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PubMed1985

Early- and late-phase activation of complement evaluated by plasma levels of C3d,g and the terminal complement complex.

Activation of the initial part (early phase) and terminal part (late phase) of the complement cascade was examined. C3d,g and the fluid-phase terminal complement complex were quantified and compared after spontaneous in vitro activation and after acute in vivo activation caused by extracorporeal circulation during coronary artery surgery. The results suggest that there is a close but not complete correlation between early- and late-phase activation of complement, that C3d,g and the terminal complement complex have different elimination rates in vivo, and that these two indicators are valuable for evaluation of early- and late-phase activation, respectively.

Complement Activation↗
PubMed1987

Immunocytochemical localisation of complement components C8 and C9 in human diseased muscle. The role of complement in muscle fibre damage.

The localisation of the complement components C8 and C9 was studied immunocytochemically in human diseased muscle to determine the role of complement in muscle fibre damage. Monoclonal antibodies to 2 epitopes of C9 and a monoclonal antibody to the alpha subunit of C8 were applied to frozen sections of muscle biopsies from 9 cases of dermatomyositis, 5 cases of polymyositis, 7 cases of Duchenne muscular dystrophy and 4 cases of Becker muscular dystrophy. These were compared with 6 control biopsies which were morphologically normal. In all cases of inflammatory myopathies several non-necrotic fibres showed discrete peripheral patches of C9 and to a lesser extent C8. In the muscular dystrophies peripheral C9 was observed on a few non-necrotic fibres and basophilic fibres showed C9 between the fibres as well as at the periphery. In all cases necrotic fibres labelled intensely with C9 and C8 but intensities varied with the different monoclonal antibodies. This was thought to result from differences in the polymerisation of the C9 molecule in the membrane attack complex. Complement C8 and C9 were also localised to blood vessels in 3 cases of muscular dystrophy, 2 cases of polymyositis and all cases of juvenile dermatomyositis. No complement was observed in the control samples. Our results provide evidence for the sublytic formation of the membrane attack complex (MAC) on non-necrotic fibres in inflammatory myopathies and muscular dystrophy. This sublytic formation of the MAC may induce sublethal metabolic damage, mediated by calcium, and suggests a primary role of complement in muscle damage not only in inflammatory disorders but also muscular dystrophy.

Adolescent↗
PubMed1981

Permeability characteristics of complement-damaged membranes: evaluation of the membrane leak generated by the complement proteins C5b-9.

Permeability characteristics of the membrane lesion generated by the terminal complement proteins are considered in light of recent observations that the measured diffusion of solute across complement-damaged membranes does not conform to the "doughnut hole" model of a discrete transmembrane pore formed by the inserted C5b-9 complex. By using the measured kinetics of steady-state tracer isotope diffusion of nonelectrolytes across resealed erythrocyte ghost membranes treated with C5b-9, a new transport model is developed. This model considers the apparent membrane lesion strictly in terms of the operational criteria of a functional conducting pathway for the observed diffusing solute, independent of a priori assumptions about the geometry or molecular properties of the membrane lesion. With this definition of the unit membrane lesion and the assumption that the exclusion size of the conducting pathway varies directly with the multiplicity of bound C5b-9 (as suggested by previous measurements under conditions of varying input of C5b-9), numerical estimates of te apparent permeability of the complement-damaged membrane to four diffusing nonelectrolytes are derived. These results suggest that the pathway for a particle diffusing across the complement lesion cannot be a pore and is functionally equivalent to an aqueous leak pathway, free of pore constraints. Implications of these results are discussed in terms of current molecular models for the mechanism of membrane damage by the complement proteins.

Biological Transport↗
PubMed1995

Purification and characterization of a human membrane protein that activates the alternative complement pathway and allows the deposition of homologous complement C3.

