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PubMed1985

Immunoglobulins and complement components in human aortic atherosclerotic intima.

Concentration and preferential retention of immunoglobulins and complement components were studied in comparison with other plasma proteins in 42 human aortae with atherosclerosis. Saline and acid extracted IgG, IgA, IgM, C1q, C3c, C4, C9, C3A, C-reactive protein, alpha 1-antitrypsin, alpha 2-macroglobulin, albumin, transferrin and fibrinogen were quantitatively determined using the radial immunodiffusion. The fibrous plaques and their adjacent areas contained higher levels of each protein than intima with only fatty streaks. No significant differences were found between the fibrous plaques and their adjacent areas presenting intimal thickenings. Saline eluted IgG and IgA were significantly higher in the fibrous plaque intima than in intimal samples with fatty streaks and were the only proteins detected in the acid eluates. The complement components were present in all saline eluates, while C-reactive protein was found in 23 samples. Crossed immunoelectrophoretic studies showed the activation of saline C3 and C4. In 8 cases serum levels of the studied proteins were compared with their concentration in saline eluates obtained from intima and media. The immunoglobulins and complement components presented higher intima/serum and lower media/intima retention ratios than the other studied proteins suggesting their preferential retention in the intima. The presence of immune related proteins in the atherosclerotic intima and their preferential retention might be explained not only by an altered permeability but also in relation to their function.

Adult↗
PubMed1982

Complement activation and complement control proteins in acute pancreatitis.

Serum levels of the complement proteins C3, C4, C1 inhibitor (C1 INH), factor I (C3b inactivator) and factor H (BIH) and plasma levels of cleavage products of C3 (C3c) and factor B were measured in 26 patients with acute pancreatitis. Breakdown of C3 occurred in 19 patients, as shown by a reduction in C3 level and the presence of C3c. C4 levels, however, did not fall and factor B breakdown products were not detected, thus suggesting that enzymatic cleavage of C3 occurred without significant involvement of either the early classical pathway or the alternative pathway. C1 INH and factor H both showed increases, presumably reflecting an acute phase response. Factor I showed an initial fall followed by a rise. There was no correlation between the presence or extent of C3 breakdown and the clinical condition of the patients. It is concluded that C3 cleavage in pancreatitis probably results from tryptic activity and that the measurement of complement components has no part to play in the management of the disease.

Acute Disease↗
PubMed1989

Interaction between C3 and IL-2; inhibition of C3b binding to CR1 by IL-2.

We previously reported that C3 has a role in the enhancement of the IL-2 dependent proliferation of helper T cells. Because the IL-2R has a structural homology with the complement proteins, such as CR1 and CR2, we studied the possible ligand crossreactions on CR1 and IL-2-receptor, and the direct interaction between C3 and IL-2. While C3 has an enhancing effect on the IL-2 dependent proliferation of HT-2, a CR1-positive mouse T-cell line, the growth of the CTLL-16 line (CR1-negative) is not affected by C3. It has been proven that neither the insolubilized C3 nor the soluble C3b-like C3 react with the IL-2 binding epitope of the IL-2 receptor. However, using human RBC we have demonstrated that the binding of aggregated C3 to CR1 is inhibited by rIL-2, in a dose-dependent manner. When RBC were incubated with rIL-2 and FITC-labelled Fab-anti-CR1 simultaneously, there was no inhibition in the fluorescence intensity. As detected by ELISA, rIL-2 was bound to the same extent by insolubilized C3, C3b, and C3c, while C3d coat had lower binding capacity. The receptor-binding epitope of IL-2 is intact in the complex of complement proteins and rIL-2, as demonstrated by the binding of DMS1, a monoclonal antibody reacting with the receptor site of IL-2. It is strongly suggested that C3b may play a role in the growth of CR1 positive T cells.

Cell Line↗
PubMed1998

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Animals↗
PubMed1992

Complement activation during low-density lipoprotein apheresis.

Complement system activation was investigated in two girls with familial homozygous hypercholesterolemia undergoing two monthly sessions on LA15 or LA40 (Kaneka liposorber). We determined blood levels of C3c and C3a, leukocyte counts, and plasma levels of C3c and C3a in the extracorporeal circulation device at the start of the sessions and 15 and either 60 or 120 min into them. Sequential eluates were collected from LA40 at the end of the sessions (0.5M NaCl, 1M hydroxylamine). Anaphylatoxin C3a increased throughout, especially with LA40. As previously reported, C3a was trapped in the dextran column but was noticeably present in efferent plasma. Besides many proteins, nonnative complement fragments bearing C3a and C3d antigens were detected in almost all the eluates, suggesting possible in situ complement activation. Practically, complement activation induced by the first filter is a risk; long-term side effects may arise from this extracorporeal circulation device.

