[Clinical study of complement breakdown products in patients with hypocomplementemic glomerulonephritis].
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Adult↗
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Complement activation during normal pregnancy.
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Complement Activation↗
The third component of complement: new functions for an old friend.
The present review has evaluated four biologic processes in which the participation of C3 as a primary mediator deserves more extensive investigation. These novel functions of C3 derive in part from the biochemistry ascribable to a thiolester-containing protein and are underscored by its remarkably high concentration in plasma and widespread presence in tissues. Such physiologic characteristics argue that we have only begun to understand the functions of this most versatile complement protein. The availability of full-length cDNA and the ability to manipulate the C3 gene in tissue culture or embryonic stem cells should help to illuminate the pluripotent nature of this fascinating protein.
Amino Acid Sequence↗
Identification of a spontaneously shed fragment of B cell complement receptor type two (CR2) containing the C3d-binding site.
CR2 is a 140-kilodalton glycoprotein expressed on B lymphocytes which binds to both C3d and Epstein-Barr virus (EBV). The present study identified a 72-kilodalton C3d-binding protein (gp72) in the spent culture media of Raji B lymphoblastoid cells as a spontaneously shed fragment of the 140-kilodalton CR2 molecule. Both polyclonal and monoclonal antibodies (AB) were used in several assay systems to detect antigenic determinants shared between the gp72 fragment and CR2. Rabbit antibodies to either intact CR2 or gp72 blocked C3d receptor activity, and this inhibitory activity was removed by absorption of anti-CR2 with purified gp72.OKB7, a monoclonal anti-CR2 AB that blocks both C3d and EBV binding to CR2, reacted specifically with both CR2 and gp72, whereas both anti-B2 and HB-5 monoclonal anti-CR2 AB, that block neither of these receptor sites, were unreactive with gp72. The data suggested that the gp72 fragment was not present as such in intact cells, but rather was a product of cells generated by proteolysis of CR2. Thus, intrinsically labeled gp72 was isolated from Raji cell media by affinity chromatography on OKB7-Sepharose, but only intact CR2 was isolated from the Raji cell fraction solubilized in the presence of protease inhibitors. Several lines of evidence suggested that gp72 was not a second type of C3d receptor that was distinct from CR2. First, Raji cells expressed nearly identical amounts of OKB7 and HB-5 epitopes when analyzed by flow cytometry or radioimmune assay, excluding the possibility that B cells expressed OKB7 antigens in both CR2 and a distinct HB-5-negative C3d receptor. Second, all Raji cell surface C3d receptor activity was associated with HB-5-reactive CR2 molecules. We conclude that gp72 represents a spontaneously shed proteolytic fragment of CR2 that contains the C3d-binding site and the closely associated OKB7 epitope.
B-Lymphocytes↗
Kinetic analysis of the interactions of complement receptor 2 (CR2, CD21) with its ligands C3d, iC3b, and the EBV glycoprotein gp350/220.
The molecular mechanisms involved in the interaction of complement receptor 2 (CR2) with its natural ligands iC3b and C3d are still not well understood. In addition, studies regarding the binding site(s) of the receptor on C3 as well as the affinities of the C3 fragments for CR2 have produced contradictory results. In the present study, we have used surface plasmon resonance technology to study the interaction of CR2 with its ligands C3d, iC3b, and the EBV surface glycoprotein gp350/220. We measured the kinetics of binding of the receptor to its ligands, examined the influence of ionic contacts on these interactions, and assessed whether immobilized and soluble iC3b bound with similar kinetics to CR2. Our results indicate that 1) gp350 binding to CR2 follows a simple 1:1 interaction, whereas that of the C3 fragments is more complex and involves more than one intramolecular component; 2) kinetic differences exist between the binding of C3d and iC3b to CR2, which may be due to an additional binding site found on the C3c region of iC3b; and 3) iC3b binds to CR2 with different kinetics, depending on whether the iC3b is in solution or immobilized on the surface. These findings suggest that binding of CR2 to iC3b and C3d is more complex than previously thought.
