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PubMed1993

The specificity of alternative complement pathway-mediated lysis of erythrocytes: a survey of complement and target cells from 25 species.

Sera from 20 species of mammals were tested for their ability to lyse erythrocytes from 18 species of mammals and birds by the alternative complement pathway. Erythrocytes were not lysed by homologous complement, with one minor exception, but all erythrocytes tested were lysed by at least one complement source, and all sera tested except that of the horse lysed at least one type of erythrocyte. Control experiments indicated that lysis was via the alternative complement pathway and that antibodies were not involved. Complement from the various species could be ranked from most active to least active, and erythrocytes could be ranked from most susceptible to least susceptible. There was an inverse correlation between complement activity and erythrocyte susceptibility. The ranking of the orders of placental mammals, from strongest to weakest complement, was carnivore > artiodactyl (ruminants and swine) > primate = armadillo > rodent > rabbit > horse. Opossum serum had activity that placed it in the centre of this range. Ferret complement, the most potent tested, lysed all erythrocytes tested except for homologous erythrocytes, with APCH50 titres as high as 4000. Although the overall reactivity pattern was clear, there were several striking exceptions. For example, the only complement source which lysed ferret erythrocytes was sera of the mouse. The amount of sialic acid present on erythrocytes of 14 mammals was determined, and was, in general, directly correlated with resistance to alternative complement pathway lysis, although there were prominent exceptions to this correlation, involving erythrocytes of the horse, burro and human. All 20 types of complement were also tested for their ability to lyse antibody-coated human tumour cells, under conditions in which both the classical and alternative complement pathways were functional. The data obtained suggest that alternative pathway activation is, in some cases, a major factor determining the effectiveness of a particular complement source in the lysis of xenogeneic tumour cells.

Animals↗
PubMed1985

Ganglioside modulation of lipopolysaccharide-initiated complement activation.

Highly purified preparations of mouse gangliosides have been demonstrated to bind to purified preparations of lipopolysaccharide (LPS). In some instances, the binding has been demonstrated to be dependent upon the presence of sialic acid in the ganglioside preparation. The binding of gangliosides to LPS from the deep rough Salmonella minnesota Re mutant has suggested that the interaction involves the lipid A-2-keto-3-deoxyoctulosanate region of the LPS macromolecule. The interaction between gangliosides and LPS has been demonstrated to result in an abrogation of lipid A dependent activation of the classical pathway of serum complement by Re LPS. Surprisingly, however, the presence of sialic acid containing glycolipids has been shown to enhance significantly the capacity of LPS to initiate activation of the alternative pathway of complement. These data suggest that sialic acid can enhance as well as inhibit the formation of a stable alternative-pathway C3 convertase.

Animals↗
PubMed1984

Substances that can trigger activation of the alternative pathway of complement have anti-melanoma activity in mice.

Intraperitoneal (i.p.) injection of substances that can ignite the alternative pathway of complement, namely isolated human C3b or C3(H2O), guinea-pig C3(H2O) or cobra venom factor, or conventionally prepared zymosan, will reproducibly and very significantly increase the mean survival time of C57BL mice previously inoculated i.p. with melanoma cells. The effect is greater at higher doses and earlier post-inoculation (p.i.) administration, but the substances are active at low doses (30-100 micrograms/mouse) if given early enough. It is likely that C3b or C3(H2O) was the previously unidentified anti-tumour factor activated in serum by S. aureus treatment or serum fractionation and described elsewhere. Activation of the alternative pathway of complement appears to have potential interest for cancer therapy.

Animals↗
PubMed1987

Complement-dependent bactericidal activity for E. coli K12 in serum of preterm newborn infants.

Complement-dependent serum bactericidal activity for E. coli K12 was assessed in 12 term infants and in 16 preterm infants. In both groups of newborns, at birth, bactericidal reaction by the classical pathway of complement activation was impaired with respect to normal controls at less than 0.001 level of significance (as estimated by Student's t-test). The serum bactericidal reaction by the alternative pathway of complement activation was significantly impaired only in preterm newborns, being normal in term infants. At a time corresponding to 40 weeks' gestational age also in preterm newborns alternative pathway mediated bactericidal activity for E. coli K12 was found normal. Classical pathway mediated bactericidal activity became normal only at an age corresponding to 52 weeks' gestational age.

Blood Bactericidal Activity↗
PubMed1990

Evolutionary implications of a new bypass activation pathway of the complement system.

