products of macrophage secretion, lysozyme, plasminogen, a1 antitrypsin and C-reactive protein and of Ia antigens revealed peak levels in tissues of most of these factors in both types of granuloma. The tuberculoid response was linked to low antigenic load and Ia-like antigen and the lepromatous response was secondary to a high antigenic load in the absence of Ia antigen. Complement and other mediators were found intracellularly in both tuberculoid and lepromatous granulomas, but extracellularly only in tuberculoid lesions. This may indicate local hypersensitivity in the tuberculoid granuloma. It is suggested that the mediators in LL macrophages remain bound to lipids of mycobacterial degenerations in the phagocytic vacuole. Secretory cells were differently sited in the two types of granulomas: peripheral in epithelioid cell lesions and central around capillaries over the whole lesion in pure macrophage granulomas of LL. In tuberculoid leprosy many of the central vessels in the granuloma were obliterated. C1q was found in fibroblasts. However, the marked absence of fibrosis in any of the lesions of leprosy, except following severe reactions, casts some doubt on the link which has been postulated between epithelioid cells and fibroblasts as an explanation of fibrosis in granulomas.

Complement System Proteins↗
PubMed1984

Correlation of C3d fixing circulating immune complexes with disease activity and clinical parameters in patients with systemic lupus erythematosus.

Using anti-C3d as a solid phase reagent, C3d fixing circulating immune complexes (CIC) were detected in sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis, membranous nephropathy and IgA nephropathy. Particularly, sera from SLE showed the highest CIC levels and highest incidence of positivity among these diseases. In the 51 serum samples from 48 patients with SLE we studied, the CIC detected by the anti-C3d assay correlated well (P less than 0.01) with the CIC detected by the solid phase C1q assay, but not with those detected by the conglutinin assay. In addition, the CIC detected by the anti-C3d assay correlated more significantly (P less than 0.001) with disease activity, as well as some clinical parameters (serum anti-dsDNA antibodies, CH50 and C3 levels) than CIC detected by the other two assays of SLE sera. The anti-C3d binding materials were found to be of intermediate (8-19S) and small (7S) sizes in a small number of SLE sera which we analysed.

Antigen-Antibody Complex↗
PubMed1985

gp140, the C3d receptor of human B lymphocytes, is also the Epstein-Barr virus receptor.

The relationship between gp140, the membrane C3d receptor (CR2) of human B lymphocytes, and the Epstein-Barr virus receptor (EBVR) was analyzed by using the polyclonal anti-gp140, previously prepared by immunizing rabbits with highly purified gp140 (isolated by some of us) from CR2/EBVR-positive Raji cells. Polyclonal anti-gp72, a C3-binding membrane component, not related to the EBVR but also expressed on the Raji cell surface, was used as a control. Binding of rabbit IgG and EBV on cells was assessed by using immunofluorescence techniques with analysis by flow cytofluorometry. A semiquantitative bioassay was also used to measure the EBV binding. Polyclonal monospecific anti-gp140 IgG inhibits directly the binding of EBV to Raji cells at the same concentration that inhibits the binding of EC3d on cells, whereas a 35 times higher concentration of anti-gp72 IgG or preimmune serum IgG does not. Anti-gp140 IgG treatment also inhibits the induction of EBV-determined nuclear antigen in normal tonsil B lymphocytes or in EBV-negative Ramos cells, whereas high concentrations of anti-gp72 IgG or preimmune serum IgG have no effect. These data strongly suggest that gp140, the CR2 of human B lymphocytes, is also the EBVR.

B-Lymphocytes↗
PubMed1992

A 16 amino acid synthetic peptide derived from human C3d triggers proliferation and specific tyrosine phosphorylation of transformed CR2-positive human lymphocytes and of normal resting B lymphocytes.

We demonstrate herein that p16, a 16 amino acid synthetic peptide derived from human C3d, which carried LYNVEA sequence of C3d reacting with CR2 and C3d present in trypsin-cleaved C3, triggered "in vitro" and "in vivo" phosphorylations and "in vitro" proliferation of human B lymphocytes, depending on the stage of cell differentiation. Indeed, p16 and C3dT induced "in vivo" tyrosine phosphorylation of pp105 and "in vitro" proliferation only of CR2-positive and not of CR2-negative cell lines. In addition, p16 and C3dT also induced "in vivo" tyrosine phosphorylation of pp100 and "in vitro" proliferation of only small dense resting B lymphocytes and not other B lymphocyte subpopulations nor T lymphocytes. These data suggest that induction of pp100 and pp105 phosphorylation by p16 and C3dT could represent an early event associated with expression of CR2 in the regulation of human B lymphocyte proliferation.

Amino Acid Sequence↗
PubMed1985

Increased plasma levels of the terminal complement complex in patients with evidence of complement activation.

