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PubMed1985

Evaluation of plasma C3d and immune complex determinations in the assessment of disease activity of patients with rheumatoid arthritis, systemic lupus erythematosus, and spondylitis ancylopoetica.

Patients with rheumatoid arthritis, systemic lupus erythematosus, and spondylitis ancylopoetica were examined, along with healthy controls, for C3d plasma levels, circulating immune complexes, C3 serum levels, and CRP. Immune complexes were determined using a Clq binding assay, a 2.75% PEG precipitation technique, including the analysis of IgG and C3, and a new laser nephelometric latex test. C3d plasma levels were significantly (P less than 1%) elevated in all groups of patients as compared to controls. With regard to the demonstration of circulating immune complexes, the PEG precipitation method discriminated best between patients and the control population. It was not possible to differentiate between the different disease entities with neither C3d serum levels or immune complexes. Concerning the assessment of disease activity, none of the evaluated parameters alone appears to be of clinical relevance. The individual application of more than one immune complex assay in combination with the measurement of C3d serum levels must be recommended if disease activity is to be assessed.

Antigen-Antibody Complex↗
PubMed1997

CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes.

The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

Animals↗
PubMed1994

Comparative study of four tests of bacterial infection in the neonate. Total neutrophil count, CRP, fibrinogen and C3d.

In a prospective study, the diagnostic value of C3d serum levels was compared with that of neutropenia, hyperfibrinogenemia and raised CRP in generalized neonatal bacterial infections. Serum C3d was evaluated using a counter-immunoelectrophoresis technique following a step of removal of C3 split products. Twelve patients with septicemia, 8 patients with highly probable infection and 134 normal controls were included in the study. The sensitivities for neutropenia, hyperfibrinogenemia, raised CRP and positive C3d were 21, 45, 60 and 70%, respectively, with a significant difference between the sensitivities of neutropenia and positive C3d (p < 0.01). The specificities were found to be 99.2, 99.2, 100 and 97.7% respectively. Thus the C3d qualitative test appears to be as reliable as CRP in the diagnosis of neonatal bacterial infections.

Bacterial Infections↗
PubMed1990

Reduced expression of the functionally active complement receptor for iC3b but not for C3d on an avirulent mutant of Candida albicans.

Pseudohyphae of Candida albicans bear surface receptors for iC3b and C3d. In order to determine a possible role for these receptors in the pathogenesis of candidiasis, a spontaneous C. albicans mutant, m-10, which exhibits reduced ability to adhere in vitro to fibrin platelet clots and epithelial cells or to cause endocarditis in a rabbit model, and its parent wild-type (wt) strain were compared for receptor expression in rosetting assays with sheep erythrocytes carrying iC3b (EAC1423bi) or C3d (EAC1423d). An equally high attachment to wt and m-10 was seen with EAC1423d, whereas rosetting with EAC1423bi was reduced by 53% in m-10 compared with wt. In inhibition studies, rosetting of wt with EAC1423bi was markedly inhibited by culture filtrate, hyphal-cell extract, and DEAE-fractionated material prepared from wt (54, 87, and 70% decreases in rosetting, respectively), thus suggesting the presence of the soluble, functionally active iC3b receptor of C. albicans in each of these preparations. Minimal inhibition of iC3b rosetting, however, was seen with the identical materials from m-10 (21, 5, and 12%, respectively). All of the preparations from the two strains were equally effective in their inhibitory activities against rosetting of C3d. A human serum specimen obtained from a patient with chronic mucocutaneous candidiasis blocked iC3b rosetting of the wt strain almost completely. When used in an immunoblot, this serum recognized proteins of 68 to 71, 55, and 50 kilodaltons (kDa) in hyphal-cell extracts of the wt. With the same preparation of the avirulent mutant, only weak reactions with the 68- to 71-kDa and 55-kDa proteins occurred, while the 50-kDa protein was not detectable. Taken together, these results indicate that the expression of the functionally active iC3b receptor on C. albicans may be involved in the virulence of the organism, possibly by mediating adherence to mammalian cells.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Intracellular interaction of EBV/C3d receptor (CR2) with p68, a calcium-binding protein present in normal but not in transformed B lymphocytes.

