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PubMed1990

The influence of the geometry of the dialyzer and the composition of the dialysate in activating the complement system.

During hemodialysis there is a complex interaction between the patient and the extracorporeal circuit that activates the complement system, among others. To better understand the influence of the dialyzer geometry and the dialysate composition, we compared hollow fiber versus parallel plate dialyzers and acetate versus bicarbonate dialysates and their role in the production of C3a, C4a and C5a. There was no significant difference in the plasmatic levels of these anaphylotoxins and their des-Arg derivates, as measured by RIA, in either dialyzer. The same was true when the dialysate in question had a different composition. We thus concluded that neither the geometric configuration of the dialyzer nor the composition of the dialysate influence their biocompatibility as regards the activation of the complement system, and that the differences that have been described shall have to be explained in another manner or assessed by methods other than those used in this study.

Adult↗

PubMed1981

Complement activation requirements for histamine release from human leukocytes: influence of purified C3ahu and C5ahu on histamine release.

The activation of human sera for histamine release by zymosan and anti-BSA-BSA complexes at equivalence was dose dependent and associated with a marked fall in CH50, C3 and C5 hemolytic activities. Heat-aggregated IgG, though able to fix greater than 90% of human CH50 activity and produce a lesser fall in C3 and C5 activities than zymosan and BSA-anti-BSA complexes, was unable to induce basophil histamine release. Chemically purified human C3a and C5a each caused histamine release from human basophils; C5a was more potent than C3a. In addition, neither zymosan nor BSA-anti-BSA complexes released histamine when incubated with homozygous C3-deficient serum. The addition of C3a and C5a at suboptimal concentrations produced an additive effect of histamine release.

Anaphylatoxins↗

PubMed1993

Adsorption of complement factor D by polyacrylonitrile dialysis membranes.

Factor D, an essential enzyme of the alternative pathway (AP) of complement, accumulates in end-stage renal failure (ESRF). Polyacrylonitrile (PAN) membrane activates complement poorly and has been shown to adsorb C3a, the main anaphylatoxin released during complement activation. In the present work we investigated whether factor D might be adsorbed on PAN. In vitro there was a loss of hemolytic factor D when normal human serum (NHS) was incubated with PAN dialysis fibers, whereas no loss was observed with cuprophan (Cu) fibers. There was a dose and time dependent binding of purified radiolabeled factor D to PAN but not to Cu. The hemolytic function of factor D released from PAN by 2 M NaCl was normal. By contrast, factor D was inactive while adsorbed to PAN fibers. When 50 ml of NHS or 100 ml of whole blood were passed through a new hollow fiber PAN dialyzer 95% of factor D was adsorbed. The eluate from a PAN filter which had been used for dialysis in a patient with ESRF contained 38.4 mg of hemolytic factor D, representing 34% of the proteins eluted. By immunoblotting, antigenic factor D from the PAN eluate was identical to purified human factor D. In six patients there was a 81.4% decrease in hemolytic factor D in blood after dialysis with PAN, contrasting with a 9.6% decrease in those dialyzed with cellulose acetate. No factor D was found in the dialysis fluid of PAN dialyzers, indicating that PAN removed factor D mainly by adsorption. In conclusion, PAN has a significant capacity to adsorb factor D, a reaction that might contribute to the diminished capacity of PAN membrane to activate the AP of complement. Whether the efficient removal of large amounts of factor D might be beneficial in uremic patients remains to be defined.

Acrylic Resins↗

PubMed1987

Biocompatibility of different hemodialysis and plasmapheresis membranes.

