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PubMed1987

Complement-mediated hemolysis of horse erythrocytes treated with equine infectious anemia virus.

Horse erythrocytes treated with equine infectious anemia virus hemagglutinin were found to be lysed after incubation with fresh horse serum at 37 degrees C. Fresh guinea pig serum induced more efficient hemolysis than horse serum. Direct immunofluorescence test revealed the adsorption of complement factors on the surface of the erythrocytes. Calcium and magnesium ions were necessary for the hemolysis to take place. Antibody against equine infectious anemia virus enhanced the virus-induced complement-mediated hemolysis. These observations indicated that the classical pathway of complement activation was responsible for this virus-induced hemolysis and suggest the possibility that virus antigen, anti-viral antibody and complement may play an important role in the genesis of the anemia of horses infected with the equine infectious anemia virus.

Adsorption↗
PubMed1986

Leishmania species: mechanisms of complement activation by five strains of promastigotes.

The interaction of fresh serum with promastigotes of Leishmania major, L. donovani, L. mexicana mexicana, L. mexicana amazonensis, and L. braziliensis guyanensis results in lysis of all strains tested with either fresh human or guinea pig serum at 37 C for 30 min. Lysis does not occur in the cold and requires divalent cations and complement that is active hemolytically. Serum deficient in the eighth component of complement is not lytic. Lysis of L. major, L. mexicana, and L. braziliensis proceeds fully in human serum containing EGTA/Mg2+ or in guinea pig serum deficient in the fourth complement component. These species consume only small amounts of C4 from human serum and do not require calcium to optimally bind C3. The data indicate that all are activators of the alternative complement pathway and that the classical pathway is not required for the lysis of these organisms. Promastigotes of L. donovani, in contrast, activate the classical pathway. The presence of calcium is required for both optimal C3 binding and parasite lysis, and L. donovani promastigotes consume C4 when incubated in human serum. In high concentrations, human serum agglutinates all tested Leishmania spp. The agglutinating factor does not require divalent cations, is heat stable, and works at 4 C, suggesting that it is an antibody. This "naturally occurring" antibody cross reacts with all Leishmania spp. and agglutinates them. The adsorption of serum with any Leishmania species or with beads that are Protein A coated, removes the agglutinogen. This factor causes a slight enhancement in alternative pathway activation by L. major and mediates the classical activation by L. donovani. In adsorbed serum, L. donovani promastigotes only weakly activate the alternative complement pathway. Increased concentrations of adsorbed serum are therefore necessary for lysis to proceed. The titer can be partially restored by the addition of heat inactivated serum. Using purified components of the classical cascade, we are unable to visualize surface bound C3 on L. donovani promastigotes unless heat inactivated serum is also present. We conclude that all Leishmania spp. promastigotes are susceptible to lysis by normal serum independent of antibody. The presence of small amounts of naturally occurring antibody in human serum enhances the susceptibility of L. donovani promastigotes to lysis by activating the classical complement pathway.

Agglutinins↗
PubMed2006

Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis.

Activation of each complement initiation pathway (classical, alternative, and lectin) can lead to the generation of bioactive fragments with resulting inflammation in target organs. The objective of the current study was to determine the role of specific complement activation pathways in the pathogenesis of experimental anti-type II collagen mAb-passive transfer arthritis. C57BL/6 mice were used that were genetically deficient in either the alternative pathway protein factor B (Bf(-/-)) or in the classical pathway component C4 (C4(-/-)). Clinical disease activity was markedly decreased in Bf(-/-) compared with wild-type (WT) mice (0.5 +/- 0.22 (n = 6) in Bf(-/-) vs 8.83 +/- 0.41 (n = 6) in WT mice (p < 0.0001)). Disease activity scores were not different between C4(-/-) and WT mice. Analyses of joints showed that C3 deposition, inflammation, pannus, cartilage, and bone damage scores were all significantly less in Bf(-/-) as compared with WT mice. There were significant decreases in mRNA levels of C3, C4, CR2, CR3, C3aR, and C5aR in the knees of Bf(-/-) as compared with C4(-/-) and WT mice with arthritis; mRNA levels for complement regulatory proteins did not differ between the three strains. These results indicate that the alternative pathway is absolutely required for the induction of arthritis following injection of anti-collagen Abs. The mechanisms by which these target organ-specific mAbs bypass the requirements for engagement of the classical pathway remain to be defined but do not appear to involve a lack of alternative pathway regulatory proteins.