To analyze direct intracellular interactions of CR2 in normal human B lymphocytes, we used polyclonal anti-Id anti-CR2 antibodies (Ab2) prepared against the highly purified CR2 molecule (gp140) as original immunogen. We previously demonstrated that this Ab2 contained specificities that mimicked extracellular and intracellular domains of CR2 and was helpful for identifying CR2-specific ligands. Indeed, some Ab2 specificities recognized human C3d and EBV, two extracellular CR2 ligands. In addition, other Ab2 specificities interacted directly, as CR2, with the intracellular p53 antioncoprotein that is expressed in transformed cells and not in normal cells. We demonstrate herein that Ab2 detected in normal B lymphocytes a 68-kDa protein, p68, that was not expressed in transformed B cells. p68 was localized in purified plasma membranes and cytosol fractions. Direct interaction of purified CR2 with purified p68 was demonstrated. Competitive studies supported that CR2 and Ab2 interacted with identical sites on p68. These interactions were calcium dependent. p68 was identified as a calcium-binding protein by its ability to be solubilized from B lymphocyte membranes by EGTA, a calcium-chelating agent, to bind specifically on phenothiazine-Sepharose in a calcium-dependent interaction, and to be recognized by specific antibodies directed against human p68, a calcium-binding protein of the annexin VI family. Thus, demonstration of different intracellular interactions of CR2 with distinct regulatory proteins, such as p53, the antioncoprotein, and p68, a calcium-binding protein, supports involvement of two regulatory pathways of signal transduction through CR2, depending on the normal or transformed state of human B lymphocytes.

Annexin A6↗
PubMed1990

Stable transfection of Epstein-Barr virus (EBV) nuclear antigen 2 in lymphoma cells containing the EBV P3HR1 genome induces expression of B-cell activation molecules CD21 and CD23.

A set of B-cell activation molecules, including the Epstein-Barr virus (EBV) receptor CR2 (CD21) and the B-cell activation antigen CD23 (Blast2/Fc epsilon RII), is turned on by infecting EBV-negative B-lymphoma cell lines with immortalizing strains of the viruslike B95-8 (BL/B95 cells). This up regulation may represent one of the mechanisms involved in EBV-mediated B-cell immortalization. The P3HR1 nonimmortalizing strain of the virus, which is deleted for the entire Epstein-Barr nuclear antigen 2 (EBNA2) protein open reading frame, is incapable of inducing the expression of CR2 and CD23, suggesting a crucial role for EBNA2 in the activation of these molecules. In addition, lymphoma cells containing the P3HR1 genome (BL/P3HR1 cells) do not express the viral latent membrane protein (LMP), which is regularly expressed in cells infected with immortalizing viral strains. Using electroporation, we have transfected the EBNA2 gene cloned in an episomal vector into BL/P3HR1 cells and have obtained cell clones that stably express the EBNA2 protein. In these clones, EBNA2 expression was associated with an increased amount of CR2 and CD23 steady-state RNAs. Of the three species of CD23 mRNAs described, the Fc epsilon RIIa species was preferentially expressed in these EBNA2-expressing clones. An increased cell surface expression of CR2 but not of CD23 was observed, and the soluble form of CD23 molecule (SCD23) was released. We were, however, not able to detect any expression of LMP in these cell clones. These data demonstrate that EBNA2 gene is able to complement P3HR1 virus latent functions to induce the activation of CR2 and CD23 expression, and they emphasize the role of EBNA2 protein in the modulation of cellular gene implicated in B-cell proliferation and hence in EBV-mediated B-cell immortalization. Nevertheless, EBNA2 expression in BL/P3HR1 cells is not able to restore the level of CR2 and CD23 expression observed in BL/B95 cells, suggesting that other cellular or viral proteins may also have an important role in the activation of these molecules: the viral LMP seems to be a good candidate.

Antigens, CD↗
PubMed1990

Isolation and characterization of cell surface mutants of Candida albicans.