A human myeloid cell subline, P39+, is found to be a target for human complement (C) via the alternative pathway and to allow the deposition of multiple C3 fragments on its membranes, though expressing the complement regulatory proteins decay-accelerating factor and membrane cofactor protein. The parent cell line, P39-, which is phenotypically similar to the P39+ subline, does not allow the deposition of homologous C3 fragments. In this study, we established a monoclonal antibody, M161 Ab, which reacted with P39+ but not P39- cells. This Ab recognized a 43-kD protein in P39+ cell lysate transblotted onto nitrocellulose. Using this Ab as a probe, we purified the 43-kD protein, namely, M161 antigen (Ag). M161 Ag had a basic isoelectric point (pI), 9.3-9.4 by chromatofocusing, and was precipitated as an insoluble material at the pI point. The purified M161 Ag was a single-chain protein and did not possess N- or O-linked carbohydrates. When the purified M161 Ag was transblotted onto nitrocellulose and incubated with Mg(2+)-EGTA serum, human C3 fragments were efficiently deposited on M161 Ag. The major species of the deposited C3 fragments was C3b. Furthermore, the C3 fragments bound to the M161 Ag were detached by 1 M hydroxylamine, suggesting that a covalent ester linkage sustains M161 Ag-C3b interaction. NH2-terminal amino acid analysis revealed that M161Ag is a novel membrane protein. Hence, it appeared that M161 Ag is a potent activator of human alternative complement pathway on human cells that activates homologous C3 and allows the deposition of C3b on itself. Thus, under some conditions, homeostasis of complement is maintained even on human cells, not only by the complement regulatory proteins, but also by membrane C3-activating molecules on which C3b is deposited.

Antibodies, Monoclonal↗
PubMed1991

Complement activation by house dust: reduced reactivity of serum complement in patients with bronchial asthma.

Among ten different allergens, house-dust extract proved to be the most potent complement activator. It was therefore chosen to investigate the susceptibility of complement in the serum and bronchoalveolar lavage fluid of patients with extrinsic asthma and control persons. Complement activation in serum was assessed by the appearance of C3d as well as the activation-specific protein-protein complexes C1rs-C1inhibitor (classical pathway) and C3b(Bb)P (alternative pathway). Complement was activated via both the classical and the alternative pathway in a dose- and time-dependent manner. In contrast to earlier observations, however, complement was less affected in the serum of asthmatics than in the serum of normal individuals. Differences were restricted to alternative-pathway activation, probably due to preactivation and/or a significantly higher serum concentration of the regulatory protein factor H in asthmatic patients. In vitro generation of C3a in bronchoalveolar lavage fluid could not be achieved, although the presence of alternative pathway proteins C3, B and D was demonstrated.

Allergens↗
PubMed1973

The complement system in bullous pemphigoid. I. Complement and component levels in sera and blister fluids.

Compared with other serum and blister fluid proteins, total hemolytic complement was reduced in the blister fluid of six serologically positive bullous pemphigold patients while four serologically negative cases had blister fluid complement levels closely approaching the serum levels. Except for pemphigus vulgaris blisters. blister fluids from most patients with other bullous diseases and experimentally induced blisters had blister fluid complement levels more closely approaching the serum levels. With the exception of the two terminal components. C8 and C9, individual components of the complement sequence were also reduced in the blister fluids of the six bullous pemphigold patients with circulating basement membrane zone antibodies. On the other hand, transferrin and IgG levels of these same six serologically positive blister fluids closely approached the corresponding serum levels. Conversion of C3 proactivator was also demonstrable in the serologically positive bullous pemphigoid blister fluids, but not in the corresponding sera. Our studies, therefore, are suggestive of local activation of the complement sequence, by both the classical and alternate pathways, in blisters of serologically positive bullous pemphigold patients.

Basement Membrane↗
PubMed1987

Alternative pathway of complement activation by stimulated T lymphocytes. II. Elevation of cytotoxic potential against complement receptor-carrying cell lines.

Exposure of lectin-stimulated (concanavalin A, phytohemagglutinin and pokeweed mitogen) blood lymphocytes to human serum or to purified C3 increased their cytotoxic capacity towards complement receptor positive targets such as Raji and Daudi cells. The lysis of complement receptor-negative lymphoblastoid cell lines was not influenced. The lytic capacity of lymphocytes exposed to 12-O-tetradecanoylphorbol 13-acetate was not elevated by human serum. Lectin-stimulated lymphocytes were previously shown to activate and bind C3. The results using lymphocytes activated in different ways and targets with or without complement receptor expression suggest that the C3b deposited on lymphocytes binds to the complement receptor on the targets. This contact elevates the avidity between the two cells as indicated also by the increased frequency of the lymphocyte-target conjugates. On the basis of immune adherence the C3 fragment bound on the lymphocytes was identified as C3b. The increase of the conjugate formation and cytotoxicity was abrogated when the target cells, Raji, were pre-exposed to purified C3d which occupy the CR2 receptor. The majority of lymphocytes responsible for the cytotoxicity were CD8+.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Role of platelet factors and serum complement in growth of fibroblasts with high-affinity Clq complement receptors.