Blood Component Removal↗
PubMed2003

Flow cytometry based detection of HLA alloantibody mediated classical complement activation.

Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) testing is used to assess recipient presensitization and post-transplant alloantibody formation in transplant recipients. However, CDC test results can be affected by false-positive reactions brought about by autoantibodies or antilymphocyte reagents. As an alternative to the CDC-PRA assay, detection of HLA alloantibodies using HLA antigen-coated microbeads (FlowPRA test) was recently established. FlowPRA testing, however, does not distinguish between (presumably more harmful) complement-fixing and noncomplement-fixing alloantibodies. In this study, we established a novel assay allowing flow cytometric detection of HLA alloantibody dependent classical complement activation using the FlowPRA test. For the detection of complement activation, FlowPRA beads were incubated with sera from highly sensitized dialysis patients (CDC-PRA reactivity >60%) and then stained for C4 (C4d, C4c) and C3 (C3d, C3c) fragments, as well as C1q deposition using indirect immunofluorescence. We demonstrate alloantibody induced induction of C4 fragment, and in parallel C1q deposition to HLA class I or class II beads. As shown by immunoblotting, C4 staining was not due to the presence of preformed C4 fragment-IgG/M complexes. Indeed, C4 fragment deposition in our in vitro system was demonstrated to result from de novo complement activation. First, inactivation of C4 by treatment of sera with methylamine, which inhibits cleavage of the internal thioester, completely abolished C4 fragment deposition. Second, C4 fragment deposition was not observed in the evaluation of C4-free immunoadsorption eluates obtained from highly sensitized dialysis patients. After supplementation with complement, however, eluates induced C4 deposition. Deposition of C4 split products and C1q was temperature-dependent with maximum binding after incubation at 4 degrees C for 60 min. In contrast, maximum C3 fragment deposition was found at 37 degrees C. At this temperature, C3 deposition occurred in an alloantibody and C4-independent fashion, presumably as a result of alternative complement activation. In summary, we describe a novel cell-independent and easy-to-perform PRA test that permits flow cytometry based detection of alloantibody induced classical complement activation. Future studies will have to evaluate its possible relevance as an alternative to CDC-PRA testing in clinical transplantation.

Case-Control Studies↗
PubMed1990

Immunohistopathologic findings in synovial biopsies before and after synovectomy in patients with chronic inflammatory joint diseases and their relation to clinical evaluation. A prospective study of biopsies taken from areas selected by arthroscopy.

Synovial biopsies were obtained from 28 patients with various kinds of chronic arthritis, at synovectomy and 6 and 12 months later. The tissues were examined by immunofluorescence technique, recording the quantities of cells and extracellular deposits staining with polyclonal antisera to IgG, IgA, IgM, C3c, fibrinogen, and chi and lambda light chains, and monoclonal antibodies to CD3, CD5, CD11b, HLA DR, and TCC (Terminal Complement Complex). These parameters were compared with scores obtained by arthroscopy and clinical evaluation (Colorado Knee Score) performed at the same time. Taken as a group, the immunological parameters showed reduction in activity 6 months after synovectomy (p less than 0.01), and a tendency to revert to base-line values after 12 months. A similar reduction in activity after 6 months was also found by arthroscopic and clinical evaluation. Thus, this longitudinal study demonstrated a relationship between changes in immunologic activity, arthroscopic findings and clinical activity after synovectomy in patients with chronic arthritis. This is consistent with an immunological pathogenesis for the inflammation in these joints.

Adolescent↗
PubMed1982

Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes.

