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PubMed1978

Steady-state analysis of tracer exchange across the C5b-9 complement lesion in a biological membrane.

Resealed erythrocyte ghosts have been used to define the kinetics of tracer exchange across the membrane-bound terminal complex of the complement cascade (C5b-9). Under steady-state conditions and at net chemical equilibrium, C5b-9 ghosts showed no significant lysis above control levels as measured by hemoglobin efflux. In 1 mM sucrose at 37 degrees C, [14C]sucrose isotopic exchange diffusion into C5b-9 ghosts occurred at 4.8 (+/- 0.5, SEM) X 10(-20) mol sec-1 per functional lesion, equivalent to an apparent permeability coefficient of 4.8 X 10(-14) cm3 sec-1 for the single C5b-9 lesion. No significant uptake of [14C]sucrose above control levels was observed in C5b67 ghosts. The apparent rate of tracer permeation through the complement lesion is one to two orders of magnitude slower than predicted by a model of a transmembrane channel of dimensions permitting free diffusion of sucrose. The data support earlier assertions from this laboratory that diffusion of small molecules across the complement lesion in biological membranes is significantly restricted.

Biological Transport↗
PubMed1986

Evasion of alternative complement pathway by Trypanosoma cruzi results from inefficient binding of factor B.

During its differentiation in the insect vector to a stage infective for the mammalian host, Trypanosoma cruzi becomes resistant to lysis by the alternative pathway of complement. To elucidate the mechanism of complement evasion, we studied control of complement activation on the surface of the noninfective epimastigote and the infective culture-derived metacyclic trypomastigote stages (CMT) of T. cruzi. It was found that the predominant form of complement component C3 on epimastigotes is C3b, whereas the majority of C3 on CMT is in the form of the hemolytically inactive fragment iC3b, which cannot participate in C5 convertase formation or lead to deposition of the lytic C5b-9 complex. Our results also showed that C3 binds by a covalent ester linkage to surface molecules of different molecular weight in the epimastigote stage and CMT. Binding studies with purified complement components indicated that CMT do not support efficient formation of an alternative pathway C3 convertase. C3b on the parasite surface fails to bind the amplification component, factor B, rather than showing enhanced binding of the control component, factor H. These results identify the biochemical basis for evasion of complement-mediated killing in T. cruzi and reveal a mechanism for developmental regulation of complement activation.

Animals↗
PubMed1978

Lysis of oncornaviruses by human serum. Isolation of the viral complement (C1) receptor and identification as p15E.

Moloney leukemia virus activated both the classical and alternative pathways of human complement. About 500,000 virions were required to detect activation of the classical pathway whereas 5,000 times as many virions were necessary to initiate the alternative pathway, indicating that in this system only the former is of biological significance. Disruption of the virus with Triton X-100 destroyed its ability to initiate the alternative pathway without affecting its ability to activate the classical pathway. After ultracentrifugation of disrupted virus the active component could be recovered in the supernate and was isolated by isoelectric focusing in granulated gels. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic and analysis and cyanogen bromide digestion studies revealed that the activity resided in a methionine-containing protein having a pI of 7.5 and a molecular weight of approximately equal to 15,000 daltons. The purified protein interacts strongly with Clq and efficiently activates Cl. RNase and lipolytic enzymes had no effect on the isolated protein but incubation with trypsin resulted in loss of activity. Enzymatic digestion studies of surface-labeled virus indicate that the active protein is a viral membrane protein. On the basis of these results it is concluded that the complement receptor of Moloney leukemia virus is the surface protein p15E.

Binding Sites↗
PubMed1988

Serine esterase and hemolytic activity in human cloned cytotoxic T lymphocytes.

Target cell lysis by most murine cytotoxic T lymphocytes appears to be mediated by a complement (C9)-like protein called perforin, contained in high-density cytoplasmic granules. These granules also contain high levels of serine esterase activity, which may also play a role in cytolysis. Analysis of 17 cloned human cytotoxic T lymphocytes revealed the presence of serine esterase that is very similar to its murine counterpart in substrate and inhibitor specificities, pH optimum, and molecular mass; dot blot hybridization with synthetic oligonucleotides corresponding to the active sites of two known murine CTL esterases suggests homology to the murine enzyme HF. However, serine esterase was present at only approximately 10% of the level found in murine CTLs, and was not secreted during CTL-target cell interaction; moreover, hemolytic activity could not be detected in any of the seven cell lines tested. The results suggest that the human CTLs examined here kill their target cells by a mechanism different from that used by most cloned murine CTLs.

Cell Line↗
PubMedDate not supplied

Clinical applications of complement measurements in rheumatic diseases.

