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At least 19 recordsLinked to original sources
PubMed1980

The blocking effect of antibodies against the products of the H-2 gene complex on lymphocyte complement (C3d) receptors. complement dependence and specificity.

Antisera against the products of the major histocompatibility system (MHS), produced by immunization between congenic mouse strains differing only at that segment of the 17th chromosome rosettes which bears the H-2gene complex, exert a reproducible blocking effect on formation of with EACm (C3d rosettes). In many instances this effect is probably due to specific antibodies reactive with the lymphocytes, as indicated by immunochemical and adsorption experiments. Purified antibodies from the C3H anti-C3H.B10 immune ascites failed to exert this blocking effect. The blocking capacity can be restored, however, by addition of fresh normal mouse, rabbit or fetal calf serum, but not by heat inactivated serum. These experiments show that the presently defined H-2K, H-2D and H-2L antigens as well as some Ia antigens are themselves not the C3d receptors. The blocking effects observed in the presence of complement are possibly due to the proximity of H-2 or Ia molecules and C3d receptors, or to a rearrangement of membrane components after reaction with anti-MHC anti-MHC antibodies and complement.

Animals↗
PubMed2000

Structure at 1.44 A resolution of an N-terminally truncated form of the rat serum complement C3d fragment.

Complement component C3 plays a key role in the complement-mediated immune defence, and occupies a central position within the complement cascade system. One of its degradation products, C3dg, was purified from rat serum and crystallised in two different crystal forms as N-terminally truncated fragment. Despite the truncation and the lack of a significant portion of the N-terminus as compared to C3d, the structure of the fragment is highly similar to that of recombinant human C3d (Nagar et al., Science 280 (1998) 1277-1281). Structural details of the reactive site have been obtained, suggesting a possible mode of thioester bond formation between Cys-1010 and Gln-1013 and thioester bond cleavage in the transacylation reaction involving His-1126. The truncation at the N-terminus of C3d leads to the exposure of a surface of the molecule that favours dimerisation, so that in both crystal forms, the fragment is present as a dimer, with monomers related by a two-fold axis.

Animals↗
PubMed2003

[Cloning and sequence analysis of the molecular-adjuvant gene of the complement C3d of mouse].

OBJECTIVE: Considering that the complement C3d plays a stronger positive role in the control of immunologic system, we constructed the recombinant plasmid of the molecular-adjuvant gene of the complement C3d in order to enhance the immunologic efficacy of the gene vaccine. METHODS: The main points were amplifying the segment of complement C3d gene by using of PCR; inserting it into PGEM-T; detecting it by digesting with Eco RI and sequencing; the whole length being 897 bp; then sub-cloning it into pVAX1. RESULTS: The DNA sequencing confirmed the C3d sequence. CONCLUSION: We have successfully cloned the gene of C3d and constructed the recombinant plasmid of pVAX1 C3d.

Animals↗
PubMed2004

The electrostatic nature of C3d-complement receptor 2 association.

The association of complement component C3d with B or T cell complement receptor 2 (CR2 or CD21) is a link between innate and adaptive immunity. It has been recognized in experimental studies that the C3d-CR2 association is pH- and ionic strength-dependent. This led us to perform electrostatic calculations to obtain a theoretical understanding of the mechanism of C3d-CR2 association. We used the crystallographic structures of human free C3d, free CR2 (short consensus repeat (SCR)1-2), and the C3d-CR2(SCR1-2) complex, and continuum solvent representation, to obtain a detailed atomic-level picture of the components of the two molecules that contribute to association. Based on the calculation of electrostatic potentials for the free and bound species and apparent pK(a) values for each ionizable residue, we show that C3d-CR2(SCR1-2) recognition is electrostatic in nature and involves not only the association interface, but also the whole molecules. Our results are in qualitative agreement with experimental data that measured the ionic strength and pH dependence of C3d-CR2 association. Also, our results for the native molecules and a number of theoretical mutants of C3d explain experimental mutagenesis studies of amino acid replacements away from the association interface that modulate binding of iC3b with full-length CR2. Finally, we discuss the packing of the two SCR domains. Overall, our data provide global and site-specific explanations of the physical causes that underlie the ionic strength dependence of C3d-CR2 association in a unified model that accounts for all experimental data, some of which were previously thought to be contradictory.

