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PubMed1998

Identification of complement activators and elucidation of the fate of complement activation products during extracorporeal plasma purification therapy.

It has been known for many years that the complement system is activated during extracorporeal plasma purification (ECCP) therapy. In a previous study, we showed that high concentrations of complement activation products (CAPs) are returned to the patient during immunoadsorption treatment. In the present study, we investigated the question of where complement activation takes place with different forms of ECPP equipments as well as the fate of the CAPs. Eleven patients (8 men and 3 women), mean age 52 +/- 18 years, were included in the study. They were treated either with plasmapheresis (PP), immunoadsorption, bilirubin adsorption, or low density lipoprotein (LDL) apheresis. It was found that during all ECPP treatments and after the plasma separation filter, the plasma concentrations of CAPs were increased, and that high concentrations of CAPs were returned to the patients, except with PP. The plasma levels of individual CAPs varied between different types of ECPP. These variations were due to several factors: (1) complement activation (CA) on the plasma separator and a secondary device, e.g., column or membrane; (2) adsorption of specific CAPs to separation columns; and (3) reduction of CAPs due to separation and waste. Since CAPs have inflammatory and immunological effects, it is possible that high serum concentration of CAPs in the treated patients may influence the clinical outcome of the treatment. In conclusion, complement activation is a fact that should not be ignored during performance of any form of an ECPP. It is the plasma separator that plays a key role in the process of complement activation. Different ECPP treatments may have different effects regarding the levels of individual CAPs.

Adult↗
PubMed2003

Molecular characterization of the pig C3 gene and its association with complement activity.

The complement system catalyzes direct lysis of micro-organisms and modulates phagocytosis, inflammation, humoral and cellular immune responses. Since the complement protein C3 is the central component within all pathways of complement activation, C3 is a candidate gene for complement activity and also for improved protection against many pathogens. The pig C3 gene was sequenced, screened for polymorphisms, and analyzed for association with hemolytic complement activity of the alternative and classical pathway (AH(50), CH(50)). C3c serum levels and haptoglobin (HP) serum concentrations were measured before and after vaccination against Mycoplasma hyopneumoniae, Aujeszky virus, and porcine reproductive and respiratory syndrome virus in F2 animals of a pig resource population based on crossbreeding of Duroc and Berlin Miniature Pig. The genomic C3 sequence covers 444 bp of promoter region, 41 exons and 40 introns, as well as 881 bp of the 3'-flanking region. The cDNA codes for a 1,661-amino acid precursor C3. Five polymorphic sites were detected in the 5'-UTR, intron 13, exon 15, exon 30, and the 3'-UTR. Within the resource population two haplotypes were found to segregate. Analysis of variance applying a repeated measures model revealed a significant effect of the interaction of C3 genotype and time of measurement relative to immunization on CH(50), AH(50,)and C3c that is likely to be due to variation of C3 expression. In contrast, the time course of the HP acute-phase reaction is not associated with C3 genomic variation. The association of C3 with complement activity indicates the importance of C3 as a candidate gene for natural resistance to micro-organisms, although the causative polymorphism modulating the expression of C3 remains to be delineated.

Alleles↗
PubMed1978

Complement activation by cell wall fractions of Micropolyspora faeni.

The ability of several cell wall fractions of Micropolyspora faeni, a thermophilic actinomycete associated with farmer's lung disease, to activate complement is reported. Cell walls, obtained by mechanical disruption, were purified by enzyme treatment and chemical extractions. Fractions containing the most purified cell walls were most active in consuming complement, as measured by reduction of hemolytic complement levels of normal human serum. Cell wall fractions activated the alternative complement pathway, as shown by monitoring the conversion of C3 proactivator (factor B) to C3 activator (activated factor B) in the presence of specific cation chelators. Selective degradation of cell walls by lysozyme resulted in a decreased ability to consume complement and implicated peptidoglycan as the major complement-reactive component. The role of this nonspecific complement activation in relation to farmer's lung disease is discussed.

Cell Wall↗
PubMed1983

Complement activation by polysaccharide of lipopolysaccharide: an important virulence determinant of salmonellae.