The classical pathway of complement activation is a highly specific and amplifiable effector system responding to recognition of foreign antigens by antibody. It comprises a group of well characterized proteins in mammalian plasma. There are many similarities with the alternative pathway of complement activation, which suggests that they have a common evolutionary origin. Both pathways have homologous components, use related activation and regulatory mechanisms, result in the release of the anaphylatoxins C3a and C5a, and deposit C3b onto activating surfaces. This fixed C3b then becomes the focus of further immune reactions, involving either the lytic complement components or C3b receptors on effector cells. Phylogenetic data indicate that the alternative pathway is the older, and that the classical pathway evolved from it. Here Timothy Farries and colleagues review this evolutionary process and present a possible sequence of events that is suggested by recent functional data from their laboratory.

Animals↗
PubMed1997

Activation of the alternative pathway of complement by calcium-loaded erythrocytes resulting from loss of membrane phospholipid asymmetry.

The aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are exposed on the outer membrane leaflet of deoxygenated and irreversibly sickled erythrocytes and senescent normal cells. PS exposure on erythrocytes results in the expression of procoagulant activity for the conversion of prothrombin to thrombin. Because liposomes or vesicles composed of aminophospholipids can activate the alternative pathway of complement, the possibility that increased exposure of PS and PE on intact erythrocytes would also make them capable of activating the alternative pathway was examined. Loss of normal membrane phospholipid asymmetry was induced by incubation of erythrocytes with calcium (Ca2+) and the calcium ionophore A23187. PS exposure on 60% of erythrocytes was confirmed by binding of fluorescein isothiocyanate-conjugated annexin V. Expression of procoagulant activity, measured with the Russell's viper venom clotting assay, was significantly increased on the Ca2+/A23187-treated erythrocytes. In addition, the erythrocytes became capable of activating the alternative pathway of complement, as judged by an increase in cell-bound C3b after incubation with serum and a decrease in alternative pathway hemolytic activity of the serum. The effect could be reversed by incubation of the Ca2+/A23187-treated erythrocytes under conditions that induced recovery of normal membrane phospholipid asymmetry. In contrast, tetrathionate-treated erythrocytes showed no increase in binding of annexin V and no procoagulant activity and failed to activate the alternative pathway of complement. These findings demonstrate that loss of phospholipid asymmetry in erythrocytes not only results in expression of procoagulant activity but also renders the cells capable of activating the alternative pathway of complement.

Annexin A5↗
PubMed1986

Brugia malayi: rat cell interactions with infective larvae mediated by complement.

Albino rat macrophages and neutrophils, in the presence of fresh normal rat serum as a source of complement, adhered to and promoted killing of Brugia malayi infective larvae in vitro. Eosinophils, by themselves, were marginally cytotoxic at a high cell-target ratio but promoted cytotoxicity when mixed with macrophages. Eosinophil culture supernatants enhanced the macrophage mediated killing of infective larvae. The complement of fresh normal rat serum was found to act by the alternate pathway. Fresh normal rat serum depleted of alternate pathway complement activity by treatment with zymosan A, or of Factor B by heating at 50 C for 20 min, or of Factor D by passing through Sephadex G75 column, failed to promote cell adherence to the parasite. C3 molecules were detected on the surface of infective larvae by immunofluorescence. There was a significant consumption of complement when Brugia malayi infective larvae were incubated in fresh normal rat serum. Albino rat cells were more potent in inducing cytotoxicity to infective larvae in vitro than those from jird or Mastomys natalensis, which may reflect the greater resistance offered by the rat to B. malayi infection. There was much less cellular infiltration on introduction of Brugia malayi infective larvae into the peritoneal cavity of jirds compared to rats and Mastomys natalensis indicating the greater susceptibility of jirds to intraperitoneally induced infections.

Animals↗
PubMed1997

A very sensitive coupled luminescent assay for cytotoxicity and complement-mediated lysis.

The demand for convenient and sensitive means of measuring cytotoxicity and complement-mediated killing is likely to be increased by the recent identification of Complement Factor H, an important regulatory protein of both the classical and alternate pathways of complement, as a tumor-associated antigen. Here we describe a simple luminometric assay capable of detecting the death of approximately 0.03 nucleated human-cell equivalent or approximately 1 rabbit-erythrocyte equivalent. The assay measures the release of glyceraldehyde-3-phosphate dehydrogenase (G3PDH) from dead or damaged cells by coupling its enzymatic activity to production of ATP, which in turn is measured by well-known methods involving firefly luciferase. This is accomplished by means of a reaction series in which the activity of G3PDH is coupled with that of phosphoglycerate kinase, the next enzyme in the glycolytic pathway. As described, the assay uses inexpensive, commercially available reagents. This coupled assay was used to demonstrate that an anti-factor-H antibody is capable of enhancing complement-mediated killing of the Raji cancer cell line by > 1000%.

