SEARCH · PubMed Health

Results for “Complement C5b”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources

PubMed1997

The role of CD11b/CD18 mediated neutrophil adhesion in complement deficient xenograft recipients.

Hyperacute rejection (HAR) of discordant xenografts is dependent on local complement activation. The formation of a functional complex of the complement components C5b-9 (membrane attack complex, MAC) causes endothelial injury and activation leading to coagulation and inflammation. In PVG rats which selectively lack the C6 component of complement, the MAC complex is not formed, whereas early split products of the complement cascade are produced normally. We reported previously that HAR is averted in C6 deficient xenograft recipients, and that subsequent accelerated acute rejection (AAR) can be delayed by inhibition of CD11b/CD18 (Mac-1) dependent neutrophil adhesion using leumedin, a member of a novel class of anti-inflammatory agents. Here we report the in vivo effects of a dose-response study using 2 new members of another class of Mac-1 directed agents designated nactins. Discordant cardiac xenografts from Hartley guinea pigs were heterotopically grafted into PVG(C6-) and PVG(C6+) rats. Experimental animals were divided into 3 groups receiving leumedin (group 1) or nactin (groups 2 and 3). Control animals received intravenous saline solution only. All C6(+) rats rejected their grafts hyperacutely within 10 to 15 min, irrespective of mode or dosage of treatment. C6 deficient controls rejected grafts within 17.7 +/- 3.5 h (n = 10). Treatment with leumedin/nactin prolonged graft survival up to 61.0 +/- 4.7 h (n = 4-6), with dose dependent differences in effectiveness among the 3 compounds tested. Histology showed that treatment was associated with less edema, hemorrhage, and neutrophil infiltrate at 2, 6, and 12 h. The marked decrease in hemorrhage seen in nactin-treated animals may reflect an interaction of Mac-1 with blood coagulation factors. Our data confirm that the neutrophil adhesion pathway is involved in AAR, especially when complement mediated injury due to MAC is restricted.

Acute Disease↗

PubMed1994

Genomic structure of the human complement protein C8 gamma: homology to the lipocalin gene family.

Human C8 is one of five complement components (C5b, C6, C7, C8, C9) that interact to form the cytolytic C5b-9 complex on target cells. It contains three subunits (C8 alpha, C8 beta, C8 gamma) which are encoded in separate genes. In relation to other proteins of the complement system, C8 gamma is unusual in that it is not structurally related to any other component nor does it have an obvious function. Based on weak but significant sequence similarity, it is proposed to be a member of the lipocalin family of widely distributed proteins that bind and transport small hydrophobic ligands. In this study, the human C8 gamma gene has been characterized and found to contain seven exons spanning approximately 1.8 kb. S1 nuclease and anchored PCR were used to identify the transcription initiation site. This site is preceded by putative regulatory elements that include two SP1 binding sites, several glucocorticoid response elements, and two SV40 enhancer core consensus sequences. A comparison to genes of other lipocalins reveals a remarkably close correlation in exon number, lengths, and phases. A close correspondence in exon boundaries is also observed and suggests that C8 gamma contains the same discrete structural elements that define the characteristic beta-barrel shape of the lipocalins. These results establish that C8 gamma is indeed ancestrally related to the lipocalin family and strengthens the likelihood that its role in the complement system is to bind an as yet unidentified ligand.