Animals↗
PubMed2002

Deficiency of complement-dependent prevention of immune precipitation in systemic sclerosis.

BACKGROUND: Previous studies have indicated that complement may be activated or inherently abnormal in systemic sclerosis (SSc), and it has been suggested that immune complex deposition plays a part in the microvascular damage of this disease. OBJECTIVE: To study several aspects of the complement system in 24 patients with SSc. METHODS: Complement dependent prevention of immune precipitation (PIP) was measured by a sensitive enzyme immunoassay, levels of C1q, C4, and C3 by rocket immunoelectrophoresis, C4 allotypes by high voltage agarose electrophoresis, and C4A, C4B, and C3d by an enzyme linked immunosorbent assay (ELISA). RESULTS: PIP was markedly decreased in the patients with SSc (p<0.001). Abnormal complement activation was detected in nine patients as raised levels of the complement split product C3d. However, a relation between low PIP and complement activation was not seen. PIP was significantly lower in patients who carried the C4A*Q0 allotype (p=0.03), and a strong correlation was found between PIP and C4A concentration (p<0.00001). The PIP defect may, at least in some patients, be associated with the initial phase of the disease. CONCLUSIONS: The results show a previously unrecognised functional defect of complement in SSc; the defect correlates with low levels of classical pathway components and, in particular, C4A.

Adolescent↗
PubMed1999

Identification of a novel complement-dependent serum-elicited inward current in the Xenopus oocyte provoking Ca2+ influx and subsequent activation of Cl- channels.

The membrane spanning complement channel is assumed to be a nonselective ion 'pore', although little evidence is available to support this hypothesis. In this paper we provide evidence that Ca2+ entry and Cl- exit occur rapidly after complement activation and precede the development of a long-lasting complement-dependent inward current. Addition of rabbit serum (a source of heterologous complement) and mouse anti-human insulin receptor antibody to a single Xenopus oocyte expressing human insulin receptor was shown to stimulate an initial hyperpolarising current followed by a sustained depolarising current. On voltage clamping the oocyte, a novel long-lasting inward current generated by serum addition was detected. Complement classical pathway-stimulated calcium influx into the oocyte was directly demonstrated using 45Ca influx measurements. In addition, we found that Ca2+ influx was required for the stimulation of the complement alternative pathway-dependent inward current. The novel conductance elicited by the classical pathway was outwardly rectifying, had a reversal potential of -35 +/- 8 mV (or -52 +/- 7 mV in the presence of chloride channel inhibitors), was inhibited by nifedipine, and was observed in the presence but not in the absence of the pore-forming complement component C9. As overactivation of complement does play a role in many inflammatory or autoimmune diseases, inhibition of early complement-mediated ion flux might restrict tissue damage and aid recovery from such diseases.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1981

Level of complement activity and components C1, C4, C2, and C3 in complement response to bacterial challenge in malnourished rats.

In experimentally induced malnutrition in rats, there was no significant difference between the measured level of complement activity of the classical pathway (50% hemolytic complement [CH50]) and that of the alternative pathway (ACH50), although the levels of complement components C1, C4, C2, and C3 were depressed significantly. The complement activity showed a temporary elevation with a peak at 2 or 3 days after bacterial challenge with Staphylococcus aureus in rats, and we call this the complement response. After 3 days, CH50 and C3 in the malnourished rats and ACH50, CH50, and C3 in the well-nourished rats showed a significant increase, and C1, C4, and C2 in both groups tended to elevate. On the basis of these observations, the significance of the elevation of C3 in the complement response to bacterial infection showed a strong influence by enhancing the activation of both the classical and the alternative pathways, since C3 is known to be the junction of both complement pathways. In this way, C3 responded to an earlier stage than did the other components and may contribute to maintaining the body defense system against infection.