Salmonellae with differences only in the O-antigenic polysaccharide of their lipopolysaccharide were previously shown to differentially activate complement via the alternative pathway, causing them to be ingested at different rates by the mouse macrophage-like cell line J774. We now show that this mechanism could explain the different virulence of these strains in vivo. Mouse peritoneal macrophages (thioglycolate induced) ingest these salmonellae at rates that are inversely proportional to the known virulence of the organisms and virtually identical to the rates observed with J774. As with J774, complement is required for this differential uptake, since serum was required and heating (56 degrees C for 30 min) or zymosan treatment of the serum destroyed activity. The known receptor for nonreducing terminal mannose-, fucose-, N-acetylglucosamine, and glucose-containing glyco-proteins did not participate, since uptake was not inhibited by high concentrations of mannan. When clearance of bacteria from the bloodstream of mice was measured, the least virulent organism was cleared very much faster than the most virulent organism, in confirmation of earlier data. When complement in the mice was destroyed by pretreatment with cobra venom factor, the clearance of the least virulent strain was greatly reduced, whereas the very slow clearance of the most virulent strain was unaffected. These data strongly support the hypothesis that when bacteria have polysaccharide in lipopolysaccharide that activates complement efficiently, the bacteria will be phagocytosed, whereas if the polysaccharide activates complement poorly, the bacteria escape ingestion and may cause disease.

Animals↗
PubMed1987

Guillain-Barré syndrome: activated complement components C3a and C5a in CSF.

Plasma and spinal fluid levels of complement activation products C3a and C5a were quantitated by radioimmunoassay in a group of 16 patients suffering from acute monophasic Guillain-Barré syndrome (GBS). Median CSF levels of C3a (118 ng/ml) and of C5a (9.6 ng/ml) were significantly elevated when compared with samples from a control group of patients with noninflammatory neurologic diseases. Plasma concentrations of these anaphylotoxic peptides were not significantly different between the two populations. Our findings indicate that the complement system is activated in the CSF of patients with acute GBS. Complement activation products may contribute to the inflammatory changes observed in this disorder.

Complement C3↗
PubMed1979

Effect of non-steroidal antiinflammatory drugs on some biological activities dependent on complement activation.

The paper presents the results of a study on the action of five non-steroidal antiinflammatory agents (phenylbutazone, indometacin, acetylsalicylic acid, niflumic and flufenamic acids) on two biological activities which are dependent on complement activation: opsonization of bacteria and membrane damage, the latter evaluated both with the classic immunohemolytic system and with a bactericidal assay. The three biological assays differ for complement sequences involved. Flufenamic and niflumic acids showed high inhibitory activity in the lytic assays. Human complement was more sensitive to inhibition than guinea-pig complement. Phagocytic test confirmed the inhibitory activity of flufenamic acid on complement dependent opsonization.

Animals↗
PubMed1979

Complement activation by pneumococci associated with acute otitis media.

Pneumococci (types, I, III, VI, XIV, XVIII, XIX and XXIII) associated with acute otitis media were shown to activate complement in normal human serum by the classical as well as by the alternative pathway. In serum incubated with pneumococci classical pathway activation was demonstrated by decreased C4 values and the appearance of C1r-C1s-C1 IA complexes. Pneumococci caused C3 conversion in C2-deficient serum and in serum chelated with Mg++ EGTA showing activation of the alternative pathway without participation of the C42 convertase. Complement activation was more efficient when both pathways were intact. This was evident from a more pronounced C3 conversion and a greater reduction of the values for properdin and factor B in non-chelated serum as compared to Mg++ EGTA chelated serum.

Acute Disease↗
PubMed1996

Distribution of activated complement, C3b, and its degraded fragments, iC3b/C3dg, in the colonic mucosa of ulcerative colitis (UC).