The terminal C5b-9 complex of human complement has recently been described and quantified in normal human plasma by an enzyme-linked immunosorbent assay (ELISA). We collected EDTA plasma samples from 20 patients clinically suspected to have complement activation. The terminal complement complex (TCC) and C3d split products were measured. The TCC was increased in 8 patients, and 6 of these also had increased C3d values, whereas 4 patients had increased C3d and normal TCC values. Two different double-antibody assays were used to detect terminal pathway activation: the combination of anti-C6 and anti-C9 detecting only the whole complex, and the combination of anti-C6 and anti-C5 detecting intermediate complexes as well. There was a close correlation between the observations in these two assays, suggesting that in general the whole cascade including C9 is involved when the terminal pathway of complement is activated in vivo. Quantification of TCC in plasma is an important supplement to already established methods for the evaluation of complement activation in vivo.

Adult↗
PubMed1982

Perioperative changes in complement associated with cardiopulmonary bypass.

The total haemolytic complement (CH50), the complement components C3 and C4, the complement breakdown product C3d, alternative pathway activation and transferrin, were measured before, during and after cardiopulmonary bypass. As expected, CH50 decreased after heparinization, remained low during bypass and decreased further up to 8 h after bypass. C3 and C4 decreased significantly during bypass, continued to decrease for a further 8 h after bypass (by 35% and 40% respectively) and thereafter increased gradually up to 48 h. Although the depletions observed were suggestive of complement activation, there were no demonstrable increases in C3d, and in all patients the concentration of C3d remained within the normal range. Hence it was concluded that complement depletions of this magnitude were unlikely to result from complement activation. Non-specific changes in protein concentrations during bypass, as a result of dilution, redistribution or other unidentified factors, are more probable causes of the observed reductions. The acute phase response to surgery may be a factor in the subsequent increase in C3 and C4 which is seen 24 h after bypass. As transferrin concentrations in the plasma are known to decrease during this response the observed decrease in transferrin concentration would support this view.

Adult↗
PubMed1985

Detection of a neoantigen on human C3bi and C3d by monoclonal antibody.

A neoantigen was detected on human C3bi and C3d by using the monoclonal antibody (MoAb) 130. The antibody bound to EC3bi and EC3d cells but not to EC3b. Although highly purified C3bi or C3d strongly inhibited the binding of the antibody to EC3d, highly purified C3c had no such effect. Native C3, C3b, or C3(H2O) inhibited this binding only weakly. The neoantigen was also detected in serum after activation with zymosan or heat-aggregated IgG, and it was found bound to the aggregated IgG and zymosan particles. Plasma samples from patients with immunologic disorders were tested for this neoantigen, and 25 out of 43 samples tested were found to have levels of neoantigen corresponding to 2 to 11.5% complement activation, whereas 13 out of 14 normal donor plasmas contained amounts of neoantigen indicating much less than 1% complement activation.

Antibodies, Monoclonal↗
PubMed2000

Structure-guided identification of C3d residues essential for its binding to complement receptor 2 (CD21).

A vital role for complement in adaptive humoral immunity is now beyond dispute. The crucial interaction is that between B cell and follicular dendritic cell-resident complement receptor 2 (CR2, CD21) and its Ag-associated ligands iC3b and C3dg, where the latter have been deposited as a result of classical pathway activation. Despite the obvious importance of this interaction, the location of a CR2 binding site within C3d, a proteolytic limit fragment of C3dg retaining CR2 binding activity, has not been firmly established. The recently determined x-ray structure of human C3d suggested a candidate site that was remote from the site of covalent attachment to Ag and consisted of an acidic residue-lined depression, which accordingly displays a significant electronegative surface potential. These attributes were consistent with the known ionic strength dependence of the CR2-C3d interaction and with the fact that a significant electropositive surface was apparent in a modeled structure of the C3d-binding domains of CR2. Therefore, we have performed an alanine scan of all of the residues within and immediately adjacent to the acidic pocket in C3d. By testing the mutant iC3b molecules for their ability to bind CR2, we have identified two separate clusters of residues on opposite sides of the acidic pocket, specifically E37/E39 and E160/D163/I164/E166, as being important CR2-contacting residues in C3d. Within the second cluster even single mutations cause near total loss of CR2 binding activity. Consistent with the proposed oppositely charged nature of the interface, we have also found that removal of a positive charge immediately adjacent to the acidic pocket (mutant K162A) results in a 2-fold enhancement in CR2 binding activity.

Animals↗
PubMed1986

Different in vitro generation of C3d by cuprammonium and polycarbonate capillary hemodialyzers.

Cellulosic membranes have been shown to activate C3 via the alternative pathway. Generation of the stable product C3d was compared in polycarbonate (PC) and cuprammonium (CU) hollow-fiber minidialyzers with identical geometry, using an in vitro recirculation system with platelet-poor plasma (recirculation rate 20 ml/min; 1,600 fibers; 0.115 m2; 40 ml system priming volume; recirculation time 120 min). After extensive washing, residual protein was removed by reverse transmembrane pressure (1.5 bar) from the air-filled dialysate compartment. Such protein fraction, functionally defined as 'secondary membrane', was similar in quantity for PC and CU fibers. Plasma proteins were present in the membrane without selective adsorption (flat-bed polyacrylamide gel electrophoresis and rocket immunoelectrophoresis using monospecific antibodies). C3d, measured by immunoelectrophoresis, increased with time in the fluid phase compartment of both dialysers, but C3d generation was consistently and significantly (p less than 0.05) less in PC than in CU dialysers. The observation documents an activation of C3 with PC, in contrast to previous reports of no activation. However, C3 activation with PC was less intense than with CU.