Amino Acid Sequence↗

PubMed1993

Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem-cell disorder in which the glycolipid-anchored membrane proteins, including the cell-surface complement inhibitors, CD55 and CD59, are partially or completely deleted from the plasma membranes of mature blood cells. To gain insight into the pathogenesis of thrombosis that is frequently observed in this disorder, the procoagulant responses of PNH platelets exposed to the human terminal complement proteins C5b-9 were investigated. C5b-9 complexes were assembled on gel-filtered platelets by incubation with purified C5b6, C7, C9, and limiting amounts of C8. Platelet microparticle formation and exposure of plasma membrane-binding sites for coagulation factor Va were then analyzed by flow cytometry. PNH platelets exhibiting undetectable levels of surface CD59 antigen showed an approximately 10-fold increase in sensitivity to C5b-9-stimulated expression of membrane-binding sites for factor Va when compared with platelets from normal controls. Expression of catalytic surface for the prothrombinase complex (VaXa) paralleled the exposure of factor Va-binding sites; the rate of prothrombin conversion by C5b-9-treated PNH platelets exceeded that of C5b-9-treated normal controls by approximately 10-fold at the maximal input of C8 tested (500 ng/mL). These data indicate that PNH platelets deficient in plasma membrane CD59 antigen are exquisitely sensitive to C5b-9-induced expression of prothrombinase activity, and suggest that the tendency toward thrombosis in these patients may be due, at least in part, to the deletion of this complement inhibitor from the platelet plasma membrane.

Adult↗

PubMed2000

Molecular basis for a link between complement and the vascular complications of diabetes.

Activated terminal complement proteins C5b to C9 form the membrane attack complex (MAC) pore. Insertion of the MAC into endothelial cell membranes causes the release of growth factors that stimulate tissue growth and proliferation. The complement regulatory membrane protein CD59 restricts MAC formation. Because increased cell proliferation characterizes the major chronic vascular complications of human diabetes and because increased glucose levels in diabetes cause protein glycation and impairment of protein function, we investigated whether glycation could inhibit CD59. Glycation-inactivation of CD59 would cause increased MAC deposition and MAC-stimulated cell proliferation. Here, we report that (i) human CD59 is glycated in vivo, (ii) glycated human CD59 loses its MAC-inhibitory function, and (iii) inactivation of CD59 increases MAC-induced growth factor release from endothelial cells. We demonstrate by site-directed mutagenesis that residues K41 and H44 form a preferential glycation motif in human CD59. The presence of this glycation motif in human CD59, but not in CD59 of other species, may help explain the distinct propensity of humans to develop vascular proliferative complications of diabetes.

Amino Acid Sequence↗

PubMed1982

Molecular organization of C9 within the membrane attack complex of complement. Induction of circular C9 polymerization by the C5b-8 assembly.

Evidence has been presented suggesting that during assembly of the membrane attack complex (MAC) of complement, the C5b-8 complex induces polymerization of C9. The C9 polymer was detected by sodium dodecyl sulfate (SDS) gel electrophoresis of MAC isolated from complement-lysed erythrocytes. It resembled the previously described polymerized C9 (poly C9) produced from isolated monomeric C9 by prolonged incubation at 37 degrees C in that it was resistant to dissociation by SDS and reducing agents and had an apparent molecular weight of approximately 1.1 million. The presence of poly C9 in the MAC was further supported by the expression of identical neoantigens by the MAC and poly C9 and by the high C9 content of the MAC relative to its other constituents. Isolated C8 in solution was found to have a single C9-binding site. In mixture, the two proteins formed a reversible equimolar complex that had a sedimentation coefficient of 10.5S. In contrast, a single, cell-bound C5b-8 complex was found to bind up to 12-15 C9 molecules and clusters of C5b- 8 bound 6-8 C9 molecules per C8 molecule. In either case, typical ultrastructural membrane lesions were observed, suggesting that the membrane lesion is identical with the tubular poly C9 consisting of 12-16 C9 molecules, and that the MAC can have either the composition (C5b-8)polyC9 or (CSb-8)(2)polyC9. When C9 input was restricted so that the molar C9/C8 ratio was less than or equal to 3, C9-induced aggregates of C5b-8 were observed but virtually no circular membrane lesions were found. We suggest, therefore, that C9, at low dosage, causes cross-linking of multiple C5b-8 complexes within the target membrane and that, at high dosage, C9 is polymerized by C5b-8 to form a transmembrane channel within the MAC assembly. It is primarily the C9 polymer that evokes the ultrastructural image of the MAC or of membrane lesions caused by complement.