The third component of complement (C3) is central to both the classical and alternative pathways in complement activation. In this study, involvement of C3 activation in the mucosal injury of UC was investigated. We examined the distribution of activated (C3b) and degraded fragments (iC3b/C3dg) of C3, terminal complement complex (TCC), and complement regulatory proteins in normal and diseased colonic mucosa including UC and other types of colitis using immunohistochemical techniques at the level of light and electron microscopy. While C3b and iC3b/C3dg staining was negligible in the normal mucosa, iC3b/C3dg and, to a lesser extent, C3b were deposited in UC mucosa along the epithelial basement membrane. The deposition was enhanced in relation to the severity of mucosal inflammation (C3b, P less than 0.05; iC3b/C3dg, P less than 0.01). Epithelial deposition of TCC was not observed in most UC mucosa. Immunoelectron microscopy showed that C3b and iC3b/C3dg were distributed mainly along the epithelial basement membrane and the underlying connective tissue in a granular, studded manner, and weakly present along the basolateral surface of epithelial cells. These C3 fragments were also deposited in inflammatory control mucosa such as ischaemic and infectious colitis. Our findings suggest that deposition of the C3 fragments occurs in inflamed colonic mucosa of diverse etiologies, including UC, but to define a role of the deposition in the development of mucosal injury in UC awaits direct study.

Adult↗
PubMed1982

Characterization of various immunoglobulin preparations for intravenous application. II. Complement activation and binding to staphylococcus protein A.

14 immunoglobulin preparations for intravenous use were tested to assess functions of their Fc portion. Inhibition of the hemolytic activity of complement, C1q binding and the interaction of IgG subclasses with Staphylococcus protein A were investigated. Complement studies were done on both the ready-for-infusion and the heat-aggregated preparations. Three groups of products could be distinguished: (1) Enzymatically and chemically treated products were devoid of complement-activating capacity, both when tested and ready-for-infusion and as heat-aggregated preparations. The chemically treated preparations showed atypical binding properties to Staphylococcal protein A. (2) The poly-(ethylene glycol) (PEG)-treated preparations and the untreated reference activated complement before and after heat-aggregation. (3) The albumin protected and the pH 4-treated product did not spontaneously activate complement in the ready-for-infusion state but did so after heat-aggregation. These results suggest that only the albumin-protected and the pH 4-treated products can be expected both to be well tolerated when given intravenously to high-risk agammaglobulinemic patients and to exhibit normal Fc functions in vivo.

Complement Activating Enzymes↗
PubMedDate not supplied

[A peptide (a magnesium salt of N-acetyl (alpha, beta)-aspartyl-glutamic acid). Demonstration of the protection against local cellular destruction induced by in situ complement activation].

A peptide of simple chemical structure has demonstrated its efficiency in preventing the large cellular destruction that locally activated complement produced on the ciliary epithelium of the respiratory tract. Previously (1980), it was demonstrated by the authors that these cellular destructions after sensitization of the epithelium was due to the local activation of the complement (alternate pathway) by immune complexes with secretory IgA. The cellular protection afforded by Naaga was demonstrated by the persistance of a normal ciliary beating when the sensitized mucosa is in contact with the antigen; by electron microscopic studies both in transmission and scanning E.M. contrasting with the complete cellular destructions of the epithelium which appear obvious. The protection appear complete when Naaga (56 mM) is present in the testing solution (or instillated before the test). By in vitro human complement studies; study of the cytolytic sequence inhibition for the classical pathway 1,5.10(-3) M of Naaga produces a 50% inhibition of 1 H50 hemolytic unit. For the alternate pathway, the same inhibition is observed with 1,75.10(-3) M of Naaga; by two-dimensions immuno-electrophoresis: a dilution of 1/2 of C3 in Naaga reduced to 1/10 of its normal value the C3b profile; the "Rockets" technique demonstrated that the same 1/2 dilution of Naaga in complement prevents the clivage of factor B and that this peptide acts by inhibition of the alternate C3 convertase formation (see illustrations). If we consider the subject of this study i.e. the upper respiratory tract mucosa and knowing the physiopathological importance of the muco ciliary complex in preventing dust, microbs and other particulate foreign materiel to penetrate the epithelium, the therapeutic importance of such a simple non toxic and unharmful chemical compound must be stressed.

Animals↗
PubMed1980

The effect of aging on complement activity (CH50) and complement protein levels.