Adsorption↗
PubMed1986

Direct quantitation of activated C3 in human plasma with monoclonal anti-iC3b-C3d-neoantigen.

We developed a microtiter solid-phase radioimmunoassay for quantitating C3 breakdown products (iC3b, C3dg, C3d) in human plasma with a unique monoclonal antibody specific for a neoantigen present on iC3b and C3d (MoAb 130). This monoclonal antibody reacts with a neoantigen which appears when C3b is converted to iC3b. The neoantigen is also present on the C3dg and C3d fragments derived from iC3b. The concentration of the neoantigen is elevated in the plasma of most patients with rheumatoid arthritis and systemic lupus erythematosus as compared to normal volunteers. Some patients with glomerulonephritis also had elevated concentration of the neoantigen in their plasma.

Antibodies, Monoclonal↗
PubMed1986

Measurement of C3 conversion by ELISA estimation of neo-determinants on the C3d moiety.

An ELISA assay estimating neo-determinants on the C3d moiety is described. The C3d neo-determinants were detected by incubating the sample on F(ab')2 anti-C3d-coated plates followed by development with biotin-labelled anti-C3d and enzyme-labelled avidin. The assay was compared with rocket immunoelectrophoresis (IE) and crossed IE. Serum from a factor I deficient patient showed no detectable C3d when analysed by rocket IE, but activation was evident when analysing by crossed IE or ELISA. The results suggest that the neo-determinants detected by ELISA become exposed when C3 is split into C3a and C3b and this interpretation was supported by kinetic analysis of C3 activation by the three methods.

Complement Activation↗
PubMed1992

Comprehensive medical examination of a group of patients with alleged adverse effects from dental amalgams.

Mercury from dental amalgams does not seem to cause dose-related intoxications. However, animal studies have shown that high-dose exposure to mercury may support various types of immunologic reactions. Ten patients claiming that their symptoms were caused and aggravated by amalgam therapy were selected for a study of the effects of removal of one amalgam restoration followed by placing of a composite filling. Clinical symptoms and the result of laboratory tests were recorded. Six patients had contact allergies to metals, three of them to mercury ammonium chloride. The comparison of pre- and post-experimental test results showed significant reductions in p-IgE and dU-albumin and significant increases in p-C3d and dU-beta 2-microglobulin. There was no laboratory evidence of a direct toxic effect by mercury on the patients. The observed response by some of the studied factors to the low acute exposure to amalgam may imply that an activation of the immune system occurred.

Adult↗
PubMed1984

Immunoelectron microscopic studies of IgA nephropathy.

Immunoelectron microscopy was used in this study of IgA nephropathy to examine the relationship between immune deposits and electron-dense deposits seen by electron microscopy, and these findings were correlated with the severity of mesangial proliferation. Immunoelectron microscopic studies for antihuman gamma-chain, alpha-chain, mu-chain, C3, and C3d were performed by the method of Nakane in 16 patients with IgA nephropathy. The patients with minimal glomerular involvement and focal proliferative glomerulonephritis showed electron-dense reaction products of IgA in the paramesangial area, while the patients with diffuse proliferative glomerulonephritis showed electron-dense reaction products of IgA throughout the enlarged mesangial matrix. Immunoelectron microscopy showed electron-dense reaction products of IgA at the same locations as the electron-dense deposits seen on electron microscopy. C3 deposits were identified in 15 out of the 16 patients, but were less dense than IgA deposits. Electron-dense reaction products of C3 contained both positive and negative sites in 7 patients. Extensive C3d deposits were found in all cases in association with IgA deposits. The locations of these deposits were the same as those of the IgA deposits. These findings suggest that C3 deposits dissociate from the immune deposits and that the locations of the immune deposits correlate well with the severity of mesangial proliferation.

Biopsy↗
PubMed1993

[Correlation of hepatic necrosis and complement system activation in fulminant viral hepatitis].

The relationship between complement activation and hepatic necrosis was investigated in 110 cases of fulminant, acute or chronic viral hepatitis by examining plasma complement conversion products C3d and C4d and intact C3 and C4 molecules, as well as the local hepatic deposition of C3 IgG globulins in necrotic areas of the liver. The results revealed an excessive activation of plasma C3 in the fluminant hepatitis group. The C3d/C3 ratio was proved to be directly related to the severity of the clinical symptoms. C3 and IgG hepatic depositions in adjacent necrotic areas were found in over 85% of the fulminant hepatitis cases, as compared to 37.5% in cases of chronic active hepatitis. The conclusion was drawn that activation of the complement cascade is responsible for liver tissue damage, while the plasma complement activation represented by increased C3d and C3c fragment production might well reflect hepatic pathology. Therefore, the C3d/C3 ratio could serve as an index to aid clinical management, as well as pointing out a new therapeutic approach.

Complement Activation↗