Animals↗

PubMed1986

Interaction of complement with serum-sensitive and serum-resistant strains of Pseudomonas aeruginosa.

The interaction of complement with the following two strains of Pseudomonas aeruginosa was examined: 144M, a mucoid, serum-sensitive strain bearing short lipopolysaccharide O chains, and 144M-SR, a mucoid, serum-resistant strain bearing long lipopolysaccharide O chains isolated by repeated passage of 144M in increasing concentrations of pooled normal human serum (PNHS). While significant killing of 144M occurred in 5 to 40% PNHS, no killing of 144M-SR was observed. Both strains activated complement, especially 144M-SR which consumed 88.7, 96.4, and 100% of the available complement 3 (C3), C5, and C9, respectively, in 10% PNHS during a 60-min incubation at 37 degrees C. Although it activated more C3 than did 144M (54.9% consumption), 144M-SR bound only half as much C3 as 144M. Similarly, although 144M-SR activated more C9 than did 144M (50.0% consumption in 60 min), there was considerably less C9 attached to 144M-SR (2,990 molecules of C9 per bacterium) than to 144M (13,700 molecules per bacterium) after 60 min of incubation. Furthermore, only 162 molecules of the C9 bound to 144M-SR remained bound after treatment with 0.1% trypsin, while 5,692 molecules of the C9 bound to 144M remained bound under similar conditions. These results show that the serum resistance of 144M-SR does not represent a failure to activate complement efficiently, but instead reflects failure of the assembled terminal complement complex C5b-9 to insert stably into the outer membrane of this strain.

Blood Bactericidal Activity↗

PubMed1993

SP-40,40 immunoreactivity in inflammatory CNS lesions displaying astrocyte/oligodendrocyte interactions.

Immunoreactivity for SP-40,40, a putative complement inhibitor, adhesion or protective molecule, has been examined in a variety of inflammatory CNS lesions that displayed associations between hypertrophic astrocytes and oligodendrocytes, a phenomenon previously suggested to be related to oligodendrocyte phagocytosis or protection. SP-40,40 staining was common and was predominantly limited to hypertrophic astrocytes within lesion areas and diminished beyond the lesion margin. However, there was no consistent relationship between SP-40,40 immunoreactivity and astrocytes associated with oligodendrocytes. Staining for terminal complement complex (C5b-9/SC5b-9) occurred in association with larger vessel walls and microglial cells in the most active lesions, but was never seen in hypertrophic astrocytes. No association between SP-40,40 and complement deposition could be demonstrated. Staining for tumor necrosis factor-alpha showed a few scattered hypertrophic astrocytes to be positive. The findings confirm the presence of these astrocyte/oligodendrocyte interactions in active CNS lesions of varied etiology (multiple sclerosis, stroke and AIDS encephalitis). SP-40,40 immunoreactivity was common to hypertrophic astrocytes regardless of their associations with oligodendrocytes but showed no colocalization with terminal complement complex. Thus, these glial interactions do not apparently involve protection against complement-mediated lysis. Furthermore, the presence of SP-40,40 in astrocytes lacking association with oligodendrocytes did not support a role for this protein functioning as an adhesion molecule in astrocyte/oligodendrocyte associations.

AIDS Dementia Complex↗

PubMed1981

Membrane attack complex of complement. Evidence for its dimeric structure based on hybrid formation.