Alanine↗
Immune complexes and complement activation following rupture of intracranial saccular aneurysms.
Circulating immune complexes (CIC) and complement activation (plasma C3d levels) were monitored during a 2-week period in patients with ruptured cerebral aneurysms and also in patients with cerebral hematoma unrelated to saccular aneurysms. Thirteen of 18 aneurysm patients were found to have CIC on admission as compared to three of 21 healthy blood donors (p less than 0.001). The presence of CIC in aneurysm patients was associated with a poor prognosis. Eight of nine patients who developed angiographic vasospasm had CIC on admission compared with one of four without vasospasm. Patients with vasospasm showed a twofold increase in plasma C3d levels at the time when the spasm occurred, whereas no significant changes in the C3d concentration could be demonstrated in aneurysm patients without spasm or in patients with hematoma unrelated to aneurysm rupture. These findings suggest that immunological processes involving complement-activating immune complexes are involved in the pathogenesis of cerebral vasospasm following rupture of saccular aneurysms.
Adult↗
Stable expression and function of EBV/C3d receptor following genomic transfection into murine fibroblast L cells.
The Epstein-Barr virus (EBV) and the C3d component of complement bind to the same cell surface receptor (EBVR/CR2) which is part of the B lymphocyte differentiation antigen recognized by the monoclonal antibodies (mAb) of the cluster of differentiation 21 (CD21). To analyze EBV and C3d binding to this receptor, mouse fibroblasts were transfected with human genomic DNA and rare CD21-positive cells were selected and cloned by cell sorting. The presence of the human gene in host cell DNA as well as its transcription product were assayed with a cloned EBVR/CR2 cDNA by Southern and Northern blotting analysis, respectively. A glycoprotein of apparent molecular mass of 140 kDa, similar to that found in human B lymphocytes, was immunoprecipitated with anti-CD21 mAb and proved to be functional since both C3d and EBV bound efficiently and specifically to mouse cells expressing EBVR/CR2. However, no expression of EBV nuclear antigens, early antigens and viral capsid antigens was detected in cells exposed to EBV. This indicates that the presence of EBVR/CR2 is not sufficient to allow full infection of mouse fibroblasts.
Animals↗
Charge and size heterogeneity of C3d following in vivo and in vitro activation of the complement system.
Split products of the third complement factor (C3) expressing D but not C epitopes (C3d) were analyzed by crossed immunoelectrophoresis and size chromatography. Four molecular forms (termed 1, 2, 3, and 4 from the anodic side) were identified. The precipitation pattern of C3d in serum following acute in vivo activation was similar to the patterns observed using in vitro activation by MgCl2, zymosan, Escherichia coli, and delta IgG. These patterns were different from those observed in normal human serum and serum from a patient suffering from systemic lupus erythematosus. The molecular weights of forms 1 and 4 were approximately 170,000 daltons and those of forms 2 and 3 approximately 40,000 daltons.
Complement Activation↗
Acute motor axonal neuropathy: an antibody-mediated attack on axolemma.
The acute motor axonal neuropathy (AMAN) form of the Guillain-Barre syndrome is a paralytic disorder of abrupt onset characterized pathologically by motor nerve fiber degeneration of variable severity and by sparing of sensory fibers. There is little demyelination or lymphocytic inflammation. Most cases have antecedent infection with Campylobacter jejuni and many have antibodies directed toward GM1 ganglioside-like epitopes, but the mechanism of nerve-fiber injury has not been defined. In 7 fatal cases of AMAN, immunocytochemistry demonstrated the presence of IgG and the complement activation product C3d bound to the axolemma of motor fibers. The most frequently involved site was the nodal axolemma, but in more severe cases IgG and C3d were found within the periaxonal space of the myelinated internodes, bound to the outer surface of the motor axon. These results suggest that AMAN is a novel disorder caused by an antibody- and complement-mediated attack on the axolemma of motor fibers.