Animals↗
PubMed1999

Immunohistologic evaluation of mechanisms mediating hyperacute lung rejection, and the effect of treatment with K76-COOH, FUT-175, and anti-Gal column immunoadsorption.

Although most investigators agree that lung dysfunction occurs rapidly in various pig-to-primate hyperacute lung rejection (HALR) models, the basic mechanisms mediating this phenomenon remain in question. Here we describe an immunohistochemical method for assessment of mechanisms driving HALR. Using an established model wherein piglet lungs are perfused ex vivo with human blood, six experimental groups (K76 COOH; FUT-175; K76 with FUT; anti-alpha-Gal column adsorption; column with FUT; and column with K76) and two control groups (unmodified human blood; autologous pig blood) were studied. Each lung was biopsied serially during perfusion, and assessed using an immunohistochemical technique, with vWF staining as an internal control to quantitate binding of human IgM, IgG, C3, C5b-9, properdin, and C1q. The effect of each treatment and subsequent lung perfusion on IgG and IgM anti-alpha-Gal titers(by ELISA) and on pig endothelial cell cytotoxicity were correlated with histologic findings. We found that [1] the classical complement activation pathway was activated, as has been shown for other pig organs in primate or human blood environments [2]; alternative complement pathway activation is also seen, which has not been described for other organs in pig-to-primate models, but only in the context of classical pathway activation; and [3] anti-Gal column absorption, pharmacologic inhibition of complement, or combination therapy each was associated with histologic evidence of partial protection, consistent with what would be predicted for each intervention. Further, immunohistologic differences correlated with physiologic outcomes [8] and with antibody assay results, and revealed that treatments used were incompletely effective. Our data suggest that more complete inhibition of antibody- and complement-driven pathways than was achieved in these experiments will be necessary to prevent the antibody and complement-mediated facets of hyperacute lung rejection. This immunohistologic technique may also help us identify additional pathogenic mechanisms important to eventual clinical application of pig-to-human lung xenografts.

Acute Disease↗
PubMed1980

Interactions of chrysotile asbestos fibres with the complement system.

Type A chrysotile fibres (white asbestos) were tested in vitro for activation of the complement system. Fibres were incubated in normal human serum (NHS), factor B-depleted human serum, and normal and C4-deficient guinea-pig sera; the supernates were assayed for the remaining complement activity. Activation of the alternative pathway (AP) was shown in three ways. First, quantitative measurement of factor B; second, kinetic analysis of rabbit red blood cell lysis in whole alternative pathway (AP) and factor B lytic assays; third, qualitative measurement of C3 and factor B conversion by crossed immunoelectrophoresis. No C3 convertase activity could be demonstrated on the fibres but other possible mechanisms of AP activation are discussed. Magnesium itself is not responsible for this activation because acid-treated fibres retain this property. The early classical pathway is not involved as shown by normal whole complement activity of a factor B-depleted human serum and the absence of decrease of C4 functional activity. Knowing that complement proteins are present in pulmonary alveoli, mainly provided by cell synthesis, we suggest that complement activation in vivo may be relevant to the genesis of the chronic inflammation and fibrosis in the lung.

Animals↗
PubMed1999

Alternative pathway of complement is activated during in vitro ventricular assist.

BACKGROUND: Although ventricular assist devices (VAD) have improved survival in selected patients, their use continues to be complicated by thromboembolism and end-organ failure. Complement activation may play a role in the pathogenesis of these complications. Previous studies have found that the complement common terminal pathway is activated during VAD circulation. C3a levels rise dramatically during VAD use. Because the C3a fragment is generated by either the alternative or classical pathway, the purpose of this study is to determine the relative importance of the respective pathways in complement activation during in vitro VAD circulation. METHODS: Six in vitro VAD circuits were simulated for 3 days using 450 mL of human blood. Temperature, activated clotting time, pH, pCO2, pO2, Ca2+, and glucose were maintained at physiologic levels. Enzyme immunoassays were used to measure concentrations of fragment Bb to indicate alternative pathway activation and fragment C4d to indicate classical pathway activation. RESULTS: Fragment Bb concentrations rise from 1.92 to 10.77 micrograms/mL during the first 6 hours of circulation. Thereafter, Bb levels plateau. C4d concentrations slowly rise from a baseline of 1.49 to 6.84 micrograms/mL in 72 hours. CONCLUSIONS: These findings suggest that both the alternative and classical pathways of complement are activated during VAD circulation. Alternative pathway activation precedes classical pathway activation during in vitro VAD circulation and may be of greater clinical importance during clinical VAD circulation.