Molecular hybridization experiments provided new evidence for the dimeric nature of the membrane attack complex (MAC) of complement. Monomeric C5b-6, which constitutes the first intermediate complex in MAC formation, was prepared in two differentially labeled forms: biotin-125I-C5b-6 and 131I-C5b-6. Using a mixture of the differentially labeled C5b-6, the MAC was assembled on phospholipid vesicles upon addition of C7, C8, and C9. The assembled MAC containing biotin-125I and 131I was extracted from the vesicles with deoxycholate, purified, and exposed to avidin-Sepharose. Biotin-mediated binding of the MAC to avidin-Sepharose not only effected binding of 125I, but also of 131I, indicating that both radiolabels resided in the same molecular entity. When equimolar amounts of differentially labeled C5b-6 were available for MAC formation, 50% of MAC formed contained one molecule of each form. Theoretical analysis of the experimental data clearly favored the dimer structure over the structure of a higher oligomer. In contrast, fluid phase SC5b-9 was clearly monomeric on the basis of the same analysis. The electron microscopic appearance of the biotinated MAC hybrid closely resembled that of the characteristic membrane lesions of complement lysed cells. An avidin-ferritin conjugate attached itself to the ring-shaped portion of the biotinated MAC and not to its perpendicular structures, suggesting that C5b-6 is an integral part of the ring structure of the MAC.

Biotin↗

PubMed1984

Complement protein C9 labeled with fluorescein isothiocyanate can be used to monitor C9 polymerization and formation of the cytolytic membrane lesion.

Human complement protein C9 was covalently labeled with the fluorescent chromophore fluorescein isothiocyanate (FITC) with only a small reduction in the cytolytic activity of the protein. Polymerization of the labeled protein--either by incubating with lipid vesicles treated with complement proteins C5b-8 (activating the C5b-9 membrane lesion) or by heating the protein [Tschopp, J., Muller-Eberhard, H.J., & Podack, E.R. (1982) Nature (London) 298, 534]--resulted in a 40-60% decrease in the fluorescence emission from FITC. The decrease in total fluorescence was accompanied by an increase in the steady-state anisotropy following activation and polymerization of FITC-C9 by C5b-8 membranes, while heat-induced aggregation of the protein resulted in a dramatic depolarization of fluorescence. Only small changes in either the absorbance spectrum or fluorescence lifetime of the chromophore were detected upon FITC-C9 polymerization. Evidence is presented that the measured changes in FITC fluorescence upon C9 activation are due to self energy transfer between closely apposed fluorescein chromophores which occur in the polymerized form of the protein. The significance of these observations to the molecular structure of the assembled C5b-9 complex is discussed, as are the potential applications of this fluorescent derivative of C9.

Animals↗

PubMed1989

Transfer of phospholipid and protein into the envelope of gram-negative bacteria by liposome fusion.

A liposome-bacterial fusion system was developed in order to introduce preformed terminal complement complexes, C5b-9, into the outer membrane of Gram-negative bacteria. Liposomes were prepared from a total phospholipid extract of Salmonella minnesota Re595. Fusion between liposomes and Salmonella sp. or Escherichia coli 17 was dependent on time, temperature, pH, and Ca2+ and PO4- concentration. Only Salmonella sp. with attenuated LPS core regions were able to fuse efficiently with liposomes. It was demonstrated that fusion of liposomes with S. minnesota Re595 or E. coli 17 under optimum conditions resulted in (i) quantitative transfer of the self-quenching fluorescent membrane probe octadecyl rhodamine B chloride from the liposomal bilayer to the bacterial envelope, (ii) transfer of radiolabeled liposomal phospholipid to the bacterial outer membrane and its subsequent translocation to the cytoplasmic membrane, demonstrated by isolation of the bacterial membranes following fusion, and (iii) delivery of liposome-entrapped horseradish peroxidase (HRP) to the periplasmic space, confirmed by a chemiluminescent assay. Following fusion of liposomes incorporating C5b-9 complexes with S. minnesota Re595 or E. coli 17, immunological analysis of the isolated membranes revealed C5b-9 complexes located exclusively in the outer membrane.

Biological Transport↗

PubMed1989

Immunohistochemical demonstration of age-related deposition of vitronectin (S-protein of complement) and terminal complement complex on dermal elastic fibers.