Acute Disease↗
Fibronectin binds to complement-coated agarose beads and increases their association to mouse macrophages.
We have studied the binding of fibronectin to complement (C3b, C3bi, C3d)-coated agarose beads and its effect on cell association of such beads to mouse macrophages. Fibronectin bound to agarose beads preincubated in human serum, whereas no binding occurred after preincubation of the beads with complement-inactivated (50 degrees C for 20 min or ethylenediaminetetraacetic acid) sera. The binding of iodine-labelled fibronectin to beads preincubated in fibronectin-depleted serum (HS-FIB) was about twice that of beads preincubated in normal serum. Unlabelled fibronectin inhibited the following binding of labelled fibronectin to beads pretreated in HS-FIB. A similar amount of fibronectin bound to agarose beads coated with equimolar amounts of C3b, C3bi, or C3d, suggesting that the common domain C3d carries the main binding site(s) for fibronectin. Preincubation of serum-treated and trypsinized agarose beads with fibronectin led to an increased association (22%) of such beads to mouse macrophages. The results indicate that fibronectin promotes binding of complement-coated agarose beads to mouse macrophages, whereas the ingestion of the beads is mediated via complement C3 receptors.
Animals↗
A prospective study of circulating immune complexes in patients with breast cancer.
Levels of circulating immune complex (cIC) and complement split product C3d were studied in 86 patients with breast cancer (BC), 22 patients with benign breast disease (BD), and 72 age- and sex-matched blood-bank donors (NC), using solid-phase Clq-protein A RIA, Clq-anti-IgG RIA, anti-C3d anti-IgG RIA, and polyclonal IgM-rheumatoid factor ELISA for clC detection. No significant differences in cIC and C3d levels were found between the groups. The incidence of raised cIC levels varied from 4.9 to 8.2% in the BC group and from 4.5 to 22.7% in the BD group in comparison with 2.9 to 3.0% in the NC group. Using the solid-phase polyclonal IgM-rheumatoid factor ELISA we found that the cIC levels of patients with stage-III cancer were significantly higher than those of patients with stage-I or stage-II cancer. However, the other tests showed no relationship to tumor burden. Likewise, an effect of mastectomy on the cIC levels was also only detectable by one of the assays, i.e., the post-mastectomy levels of cIC as measured by the solid-phase anti-C3d anti-IgG RIA were significantly lower than the pre-mastectomy levels. Serial analyses of cIC and C3d levels were performed pre-operatively, one month post-operatively and every 3 months during the first year after mastectomy in 46 of the patients. During a I-year observation period, 7 patients developed metastatic disease. The occurrence of metastatic disease was not, however, preceded by characteristic changes in serially determined cIC and C3d levels.
Adult↗
Search for circulating immune complexes and activation of the complement system in relation to estrogen treatment.
By employing an ammonium sulphate precipitation technique, previous studies have shown circulating immune complexes (cIC) in an increased proportion of women using oral contraceptives, as compared with non-users. The pathogenicity of cIC is well established, as deposition in organs may lead to activation of the complement system and thereby inflammation and tissue destruction. The purpose of the present study was to determine whether estrogen treatment could induce the formation of cIC, as measured by more specific immune complex assays. To test for complement activation, plasma samples were analysed for the complement split product C3d. Thirty-one women treated with estrogen for menopausal hormone deficiency symptoms and 38 untreated controls were analysed for cIC. Using a solid-phase C1q-anti-IgG binding assay, the mean level of cIC in the estrogen-treated group did not differ significantly from that of the untreated control group (p greater than 0.05). In a solid-phase C1q-protein A binding assay a very small average increase in the cIC values for the estrogen-treated group in comparison with the untreated group was found, expressing a significant difference (p = 0.04). Moreover, the C3d levels for the estrogen-treated group did not differ from the untreated control group. Finally, no differences could be demonstrated in cIC and C3d levels between patients treated with synthetic estrogens and patients treated with natural estrogens.