Cultures of human diploid fibroblasts are heterogeneous in that a subpopulation interacts via high-affinity receptors with the globular head regions of the Clq complement protein. Growth and synthetic properties of these cells are characteristic of cells residing in healing wounds and inflammatory lesions. At these sites, fibroblasts are exposed to regulatory molecules such as complement components and factors released from blood platelets. We assessed the effects of native complement proteins and platelet-derived factors on proportions and phenotypic stability of high-affinity and low-affinity receptor cells generated from explants of adult and embryonic connective tissue, using radioligand binding assays and immunofluorescence analysis by flow cytometry. Fibroblasts expressing high-affinity Clq receptors could be generated from explants only when factors from platelets were present in the medium; native complement proteins were not essential. High-affinity receptor cells could be generated only from tissue; they could not be generated by incubating cultures of the low-affinity receptor phenotype in medium containing platelet-derived factors. High-affinity receptor cells, once established from explants in the presence of platelet-derived factors, persisted through many replications in the absence of platelets. We obtained the same fibroblast phenotypes from embryonic skin as from adult gingiva, but the proportion of high-affinity receptor cells from skin was much greater. We conclude that factors derived from platelets are essential for generating cultures containing fibroblasts expressing high-affinity Clq receptors, but not for their maintenance. High-affinity receptor cells may comprise a rapidly dividing subpopulation giving rise only to like progeny or to other, more differentiated cells.

Adult↗
PubMed1982

Studies on the mechanism of bacterial resistance to complement-mediated killing. I. Terminal complement components are deposited and released from Salmonella minnesota S218 without causing bacterial death.

The mechanism of resistance of gram-negative bacteria to killing by complement was investigated. Complement consumption and uptake of purified, radiolabeled complement components on bacteria was studied using a serum- sensitive and a serum-resistant strain of Salmonella minnesota. Twice as many molecules of (125)I C3 were bound per colony-forming unit (CFU) of the smooth, serum-resistant S. minnesota S218 as were bound per CFU of the rough, serum-sensitive S. minnesota Re595 in 10 percent pooled normal human serum (PNHS), although 75-80 percent of C3 was consumed by both organisms. Hemolytic titrations documented total consumption of C9 by 5 min and more than 95 percent consumption of C5 and C7 by 15 min in the reaction with S218 with 10 percent PNHS. In contrast, negligible C5 depletion, 10 percent C7 consumption, and only a 26 percent decrease in C9 titer occurred with the serum-sensitive Re595. Binding of (125)I C5, (125)I C7, and (125)I C9 to S218 and Re595 was measured in 10 percent PNHS. A total of 6,600 molecules C5/CFU, 5,200 molecules C7/CFU, and 3,100 molecules C9/CFU bound to S218 after 5-10 min of incubation at 37 degrees C, but 50-70 percent of the C5, C7, and C9 bound to S218 was released from the organism during incubation at 37 degrees C for 60 min. Binding of 2,000 molecules C5/CFU, 1,900 molecules C7/CFU, and 9,000 molecules C9/CFU to Re595 was achieved by 20 min and was stable. The ratio of bound C9 molecules to bound C7 molecules, measured using (131)I C9 and (125)I C7, was constant for both organisms after 15 min and was 4.3:1 on Re595 and 0.65:1 on S218 in 10 percent PNHS. With addition of increasing amounts of purified, unlabeled (29 to 10 percent PNHS, there was no change in the C9:C7 ratio on Re595. However, with S218 there was a linear increase of the C9:C7 ratio, which approached the ratio on Re595. There was no (14)C release from S218 incubated in PNHS, nor was there evidence by electron microscopy of outer membrane damage to S218. Therefore, S. minnesota S218 is resistant to killing by PNHS, despite the fact that the organism consumes terminal complement components efficiently and that terminal components are deposited on the surface in significant amounts. The C5b-9 complex is released from the surface of S218 without causing lethal outer membrane damage.

Adsorption↗
PubMed1982

Antibody-independent complement activation by myelin via the classical complement pathway.