Complement C3d↗
PubMed2001

Increased immunogenicity and induction of class switching by conjugation of complement C3d to pneumococcal serotype 14 capsular polysaccharide.

Previous studies have demonstrated an adjuvant effect for the C3d fragment of complement C3 when coupled to T-dependent protein antigens. In this study, we examined the antibody response to covalent conjugates of C3d and a T-independent antigen, the capsular polysaccharide of serotype 14 Streptococcus pneumoniae (PPS14). We prepared a conjugate of mouse C3d and PPS14 and compared its immunogenicity with that of a conjugate of PPS14 and ovalbumin (OVA). When BALB/c mice were immunized with PPS14-C3d, there was a significant increase in serum anti-PPS14 concentrations compared with either native PPS14 or control PPS14-glycine conjugates. This was accompanied by a switch in anti-PPS14 from predominantly immunoglobulin M (IgM) to IgG1 by day 25 following primary immunization. Following secondary immunization with PPS14-C3d, there was a marked booster response and a further increase in the ratio of IgG1 to IgM anti-PPS14. Although the primary antibody response to the PPS14-OVA conjugate exceeded that induced by immunization with PPS14-C3d, serum anti-PPS14 concentrations after a second injection of PPS14-C3d were nearly identical to those induced by secondary immunization with PPS14-OVA. Experiments with athymic nude mice suggested that T cells were not required for the adjuvant effect of C3d on the primary immune response to PPS14 but were necessary for enhancement of the memory response after a second injection of PPS14-C3d. These studies show that the adjuvant effects of C3d extend to T-independent antigens as well as T-dependent antigens. As a means of harnessing the adjuvant potential of the innate immune system, C3d conjugates may prove useful as a component of vaccines against encapsulated bacteria.

Animals↗
PubMed1991

Effects of renal failure on complement C3d levels.

Elevated plasma concentrations of complement split product C3d have been reported to represent activation of the complement system. In the present study the effect of renal function on C3d concentrations was investigated in patients with various degrees of renal impairment, in patients with chronic renal failure and in CAPD patients. It appeared that elevated plasma C3d concentrations were present in patients with plasma creatinine concentrations in excess of 200 mumol/l regardless of the type of kidney disease. It is very likely that this can be attributed to renal handling (i.e. glomerular filtration, tubular reabsorption and renal catabolism) of C3d in a similar way as has been demonstrated for other low molecular weight proteins. The peritoneal permeability to C3d was slightly less than could be expected on the basis of its molecular weight without evidence of local production of C3d. Renal function should be taken into account in the interpretation of elevated plasma concentrations of C3d.

Complement Activation↗
PubMed2005

Role of complement receptor type 2 and endogenous complement in the humoral immune response to conjugates of complement C3d and pneumococcal serotype 14 capsular polysaccharide.

Conjugation of the complement fragment C3d to both T-cell-dependent (TD) protein and T-cell-independent type 2 (TI-2) polysaccharide antigens enhances the humoral immune response in mice immunized with either type of antigen. However, the ability of C3d-protein conjugates to enhance the antibody response in mice deficient in complement receptor types 1 and 2 (CR1 and CR2) has raised questions about the role of C3d-CR2 interactions in the adjuvant effect of C3d. In this study, we examined the role of CR2 binding and endogenous complement activation in the antibody response to conjugates of C3d and serotype 14 pneumococcal capsular polysaccharide (PPS14). To block binding of PPS14-C3d conjugates to CR2, mice were immunized with a mixture of vaccine and (CR2)2-immunoglobulin G1 (IgG1). Mice receiving (CR2)2-IgG1 at the time of primary immunization had a marked reduction in the primary anti-PPS14 antibody response but an enhanced secondary anti-PPS14 response, suggesting that C3d-CR2 interactions are required for the primary response but can have negative effects on the memory response. Further, compared with mice receiving PPS14-C3d having a high C3d/PPS14 ratio, mice immunized with PPS14-C3d with low C3d/PPS14 ratios had an enhanced secondary antibody response. Treatment of mice with cobra venom factor to deplete complement had insignificant effects on the antibody response to PPS14-C3d. Experiments with CBA/N xid mice confirmed that PPS14-C3d conjugates retain the characteristics of TI-2 rather than TD antigens. Thus, the adjuvant effect of C3d conjugated to PPS14 requires C3d-CR2 interactions, does not require activation of endogenous complement, and is not mediated by TD carrier effects.