Assisted Circulation↗
PubMed2004

Cutting Edge: NK cells mediate IgG1-dependent hyperacute rejection of xenografts.

Classic hyperacute rejection is dependent on the activation of the terminal components of complement. Recently, xenoantibodies with limited abilities to activate the classical pathway of complement in vitro have been implicated in the acute vascular rejection of xenografts. It is unclear how these Abs affect their pathogenic activities in vivo. In this study, we demonstrate the ability of an anti-Gal-alpha1,3Gal (Gal) IgG1, with modest complement-activating abilities in vitro, to induce xenograft rejection. This rejection was dependent on the activation of complement, on FcgammaR-mediated interactions, and on the presence of NK cells. Inhibition of any one of these factors resulted in the abrogation of IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic, hyperacute rejection that was solely dependent on complement activation. Our observations implicate two types of IgG-mediated rejection; one that is dependent on complement activation, and a second that is uniquely dependent on complement, FcgammaR, and NK cells.

Animals↗
PubMed1984

Activation of complement by tetrathyridia of Mesocestoides corti: enhancement by antibodies from infected mice and lack of effect on parasite viability.

Tetrathyridia of the cestode Mesocestoides corti were isolated from the peritoneal cavity of infected mice. The parasites activated guinea pig and mouse complement (C) in vitro by both the classical and alternative pathways as shown by quantitative C fixation and crossed immunoelectrophoresis. The ability of tetrathyridia to activate mouse C was enhanced by preincubating the parasites in serum obtained from mice infected with M. corti. Antibodies of the IgG1 class, an immunoglobulin found in profoundly increased amounts in mice infected with M. corti, as well as IgM and IgG2 antibodies, bound to cultured tetrathyridia and facilitated deposition of the third component of C (C3) from dilute mouse serum, presumably via classical pathway activation. The results demonstrate that mouse IgG1 antibodies do not prevent the activation of C by the tetrathyridia or by C-fixing antibodies of other classes which become attached to the tetrathyridia. The activation of C in vitro by tetrathyridia did not affect their ability to grow in mice, even though C3-derived polypeptides could be detected by immunofluorescence on the surface of the parasites.

Animals↗
PubMed1979

Incompatibility between complement components C3 and C5 of guinea-pig and man, an indication of their interaction in C5 activation by classical and alternative C5 convertases.

The use of heterologous combinations of guinea-pig and human complement components for titration of C5 with convertases of the alternative and classical pathway has been investigated. In addition to the known unfavourable combination of C2hu with C4gp partial incompatibilities were detected between heterologous C3 and C5 as well as between CZhu and C5gp. The incompatibility between heterologous C3 and C5 is of special interest since it indicates an interaction of these two non-enzymic components. Concomitant binding studies have demonstrated that a reduced efficiency of C5 convertases correlates with decreased binding affinity of surface-fixed C3b for C5 when heterologous components are offered. Hence, the present studies give further evidence that surface-bound C3b has the function of a co-factor which binds C5; this interaction is required for C5 activation via the classical as well as the alternative pathway, i.e. by the C3/C5 convertases C42 and C3bB.

Animals↗
PubMed1996

Complement activation by IgG immobilized on methylated silicon.