The biocompatibility of different membranes was assessed by measuring changes in different white blood cell counts, PGE2 concentrations, thromboplastin activity, production of anaphylatoxins and clinical parameters during treatment. The in vivo recorded complement activation was compared with in vitro experiments. Hemodialysis (HD) treatment was performed with 5 different membranes. Plasmapheresis was run with cellulose diacetate membranes in single (SMF) and double (DMF) membrane filtration and with a new polycarbonate membrane in SMF. The polysulfone membrane was found to be the most, and the cuprophane membrane the least biocompatible membrane in HD. However, large individual differences from one HD patient to the other were found. In contrast to the cellulose diacetate membrane, the polycarbonate membrane apparently activated no complement along the blood-membrane interface during plasmapheresis, but activated large amounts within the membrane matrix. High blood concentrations of C5a were promptly cleared in the body, while high concentrations of C3a seemed to block the removal of this substance from the blood compartment. Even when the patients had high blood concentrations of anaphylatoxins throughout the plasmapheresis treatments using cellulose diacetate membranes and when a significant activation of PGE2 was found in patient plasma, no activation of thromboplastin was recorded on the surface circulating monocytes.

Biocompatible Materials↗

PubMed2004

The possibilities and pitfalls for anti-complement therapies in inflammatory diseases.

The complement system is a key component of innate immunity, acting to protect the host from micro-organisms such as bacteria and other "foreign" threats, including tumor cells. However, excessive activation of complement can injure the host and can even be life threatening. These toxic effects are caused primarily by the excessive production of the anaphylatoxins C3a and C5a during complement activation and excessive formation of membrane attack complex on the host cell membrane. Many inflammatory diseases, including rheumatoid arthritis and glomerulonephritis, are thought to involve excessive activation of complement, both for their development and perpetuation. Uncontrolled complement activation is also implicated in post-ischemic inflammation and tissue damage and in sepsis. Therefore, it is important to regulate the complement system to treat disease. There are still no broadly applicable agents for the therapeutic regulation of excessive complement activation. However, there are now some agents in the development that might provide useful anti-complement therapies in the near future. Current strategies include the use of neutralizing antibodies, small synthetic antagonists, soluble recombinant forms of the natural complement regulators, and gene therapies to control excessive complement activation. Here we describe these new agents, their strengths and weaknesses and progress in testing the agents in relevant animal models.

Animals↗

PubMed1991

Blood flow dependent granulocyte activation in membranes with and without complement activation.

Synthetic membranes activate the complement system to some degree but also clear complement fragments from the circulation by adsorption and/or filtration and dialysis, PAN and PMMA even lower preexisting plasma levels of C3a. Activation of granulocytes measured as elastase release does occur with all membranes and might be due to complement activation. However, in synthetic membranes no correlation exists between levels of complement fragment C3a and elastase release. Instead, even when PMMA membrane lowered preexisting plasma levels of the C3a below baseline, activation of granulocytes to a similar degree as known from cuprophane membranes was observed. This activation did occur with blood flow of 200 ml/min during recirculation, but not without blood flow during incubation of membrane material. We conclude that granulocyte activation in synthetic membranes does not require an activated complement system, but may be a blood flow dependent phenomenon.

Acrylic Resins↗

PubMed1998

Complement activation during plasma production depends on the apheresis technique.

Elevated anaphylatoxin concentrations have been found in fresh frozen plasma packs produced by apheresis. The aim of this study was to investigate anaphylatoxin generation during apheresis production in relation to two frequently used techniques: employing either centrifugation alone or centrifugation with simultaneous filtration. The concentrations of C3a. C5a and sC5b-9 were measured in 50 plasmas after apheresis and before freezing generated by combined centrifugation and filtration and in 50 plasmas generated solely by centrifugation and in the corresponding 100 donors before apheresis. The median C3a concentration increased during apheresis by centrifugation alone from 62 (donor) to 380 micrograms L-1 (FFP pack) and during apheresis by combined centrifugation and filtration from 70 to 992 micrograms L-1. The median C5a concentration increased during apheresis by centrifugation alone from 0.38 to 0.83 microgram L-1 and during apheresis by combined centrifugation and filtration from 0.29 to 4.9 micrograms L-1. The soluble terminal complement complex increased only by combined centrifugation and filtration apheresis from 162 to 426 micrograms L-1. Complement activation during apheresis by combined centrifugation and filtration is more pronounced than that obtained by the centrifugation method alone. Changes in the construction or the materials used in the membrane-type separation units may reveal possibilities of prevention.