The main finding of this paper is that CR1, the membrane receptor for C3b and C4b, together with C3b/C4b-inactivator (I), degrades C3b bound to immune complexes (C3b*). Two fragments are generated: C3c, which is released from the immune complexes, and C3d*. The C3c fragment released from the cell intermediate EAC1423b prepared with 125I-C3 was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and radioautography. It has a 135,000 mol wt and contains disulfide bonded labeled polypeptide chains of 75,000 and 31,000 mol wt, which presumably represent the beta and a fragment of the alpha-chain of C3b*. Silver staining of the SDS-PAGE gels revealed other C3-derived bands with 39-42,000 mol wt. Human erythrocytes + I also cleave C3b* into C3c and C3d*. The activity of the erythrocytes is CR1 mediated because it can be totally inhibited by monoclonal antibodies to CR1. In contrast with these results, I together with the serum protein beta 1H (H) transform EAC1423b into hemolytically inactive EAC1423bi and cleave the alpha' chain of C3b* into fragments of 70,000 and 40,000 mol wt. Small amounts of C3c are also released at relatively high concentrations of H. On a molar basis, the efficiency of CR1 in the generation of C3c and C3d is 10(4)-10(5) greater than H. An additional observation was that C3c could be released by treating EAC1423bi with CR1 + I and that this reaction was also inhibited by monoclonal antibodies to CR1. Therefore, it is likely that CR1 has binding affinity for iC3b and that the degradation of C3b* proceeds as follows: C3b (formula, see text) C3c + C3d*. Taken together, our findings argue that the processing of C3b* in vivo occurs in solid phase, that is, on the surface of cells bearing CR1.

Antigen-Antibody Complex↗
PubMed1987

Biochemically damaged erythroblasts bind natural serum antibodies and activate complement.

Friend leukaemia erythroblasts which had been damaged biochemically by treatment with inhibitors of cellular metabolism (sodium fluoride, sodium azide) or of protein synthesis (cycloheximide, puromycin) were incubated with heat-inactivated or fresh mouse serum and tested for surface-bound IgG and C3c, respectively, by reaction with FITC-immunoconjugates followed by flow-cytofluorometry. Erythroblasts exposed to sodium azide, cycloheximide or puromycin showed specific binding of IgG; the extent of binding was related to the concentration of the drugs and duration of treatment. Moreover, prolonged exposure of the cells to the inhibitors of protein synthesis lead to a dose-dependent activation of complement. The results suggest that the opsonization of biochemically-damaged Friend leukaemia erythroblasts with IgG and C3 may facilitate their interaction with macrophages.

Antibodies, Anti-Idiotypic↗
PubMed1988

A sensitive method to detect synthesis of the functional classical, alternative and terminal pathway of complement by cells cultured in vitro.

A new method used to study in vitro synthesis by human monocytes and alveolar macrophages of the essential complement components for the functional classical, alternative and terminal pathway is presented. The method is based on accumulation of major complements components on activators of the alternative (agarose beads) and classical (lgM-sensitized sheep erythrocytes; ElgM) pathway during co-culture with the phagocytes. There was a time-dependent increase in binding of labelled protein to the co-cultured activators, demonstrating de novo protein synthesis by the phagocytes. Moreover, there was a significant binding to the co-cultured agarose beads and ElgM of monoclonal anti-C3c, anti-C3g, polyclonal anti-C5-C9 and of two monoclonal antibodies (poly C9-MA and MCaEll) to a neoantigen of polymerized C9 present in the terminal complement complex (TCC). In addition, we found a significant binding of polyclonal anti-C4 antibodies to co-cultured ElgM. Incubation of the activators in human serum, subsequently revealed the same pattern of antibody binding. There was no binding of anti-S protein antibodies to the activators after incubation with serum or with the phagocytes. We thus conclude that mononuclear phagocyte-produced complement in the form of C3b, iC3b, and the TCC (C5b-9) was deposited on both activators, whereas C4b was detected on the ElgM. It is our hope that this method can be applied when studying complement biosynthesis by cells other than mononuclear phagocytes.

Animals↗
PubMed1984

Localisation of a group of antigenic sites in complement component C3, and identification of a new fragmentation pattern.

Immunisation of rabbits or goats with denaturated human C3 reproducibly gives rise to an antiserum of restricted specificity which precipitates native C3, C3b and iC3b, but not C3c or C3d isolated from 'aged' serum. The antigenic sites recognised by the antiserum appear to be localised in a small segment of the polypeptide chain located close to the N-terminus of the C3b alpha' chain. Affinity chromatography using antibodies developed by this procedure reveals an unusual pattern of degradation of C3 which occurs on conventional 'ageing' of serum at 37 degrees C.

Amino Acids↗
PubMed1989

[Changes in complement breakdown products and terminal complement complex in patients with acute glomerulonephritis].