Adenosine Triphosphate↗
PubMed1986

Interaction of bovine complement with Fasciola hepatica.

The host-parasite relationship of Fasciola hepatica in cattle was characterized by determining the effects of the parasite on the bovine complement system. Phosphosaline extracts of F. hepatica adults inhibited both the classical and alternative pathways of complement activation in normal bovine and human sera in a protein dose-dependent manner. The in vitro reaction of viable newly excysted juveniles (NEJ) with bovine serum (NBS) and with bovine serum containing antibodies specific to F. hepatica (IBS) resulted in no detectable changes in serum hemolytic complement activity for either pathway. This lack of complement consumption occurred even though these same flukes incubated in IBS for at least 24 h developed a precipitate that adhered to the parasite tegument, a feature that may reflect antibody--antigen reactions.

Animals↗
PubMed1994

The synthesis of a water soluble complement activating polyacrylic acid-IgG polymer.

Polyacrylic acid-IgG polymer (PAA-IgG) activates the classical and alternative pathway of complement as shown by specific Clq-(IgG-PAA) interaction and the generation of C4d, Bb, C3b, C3a and C5a. This water soluble and stable PAA-IgG polymer represents a model substance for the study of humoral and cellular inflammatory mechanisms, mediated by the complement system.

Acrylic Resins↗
PubMed1992

Regulation of complement functional efficiency by histidine-rich glycoprotein.

The modulation of complement functional efficiency by serum histidine-rich glycoprotein (HRG) was investigated. Addition of exogenous HRG to prewarmed diluted serum, followed immediately by sensitized sheep erythrocytes (EA), resulted in enhanced hemolysis. However, when HRG was incubated with diluted serum for 10 minutes at 37 degrees C, inhibition of hemolysis occurred. The biphasic modulation of complement function was also obtained with the complement alternative pathway when HRG was added to diluted serum for hemolysis of rabbit erythrocytes. Partial reduction of complement functional activity was shown when serum was absorbed by an HRG-Sepharose 6MB column. Western blot analysis showed that complement C8, C9, factor D, and S-protein in diluted serum were bound by nylon membrane-immobilized HRG. However, by immunoprecipitation of relatively undiluted serum with anti-HRG IgG beads, HRG was found to coprecipitate with S-protein and plasminogen, which suggested that HRG may complex with these proteins in serum. In functional tests, HRG inhibited C8 hemolytic activity, probably by preventing C8 binding to EAC1-7 cells. HRG also enhanced polymerization of purified C9 as well as the generation of a 45-Kd C9 fragment. Such an effect was even more pronounced in the presence of divalent cations with the reaction mixtures of C9 and HRG. Partial dimerization of C9 was shown when exogenous HRG was added to normal serum. In contrast, polymerization of serum C9 was inhibited by exogenous HRG during poly I:C activation of serum or incubation under low ionic strength conditions. HRG was further shown to inhibit factor D-mediated cleavage of factor B when bound by cobra venom factor. The molecular basis by which HRG regulates serum complement function is not clear. Hypothetically, the tandem repetitions of a consensus histidine-rich penta-peptide sequence in HRG may provide a highly charged area that interacts with complement components.

Animals↗
PubMed1981

Activation of the alternative pathway of complement: efficient fluid-phase amplification by blockade of the regulatory complement protein beta1H through sulfated polyanions.

Current concepts of activation of the alternative pathway of complement (APC) focus on the central role of an amplification mechanism triggered by C3b which is covalently bound to the surfact of activating substances. Using sulfated polyanions as model substances, an efficient fluid-phase activation of complement is demonstrated in contrast to solid-phase activation. It is shown that particulate high-molecular weight sulfated polyanions are capable of reversible binding the guinea pig and human regulatory protein beta1H. This fixation leads to an extensive activation of C3 and factor B because the regulatory function of beta1H is blocked in the fluid-phase C3b-dependent amplification system of the APC. Addition of beta1H-depleted C4-deficient guinea pig serum reconstitutes the physiological control mechanisms of the APC. Guinea pig beta1H, purified to homogeneity, is described as a 160000 dalton protein of a single-chain structure. In addition, highly specific and sensitive test systems for beta1H are described.

Absorption↗
PubMed2006

The paralogous salivary anti-complement proteins IRAC I and IRAC II encoded by Ixodes ricinus ticks have broad and complementary inhibitory activities against the complement of different host species.