Adolescent↗

PubMed1989

Proton nuclear magnetic resonance study of the solution conformation of C3a-Arg69, a 69-residue N-terminal fragment of the third component of complement.

A proton nuclear magnetic resonance (NMR) study is reported of human C3a-Arg69, which is a 69-residue fragment obtained by the tryptic cleavage of human C3. It has been shown that the combined use of a CPase/digestion difference spectroscopy method (Endo and Arata (1985) Biochemistry 24, 1561-1568) with a variety of two-dimensional NMR techniques is effective in advancing spectral assignments for structural analyses. On the basis of the results of the NMR measurements, we have concluded that: 1) the N-terminal region of the C3a molecule plays a crucial role in stabilizing the conformation of the C-terminal segment Leu63-Arg69 and 2) the existence of the core region, which is formed by segment Tyr15-Tyr59 (Huber et al. (1980) Hoppe Seyler's Z. Physiol. Chem. 361, 1389-1399), is essential in maintaining this conformation. We also suggest that the disorder of the N-terminal region, which is invisible by the X-ray crystallographic study, is due to dimerization of this molecule in the crystal.

Amino Acid Sequence↗

PubMed2003

Activation of the complement system by different autologous transfusion devices: an in vitro study.

BACKGROUND: The aim of the present investigation was to study whether autologous transfusion devices activate the complement system and whether complement-activated blood is more vulnerable to further activation during processing. STUDY DESIGN AND METHODS: Forty-eight blood units were randomized to be processed by one of three different salvage systems: Group 1 underwent whole blood filtration (hemofiltration) (n=16); Group 2 underwent continuous processing, saline washing, and centrifugation (CATS, Fresenius AG ) (n=16); and Group 3 underwent saline washing and centrifugation (Cell-Saver, Haemonetics Corp.) (n=16). Eight blood units for each system were activated with cobra venom factor (CVF) at a concentration of 0.2 U per mL whole blood before processing. C activation was studied by determinations of C4d, Bb, C3a, and SC5b-9. Samples were drawn from whole blood, processed blood, and the waste bags. RESULTS: The concentrations of Bb, C3a, and SC5b-9 in whole blood after activation with CVF were significantly elevated compared to blood that was not activated (p < 0.01). Processed blood from hemofiltration contained significantly higher levels of complement-split products than techniques that use washing and centrifugation. The concentrations of SC5b-9 in blood processed by hemofiltration were higher in the experiments with CVF activation (p < 0.05). CONCLUSION: The tested autologous transfusion systems did not themselves activate the complement system, and complement-activated blood was not more vulnerable to further activation during processing. A blood-salvaging technique that used washing and centrifugation reduced elevated concentrations of complement-split products, whereas hemofiltration did not.

Blood Transfusion, Autologous↗

PubMed1986

Anaphylatoxins: possible roles in disease.

Anaphylatoxins, in particular C3a and C5a, have various biological activities which suggest a role as mediators of inflammatory reactions: they cause contraction of smooth muscle, histamine release, increase in capillary permeability, adhesion of leukocytes to vascular endothelium, leukocyte chemotaxis, and aggregation of platelets and leukocytes. Most of these effects are supported by the cooperation of other mediators, in particular arachidonic acid derivatives which may be produced by anaphylatoxin-stimulated cells, e.g. leukocytes or endothelium. In vivo effects of the complement peptides depend very much on the site of their generation: intravascular release in the general circulation leads to adverse symptoms such as adult respiratory distress syndrome and shock lung, mainly due to leukocyte activation, aggregation and their accumulation in lung vessels. Intravascular release may be induced by certain drugs, and by contact of blood with the surfaces of bypass or dialysis apparatus. Induction of local inflammatory and defense reactions requires release of anaphylatoxins in tissue spaces. Tissue fluid differs quantitatively from blood plasma in its concentration of complement components. This raises some problems of how efficient concentrations of C3a and C5a can be attained at the site of a lesion to generate a chemotactic gradient capable of attracting blood leukocytes.