Immunoreactivity of vitronectin was investigated in 100 skin specimens from different body regions in 87 individuals of different ages using monoclonal and polyclonal anti-vitronectin antibodies in an avidin-biotin-peroxidase complex technique. Vitronectin immunoreactivity was found in conjunction with dermal elastic fibers in all subjects older than 13 years. No vitronectin immunostaining was detected in subjects younger than six years, suggesting deposition of vitronectin during late childhood or early adolescence. Using an immunogold staining procedure, vitronectin immunoreactivity was ultrastructurally localized to the periphery of elastic fibers. The blood level of vitronectin in 20 healthy newborns was 67% of the adult level, suggesting active biosynthesis already in the fetus. To investigate whether vitronectin is deposited as part of the SC5b-9 complex or as uncomplexed protein, the immunoreactivity of vitronectin was compared with that of C9, using monoclonal and polyclonal antibodies against the C9 neoantigen. Distinct C9 neoantigen immunoreactivity was demonstrated in association with dermal elastic fibers in human skin in adults but only in subjects older than 30 years. The intensity of C9 neoantigen immunoreactivity appeared to increase with age and was found to be stronger in sun-exposed skin than in sun-protected skin. These findings indicate that uncomplexed vitronectin is deposited during childhood or early adolescence and that terminal complement complexes (C5b-9 and/or SC5b-9) are deposited on elastic fibers later on in life. Hypothetically, the tissue form of vitronectin may be involved in the prevention of tissue damage in proximity to local complement activation. In addition, it may be physiologically important as substratum for cells, stimulating cell migration and anchorage.

Adolescent↗

PubMed1990

Role of the terminal complement pathway in accelerated autologous anti-glomerular basement membrane nephritis.

The terminal complement pathway (C5b to C9) has been demonstrated to have an important role in the mediation of glomerular immune injury in various models of experimental glomerulonephritis. In the present studies, the role of the terminal complement pathway in the accelerated autologous phase of anti-glomerular basement membrane (GBM) nephritis in the rabbit was investigated. Normocomplementemic rabbits and rabbits deficient in C6 (C6D) who are therefore unable to form the terminal complement pathway were immunized with sheep immunoglobulin G (IgG) before being injected with a subnephrotoxic dose of the gamma 2 fraction of sheep anti-rabbit GBM. C6D animals had a delay in the onset of the glomerular injury, as manifested by proteinuria. At 72 hours, controls had a greater degree of proteinuria (15.2 +/- 8.8 mg protein/mg creatinine vs. 2.6 +/- 2.1, P = 0.197), but at 120 hours there were no differences in proteinuria between C6D and control animals (11.1 +/- 3.6 mg protein/mg creatinine vs. 12.2 +/- 6.2, P = 0.89). Light microscopy demonstrated more severe glomerular injury in C6D animals with marked cellular proliferation and large areas of glomerular necrosis. Interestingly, C6D animals had significantly higher levels of sheep IgG remaining in their glomeruli at 120 hours (0.95 +/- 0.12 micrograms sheep IgG/1 x 10(4) glomeruli, N = 11, vs. 0.57 +/- 0.07, N = 11, P = 0.014) and 72 hours (1.22 +/- 0.25 micrograms, N = 3, vs. 0.60 +/- 0.15, N = 3, P = 0.104) compared with 24 hours when there was no difference (1.25 +/- 0.22 micrograms, N = 7, vs. 1.08 +/- 0.14, N = 7, P = 0.53). C6D rabbits had a greater rise in serum creatinine at 120 hours (2.3 +/- 0.5 mg/dl vs. 1.3 +/- 6.4, P = 0.132). We conclude that in C6D animals, the persistence of glomerular immune deposits is responsible for more severe renal injury and renal failure.

Animals↗

PubMed1989

Immunohistochemical study of complement S protein (Vitronectin) in normal and diseased human kidneys: relationship to neoantigens of the C5b-9 terminal complex.