Murine or rabbit whole brain homogenates were shown to activate human complement via the classical pathway by an antibody-independent reaction. This activity required Ca++ ions. Anticomplementary activity in fractionated murine brain was found to reside in the myelin fraction and in purified myelin. It was absent, however, both from highly purified myelin basic protein (MBP) and from the MBP-free residue. Because purified MBP is a monomer and this protein exists in brain tissue largely as a dimer, the ability of the cross-linked form of MBP to activate complement was investigated. MBP, dimerized with difluorodinitrobenzene, was highly anticomplementary. The murine brain, inactive when taken from the newborn mouse, was shown to first acquire the capacity to activate complement at 7 d after birth. This finding is consistent with the report that the synthesis of myelin protein has been shown to be initiated in murine brain 8 d after birth. Complement activation by MBP could play an important role in the pathological changes observed in neurological disorders.

Animals↗
PubMed1980

A newly described control mechanism of complement activation in patients with mixed cryoglobulinemia (cryoglobulins and complement).

Levels in serum of components of complement were studied in a group of 10 patients with mixed cryoglobulinemia. The profiles found in most patients showed decreased levels of the early complement components C1, C4, and C2, with normal levels of C3. Experiments performed to define the mechanism(s) responsible for this unusual complement profile showed that activation of the early complement components in serum was due to the activation of the classical pathway by mixed cryoglobulins. They also showed that the characteristic lack of effect on C3 was due to the action of a previously unrecognized regulatory mechanism upon C3 convertase of the classical pathway mediated by 2 normal serum proteins, namely, the C4 binding protein (C4-bp) and the C3b inactivator (C3bINA).

Complement Activating Enzymes↗
PubMed1986

Suppression of complement-mediated vascular injury at Arthus reaction sites by complement inhibitors.

Certain complement inhibitors, namely chlorpromazine, suramin, 2-hydroxystilbamidine and chlorophenothiazine sulphonate were tested for their ability to suppress complement deposition and vascular injury at the site of an Arthus reaction. Deposition of complement was suppressed in the order 2-hydroxystilbamidine greater than suramin greater than chlorpromazine. All the above mentioned four compounds strongly protected vascular injury as observed by electron microscopic studies. At Arthus reaction sites prepared without drug treatment venules ranged from normal to severely altered and damaged. Discontinuities in endothelial linings varied from small to longer stretches. In the latter situation remaining endothelial cells were degenerated and endothelial remnants did not have an intact basal lamina. After treatment with the above complement inhibitors, at arthus reaction sites some venules appeared normal, whereas others were altered but in all cases the endothelium and its basal lamina remained intact.

Animals↗
PubMed1988

Effect of time, temperature and anticoagulants on in vitro complement activation: consequences for collection and preservation of samples to be examined for complement activation.

The effects of time, temperature, ethylene-diamine-tetra-acetic acid (EDTA), citrate and heparin on in vitro complement activation were examined in enzyme immuno assays (EIA) for detection of C3 activation products and the terminal complement complex (TCC). In vitro complement activation occurred during coagulation since baseline concentrations of activation products were considerably higher in serum than in plasma. EDTA was more efficient than citrate and heparin in inhibiting in vitro activation. Minimal activation was observed in all preparations when samples were kept at 4 degrees C for up to ten days, whereas a very rapid increase in activation products occurred even in EDTA plasma when the temperature was elevated. Based on the data obtained, guidelines for the collection and preservation of samples to be examined for complement activation are given.

Blood Preservation↗
PubMed1977

Pleural fluid complement, complement conversion, and immune complexes in immunologic and nonimmunologic diseases.

Forty-four pleural fluids and 41 blood specimens from patients with various diseases were examined for concentration of whole complement, C4, C3, conversion products of C3 and C3PA, and immune complexes. C3 conversion was found in all eight pleural fluids from patients with rheumatoid arthritis, five of seven with lupus erythematosus, two of six with congestive heart failure, and nine of 23 with malignant diseases. Conversion of C3PA correlated closely with C3 conversion and both were significantly inversely related to whole complement, C4, and C3. Concentration of immune complexes was highest in patients with rheumatoid arthritis. Pleural fluid immune complex concentrations correlated positively with conversion of C3 and C3PA. These findings suggest that the reduced levels of pleural fluid complement in rheumatoid arthritis and lupus erythematosus may be secondary to complement conversion by immune complexes.