There is now convincing evidence that the complement system is involved in the pathogenesis of at least some of the manifestations of human rheumatic diseases. Complement measurements in serum and/or pathologic fluids from patients with these disorders not only reflect this involvement but also may provide important clues regarding the activity and extent of the disease processes. Future studies should provide additional information concerning the usefulness of such measurements for predicting the outcome of specific therapeutic regimens, and perhaps also be the basis for the evolution of new and more rational forms of therapy.

Antigen-Antibody Reactions↗
PubMed1991

Functionally active complement proteins C6 and C7 detected in C6- and C7-deficient individuals.

Two sensitive sandwich ELISAs based on monoclonal antibodies directed to native C6 and C7 allowed the detection and quantitation of these complement proteins in 20 out of 37 serum samples from individuals who had previously been classified as deficient in these proteins as assessed by immunochemical and/or functional assays. Furthermore, serum from four C6-deficient and one combined C6-/C7-deficient individual showed an increase in the terminal complement complex (TCC) and a decrease in native C6 and C7 after complement activation as assayed by specific ELISAs. Despite their (incomplete) deficiencies, these individuals therefore possess functionally active terminal complement proteins with respect to their ability to generate the TCC. As these individuals have no history of a susceptibility to neisserial infections, even low concentrations of functionally active C6 and C7 may provide sufficient protection against those micro-organisms whose destruction requires TCC formation.

Antibodies, Monoclonal↗
PubMed1991

Coronavirus induced primary demyelination: indications for the involvement of a humoral immune response.

Coronavirus MHV-JHM infection of rodents can result in demyelinating encephalomyelitis. We analysed histological changes induced by coronavirus MHV-JHM infection in Lewis rats. Besides an acute disease (AE), chronic panencephalitis (CPE) and subacute demyelinating encephalomyelitis (SDE) were induced. These disease types were differentiated by the incubation period, the localization of lesions, the type of tissue damage and distribution of virus antigen. In AE and CPE, virus antigen was detected in neurons, astrocytes and oligodendrocytes, whereas in SDE neurons lacked virus antigen. Viral nucleocapsid protein (N) was present in the cytoplasm and the spike protein (S) was displayed on the surface of infected neural cells. However, expression of S protein relative to N protein was severely impaired in SDE lesions. Quantitative analysis of infiltrating inflammatory cells revealed that the number of macrophages and T cells were similar in lesions of AE, CPE and SDE. In contrast to that, SDE lesions contained a significantly higher number of IgG + B cells and plasma cells. In addition active demyelinating SDE lesions displayed an enhanced IgG content and deposits of complement C9. These results indicate that virus induced primary demyelination could be a consequence of antibody mediated cytotoxicity. Furthermore, a reduction in the number of cells producing spike protein in the chronic forms of the disease indicates down-regulation of this protein, possibly mediated by anti-S antibodies.

Animals↗
PubMed1978

Complement lysis: the ultrastructure and orientation of the C5b-9 complex on target sheep erythrocyte membranes.

The C5b-9 complex derived from human serum and assembled on target sheep erythrocyte membranes is a thin-walled cylinder rimmed by an annulus at one end. The total height of the cylinder is 150 A, towards which the annulus contributes 30 A. The cylinder has an apparently uniform internal diameter of 100 A. The external diameter of the annulus is 200 A. The classical complement 'rings' visualized on membranes after complement lysis represent such C5b-9 cylinders perpendicularly oriented on the membranes. The thin-walled cylinder is anchored in the membrane matrix and the annulus located in the exterior membrane glycocalyx. At the sites of attachment of the C5b-9 complexes, the continuity of the membrane bilayer is disturbed and the presence of trans-membrane pores is indicated. The data essentially support the 'doughnut' theory of complement lysis.

Animals↗
PubMed1975

Complement.

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Anaphylaxis↗
PubMed1989

Effect of the late complement components C5b-9 and of platelet-derived growth factor on the prostaglandin release of human synovial fibroblast-like cells.

We examined the prostaglandin E (PGE) synthesis of cultured adherent synovial fibroblast-like cells (SFC) from patients with osteoarthritis (OA) in the noninflammatory state as well as with rheumatoid arthritis (RA). In cells from RA patients the spontaneous PGE release was generally higher compared to that of OA patients, but decreased fast with time in culture. After cell passage, similar PGE baseline levels were seen in cells of the two patient groups. The cells could then be stimulated by the terminal complement components C5b-9 or C5b-8. PGE synthesis was also stimulated by the platelet-derived growth factor (PDGF), interleukin-1 (IL-1), or lipopolysaccharide (LPS). The amount of PGE synthesis after incubation with PDGF, LPS and IL-1 was comparable to that released after C5b-9. Thus, like other inflammatory mediators C5b-9 and PDGF trigger the increased PGE production by SFC and thus may participate in the development of synovial inflammation and contribute to the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed2026

Large-Scale Proteomic Profiling of Incident Heart Failure and Its Subtypes in Older Adults.