Total complement activity (CH50), and the protein levels of C1q, C4, C3, C5, C9, factor B and C1 inactivator were measured in the 1,130 sera obtained from healthy subjects aged between 20 and 79 years old. Increase in the levels of CH50, C1q, C4, C3, C5 and C9 and decrease of factor B were found in the older age group. The level of C1 inactivator showed little variation with aging.

Adult↗
PubMed1991

Complement fragment C4d and Bb levels in inflammatory skin diseases (e.g. SLE, atopic dermatitis, erythroderma and pustulosis palmaris et plantaris) for assessment of complement activation.

The complement is one of the major effector system in the process of inflammation. Complement activation has been shown to occur in inflammatory dermatoses such as systemic lupus erythematosus, atopic dermatitis, erythroderma of unknown origin, and pustulosis palmaris et plantaris by the elevated blood levels of complement fragments. To clarify the complement activation, especially the alternative pathway involvement, we have measured the concentrations of classical pathway-specific C4d and alternative pathway-derived Bb in the plasma of patients with these inflammatory disorders at a mild to exacerbated stage. Only the SLE plasma showed significantly elevated Bb levels. These results suggest that assessments of plasma C4d and Bb levels may be of value in monitoring the involvement of the complement system in patients with inflammatory dermatoses with significant complement activation.

Adult↗
PubMed1979

Activated complement in the sputum from patients with cystic fibrosis.

14 cystic fibrosis (CF) patients chronically infected with mucoid P. aeruginosa and presenting multiple precipitins in serum against this bacterium (CF + P) and 13 CF patients without P. aeruginosa infection (CF-P) had their plasma and sputum sol phase examined for albumin, Clq. C3/C3c, C4 and C5 by means of electroimmunoassays. Their sputum sol phase was examined also for factor B by rocketimmunoelectrophoresis. C3c was demonstrated in the sputum sol phase but significantly more frequent (p less than 0.01) among the CF + P patients than among the CF-P patients. Factor B was also demonstrated in the sputum sol phase, but no significant difference in frequency could be demonstrated between the CF + P and the CF-P patients. None of the results indicated that a local pulmonary production of complement factors took place. Complement activation was significantly (p less than 0.01) associated with inflammation expressed as increased (formula: see text). The results show the importance of complement mediated inflammation in the pathogenesis of pulmonary tissue damage in patients with CF and support the concept of chronic P. aeruginosa lung infection as an immune complex disease in CF patients.

Adolescent↗
PubMed2000

[Complement activation in heparin--plasma inhibitory effect of anticoagulants on serum complement activation, 2nd report].

Our previous study of the inhibitory effect of EDTA and citrate in plasma on complement activation revealed that complement is activated in usual citrate plasma but not in usual EDTA plasma. The present study is a similar one using other anticoagulants containing heparin. CH50 and activities of C4 and C2 were assayed in serum or plasma containing various concentrations of anticoagulant after incubation with latex particles bearing immunoglobulin(Ig-Latex). It was found that complement activation is inhibited by heparin in a dose-dependent manner and that 10 U/ml of heparin does not inhibit CH50 reduction and C2 inactivation but inhibit C4 inactivation partially, indicating that complement activation proceeds in plasma containing usual concentration of heparin. Similar results were obtained in cases of low molecular weight heparin(LMWH) and nafamostat mesilate(Futhan). Complement activation was not inhibited by gabexate mesilate(FOY) in the tested range of concentrations. Thus, it was revealed that complement activation is not inhibited by usual concentrations of heparin, LMWH, Futhan and FOY.

Adult↗
PubMed1993

Activated complement directly modifies the performance of isolated heart muscle cells from guinea pig and rat.