In this study we examined the role of the complement system in acute glomerulonephritis (AGN). Breakdown products of complements (iC3b, C4d and Bb) and Terminal complement complex (TCC, SC5b-9 complex) in plasma samples were measured by ELISA. The microassay plates were coated with monoclonal antibodies which bind specifically to human iC3b, C4d, Bb and SC5b-9 complex. This assay accurately quantitates small amounts of in vivo complement activation. The plasma samples were drawn from patients with AGN and other glomerulonephritis. There were some patients with various glomerulonephritis whose plasma iC3b, C4d and Bb concentrations were higher than those in normal human. However specificity was not found. The ratios iC3b/C3 and C4d/C4 were increased in the early stages of AGN, but plasma Bb concentrations revealed no significant changes. Plasma SC5b-9 complex concentrations were increased in the early stages of AGN. C3c, C3d, C4d and SC5b-9 were found to be localised in the glomeruli of those AGN patients. It is suggestive that in these cases of AGN (especially case 2) complement activation is predominantly mediated through the classical pathway and TCC is formed by this activation. This complement activation in the blood and the renal tissue is presumed to be involved in the initiation and progression of AGN.

Acute Disease↗
PubMed1990

Immunohistologic study of epiretinal membranes in proliferative vitreoretinopathy.

We performed an immunohistologic study on 11 specimens of epiretinal membranes surgically obtained from patients who had rhegmatogenous retinal detachment with proliferative vitreoretinopathy. Immunostaining procedures were used to identify immunoglobulin and complement deposits, to visualize class II antigen expression by proliferating cells, and to determine eventual infiltration by cells of the immune system. Diffuse deposits of IgG, IgA, IgE, C1q, C3c, and C3d were found in epiretinal membranes, whereas numerous cells, including glial or pigmented epithelial cells, expressed HLA-DR and HLA-DQ antigens. Some macrophages and B or T8 lymphocytes were identified. These results suggest activation of the immune system during the course of proliferative vitreoretinopathy. Class II antigen expression could be dependent upon growth-promoting factors and interferon gamma and could play a crucial role in this immune reaction, which resulted in immunoglobulin deposition and activation of complement. However, the eventual role of immune phenomena in the extension of proliferative processes remains to be determined.

Adult↗
PubMed1983

Differential characteristics of immune-bound antibodies in diffuse proliferative and membranous forms of lupus glomerulonephritis.

Diffuse proliferative (PGN) and membranous (MGN) glomerulonephritis represent contrasting histologic lesions in systemic lupus erythematosus (SLE). Serum, cryoglobulins, and renal biopsies in 8 SLE patients with PGN and 8 with MGN were studied in order to determine whether variations in the properties of immune-bound antibodies correlate with the pattern of glomerular involvement. Several immunologic parameters suggested differences in complement activation between the two groups. PGN cryoglobulins demonstrated immunoglobulin G (IgG) anti-native DNA (nDNA) subclass heterogeneity with highest titers of IgG3. These findings contrasted with the observation that MGN was characterized by a predominance of IgG4 in cryoglobulins. The major glomerular IgG subclasses in PGN were IgG3 and IgG1, while MGN biopsies demonstrated IgG4 in largest amount. Serum C1q was lower in PGN than in MGN. Serum anti-nDNA antibodies, solid-phase C1q-binding IgG immune complexes, and cryoglobulin protein concentrations were higher in PGN sera. Cryoglobulin complement component and control protein concentrations were greater in PGN than in MGN, while cryoglobulin Ig and immune-bound anti-nDNA were not different. In vitro C3 fixation by cryoglobulin anti-nDNA was greater in PGN than in MGN. Glomerular C1q, C4-binding protein (C4bp), and C3c were present in comparable amounts to IgG deposits in PGN biopsies, while in MGN IgG was demonstrable in greater quantities than C1q, C4bp, and C3c. In contrast, glomerular C3d (alpha 2d), C5, C6, P, and H were comparable in the two groups. It was concluded that immune-bound antibodies in cryoglobulins and in glomerular immune deposits in SLE PGN appear to activate complement via the classical and alternative pathways, while complement activation in MGN appears to occur predominantly via the alternative pathway. These differences in IgG subclass composition may account for the differential complement activation and may explain the contrasting histologic expression of immune aggregate localization in glomerular capillaries in these variants of lupus nephritis.

Antibodies, Antinuclear↗
PubMed1992

[Immune function and abdominal surgery in blood stasis syndrome in patients with gastrointestinal diseases].