BACKGROUND: Heart failure (HF) and its main subtypes, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), impose an enormous health burden on elders. Assessment of the circulating proteome to illuminate pathogenesis could open new opportunities for treatment. METHODS: We conducted a plasma proteomics screen of incident HF and its subtypes in 2 older population-based cohorts, the CHS (Cardiovascular Health Study) and the AGES-RS (Aging, Gene/Environment Susceptibility-Reykjavik Study). The 2 studies used SomaLogic platforms, with 4404 aptamers in common. Multivariable Cox models were fit to evaluate individual-protein associations with HF, HFpEF, and HFrEF separately in each cohort, and study-specific associations were combined by fixed-effects meta-analysis. Replication was performed in the ARIC (Atherosclerosis Risk in Communities) cohort. Two-sample Mendelian randomization of HF and its subtypes, along with colocalization analysis, was performed to support causal inference. RESULTS: Among 8599 participants, 1590 experienced incident HF (536 HFpEF, 471 HFrEF). There were 119 proteins associated with HF, 15 proteins with HFpEF, and 11 proteins with HFrEF, at Bonferroni-corrected significance. Among these, 9 have never previously been identified for cardiovascular diseases, and another 61 represent new associations with incident HF or its subtypes. Of these 70 proteins, 55 of the 66 available replicated externally. Mendelian randomization analysis revealed 7 proteins genetically associated with HF at nominal significance; 2 were separately associated with HFpEF, and another 2 with HFrEF. Seven of these 9 proteins (NPDC1 [neural proliferation differentiation and control protein 1], APOF [apolipoprotein F], LMAN2 [lectin, mannose-binding 2], ADIPOQ [adiponectin], CD14 [cluster of differentiation 14], ARHGAP1 [Rho GTPase-activating protein 1], C9 [complement 9]) showed new, possibly causal associations, although we did not detect evidence for colocalization. CONCLUSIONS: In this large-scale proteomic study involving 3 longitudinal cohorts of older adults, we identified and replicated 55 novel protein markers of HF or its subtypes, and 7 new, possibly causal proteins. These proteins may enhance risk prediction, improve understanding of pathobiology, and help prioritize targets for therapeutic development of these foremost disorders in elders.

Humans↗
PubMed1992

Human natural anti-Gal IgG regulates alternative complement pathway activation on bacterial surfaces.

One percent of circulating IgG in humans recognizes galactose alpha 1,3 galactose residues (anti-Gal) and is synthesized in response to stimulation by enteric bacteria. In this study, we found that the prevalence of binding of anti-Gal to blood isolates is significantly higher than its binding to normal stool isolates. When anti-Gal bound onto the lipopolysaccharide of a representative blood isolate, Serratia marcescens #21, it blocked its alternative complement pathway (ACP) lysis and made the organism serum resistant. In contrast, when anti-Gal bound to the capsular polysaccharide of a serum sensitive Serratia, #7, it increased ACP killing of this strain. The mechanism of blockade of ACP lysis by anti-Gal did not involve a decrease in the number of C3 molecules deposited onto Serratia #21 or an inhibition of the binding of C3b to its LPS, nor did it change the iC3b and C3d degradation products of bound C3b or prevent membrane attack complex formation on this organism. Our findings suggest that the effect of anti-Gal on immune lysis is dependent on the bacterial outer membrane structure to which it binds. We postulate that anti-Gal may play a role in the survival of selected Enterobacteriacae in Gram-negative sepsis by blocking ACP-mediated lysis of such bacteria by the nonimmune host, and that this effect depends on where anti-Gal finds its epitope on the bacterial outer membrane.

Complement C3↗
PubMed1975

Hypochlorite-induced alterations to canine serum complement.

Changes in the concentration of the components of complement produced by NaOC1 both in vitro and in vivo are recorded. C1, C4 and C7 are particularly sensitive to this oxidizing agent, although all components decrease at high concentrations of NaOC1. Following oxidation, complement componenets return rapidly to normal. Data are presented to indicate that part of this repair mechanism is due to the action of reducing agents such as ascorbic acid and part is due to the synthesis of the individual components. The unique sensitivity of complement components to oxidation make this treatment of potential value in suppressing the inflammatory response.

Animals↗