Activation of the complement system by immobilized IgG on methylated silicon was studied by ellipsometry/antibody-, ELISA-, and RIA techniques after exposure to human serum at 37 degrees C for up to 1 h. The IgG-covered surfaces rapidly activated the complement system and the combined results suggest an initial classical pathway activation. Complement factor 1q (C1q) and IgG were antibody-detectable on the surfaces for serum incubations up to 5 min but not thereafter. Anti-C3c and anti-properdin bound to the surfaces at all serum incubation times. Experiments with 125I-IgG preadsorbed to surfaces, or added to normal-, EGTA-, and EDTA-sera, showed that IgG was not displaced from the protein film by serum.

CD4 Antigens↗
PubMed2006

Complement modulating and anticoagulant effects of a sulfated exopolysaccharide released by the cyanobacterium Synechocystis aquatilis.

During batch cultivation, the cyanobacterial strain Synechocystis aquatilis Sauvageau B90.79 was found to release a fucose-rich sulfated polysaccharide, which was mainly composed of arabinose (45%) and fucose (47%) and had a degree of sulfation of 0.43. The released polysaccharide showed merely an anticoagulant activity of less than 10% compared to the reference compound, unfractionated heparin. However, distinctive effects on the complement activation were observed: its inhibitory effect on the classical pathway of complement activation was 600-fold stronger than that of unfractionated heparin, whereas that on the alternative pathway of complement activation was 2- to 3-fold weaker. The results indicate that this biotechnologically producible, released polysaccharide represents a specifically acting complement modulator.

Anticoagulants↗
PubMed1976

Herpes gestationis. Immunopathology and characterization of the HG factor.

Five patients with herpes gestationis, a blistering disease of pregnancy, were studied immunologically. All had in vivo deposition of C3 in a linear band along the basement membrane zone of lesional and normal-appearing skin, the location of early blister formation. Immunoglobulin deposition was more variable, though four patients had evidence of in vivo bound IgG at the same site. A circulating, complement binding herpes gestationis factor was demonstrated in the sera of four of the patients, its concentration unrelated to the activity of clinical disease. Characterization of this factor by sucrose gradient ultracentrifugation, specific absorption studies, and papain digestion indicates that it is an IgG. Evidence exists for involvement of both the classical and alternate complement pathways in vivo, though in vitro studies implicate the classical pathway as the primary route of complement activation. Three offspring were studied, none with clinical involvement; one showed in vivo deposition of C3 at the basement membrane zone of normal skin and a second showed the herpes gestationis factor in cord blood.

Absorption↗
PubMed1988

The regulation of IgG subclass production in man: low serum IgG4 in inherited deficiencies of the classical pathway of C3 activation.

Human serum IgG subclasses have been measured by a sensitive enzyme-linked immunoassay in 52 subjects with severe genetic deficiency of a complement component. The mean serum IgG4 in 4 subjects with C3 deficiency was 8.2 micrograms/ml and in 14 subjects with C1-4 deficiency was 27.9 micrograms/ml. These means are severely depressed compared with the mean normal IgG4 of 292 micrograms/ml. IgG4 levels in C5-9 deficiency (175 micrograms/ml) and C1INH deficiency (179 micrograms/ml) did not differ significantly from normal. Serum IgG2 was reduced significantly, but far less severely than IgG4, in C3 and in some cases of C1-4 deficiency. IgG1 and IgG3 levels were within the normal range in all complement-deficient groups. Age differences between the groups do not explain the very low levels of IgG4 in C1-4 and C3 deficiency. These data suggest that serum IgG4 synthesis is dependent on an intact classical, but not alternative, pathway for activation of C3 and that IgG4-committed B cells require a complement-dependent maturation pathway not required by B cells committed to other IgG isotypes. IgG4 antibody responses are associated with secondary responses to T-dependent antigens. The possibility that IgG4 may be the product of a memory B cell which has been through a stage of differentiation in a germinal centre is discussed.

Complement Activation↗
PubMed1991

C1: molecular interactions with activating systems.

The molecular events controlling complement activation have been gradually unravelled over the past three decades, stimulated by improved isolation procedures and a better understanding of the roles of individual proteins. In this review, Bob Sim and Ken Reid examine the interactions between C1q and its numerous ligands in the initiation of the classical pathway cascade.

Animals↗