Antigen-Antibody Complex↗
On the kinetics of complement activation, leucopenia and granulocyte-elastase release induced by haemodialysis.
In order to elucidate the kinetics of haemodialysis-induced activation of complement, leucopenia and release of granulocyte-elastase, 10 patients (three females and seven males; mean age 47.8 years) were extensively studied during a 4 h haemodialysis treatment and for the following 24 h, and further compared with a healthy control group. Prior to dialysis patients had normal leucocyte count, plasma elastase bound to alpha 1-proteinase inhibitor (E-alpha 1P1) and total haemolytic complement, whereas plasma C3d was higher and plasma C5a lower than in controls. Haemodialysis induced initial leucopenia and subsequent rebound phenomenon lasting 24 h post treatment. These alterations were due to almost selective changes in neutrophile count as monocyte and lymphocyte counts, apart from decrease in the first 30 min, were unchanged. Total haemolytic complement decreased initially during dialysis and rose at the end. Generation of C5a within the dialyser was evident by demonstration of high levels of this anaphylatoxin in dialyser effluent plasma; maximal values observed coincided with the nadir of leukopenia. Plasma C3d and E-alpha 1P1 both progressively rose during dialysis. After termination of extracorporeal circulation the disappearance rates (T/2) were approximately 6 h and 2.5 h respectively. Haemodialysis thus induces changes in the complement and leucocyte system resembling an acute inflammation, which out-lasts the treatment period.
Adult↗
CD5 and CD21 molecules are a functional unit in the cell/substrate adhesion of B-chronic lymphocytic leukemia cells.
The modulation of surface molecules on B-chronic lymphocytic leukemia (B-CLL) cells was studied in vitro by incubation with CD19, CD20, CD21, CD5 and anti-IgM antibodies. The cytoplasmic changes were evaluated by analyzing the organization of cytoskeletal F-actin and the adhesive properties of stimulated B-CLL cells. The following observations were made: (a) CD5 antigen is capped on the surface of B-CLL cells (but not on normal CD5+ B and T lymphocytes). (b) On B-CLL cells, CD5 and CD21, the receptors for the C3d fraction of complement, co-cap and co-modulate while surface IgM as well as CD19 and CD20 do not cap. (c) B-CLL cells, after capping of CD5 or CD21 surface molecules, fail to organize F-actin into podosomes. (d) The pre-incubation of B-CLL cells with either CD5 or CD21 antibodies prevents their binding to purified C3d protein used to coat coverslips. These data indicate that an intimate spatial relationship exists between CD5 and CD21 molecules on the B-CLL surface. The CD5-CD21 complex is involved in the redistribution of cytoskeletal proteins which may control the adhesive properties of these malignant B cells.
Actins↗
Complement-mediated demyelination in patients with IgM monoclonal gammopathy and polyneuropathy.
We investigated the role of complement in the pathogenesis of the demyelinating polyneuropathy that occurs in some patients with IgM monoclonal gammopathy. Seven patients with chronic sensorimotor polyneuropathy and IgM monoclonal gammopathy were examined. In six patients, the monoclonal protein recognized an epitope shared by myelin-associated glycoprotein and two peripheral-nerve glycolipids, whereas in one patient, IgM bound to an unidentified myelin antigen. Direct and indirect immunofluorescence and immunoperoxidase assays showed colocalization along the myelin sheaths of peripheral-nerve fibers of monoclonal protein with complement components C1q, C3d, and C5. In addition, terminal-complement complex that was not associated with S protein was detected in myelin sheaths. It appeared that alterations in myelin geometry caused by the separation of myelin lamellae corresponded to sites at which terminal-complement complex was deposited. We conclude that demyelination in polyneuropathy associated with IgM monoclonal gammopathy may be mediated by complement.
Aged↗
Free radical involvement in hypertrophic scar formation.