Anaphylatoxins↗

PubMed1993

Ozone-induced increases in substance P and 8-epi-prostaglandin F2 alpha in the airways of human subjects.

We are interested in the mechanisms of ozone-induced lung effects after short-term exposure and the relationship with subsequent pulmonary inflammation and disease. Our hypothesis is that ozone, as a powerful oxidant, will diminish the activity of neutral endopeptidase (NEP) in the airways of humans with resulting increased concentrations of neuropeptides such as substance P (SP). We have exposed seven (two women, five men) healthy, nonsmoking individuals (22 to 30 yr of age) to filtered air and ozone (0.25 ppm) for 1 h in an environmental chamber during heavy exercise. Bronchoscopy with airway lavage (AL) and bronchoalveolar lavage (BAL) was performed immediately after ozone exposure. The lavage samples were analyzed by enzyme immunoassay for SP and 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) (a marker for oxidative free radical reaction) and by radioimmunoassay for complement fragments. FEV1 had declined 12.4 +/- 1.9% (mean +/- SEM) as a result of ozone exposure. The AL concentration for SP and 8-epi-PGF2 alpha and BAL concentration of C3a after ozone exposure were significantly higher than after the filtered air exposure (P < 0.05). There was a significant correlation between SP and 8-epi-PGF2 alpha concentrations in the AL fluid (r2 = 0.89 and P < 0.05). There were no changes in C5a in either compartment or any of the mediators in the plasma samples. These results extend previous results from animal studies suggesting that ozone's mechanism of action is through an oxidative reaction resulting in a decreased activity of NEP in the airways with a subsequent increase in the concentration and activity of SP.

Adult↗

PubMed2026

Complement Activation Linked to Type II Interferon Signaling in Still Disease.

OBJECTIVE: Still disease (SD) is an autoinflammatory syndrome characterized by innate immune dysregulation. Although complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD. METHODS: Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n = 15), those with nonsystemic juvenile idiopathic arthritis (JIA; n = 8), patients with SD at onset (n = 19) and remission (n = 18), and those with macrophage activation syndrome (n = 2). Whole-blood NanoString analysis of complement and interferon (IFN)-related gene expression was conducted in patients with SD (active n = 41, inactive n = 33) and JIA (n > 600). Complement products and inflammatory mediators were measured by Luminex and enzyme-linked immunosorbent assay. Functional complement activity was evaluated in SD (active n = 30, inactive n = 67) and JIA sera (n = 12). In vitro assays examined monocytic C1q induction and complement-mediated CD8+ T cell activation. RESULTS: Transcriptomic analysis of monocytes from patients with SD at onset revealed enrichment of the complement cascade compared with patients in remission (adjusted P = 3.7 × 10-36), ranking among the top 10 up-regulated pathways. Classical complement genes (C1QB/C1QC) were markedly up-regulated in onset SD compared with patients with remission SD and JIA. Patients with active SD showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole-blood C1QB/C1QC expression correlated with IFN-related markers, including interleukin-18, CXCL9, and CXCL10. Recombinant IFN-γ induced monocytic C1q, whereas C1q enhanced IFN-γ production by CD8+ T cells, supporting a feed-forward loop. CONCLUSION: SD is characterized by complement activation with marked up-regulation of C1q, which is closely linked to IFN-γ/type II signaling.

Journal Article↗

PubMed1987

Plate, coil, and hollow-fiber cuprammonium cellulose dialyzers: discrepancy between incidence of anaphylactic reactions and degree of complement activation.