Adjuvants, Immunologic↗
PubMed2003

Urinary excretion of complement C3d in patients with renal diseases.

INTRODUCTION: Complement-mediated tubular injury may play an important role in the progression of renal diseases. C3d is a presumed marker of complement activation. Its precursor C3dg has been detected in the urine of patients with membranous nephropathy. However, little is known of the renal handling of C3d or its excretion in other renal diseases. METHODS: We measured the urinary excretion of albumin, IgG, beta2-microglobulin (beta2m), and of complement C3d in patients with tubulo-interstitial nephritis (TIN; n= 8), in patients with membranous nephropathy (n = 35) and in patients with nonmembranous glomerular diseases (23 nonproliferative and 21 proliferative). Fractional excretions (FE) were calculated using creatinine clearance as marker of GFR. RESULTS: C3d was not measurable in the urine of the healthy controls, but was detectable in seven out of eight of the TIN patients (median excretion 0.11 mU min-1, range 0.006-2.4 mU min-1). In these patients the urinary excretion of beta2m was clearly elevated (median 26.6 micro g min-1, range 1.0-103 micro g min-1). The FE of C3d correlated with the FE of beta2microglobulin (r = 0.83, P = 0.01), and their ratio amounted to 0.03 (range 0.003-0.06), a value in agreement with the expected sieving coefficient. Urine C3d was detectable in all but three of the patients with glomerular diseases (median excretion 0.36 mU min-1, range 0.004-7.9 mU min-1); C3d-excretion did not differ between the three subgroups of patients with glomerular diseases. FEC3d correlated with FEIgG (r = 0.88, P < 0.01). The ratio FEC3d/FEbeta2m was 0.78 (range 0.04-9.99). Selected patients with membranous nephropathy were re-analyzed after (partial) remission of proteinuria. Reduction of proteinuria resulted in a decrease of C3d excretion. CONCLUSION: Urinary excretion of C3d is elevated in patients with TIN, most likely as a mere consequence of decreased tubular reabsorption. In patients with glomerular diseases urinary excretion of C3d is increased and related to proteinuria, independent of the underlying glomerular disease. In these patients there is evidence of increased local formation of C3d.

Adult↗
PubMed1989

Changes in PMN leukocyte migration activity and complement C3d levels in RA patients with high disease activity during steroid treatment.

We have investigated chemotaxis of polymorphonuclear granulocytes (PMN) from 7 well characterized RA patients with intense disease activity, before and after steroid treatment. Increased spontaneous and directed granulocyte migration was observed in 6 out of 7 patients before steroid treatment. In 5 patients these parameters were reduced after treatment. In contrast to this, decreased chemotaxis of polymorphonuclear granulocytes (PMN) from patients with Rheumatoid Arthritis (RA), have been reported earlier. This has been suggested as a partial explanation of the increased morbidity of these patients. Plasma levels of Complement C3d were initially increased in all patients and were slightly reduced following treatment. PMN migration in highly active RA cases is increased and responds markedly to steroid treatment, in contrast to the complement activation. The mainly unaffected, increased levels of plasma C3d might, in part, explain the early recurrence of symptoms often seen when steroid medication is withdrawn. Our results contrast with earlier findings and need to be confirmed in further studies.

Acute Disease↗
PubMed2005

Efficient production of complement (C3d)3 fusion proteins using the baculovirus expression vector system.

