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PubMed2000

Activation of the acute phase response and complement C3 in patients with IgA nephropathy.

UNLABELLED: Recently we showed systemic complement activation in patients with immunoglobulin A (IgA) nephropathy (measured by "activated C3" [actC3], in other words, neoantigens developing on breakdown products after C3 activation) and reported that plasma levels of actC3 can indicate disease activity and renal outcome. In this study we investigated whether plasma C3a and C-reactive protein (CRP), which require tests that are more readily available, have a similar diagnostic and predictive value. CRP was measured using a highly sensitive enzyme-linked immunosorbent assay and C3a using a specific immunoassay. CRP and C3a levels were significantly higher in 56 patients with IgA nephropathy as compared with 55 healthy controls. C3a levels in IgA nephropathy patients were also significantly increased in comparison with 42 patients with hypertension or nonimmune renal diseases. Neither C3a nor CRP levels correlated with those of actC3 in IgA nephropathy patients. We also compared 10 IgA nephropathy patients with stable, normal renal function with eight IgA nephropathy patients progressing from normal to impaired renal function during mean follow-ups of 7.1 and 5.1 years, respectively. Mean CRP but not C3a levels during the observation period were significantly higher in IgA nephropathy patients with disease progression than in those with stable renal function. CONCLUSION: Systemic complement activation can be detected by measurement of plasma C3a in IgA nephropathy, but C3a levels cannot substitute for actC3 in predicting renal prognosis. Subclinical induction of the acute phase response is also present in patients with progressive IgA nephropathy, but again its prognostic value is limited. Repeated determinations performed over prolonged time courses may possibly improve the prognostic value of CRP levels.

Acute-Phase Reaction↗
PubMed1988

Disruption of the internal thioester bond in the third component of complement (C3) results in the exposure of neodeterminants also present on activation products of C3. An analysis with monoclonal antibodies.

Hydrolysis of the internal thioester bond in native C3 is thought to be a key event in initiating the alternative pathway of C activation, because the resulting C3(H2O) acquires "C3b-like" properties. Therefore, disruption of the internal thioester bond is probably accompanied by conformational changes in the C3 molecule. In this study, we demonstrate that such conformational changes indeed occur; 7 of the 19 mAb raised against C3 or C3 activation products recognized epitopes exposed on C3(H2O) but not on native C3. One of these epitopes is located on the C3a part, three on the C3c part, and another three on the C3d,g part. Because the 7 mAb bound equally well to C3 incubated either with MgCl2 or with methylamine (which primarily disrupts the thioester), the conformational changes detected by the mAb apparently occur after disruption of the thioester. Furthermore, the epitopes were also present on the corresponding C3 activation products. Immunoblotting experiments revealed that the epitopes for the three anti-C3d,g mAb were located on the C3d part, C-terminal to the thioester. The epitopes for 2 of the 3 anti-C3c mAb were located on the C-terminal alpha-chain fragment of C3c. Thus, this study provides immunochemical evidence for the biologic resemblance between C3(H2O) and C3 activation products. Implications of these findings for the activation process of C3 are discussed.

Animals↗
PubMed1991

Role of complements C3 and C5 in the phagocytosis of liposomes by human neutrophils.

During the course of a previous investigation, we noticed that the uptake of liposomes by human polymorphonuclear neutrophils (PMNs) was significantly lower in the presence of heat-inactivated serum compared to that in intact whole serum (Scieszka et al., Pharm. Res. 5:352, 1988). This observation suggested the participation of heat-labile complement components in the phagocytic process. In this report we conclude that complement C3bi is the component responsible for opsonization of the liposome surface. Phagocytosis was not supported by C3-deficient serum, and phagocytosis in whole serum was blocked by the antibody to the receptor for C3bi (CR3) but not by the antibody to the receptor for C3b (CR1). We also found that with C5-deficient serum the level of uptake was minimal but slightly higher than without any serum. When exogenous C5a was added along with C5-deficient serum, uptake levels similar in magnitude to those observed with intact serum were obtained. We conclude that C5a enhances phagocytosis of opsonized liposomes by activating the phagocytic capacity of CR3 on the PMN.

Adolescent↗
PubMed1980

A new method for the simultaneous quantitation of platelet-bound immunoglobuin (IgG) and complement (C3) employing an enzyme-linked immunosorbent assay (ELISA) procedure.

An ELISA technique for the quantitation of platelet-bound IgG and C3 is described. This is an antiglobulin consumption assay using commercial horseradish peroxidase conjugated anti-IgG and anti-C3 antisera. The greater the amount of antiglobulin consumed by the reaction with platelets the less is available to bind to an immune adsorbent in the form of human serum-coated polystyrene balls. This test can be calibrated by adding known quantities of IgG of C3 to the specific enzyme-linked antibody and the unbound fraction of antiserum is quantitated by allowing it to react with a chromogenic substrate for the enzyme and measuring the intensity spectrophotometrically, thus establishing an inverse relationship with the amount of antigen. Platelets from normal donors and those with non-immunological thrombocytopenia gave values of 1.3--15.5 ng IgG/10(6) platelets and 0.22--0.96 ng C3/10(6) platelets which are in accordance with the normal ratio of these proteins in normal serum. Fifteen patients in whom immune destruction of platelets weas suspected had excess platelet-bound IgG ranging from 30 to 450 ng IgG/10(6) platelets. In none of these patients could excess platelet-bound C3 be demonstrated. Compared to the antiglobulin consumption test we have found this test to be superior both technically and in terms of sensitivity and reproducibility.