During the past 10 years, the incidence of severe anaphylactic reactions during dialysis [type A first-use syndrome (FUS)] at our center has been much lower when using cuprammonium cellulose plate (CC-P) dialyzers (0/37, 750 dialyses) or coil (CC-C) dialyzers (0/32, 500) than when using cuprammonium cellulose hollow-fiber (CC-F) dialyzers (8/21,022 dialyses, p less than 0.005 by Chi-square). To determine if the difference in type A FUS incidence between the three dialyzer types could be explained by differences in complement activation, we compared plasma concentrations of C3a des-arginine (des arg) in patients undergoing dialysis with these three varieties of dialyzers. Plasma C3a des arg values increased markedly in the dialyzer outflow blood with the three dialyzer configurations. The levels were similar with the dialyzer types when results were corrected for membrane surface area. Also, the degree of leukopenia was not markedly different with the three dialyzer types. Our findings suggest that complement activation per unit surface area is similar during dialysis with plate, coil, and hollow-fiber cuprammonium cellulose dialyzers. The lack of correlation between the degree of complement activation and the incidence of type A FUS suggests that membrane-induced complement activation is not of primary importance to type A dialyzer hypersensitivity reactions.

Adult↗

PubMed1999

Complement anaphylatoxin receptors on neurons: new tricks for old receptors?

Activation of the complement system has been reported in a variety of inflammatory diseases and neurodegenerative processes of the CNS. Recent evidence indicates that complement proteins and receptors are synthesized on or by glial cells and, surprisingly, neurons. Among these proteins are the receptors for the chemotactic and anaphylactic peptides, C5a and C3a, which are the most-potent mediators of complement inflammatory functions. The functions of glial-cell C3a and C5a receptors (C3aR and C5aR) appear to be similar to immune-cell C3aRs and C5aRs. However, little is known about the roles these receptors might have on neurons. Indeed, when compared with glial cells, neurons display a distinct pattern of C3aR and C5aR expression, in either the normal or the inflamed CNS. These findings suggest unique functions for these receptors on neurons.

Anaphylatoxins↗

PubMed2001

Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models.

The anaphylatoxin C3a is a potent chemotactic peptide and inflammatory mediator released during complement activation which binds to and activates a G-protein-coupled receptor. Molecular cloning of the C3aR has facilitated studies to identify nonpeptide antagonists of the C3aR. A chemical lead that selectively inhibited the C3aR in a high throughput screen was identified and chemically optimized. The resulting antagonist, N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (SB 290157), functioned as a competitive antagonist of (125)I-C3a radioligand binding to rat basophilic leukemia (RBL)-2H3 cells expressing the human C3aR (RBL-C3aR), with an IC(50) of 200 nM. SB 290157 was a functional antagonist, blocking C3a-induced C3aR internalization in a concentration-dependent manner and C3a-induced Ca(2+) mobilization in RBL-C3aR cells and human neutrophils with IC(50)s of 27.7 and 28 nM, respectively. SB 290157 was selective for the C3aR in that it did not antagonize the C5aR or six other chemotactic G protein-coupled receptors. Functional antagonism was not solely limited to the human C3aR; SB 290157 also inhibited C3a-induced Ca(2+) mobilization of RBL-2H3 cells expressing the mouse and guinea pig C3aRS: It potently inhibited C3a-mediated ATP release from guinea pig platelets and inhibited C3a-induced potentiation of the contractile response to field stimulation of perfused rat caudal artery. Furthermore, in animal models, SB 290157, inhibited neutrophil recruitment in a guinea pig LPS-induced airway neutrophilia model and decreased paw edema in a rat adjuvant-induced arthritis model. This selective antagonist may be useful to define the physiological and pathophysiological roles of the C3aR.

Animals↗

PubMed1987

Deposits of immunoglobulins, complement, and immune complexes in inflamed human gingiva.