Several observations suggest that inhibition of the host complement alternative pathway by Ixodes tick saliva is crucial to achieve blood feeding. We recently described two paralogous anti-complement proteins called Ixodes ricinus anti-complement (IRAC) proteins I and II co-expressed in I. ricinus salivary glands. Phylogenetic analyses suggested that these sequences were diversifying by a process of positive Darwinian selection, possibly leading to molecules with different biological properties. In the present study, we tested the hypothesis that each paralogue may have different inhibitory activities against the complement of different natural host species, thereby contributing to broaden the host range of I. ricinus ticks. IRAC I and IRAC II were tested against the complement of eight I. ricinus natural host species (six mammals and two birds). The results demonstrate that IRAC I and IRAC II have broad and complementary inhibition activities against the complement of different host species. This report is the first description of paralogous anti-complement molecules encoded by a pathogen with broad and complementary inhibitory activities against the complement of different host species.

Animals↗
PubMed1994

Isolation, partial characterisation and complement inhibiting activity of a new glycoprotein from Cuscuta europea.

A new complement inhibiting factor (CIF) was isolated from the seeds of Cuscuta europea parasitic plant. When activated via both classical and alternative pathway, the complement activity was completely depleted by CIF at a concentration of 0,25 mg per ml serum. Studies concerning the precipitation showed that CIF developed one or two precipitin bands against human sera. It was established that the precipitation is as a result of the specific association of CIF to the C3 component of complement. A partial characteristic of the CIF was carried out. It is a glycoprotein with molecular weight between 27000 and 28000 Da. Its molecule consists of one polypeptide chain.

Chromatography, Affinity↗
PubMed1992

The role of complement in the host's defense against Haemophilus influenzae.

In vitro studies have shown that Haemophilus influenzae type b (Hib) can activate both the classical and alternative pathways of complement and generate complement-dependent opsonic and bactericidal activities. In vivo studies and observations in complement-deficient patients have established the biologic significance of complement in the host's defense against H. influenzae. The complement system plays a significant role in the host's defense against Hib and against other encapsulated and unencapsulated H. influenzae, mainly by enhancing clearance from the bloodstream through its action as an opsonin in both nonimmune and immune hosts. Patients with genetically determined deficiencies of C3 or of the complement components involved in C3 activation have an increased susceptibility to H. influenzae. More recently, a relatively common deficiency of one isotype of C4 (C4B) has been shown to be associated with invasive Hib disease, suggesting that defects in complement-mediated host defense may be more common in systemic Hib infections than previously appreciated.

Animals↗
PubMed1999

Mouse-to-rabbit xenotransplantation: a new small animal model of hyperacute rejection mediated by the classical complement pathway.

BACKGROUND: Hyperacute rejection of porcine organs transplanted into primate recipients is initiated by the binding of preformed xenoreactive natural antibodies to the vascular endothelium of the graft and activation of the classical complement pathway. Several small animal models are currently employed to study various aspects of xenograft rejection; however, none has been shown to manifest hyperacute rejection mediated by the classical pathway of complement activation. METHODS: We performed heterotopic mouse heart transplants into weanling rabbits, adult rabbits, and C6-deficient rabbits. The recipients received no immunosuppression. Rejected grafts were subjected to histologic analysis and immunofluorescence staining for rabbit IgG, IgM, and C3. Levels of preexisting cytotoxic antibodies as well as classical and alternative complement pathway activities were determined in rabbit serum using mouse red cells as targets. RESULTS: Mean graft survival was 37+/-9.6 min for mouse-to-weanling rabbit transplants (n=10), and 40+/-11.1 min for mouse-to-adult rabbit transplants (n=5). Rejected grafts showed diffuse interstitial hemorrhage, endothelial cell damage, myocyte necrosis, moderate diffuse deposition of rabbit IgG, and dense deposition of rabbit IgM and C3 on the vascular endothelium of the graft, consistent with hyperacute rejection. One mouse-to-C6-deficient rabbit transplant was rejected at 21 hr with severe interstitial hemorrhage, cellular necrosis and a moderate cellular infiltrate consisting primarily of neutrophils and some mononuclear cells. A second transplant in a C6-deficient rabbit was functioning when the recipient died at 6.5 hr as a result of complications of surgery; the graft had normal myocytes and vasculature with minimal spotty interstitial hemorrhage. Both weanling and adult rabbit serum were found to have high titers of cytotoxic IgM anti-mouse antibodies and strong classical complement pathway activity with minimal alternative pathway activity towards mouse red cells. CONCLUSIONS: The mouse-to-rabbit species combination manifests hyperacute xenograft rejection. In vitro studies suggest that this process is mediated by IgM anti-mouse natural antibodies and activation of the classical pathway of complement.

Aging↗