Blood Platelets↗
PubMed1993

Complement C3 fragments in urine: detection in systemic lupus erythematosus patients by western blotting.

We characterized urinary excretion of C3 fragments among patients with systemic lupus erythematosus (SLE) as a possible indicator of renal involvement. 28 patients, representing a broad range of disease activity were admitted to our study. Urinary proteins were separated on 4-20% gradient SDS-PAGE gels, under reducing conditions, and transblotted to nitrocellulose. Western blots were developed with a polyvalent goat-anti-human C3d antiserum, and an alkaline phosphatase-conjugated rabbit anti-goat IgG. Three patterns were obtained: 1) no bands detected; 2) bands suggesting the presence of intact C3; and 3) samples with additional low molecular (< 4 x 10(4)) bands. The 12 patients with no C3 bands had minimal disease activity (e.g. fatigue, arthralgia, arthritis, rash, oral ulcers). The seven patients with intact C3 patterns also had minimally active disease. Their primary clinical findings included fatigue, pleurisy, renal disease which had been treated, hemolytic anemia, and arthritis. Patients with low molecular weight C3 fragments in their urine formed two sub-sets, based upon their presenting features. The first group had severe disease and contained all patients with active lupus nephritis (n = 4), while the second consisted of non-renal patients with primary clinical findings of moderate disease activity (e.g. thrombocytopenia, pneumonitis, arthritis). Our results suggest urinary excretion of low molecular weight C3 fragments correlates with active renal disease, but is a variable finding among SLE patients with non-renal manifestations of disease activity.

Blotting, Western↗
PubMed1987

Polymorphism of the complement C3 gene in the Lebanese population.

The C3 protein polymorphism was studied in 300 unrelated Lebanese. The gene frequencies were calculated and compared with other populations. DNA samples digested with various endonucleases were hybridized with a C3 probe, which was found to detect a frequent Sac I restriction fragment length polymorphism (RFLP) and a less frequent Taq I RFLP in the Lebanese population, as well as in the French populations.

Alleles↗
PubMed2004

Association of high serum concentration of the third component of complement (C3) with pre-existing severe coronary artery disease and new vascular events in women.

Atherosclerosis is an inflammatory disease. The complement system plays an important role in the atherosclerotic process. However, lesser data is available on the possible role of C3 as a risk factor for atherosclerosis. Therefore, in a follow up study we determined C3 levels in 266 patients with pre-existing severe coronary artery disease (CAD) and compared their serum C3 concentrations with the cause of the disease. We investigated whether C3 levels predict the major complications of severe CAD during a 5-year long follow up period in patients, who have received an aorto-coronary bypass graft surgery. C3 concentrations were elevated in the patients with severe CAD compared to 182 healthy controls, and women had higher C3 concentrations than men. Pathological C3 levels (C3> or =1.8 g/L) were able to predict major complications of atherosclerosis (death by cardiac events, new acute myocardial infarction, stroke, carotid surgery and peripheral arterial disease) that developed during the follow up period only in women (OR: 4.1, 95% C.I. 1.23-13.61, p = 0.0249) independent of other risk factors for atherosclerosis. Our data supports the assumption that high C3 indicates the progression of atherosclerosis as a special marker of chronic inflammation.

Arteriosclerosis↗
PubMed1999

Distinction between processing of normal and mutant complement C3 within human skin fibroblasts.

Inherited C3 deficiency may result from mutations in the C3 gene affecting transcription or translation (type I deficiency). We described a type II C3 deficiency caused by a mutation yielding an abnormal non-secreted C3. The post-translational processing of mutant and normal C3 was analyzed in fibroblasts grown from skin biopsies. Mutant C3 is located mainly in the endoplasmic reticulum (ER), whereas normal C3 is seen evenly distributed throughout the cytoplasm. Most of the mutant C3 is degraded within the cell, and only a small fraction (around 8%) is secreted after 20 h chase. Processing of C3 at 19 degrees C was reduced in normal fibroblasts but completely blocked in mutant fibroblasts. ATP depletion blocked processing of normal proC3 to C3. In contrast, the mutant proC3 was partly degraded in ATP-depleted cells, yet its complete degradation and secretion were blocked. Intracellular degradation of the mutant C3 was not inhibited by NH4Cl, thus excluding cleavage within lysosomes. These results demonstrate that the type II mutant C3 studied here is retained in the ER probably by a quality contol machinery that identifies abnormal protein folding. Consequently, it is destined to undergo a two-step intracellular degradation; an initial ATP-independent step followed by an ATP-dependent step.