Hypertrophic scarring following thermal injury has become a major problem in Hong Kong. There is evidence that immunological and biochemical changes are associated with thermal injury, including pyridinoline crosslinks which are present in large quantities in hypertrophic scar, but the primary cause of hypertrophic scar formation still remains to be established. It has been reported that free radicals are assosciated with the formation of pyridinoline. In this study, attempts have been made to elucidate the involvement of free radicals in hypertrophic scar formation after thermal injury by determining the concentrations of Complement, free iron and pyridinoline crosslinks in collagen fibres. The results showed that the Complement activation product, C3d, was increased in the first week (i.e., day 7) postburn, indicating an acute inflammatory response. Free radicals, reported to be associated with the formation of pyridinoline crosslinks, and free iron content, were also found to have higher concentration in hypertrophic scar than in normal skin. The data suggest the involvement of free radical in hypertrophic scar formation. The observed increase in serum C3d concentration in about the first week indicates an acute inflammatory response to thermal injury. Both C3d and free iron concentrations (in vitro) are found higher in hypertrophic scar than in normal skin may suggest their roles in the generation of free radicals.
Amino Acids↗
Prognostic value of serial determinations of circulating immune complex levels in malignant melanoma.
A total of 50 melanoma patients free of distant metastatic disease and 54 healthy controls were analyzed for circulating immune complexes (cIC) and complement split product (C3d), using solid-phase Clq-anti-IgG radioimmunoassay (RIA), Clq-protein A RIA, and anti-C3d anti-IgG RIA for cIC detection. No significant differences in cIC and C3d levels could be demonstrated between the controls and the 31 patients with primary malignant melanoma analyzed before surgery. To evaluate the prognostic value of serial measurements, samples from the 50 patients were taken at regular intervals for 4 to 27 months (median, 20 months). Surgery was the only treatment given. Significant changes in the cIC and C3d levels were defined by reference to the changes that occurred in 23 of the 54 healthy controls observed for a period of 6 to 55 months (median, 23 months). During the period of serial sampling, recurrent disease developed in 8 of the patients. In only 3 of these 8 patients (versus 10 of 42 patients without recurrence) did significant changes occur, and the changes occurred either at the same time or after the clinical diagnosis of recurrence. During the entire clinical observation period of 6 years, a total of 11 patients developed recurrences. Significant changes were only observed in 4 of these 11 patients versus 8 of 37 patients without recurrence. In conclusion, changes in cIC and/or C3d levels were not found to be indicative of early or long-term recurrence of malignant melanoma.
Adolescent↗
Complement C3b receptors on erythrocytes in patients with juvenile rheumatoid arthritis.
Forty patients with juvenile rheumatoid arthritis (JRA) were examined for C3b receptor (CR1) levels on erythrocytes (by an enzyme-linked immunosorbent assay), levels of circulating immune complexes (IC) (by a polyethylene glycol precipitation-complement consumption method), C3d split products (by intermediate gel rocket immunoelectrophoresis), and HLA-A, B, and C (by microdroplet lymphocytotoxicity test). Lower CR1 levels were found predominantly among patients with JRA (mean 57%) compared with 40 age-matched controls (mean 68%) (P = 0.008). The CR1 levels differed when the JRA patients were grouped by mode of disease onset and by clinical state at the time of testing (levels in patients with pauciarticular disease were higher than those in patients with polyarticular disease, and levels in patients with polyarticular disease were higher than those in patients with systemic disease) or by sex (girls had higher levels than boys; P = 0.01). The levels of circulating IC and C3d were elevated in 25% and 40% of JRA patients, respectively, and were mutually correlated (P less than 0.05, tau = 0.20). A negative correlation was found between levels of C3d and the numbers of CR1 (P less than 0.01, tau = -0.28), but concentrations of circulating IC did not correlate with CR1 values. CR1 levels were the same in 6 HLA-B27 positive and 25 HLA-B27 negative patients. These findings do not represent conclusive evidence that the number of CR1 on erythrocytes serves as a predictor of disease severity or as an indicator of disease activity in patients with JRA.
Adolescent↗