Gingival biopsy specimens from 20 patients with moderate to advanced periodontitis were obtained from inflamed sites with pockets of 5 mm or more. Sections were studied by an immunofluorescence technique, using polyclonal rabbit or goat anti-IgG, anti-IgM, anti-C1q, anti-C3a, and anti-C3c and mouse monoclonal anti-C9. Prewashed ethanol-fixed and nonwashed ethanol-fixed or frozen specimens showed many plasma cells staining for IgG or C3a, suggesting the possible occurrence of a receptor for C3a in plasma cells. Plasma cells containing IgM were also seen. Deposits of IgG and IgM with C1q, C3a, and C3c, suggesting immune complexes, were demonstrated by a double staining technique, combining fluorescein (FITC) or rhodamine (TRITC)-labeled anti-immunoglobulins with TRITC- or FITC-conjugated antibody to C3a, C3c, and C1q. The complexes were located mainly within or around vessel walls. Deposits of C3a and C1q were found in vessel walls, in the basement membrane zone of oral gingival epithelium, or diffusely distributed in the tissues. Deposits of C3c were found to a lesser extent and only in vessel walls. Mouse monoclonal anti-C9, visualized with FITC-labeled rabbit anti-mouse and swine anti-rabbit antiserum, showed granular deposits of C9, mainly in the basement membrane zone of oral gingival epithelium. The study indicates the involvement of immune complex vasculitis in inflammatory periodontal lesions. Also, our observations of the occurrence of deposits of complement factors support the hypothesis that complement factors play an important role in the immunopathology of the periodontal lesion.

Antigen-Antibody Complex↗

PubMed1999

Modulation of C3a activity: internalization of the human C3a receptor and its inhibition by C5a.

The C3a receptor (C3aR) is expressed on most human peripheral blood leukocytes with the exception of resting lymphocytes, implying a much higher pathophysiological relevance of the anaphylatoxin C3a as a proinflammatory mediator than previously thought. The response to this complement split product must be tightly regulated in situations with sustained complement activation to avoid deleterious effects caused by overactivated inflammatory cells. Receptor internalization, an important control mechanism described for G protein-coupled receptors, was investigated. Using rabbit polyclonal anti-serum directed against the C3aR second extracellular loop, a flow cytometry-based receptor internalization assay was developed. Within minutes of C3a addition to human granulocytes, C3aR almost completely disappeared from the cell surface. C3aR internalization could also be induced by PMA, an activator of protein kinase C. Similarly, monocytes, the human mast cell line HMC-1, and differentiated monocyte/macrophage-like U937-cells exhibited rapid agonist-dependent receptor internalization. Neither C5a nor FMLP stimulated any cross-internalization of the C3aR. On the contrary, costimulation of granulocytes with C5a, but not FMLP, drastically decreased C3aR internalization. This effect could be blocked by a C5aR-neutralizing mAb. HEK293-cells transfected with the C3aR, with or without Galpha16, a pertussis toxin-resistant G protein alpha subunit required for C3aR signal transduction in these cells, did not exhibit agonist-dependent C3aR internalization. Additionally, preincubation with pertussis toxin had no effect on C3a-induced internalization on PMNs. C3aR internalization is a rapid negative control mechanism and is influenced by the C5aR pathway.

Acids↗

PubMed1985

Is the dialysate fluid source of complement activating factors?

To distinguish between membrane-induced and dialysate-induced mechanism of complement activation attending hemodialysis (HD), the C3a plasma level and blood neutrophil count profiles have been determined during procedures performed with noncellulosic membranes, as PAN and PMMA (with minimal complement-activating potential) and, by comparison, with new cuprophane (that displays the greatest complement-activating potential). Furthermore, PAN and PMMA membranes have been used in 2 other blood purification methods: high efficiency hemofiltration (HEHF), in which there is no dialysate on the other side of the membrane, and hemofiltration without substitution fluid and with reinfusion of dialysis-regenerated hemofiltrate (HWSF), in which the dialysate is separated from the blood circuit by the hemofiltrate circuit. In addition, sequential dialysis-ultrafiltration (UFD) experiments with PAN membranes have been performed, where dialysate was present only in the second part of the procedure. In all the HD and UFD procedures LAL test assays were performed on dialysate at the same times as C3a and neutrophil determinations. Our findings seem to suggest that the dialysate can be a source of complement activating factors; complement activation detectable by C3a plasma levels can ensue when LAL test-positive material is present in the dialysate.

Blood↗