Proteins fused to activated complement (C) fragments elicit enhanced immunogenicity. This "natural adjuvant" effect may have important implications when considering novel vaccination approaches. Here we describe both the construction of a novel fusion protein, consisting of a well characterized test antigen fused to multiple copies of the activated complement component (C3d)3, as well as an efficient method for its expression and production in insect cells. Using the inherent biological advantages of the baculovirus expression system, as well as applying specific infection and harvesting modifications, we have optimized the efficiency of protein production. Our modifications allow purification of fusion proteins directly from cell supernatant in a single anion exchange chromatographic step. This alleviates the requirement for the inclusion of protein affinity tags. The integrity of the purified recombinant protein was evaluated by SDS PAGE analysis, reactivity with antibodies, as well as in vivo by administration as an immunogen.

Adjuvants, Immunologic↗
PubMed1990

Specificities of monoclonal antibodies against the complement C3d split product.

The only specific method at present for the quantification of the complement split product C3d, the double-decker rocket immunoelectrophoretic assay, is work intensive and expensive. We investigated the possibilities for developing an ELISA for the direct quantification of C3d in plasma. Available antibodies were examined for their specificity for C3 and its degradation products by the PAGE immunoblotting method. None of the antibodies were specific for C3d, as cross-reactivities against C3 and/or C3b and C3bi were demonstrable.

Animals↗
PubMed1985

Dual cutaneous reactions to anti-human IgE; no change in plasma level of the split product complement C3d or effect of heparin.

The possible dependence of the dual cutaneous reaction (DCR) on activation of the complement and coagulation systems was further elucidated. Heterologous whole anti-human IgE was injected intradermally (i.d.) on the volar aspect of the forearms of 17 drug-free healthy volunteers and venous samples for the selected laboratory test collected from the adjacent cubital vein. Plasma level of C3 split products (C3d) did not change significantly 6 h and 96 h after the injection of anti-IgE inducing immediate cutaneous reactions (ICRs) or DCRs as compared with prechallenge values. Conventional heparin, a compound with anti-coagulant and anti-complementary effects, injected i.d. (200 IE) concomitantly with and by s.c. (1000 IE) infiltration of the whealing 15 and 90 min subsequently to anti-IgE challenge produced no significant inhibition of the resulting ICRs or DCRs. The results suggest that the previously reported involvement of the coagulation process is a secondary phenomenon and do not support the concept that activation of the complement system is necessary for the evolution of DCRs.

Adult↗
PubMed2002

Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy.

PURPOSE: To determine the presence of activated complement components in eyes affected by diabetic retinopathy. METHODS: Eyes of 50 deceased donors with diabetic retinopathy and of 10 nondiabetic subjects with uveal melanoma (n = 6) or phthisical eyes (n = 4), as well as eyes of 16 deceased donors without diabetic retinopathy were subjected to immunohistochemical studies, using a panel of antibodies directed against candidate markers of complement activation. RESULTS: Extensive deposits of complement C5b-9 complexes were detected in the choriocapillaris immediately underlying the Bruch membrane and densely surrounding the capillaries, in all 50 diabetic retinopathy specimens. Complement deposition was sometimes also observed around the larger choroidal vessels. Similarly intense staining for C5b-9 was absent in 25 of the 26 of the other donor eyes. Positive staining was observed in a case of systemic amyloidosis. Staining for C3d positively correlated with C5b-9 staining, corroborating the notion that complement activation had occurred in situ. Furthermore, positive staining was found for vitronectin, which forms stable complexes with extracellular C5b-9. When present, deposits under the pigment epithelium and drusen also stained positively for the activated complement components, independent of diabetic retinopathy. In contrast, there was no positive staining for C-reactive protein (CRP), mannose-binding lectin (MBL), C1q, or C4, indicating that complement activation did not occur through a C4-dependent pathway. CONCLUSIONS: The presence of C3d, C5b-9, and vitronectin indicates that complement activation occurs to completion, possibly through the alternative pathway in the choriocapillaris in eyes affected by diabetic retinopathy. Complement activation at this site may evoke a spectrum of pathologic sequelae that could contribute to ocular tissue disease and visual impairment.

Aged↗
PubMed2005

A critical role for complement C3d and the B cell coreceptor (CD19/CD21) complex in the initiation of inflammatory arthritis.