52 Patients with Blood Stasis Syndrome (BSS) in abdominal surgical diseases were divided into 3 types according to their symptoms, signs and natures of diseases. Peripheral blood T lymphocyte subsets of these BSS patients and 12 healthy persons were studied with Flow Cytometry and monoclonal antibodies. The immunoglobulins and complements of these cases were also studied. There were no difference in T cell subsets, immunoglobulins and complements between Qizhi-BSS group and normal control. The Shire-BSS group showed that CD8 cell, IgG, IgM, and C1, C3c were increased. These results showed that the immune response increased in this type of BSS patients. In the Qixu-BSS group, the CD3 was nearly normal, and the CD4+, CD4+/CD8+ ratio, and CD16+ were statistically decreased. However, the CD8+ cells markedly increased, the IgG, IgM and IgD were also lowered significantly in this type. The marked morphologic abnormal changes in ultrastructures of T lymphocyte were found in 6 patients with Qixu-BSS group. These results showed that the Qixu type of Blood Stasis Syndrome patients were in the immuno-suppressive status.

Abdomen↗
PubMed1995

Participation of CR1 (CD35), CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in membranoproliferative glomerulonephritis type I.

Intraglomerular expression of complement receptors (CR) was investigated chronologically in 22 repeatedly biopsied patients with membranoproliferative glomerulonephritis (MPGN) type I by indirect immunoperoxidase staining using MoAbs. Patients were divided into two groups based on whether intraglomerular C3c deposition was decreased at the second biopsy (2nd Bx) (group A, n = 12), or not (group B, n = 10). At the first biopsy (1st Bx), the severity of glomerular injury and the degree of glomerular C3c deposition were compatible between the two groups. Four patterns of CR1 (CD35) expression on podocytes were recognized: normal; generally decreased; focally/segmentally lost; and completely lost. The numbers of CR3 (CD11b/CD18)- and CR4 (CD11c/CD18)-positive cells per glomerular cross-section were counted. At the 1st Bx, no significant difference was found in the number of CR3+ or CR4+ cells between the two groups. At the 2nd Bx, the numbers of both the CR3+ and CR4+ cells were significantly decreased only in group A (P < 0.01). The numbers of CR3+ and CR4+ cells were significantly higher in cases with moderate or marked C3c deposits than in those with no or mild C3c deposits. The intensity of CR1 expression in group B was less than that in group A at both the 1st and 2nd Bx (1st, P < 0.05; 2nd, P < 0.01), and chronological improvement of CR1 expression was observed only in group A. The severity of glomerular injury was increased only in group B (P < 0.01), and was associated with persistent massive proteinuria and hypocomplementaemia. Our results suggest that, in cases with an adverse outcome, a more severe defect of CR1 initially exists and the expression of CR1 is not recoverable chronologically. This irreversible decrease or loss of CR1 may partly contribute to the continuous C3c deposition and intraglomerular infiltration of CR3+ and CR4+ cells.

Adolescent↗
PubMed1987

Functional and antigenic properties of complement receptor type 2, CR2.

This is the first report demonstrating that C3d receptor (CR2) has functional activity in regulating complement cascade. Purified CR2 was examined for its cofactor activity in factor I-mediated cleavage of membrane-bound iC3b. CR2 plus C3b inactivator (I) released C3c from EA 125I-iC3b, and the release was inhibited when CR2 was preincubated with OKB7 monoclonal anti-CR2. Furthermore, immunoelectroblotting analysis showed crossreactivity of CR2 with 57H anti-CR1. These results indicate that CR2 has functional and antigenic similarity to CR1, thus providing a supporting evidence for placement of CR2 as a member of the recently defined gene family of C3- and C4-regulatory proteins composed of CR1, C4-binding protein, and factor H.

Collodion↗
PubMed1991

The use of flow cytometry to detect the biosynthesis of complement components.

Agarose beads, an activator of complement, were incubated with MRC-5 or He 9 fibroblast cell lines under serum-free conditions. The beads were tested for binding of anti-complement antibodies by flow cytometry with a FACS 440 using FITC-labelled anti-Ig detection antibodies. Controls consisted of co-cultured beads incubated with irrelevant antibody or albumin, beads maintained in cell cultures containing cycloheximide, and beads which were not exposed to cells. The histograms demonstrated positive staining with anti-C3c, -C5, -C7 and -C9, but not with anti-C6 and -C8. Flow cytometry with multiple histogram analysis confirmed that the differences between the positive curves and the controls were statistically significant. The results show that cell-derived complement components (C3, C5, C7 and C9) were deposited on the beads and could be detected by flow cytometry.

Cell Line↗