Cells, Cultured↗
PubMed1993

Effect of complement (C3) depletion on the generation of memory in rabbits primed with antigens of Trypanosoma evansi.

Using the antibody response during secondary exposure of rabbits primed with antigens of Trypanosoma evansi as an indirect measure of immunological memory, it was shown that C3 decomplementaemia resulted in a reduced antibody response, with IgM being predominant in the sera samples followed by IgG and then IgA [corrected]. While significant differences were observed in the levels of IgG produced by the C3-depleted and C3-intact rabbits no differences were recorded in the levels of IgM and IgA produced by the two groups after C3 decomplementaemia. These results demonstrate that C3 depletion did not abolish memory of the T. evansi antigen in these rabbits but only modified the magnitude and pattern of their response. The host response to reinfection may be affected by such changes as those observed in this study.

Animals↗
PubMed1996

An immunohistochemical study of IgG, complement C3, collagen type III and macrophage-marker Ki-M7 in epiretinal membranes.

PURPOSE: To observe the immunological changes in epiretinal membranes from the patients with proliferative vitreoretinopathy (PVR). METHODS: Twelve samples of epiretinal membranes obtained during vitreous surgeries for PVR were examined by direct and indirect immunofluorescein histochemistry. RESULTS: The cellular membranes in 8 cases were composed of retinal pigment epithelial cells, fibroblast-like cells, macrophages and collagen. Positive stainings of IgG, C3+ collagen type III and macrophage-marker Ki-M7 (CD68) was seen in the membranes. CONCLUSION: The results indicate that humoral immune components and macrophages may play an important role in the development of epiretinal membrane formation.

Adolescent↗
PubMed1998

Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component.

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell-dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6-deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti-mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3-deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6-deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.

Animals↗
PubMed1982

Platelet-associated complement C3 in immune thrombocytopenic purpura.

Platelet-associated C3 (PA-C3) was measured with a quantitative immunofluorescence assay. With this assay, PA-C3 levels were determined for 78 normal volunteers, 30 patients with immune thrombocytopenic purpura (ITP), and 20 patients with nonimmune thrombocytopenias. Platelet-associated IgG (PA-IgG) levels were also measured with our standard quantitative immunofluorescence assay. All patients with nonimmune thrombocytopenias and ITP in remission had normal PA-C3 levels. Twenty-four patients with active ITP were classified into 3 groups: 9 (38%) with increased PA-IgG and normal PA-C3 levels, 10 (42%) with elevated PA-C3 and PA-IgG levels, and 5 (20%) with increased PA-C3 values only. A direct correlation was found between PA-C3 and PA-IgG levels. PA-IgG levels were higher in the group of patients with elevated PA-C3 levels than in those with normal values. Platelet survival studied showed reduced survival times of 1.5--2.5 days for the 5 patients with elevated PA-C3 levels only. Elevated PA-C3 levels returned to normal in 7 ITP patients whose platelet counts increased in response to corticosteroid therapy or to splenectomy. Therefore, PA-C3 and PA-IgG assays can be used to identify patients with ITP, to follow their response to therapy, and to classify them into immunologic subgroups similar to red cell classification by Coombs' testing in immune hemolytic anemia.

Adolescent↗
PubMed1997

Renal cortical complement C3 gene expression in IgA nephropathy.

Glomerular C3 deposits are commonly found in immunoglobulin A (IgA) nephropathy. Renal gene expression and protein synthesis of complement components have been shown in settings of tissue inflammation. In this study, the pathogenetic involvement of locally produced C3 in IgA nephropathy was analyzed. C3 gene expression was analyzed by reverse transcription, polymerase chain reaction, and in situ hybridization techniques. C3 mRNA was detected in 56% of cases, with a significantly higher percentage in patients with moderate-to-severe lesions than in those with mild lesions (P < 0.01). By in situ hybridization, C3 transcript was predominantly expressed by tubular cells and some interstitial cells. C3 mRNA was also observed on glomerular parietal epithelial cells. Immunoreactive native C3 was detected on cortical tubuli by an anti-C3c immunoalkaline-phosphatase technique. A significant correlation was found between renal C3 transcription and glomerulosclerosis, intracapillary proliferation (both P < 0.005) and markers of interstitial damage, including tubular atrophy (P < 0.05), interstitial infiltration (P < 0.05), and fibrosis (P < 0.005). Proteinuria (P < 0.05), but not serum creatinine, at the time of renal biopsy correlated with C3 mRNA. In conclusion, it was demonstrated that the C3 gene was expressed primarily in proximal tubular cells and occasionally in glomerular crescents, and that its expression correlated with clinical and histologic markers of severity and poor outcome of IgA nephropathy. Thus, a pathogenetic involvement of the local transcription and translation of the C3 gene in IgA nephropathy was suggested.

Adolescent↗