Antigen-Antibody Complex↗
PubMed1979

The presence of complement in human cervical mucus and its possible relevance to infertility in women with complement-dependent sperm-immobilizing antibodies.

Full-complement component lytic activity was measured in human midcycle cervical mucus, using a sensitive 51Cr release hemolytic assay. The level measured was 11.5% of the activity of complement in an equal volume of undiluted human serum. The relevance of this level of complement to complement-dependent sperm-immobilizing antibody activity was studied. After 1 hour's incubation with mucus levels of complement, immobilization of about 50% of spermatozoa occurred and after 3 hours' incubation, immobilization of about 70% of spermatozoa occurred.

Antibodies↗
PubMed1980

The role of complement in viral infections. II. the clearance of Sindbis virus from the bloodstream and central nervous system of mice depleted of complement.

The following studies were performed to investigate the mechanism(s) by which the complement system limits Sindbis virus infection in the central nervous system of mice. After the intracerebral inoculation of Sindbis virus, no differences in mortality or viral growth in the central nervous system were observed between normal mice and mice depleted of complement by treatment with cobra venom factor. In addition, animals that had been inoculated subcutaneously with Sindbis virus and depleted of complement after the viremic phase had ended did not show any differences in mortality or viral growth in the central nervous system. In contrast, it was found that after the intracardiac inoculation of virus, complement-depleted mice demonstrated a defect in the clearance of infectious virus from the blood. These studies suggest that the increased growth of virus in the brains of complement-depleted mice after the subcutaneous inoculation of Sindbis virus is due to a defect in clearance of infectious virus from the bloodstream rather than to a primary defect within the central nervous system.

Animals↗
PubMed1995

Complementation of Xanthobacter Py2 mutants defective in epoxyalkane degradation, and expression and nucleotide sequence of the complementing DNA fragment.

Three Xanthobacter Py2 mutants (M3, M8 and M10) lacking epoxyalkane-degrading activity were isolated and characterized. All mutants were able to grow on acetone, the degradation product of 1,2-epoxypropane conversions. Furthermore, they contained the unidentified 'low molecular mass fraction' (LMF) necessary for epoxyalkane-degrading activity. Three cosmids from a gene bank complemented the mutation in M10 and M8 but not in mutant M3. Epoxyalkane-degrading activity in crude extracts of 1,2-epoxypropane-grown complemented mutants was similar to the wild-type activity. Surprisingly, M10 transformed with complementing cosmid pEP9 showed a constitutively expressed epoxyalkane-degrading activity, which was not observed in the wild-type strain. The cosmid pEP9 was conjugated into Xanthobacter autotrophicus GJ10, which is not able to degrade 1,2-epoxypropane. In crude extracts of X. autotrophicus GJ10(pEP9), epoxyalkane-degrading activity was demonstrated, but only after the addition of the LMF from Xanthobacter Py2. Hybridization experiments demonstrated an overlap on complementing cosmids pEP1, pEP3 and pEP9. Subcloning revealed a 4.8 kb EcoRI-HindIII fragment to be necessary for complementing the mutant M10. In the sequence of this fragment four different ORFs were found.

Alkanes↗
PubMed1980

A complement-fixation test for enzootic pneumonia of pigs using a complement dilution method.

Complement-fixing antibody to Mycoplasma hyopneumoniae in the serums of pigs experimentally infected with enzootic pneumonia was demonstrated by comparing the haemolytic titre of guinea-pig complement titrated in the presence of heated test serum, M. hyopneumoniae antigen and unheated normal pig serum with the titre obtained when the antigen was omitted. The haemolytic titres against sensitised sheep erythrocytes were determined after a fixation period of 16 to 18 hours at 5 degrees C. When serums, collected at intervals of 3 to 7 days, from 43 pigs exposed to pigs experimentally infected with enzootic pneumonia were tested, 4.6 or more complement units were first fixed 14 to 44 (mean 23.4) days after contact began. Serums collected subsequently fixed from 4.6 to more than 31 complement units. This positive reaction usually persisted until the pigs were killed 4 to 35 weeks after contact began. Thirty-three had gross enzootic pneumonia lesions and 9 had lung lesions detected microscopically. Serum antibody was not detected in 73 weaned pigs aged 7 weeks in a pneumonia-free herd but serums from 9 of 15 unweaned piglets aged 9 to 14 days in the same herd, fixed between 3 and 7 complement units.

Animals↗