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PubMed2000

Borreliacidal activity of early Lyme disease sera against complement-resistant Borrelia afzelii FEM1 wild-type and an OspC-lacking FEM1 variant.

Sera obtained from 14 Lyme borreliosis patients at early stages (stages I and II) of the disease were examined for their borreliacidal properties against Borrelia afzelii isolate FEM1 by use of a growth inhibition assay. Five of 14 immune sera exhibited borreliacidal activity against isolate FEM1. Heat-inactivated immune sera failed to kill the spirochaetes. Immunoblotting experiments with outer-membrane preparations showed that OspC and 11 additional proteins of 14.0, 16.0, 17.7, 19.3, 21.7, 27.5, 32.7, 40.7, 48.9, 51.3 and 53.6 kDa were recognised by borreliacidal immune sera. To analyse the borreliacidal properties of anti-OspC antibodies, two sera (EM4 and EM5), which beside antibodies against a 51.3-kDa protein contained exclusively anti-OspC antibodies, were further investigated by comparative analysis with a FEM1 wild-type and a FEM1 variant lacking OspC in a growth inhibition assay. Only FEM1 wild-type and not variant FEM1OspC(-) was killed by immune sera EM4 and EM5. Complement-dependent killing of FEM1 wild-type was mediated by formation of the terminal complement complex that was found to be attached directly to the outer membrane as confirmed by immuno-electron microscopy. No complement deposition was observed on the surface of variant FEM1OspC(-) after incubation with immune sera EM4 and EM5, thereby suggesting that only anti-OspC antibodies in these two immune sera were responsible for borreliacidal activity. These results provide direct evidence that anti-OspC antibodies, once developed during the immune response, are of critical importance for efficient killing of borreliae in the early phase of infection.

Antibodies, Bacterial↗
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↗
PubMed1986

The terminal complement complex in sera deficient in the eighth component of complement (C8).

The terminal complement complex (TCC) was quantified in sera from patients with a genetic deficiency of C8 alpha-gamma or C8 beta. The individual sera contained only trace amounts of TCC compared with a normal serum pool. The content of TCC increased after mixing the two sera, which was consistent with reconstitution of C8 activity. Only a moderate increase in TCC was obtained after zymosan activation of the individual sera, whereas activation of the mixture resulted in high amounts of TCC. C8 was demonstrated in the TCC of both deficient sera. These results may indicate that functional C8 is present in trace amounts despite the genetic deficiency, and that the terminal pathway may function to some extent although not enough to be detectable in less sensitive assays.

Antibodies, Monoclonal↗
PubMed1994

Type C retrovirus inactivation by human complement is determined by both the viral genome and the producer cell.

The inactivation of type C retroviruses by human serum may be a considerable impediment to the use of retroviral vectors in vivo for gene therapy. Here we show that virus inactivation is dependent both on the virus and on the cell line used to produce the virus. All viruses produced from murine NIH 3T3 or dog Cf2ThS+L- cells are sensitive to human serum. In contrast, those produced from mink Mv-1-Lu and human HOS or TE671 cells are at least partially resistant, with the exception of murine leukemia viruses. In particular, the feline endogenous virus RD114 is completely resistant to a panel of eight human sera when produced from Mv-1-Lu or HOS cells. This differential resistance is controlled by the viral envelope proteins. Virus inactivation can be correlated with the ability of the producer cells to be lysed by human serum. Inactivation of sensitive viruses requires the classical pathway of complement but does not require virion lysis.

3T3 Cells↗
PubMed1975

Complement.

Explore the source record for details and available documents.

Anaphylaxis↗
PubMedDate not supplied

Sublytic complement injury does not activate NF-kappa B, or induce mitogenesis in rat mesangial cells.

Sublytic complement injury to glomerular mesangial cells, mediated by the terminal membrane attack complex of complement (C5b-9), is a potential initiating mechanism in IgA nephropathy. Sublytic complement injury has been reported to result in the production of a variety of pro-inflammatory molecules and growth factors, including many regulated by the transcription factor NF-kappa B. To determine the importance of complement injury in the pro-inflammatory signalling which occurs in IgA nephropathy, we investigated NF-kappa B activation following sublytic complement injury to cultured rat glomerular mesangial cells (RMCs). A sublytic dose of rabbit anti-Thy 1.1 (THY) serum and normal human serum was selected based upon flow cytometry, chromium-release assay, and induction of superoxide production. No significant C5b-9-induced NF-kappa B activation was detected by electrophoretic mobility shift assays, luciferase activity of RMCs transfected with a NF-kappa B-driven luciferase reporter construct, nor by Northern blots for the NF-kappa B-responsive mRNA species monocyte chemoattractant protein-1 or I kappa B alpha. Furthermore, measurements of (3)H incorporation following sublytic complement injury showed inhibition of mesangial cell mitogenesis in comparison to the heat-inactivated serum treatment and to THY alone. The results of this study suggest that sublytic complement injury to RMC does not directly activate NF-kappa B nor induce mesangial cell proliferation in mesangial cells. Other mechanisms such as IgA immune complex formation must be required to produce these events in IgA nephropathy.

Animals↗
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↗
PubMed2001

CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59.

Complement-dependent cytotoxicity is thought to be an important mechanism of action of the anti-CD20 monoclonal antibody rituximab. This study investigates the sensitivity of freshly isolated cells obtained from 33 patients with B-cell chronic lymphocytic leukemia (B-CLL), 5 patients with prolymphocytic leukemia (PLL), and 6 patients with mantle cell lymphoma (MCL) to be lysed by rituximab and complement in vitro. The results showed that in B-CLL and PLL, the levels of CD20, measured by standard immunofluorescence or using calibrated beads, correlated linearly with the lytic response (coefficient greater than or equal to 0.9; P <.0001). Furthermore, the correlation remained highly significant when the 6 patients with MCL were included in the analysis (coefficient 0.91; P <.0001), which suggests that CD20 levels primarily determine lysis regardless of diagnostic group. The role of the complement inhibitors CD46, CD55, and CD59 was also investigated. All B-CLL and PLL cells expressed these molecules, but at different levels. CD46 was relatively weak on all samples (mean fluorescence intensity less than 100), whereas CD55 and CD59 showed variability of expression (mean fluorescence intensity 20-1200 and 20-250, respectively). Although CD55 and CD59 levels did not permit prediction of complement susceptibility, the functional block of these inhibitors demonstrated that they play an important role in regulating complement-dependent cytotoxicity. Thus, lysis of poorly responding B-CLL samples was increased 5- to 6-fold after blocking both CD55 and CD59, whereas that of high responders was essentially complete in the presence of a single blocking antibody. These data demonstrate that CD20, CD55, and CD59 are important factors determining the in vitro response to rituximab and complement and indicate potential strategies to improve the clinical response to this biologic therapy.

Antibodies, Monoclonal↗
PubMed1980

The hemolytic equivalence of human, guinea pig and canine complement proteins.

The ability of functionally pure human, guinea pig and canine complement proteins to fulfill the hemolytic function of a substituted analagous component in an otherwise totally homogeneous complement sequence was investigated by means of conventional hemolytic assays. A striking feature was the observation that for hemolysis to occur, differing requirements for enzyme-substrate homology were exhibited by each of the three species of C3 and C5 convertases (C3 and C5 CVA). The results suggest that different strategies of molecular interaction evolved in complement systems of different species.

Animals↗
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↗