The localization of S protein (Vitronectin) antigen was studied by indirect immunofluorescence and immunoelectron microscopy in normal adult human kidneys and in biopsy specimens from patients with a wide range of renal diseases, and compared with that of neoantigens of the C5b-9 terminal complement complex. S protein antigen was diffusely present in arteriolar perimyocytic matrices, the glomerular basement membrane and mesangial matrix, and tubular basement membranes in the cortex of normal and diseased kidneys without superimposable staining for C5b-9 neoantigens. Cell remnants embedded in normal and sclerotic extracellular matrices expressed S protein antigen and also stained for C5b-9 neoantigens. Several lines of evidence suggested that S protein present in connective matrices most likely represents S protein or C5b-9 complexes trapped from the circulation. Glomerular immune deposits and arteriolar hyalin deposits which contained C5b-9 neoantigens also contained S protein antigen in the same location. In a few specimens from patients with membranous nephritis stage I and IgA nephropathy, immune deposits contained neither detectable C5b-9 neoantigens nor S protein. The observed strong co-staining of immune deposits for S-protein and C5b-9 caution against the generalization that C5b-9 within glomerular immune deposits represent membrane-bound cytolytic complement complexes.

Adult↗

PubMed1982

On the lysis of paroxysmal nocturnal hemoglobinuria erythrocytes by complement: dual role of C3b.

The efficiency of cytolysis by the terminal complement proteins C5b-9 can be markedly enhanced by C3b molecules bound on the target cell membrane (Hammer et al. 1976). This enhancement was shown to be proportional to the number of C3b molecules on the cell membrane. The present experiments have shown that the hemolytic efficiency of the complement membrane attack system is two to five times greater on paroxysmal nocturnal hemoglobulinuria erythrocytes (PNHE) than on normal human E. This difference is attribute to a derivative of C3, probably C3b, on PNHE since it was abolished by anti-C3 but not by anti-C2. The efficiency of C5b-9 to lyse PNHE was only partially decreased by C3b inactivator and beta 1 H, indicating that the C3b on PNHE is not readily inactivated by its regulatory proteins. Furthermore, cells from a single severely affected patient consumed 3-fold more C5b6 than normal human E yet concommitantly measured membrane fluidity was normal. From these observations we conclude that cell-bound C3b on PNHE serves two functions: (a) it increases the hemolytic efficiency of membrane attack components of the complement system; and (b) it provides sites for assembly of the alternative pathway convertases.

Complement C3b↗

PubMed1999

Up-regulation of intracellular calcium, cyclic adenosine monophosphate and fibronectin synthesis in tubuar epithelial cells by complement.

The terminal complement complex C5b-9 is known to participate in inflammatory processes including glomerular or tubulointerstitial injury. Injury appears to be a direct consequence of C5b-9-mediated cell stimulation. In that context we studied activation of tubular epithelial cells by C5b-9 particularly with regard to fibronectin synthesis and the transmembrane signals involved. C5b-9 in sublytic concentrations caused a rise of intracellular calcium and of cAMP, followed by an increase in abundance of fibronectin-specific mRNA and accumulation of protein. Stabilized cAMP or increasing the cAMP level by forskolin enhanced fibronectin synthesis with similar kinetics. The effect of cAMP could be enhanced by adding a calcium ionophore. Since the fibronectin gene is known to have a cAMP-responsive element, the data suggest that C5b-9 increases fibronectin synthesis via generation of cAMP.

Bucladesine↗

PubMed1999

Peritoneal mesothelial cells produce complement factors and express CD59 that inhibits C5b-9-mediated cell lysis.

The CD59 membrane protein confers protection from C5b-9-mediated cell lysis. Because evidence exists for complement (C) activation and generation of C5b-9 in the peritoneal cavity during chronic peritoneal dialysis (CPD), we investigated, on mesothelial cell (MC) lines, the expression of CD59 and the production of C components. Four MC lines were obtained from children on CPD, and two from non uremic children. CD59 expression on MCs was investigated with anti-CD59 monoclonal antibody (mAb) and polyclonal goat immunoglobulin G (IgG). MC lines were positive for staining with anti-CD59 mAb. Western blotting analysis of MC membrane demonstrated a band with the same molecular weight as CD59. Incubation of MC with anti-CD59 mAb abrogated the protective effect of CD59 (100% cytotoxicity). C3, C4, and C6 were detected in the supernatants of MC; in non uremic MC supernatants, C5, C7, C8, and C9 were also detectable, and C4 concentration was tenfold higher. CD59 expression confers to MCs protection from C5b-9-mediated lysis. MCs produce C factors. These findings suggest that production of complement components and expression of CD59 on MCs could play a role both in peritoneal cavity infection (decreased complement production) and in peritoneal membrane damage (decreased CD59 expression and reduced remesothelialization owing to MC lysis).