Complement C3 cleavage products mediate the recognition and clearance of toxic or infectious agents. In addition, binding of the C3d fragment to Ag promotes B lymphocyte activation through coengagment of the BCR and complement receptor 2 (CD21). Signal augmentation is thought to be achieved through enhanced recruitment and activation of CD21-associated CD19. In this study we show, using the DBA/1 collagen-induced arthritis (CIA) model, that conjugation of C3d to heterologous type II collagen is sufficient to cause disease in the absence of the mycobacterial components of CFA. Transient depletion of C3 during the inductive phase of CIA delays and lessens the severity of disease, and DBA/1 mice deficient for coreceptor components CD19 or CD21 are not susceptible to CIA. Adoptive transfer experiments revealed that CD21 expression on either B cells or follicular dendritic cells is sufficient to acquire disease susceptibility. Although CD19(-/-) and CD21(-/-) mice produce primary Ab responses to heterologous and autologous type II collagen, they are impaired in the ability to activate T cells, form germinal centers, and produce secondary autoantibody responses. These findings indicate that binding of C3d to self-Ags can promote autoimmunity through enhanced Ag retention and presentation by follicular dendritic cells and B cells, respectively.

Animals↗
PubMed1985

Identification and characterization of the Epstein-Barr virus receptor on human B lymphocytes and its relationship to the C3d complement receptor (CR2).

In pursuing studies on the early events in the infection of human B cells by Epstein-Barr virus (EBV), we examined the host cell attachment phase with a panel of B-cell-specific monoclonal antibodies. One of the monoclonal antibodies, OKB7, directly blocked the attachment of purified EBV to B lymphocytes in the absence of a second anti-immunoglobulin antibody and thereby prevented EBV infection of tonsil and peripheral blood B cells. Although earlier studies have shown a close association of the EBV and complement receptor (CR2), an anti-CR2 monoclonal antibody, anti-B2, did not directly block the binding of EBV to B cells. A comparison of the structures recognized by these monoclonal antibodies on various cell types and their functional and physiochemical properties was undertaken. Flow cytometric analysis revealed that the molecules detected by OKB7 and anti-B2 were coexpressed to the same extent on B cells but were not expressed on T-cell lines. OKB7 and anti-B2 both immunoprecipitated a 145,000-molecular-weight membrane protein with an isoelectric point of 8.2 from membrane extracts of Raji lymphoblastoid cells. OKB7 and, to a lesser extent, anti-B2 directly blocked the attachment of C3d,g-coated fluorescent microspheres and sheep erythrocytes bearing C3d to B cells, indicating that these antibodies also react with CR2. These studies indicate that the EBV-CR2 receptor is a single membrane glycoprotein which possesses multiple antigenic and functional epitopes.

Antibodies, Monoclonal↗
PubMedDate not supplied

Detection of complement (c3d) coated cells in a newborn due to maternal anti-i.

A case of a positive direct antiglobulin test on a newborn's cord red blood cells caused by maternal anti-i is reported. The direct antiglobulin test was moderately positive using polyspecific antiglobulin reagent and monospecific anti-C3d, but negative using monospecific anti-IgG. The infant showed no clinical signs of hemolytic disease of the newborn.

Blood Group Antigens↗
PubMed1988

Complement C3d,g/Epstein-Barr virus receptor density on human B-lymphocytes estimated by immunoenzymatic assay and immunocytochemistry.

The density of the C3d,g/Epstein-Barr virus receptor (CR2) on human mononuclear cells (MNC) isolated from CPD stabilized blood, was determined by comparing the concentration of CR2 antigen in extracts from Raji cells, with a known receptor density, with extracts of MNC. The concentration of CR2 was determined by a sandwich ELISA using two mutually non-inhibiting monoclonal anti CR2 antibodies (HB5 and OKB7). The percentage of CR2+ MNC was determined by an immunocytochemical staining method. Analysis of MNC from 20 healthy donors, revealed that the density of CR2 molecules varied from 3,600-7,700 on CR2+ cells, and that the percentage of CR2+ MNC had a mean of 13%.

B-Lymphocytes↗