The complement system has been implicated in the pathogenesis of cardiovascular disorders including ischemia and atherosclerosis. Selective deposition of C5b-9, the membrane attack complex of complement, has been histochemically documented in human myocardium early after reperfusion of ischemic areas and in infarcted zones. However, functional sequelae of the C5b-9 complex binding to myocardial cells have not been identified. Insertion of C5b-9 complexes into the membrane of other cell types can generate transient changes in membrane permeability in the absence of cell lysis. We demonstrate in beating isolated adult guinea pig and rat cardiac myocytes that human derived C5b-9 can transiently augment in a dose-dependent manner both basal cytosolic calcium concentration and calcium transients, resulting in a temporary increase in contractility. If similar changes occur in human heart cells in vivo, they could significantly affect myocardial performance and contribute to functional abnormalities seen in ischemia and other pathological conditions associated with complement activation.

Animals↗
PubMed1999

Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer disease.

Proteins characteristic of activated complement are associated with Alzheimer disease (AD) lesions. The classical complement pathway can be activated only when the influence of such endogenous regulators as C1-inhibitor (C1-inh) and CD59 are overcome. We used the techniques of reverse transcriptase-polymerase chain reaction and Western blotting to assess the mRNA and protein levels of C1-inh and CD59 in AD and control brains in comparison with levels of the complement components with which they interact. The inhibitors were only slightly upregulated and then only in heavily affected areas of AD brain such as the entorhinal cortex, hippocampus, midtemporal gyrus and midfrontal gyrus. The ratio of AD to control mRNAs in these four areas was 1.17 for C1-inh and 1.12 for CD59, compared to 3.06 for C1r, 2.67 for C1s, 2.35 for C5, 2.56 for C6, 2.42 for C7, 5. 08 for C8 and 16.3 for C9. Peripheral organ expression of C1-inh and CD59 mRNAs was no different in AD than controls but was slightly upregulated in infarcted heart tissue. Again, the increase was small compared with that of the competitive complement components. These data indicate that the forces which upregulate and activate complement in AD and myocardial infarction are not effectively suppressed by the endogenous regulators, C1-inh and CD59.

Adult↗
PubMed1991

Complement activation by vascular sutures both alone and in combination with synthetic vascular prostheses.

Polymer surfaces activate complement pathways resulting in platelet and leucocyte deposition as well as possible release of growth factors. A consequence of these interactions may be early graft failure or intimal hyperplasia leading to late graft failure. C5a generation in human plasma by vascular sutures, both alone and in combination with synthetic vascular prostheses was measured by radioimmunoassay to determine the influence of suture materials on C5a activation. Prolene and ePTFE suture material caused significant activation of C5a (p less than 0.01), while Novafil did not. Both Dacron and ePTFE graft material caused significant activation (p less than 0.01) of C5a. The addition of the suture materials to the ePTFE did not increase the C5a levels above the ePTFE material alone. In contrast, the addition of either Prolene or Novafil suture to Dacron material elevated C5a levels significantly over Dacron alone (p less than 0.01). The combination of Dacron material with ePTFE suture did not increase C5a levels over Dacron alone. The pattern of C5a activation by Prolene, ePTFE and Novafil sutures parallels the relative degree of in-vivo platelet accumulation on these suture materials as previously reported by our group. Since these experiments demonstrate that vascular suture material influences human complement activation, it may be that this interaction contributes to either early or late graft failure by enhancing platelet reactivity or neointimal proliferation, respectively.

Blood Vessel Prosthesis↗
PubMed1989

Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement.

Oligodendrocytes synthesize myelin in the central nervous system and maintain it in lamellar sheaths around axons. Techniques for studying oligodendrocyte development in vitro can be used, indirectly, to investigate the myelin injury that occurs in human and experimental demyelinating disease. Cell-mediated immune mechanisms are necessary but not sufficient to induce myelin damage in vivo; more recently complement has also been implicated in the pathogenesis both of multiple sclerosis and experimental allergic encephalomyelitis. Previously we have demonstrated that antibody-independent complement activation occurs in vitro at the oligodendrocyte surface. Here we show that the ensuing oligodendrocyte injury is reversible, and that recovery involves the release of membrane-attack complex-enriched vesicles from the surface of viable cells. The demonstration of morphologically and immunochemically identical vesicles in the cerebrospinal fluid of patients with multiple sclerosis suggests that reversible complement-mediated injury contributes to myelin damage in vivo.

Animals↗