CD59 Antigens↗

PubMed2004

Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration.

PURPOSE: Recent studies strongly suggest that drusen, the extracellular deposits associated with age-related macular degeneration (AMD), are a manifestation of local inflammatory events. New evidence indicates that substructural elements within drusen contain activated complement components as well as amyloid beta (Abeta), a major pro-inflammatory component of Alzheimer's disease plaques. We characterized the ultrastructural organization and histochemical staining properties of these Abeta-containing elements in order to further assess their significance in drusen formation and AMD pathogenesis. METHODS: We used differential interference contrast optics, laser scanning confocal immunofluorescence, and immunogold electron microscopy to characterize the structural properties and molecular composition of Abeta-containing elements in drusen. We obtained estimates of their frequency from montages of electron micrographs gathered from 152 human donor eyes ranging from 9 to 91 years of age. RESULTS: Spherical Abeta-containing elements, which are typically organized as concentric ring-like structures, are common substructural components of drusen. They stain with thioflavin T, but are not stained by Congo red; nor do they bind cationic, lipophilic, or nucleic acid-binding fluorescent dyes. Ultrastructurally, they are composed of a central core, one or more concentric inner rings with intervening electron lucent layers, and an electron dense outer shell. Immunogold labeling indicates that most Abeta immunoreactivity is associated with the outer layers that consist of densely-packed spherical subunits. No longitudinally-oriented fibril arrays, characteristic of aggregated amyloid fibrils in the brain, are evident. Other prominent drusen-associated proteins including the terminal complement complex C5b-9, vitronectin, apolipoprotein E, serum amyloid P component, and ubiquitin are excluded from the spheres.Conclusions. These structures embedded in drusen appear to represent a new type of macromolecular assembly that contains Abeta as well as activated complement components. The presence of Abeta in these extracellular deposits is an additional indication that some of the pathogenic pathways that give rise to drusen and AMD may be shared with other neurodegenerative diseases characterized by misfolded protein deposition and aggregation.

Adolescent↗

PubMed1997

Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.

BACKGROUND: Acquired deficiencies of certain complement proteins and impaired opsonisation activity have been implicated in the pathogenesis of the increased susceptibility to infections of patients with alcoholic cirrhosis. METHODS: Serum concentrations of C3 and C4, plasma concentrations of C3bc, C9, and the terminal C5b-9 complement complex (TCC), and haemolytic complement activity (classic and alternative pathway) of serum, and serum opsonic activity were determined in 46 patients with compensated alcoholic cirrhosis, 31 who were decompensated, and in 15 healthy subjects. After 19 months (median) the investigated variables were analysed for their use in prognosis of recurrent infections and survival. RESULTS: C3 and C4 concentrations and the haemolytic complement activity of the alternative pathway were decreased in decompensated cirrhotic patients compared with controls (p < 0.01). Univariate analysis (log rank test) showed that low concentrations (< or = lower quartile) of C3 (p < 0.001) and C3bc (p < 0.05), haemolytic complement activity of the alternative pathway (p < 0.01) and classic pathway (p < 0.05), and decompensated cirrhosis (p < 0.001) were associated with an increased risk of infection and increased mortality. Multivariate (Cox) analysis showed that low C3 concentrations and decompensation of cirrhosis were significant predictors of infections and mortality (p < 0.02). CONCLUSIONS: Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.

Adult↗