Mutant strains of Candida albicans were obtained by selecting for cells that escaped agglutination by a polyclonal antiserum raised against standard C. albicans serotype A isolate B311. Mutants were obtained from strains B311 and B792 and from four strains isolated from patients with acquired immunodeficiency syndrome. All 15 tested mutants retained characteristic sugar assimilation patterns. All but one of the mutants retained the ability to form germ tubes and chlamydospores. Two mutants from an acquired immunodeficiency syndrome-derived isolate were deficient in binding complement ligands iC3b and C3d, whereas another mutant was deficient in binding ligand iC3b but not C3d. The hyphae of these three mutants lacked antigens when examined by Western immunoblotting with monoclonal antibody Ca-A, which detects several glycoproteins, including C3d-binding proteins. One of the complement-binding-deficient mutants was tested for its ability to colonize the gastrointestinal tract of rabbits but did not differ from the wild-type parent in site or degree of colonization. The proton magnetic resonance spectra of bulk mannan carbohydrate extracted from tested mutants showed the loss of a signal characteristic of the mannosyl alpha-PO4 linkage; each mutant also had a distinct pattern of other changes.

Agglutinins↗
PubMed1984

Intrauterine devices and pelvic inflammatory disease.

There is convincing clinical evidence that PID is more common in IUD users than in users of other contraceptive methods. There appears to be a smaller but significant increase when IUDs are compared with sexually active noncontraceptive users. However, the incidence of PID severe enough to warrant hospitalization is only of the order of 1 to 2 per 1,000 women per year. The question which remains is whether beyond this low figure of moderate and severe disease there is a much higher incidence of subclinical PID which may result in complications for IUD users. Development of a marker such as C-Reactive protein or the split complement component C3d to detect mild PID would prove invaluable in the elucidation of several crucial problems in the clinical management of women using IUDs.

Actinomycosis↗
PubMed1991

Interaction of iC3b with recombinant isotypic and chimeric forms of CR2.

CR2 is a component of a signal transduction complex on B lymphocytes that augments B cell responses to Ag. We have quantitatively assessed binding by the two isotypic forms of CR2 for two of its ligands, the polymerized iC3b (p(iC3b)) fragment of C3, and gp350/220, the EBV membrane protein. The recombinant 15-SCR or 16-SCR forms of CR2 bound p(iC3b) with identical affinities. Full binding activity of CR2 for p(iC3b) was observed with a chimera comprised of SCR-1 and -2 of CR2 fused to SCR-17 through -30 of CR1. Therefore, the alternatively spliced SCR-10a has no role in binding p(iC3b), and the binding activity of wild type receptor for iC3b can be reconstituted with SCR-1 and -2 of CR2. The binding affinities of the two isoforms of CR2 for soluble gp350/220 were also similar. Additional sites in the C3c region of C3 have been postulated also to interact with CR2. However, monomeric iC3b and C3d were equally effective in inhibiting the binding of p(iC3b) to CR2, indicating that the C3c region of iC3b does not contribute to the interaction of iC3b with CR2. Finally, the relative abilities of C3b and iC3b to bind to CR1 and CR2 were compared. The conversion of C3b to iC3b generated a ligand with an approximate 100-fold decrease in affinity for CR1 and a 10-fold increased affinity for CR2, resulting in a 1000-fold greater likelihood for binding to the latter receptor that may then promote B cell activation.

Animals↗
PubMed1990

Changes in neutrophil oxidative potential in patients undergoing cardiopulmonary bypass with polypropylene hollow fiber oxygenators.

Neutrophil oxidative metabolism, C3d and beta 2 microglobulin levels, were assessed in nine consecutive patients undergoing cardiopulmonary bypass surgery with polypropylene hollow fiber oxygenators for open cardiac operations. Generation of oxygen free radicals by neutrophils was measured as luminol-enhanced chemiluminescence after stimulation with opsonized Zymosan and phorbol myristate acetate. A significant increase in light emission was detected by using both of the chemiluminescence stimulators. Moreover, a remarkable and significant increase in C3d levels was found already at 10 min. Conversely minimal changes in levels of beta 2 microglobulin were detected during cardiopulmonary bypass surgery. These data suggest that the impact of the patient blood with the foreign surface of cardiopulmonary bypass results in activation of phagocyte cells with increased potential in oxygen consumption. These effects could be partially complement-mediated.

Cardiopulmonary Bypass↗
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↗
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↗