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At least 865 records · Page 48Linked to original sources
PubMed1997

Glomerular handling of immune complex in the acute phase of active in situ immune complex glomerulonephritis employing cationized ferritin in rats. Ultrastructural localization of immune complex, complements and inflammatory cells.

The ultrastructural localization of immune complex (IC) and inflammatory mediator systems in the glomerulus was investigated in active in situ IC glomerulonephritis employing cationized ferritin in rats. Glomerulonephritis was induced by unilateral renal perfusion of cationized ferritin as antigen (Ag) in preimmunized rats, and anti-ferritin antibody (Ab), C3 and the rat C5b-9 complex were localized by means of immunogold electron microscopy. Ag-Ab complexes were initially formed subendothelially, associated with C3, and attracted platelets, polymorphonuclear leucocytes (PMN) and monocytes. Then Ag-Ab complexes, without C3, passed across the glomerular basement membrane to re-aggregate subepithelially accompanied by C3 deposition after 1 day. Ag-Ab complexes without C3 accumulated in the inter-podocyte space within 1 day and were seen in the epithelial cells at 6 h. C5b-9 complexes were found in subepithelial immune deposits and in membrane vesicles of the epithelial cells, but only in very small amounts in subendothelial immune deposits. Accumulated platelets, PMN, and monocyte were in direct contact with endothelial cells or subendothelial IC. PMN and monocytes contained Ag, Ab and C3 in intracytoplasmic vacuoles. Ag-Ab complexes were also found in the mesangial matrix adjacent to the subendothelial region after 2 h and increased slightly in number, with expansion of the mesangial area thereafter. Most ICs formed in the subendothelial space rapidly formed lattices of a size that activated C3 and were then translocated to the subepithelial space. The potential ability of C3 to solubilize ICs in the subendothelial region may be important in this process. Endocytosis of subendothelial ICs by PMN and/or monocytes and the movement of ICs to the mesangial matrix may also contribute to the removal of IC from the subendothelial space.

Acute-Phase Reaction↗
PubMed1991

Decreased expression of decay-accelerating factor on endothelial cells of immune complex-mediated vasculitic skin lesions.

Endothelial cells may be damaged directly by the membrane attack complex of complement in immune complex vasculitis of the skin. However, for endothelial cell membrane injury to occur, normal regulatory mechanisms must fail. One of the main complement regulatory proteins of endothelial cells is decay-accelerating factor, a surface protein which interferes with either the classical or alternative pathway C3 and C5 convertases. We have investigated the expression of decay-accelerating factor in 4 patients with histologically proven cutaneous immune complex vasculitis, using an immuno-electronmicroscopic technique. We demonstrated that endothelial cells of upper dermal vessels in vasculitic lesions were almost completely devoid of decay-accelerating factor. By contrast, the expression of this protein on endothelial cells in uninvolved skin of the patients was the same as in skin of healthy volunteers. As yet, the mechanism responsible for depletion of decay-accelerating factor is not clear. Absence of decay-accelerating factor may follow enzymatic release from the phosphatidylinositol anchor, proteolytic stripping from the cell membrane or a down-regulation of decay-accelerating factor synthesis. Regardless of mechanism, endothelial cell injury or death could serve a phlogistic function to facilitate complement-mediated destruction of endothelial cells for removal and repair.

Adolescent↗
PubMed1994

Molecular characterization of human TRPM-2/clusterin, a gene associated with sperm maturation, apoptosis and neurodegeneration.

The TRPM-2/clusterin gene and its cognate protein has been characterized in a number of species. Although the functional role, or roles, of the TRPM-2/clusterin protein remains to be firmly established, the gene has been implicated in a variety of physiological processes, including sperm maturation, lipid transport, membrane remodelling and inhibition of the complement cascade. TRPM-2/clusterin is induced de novo during the regression of the prostate and other hormone-dependent tissues after hormone ablation, and is over-expressed in several human neurodegenerative diseases including Alzheimer's disease, epilepsy and retinitis pigmentosa. We describe the genomic structure of the human TRPM-2/clusterin gene which is organized into nine exons, ranging in size from 47 bp (exon I) to 412 bp (exon V), spanning a region of 16,580 bp. Comparison with sequences registered in the databases shows that it has extensive similarity to the human protein designated as SP-40,40 or complement-lysis inhibitor (CLI), a protein that appears to block the membrane-attack complex of complement. However, the cDNA sequences reported for SP-40,40 and CLI diverge significantly in the 5' untranslated region of the mRNA (coded for by exon I), raising the possibility that the TRPM-2/clusterin gene is present in the human genome as a small multi-gene family or that there are several alternate exon I sequences in the TRPM-2 gene. Southern analysis and fluorescent in situ hybridization suggest that the clusterin gene is a single-copy gene, and that, if alternative exon I sequences are present in the genome, they lie outside of the lambda clones that have been characterized. Analysis of the promoter region of the human TRPM-2/clusterin gene shows many similarities to the rat TRPM-2/clusterin promoter including a putative control region containing several potential regulatory elements that may regulate the complex tissue-specific control of the gene which must be constitutively expressed in some tissues but is inducible in others.

Amino Acid Sequence↗
PubMed1991

[The role of immunological factors in the pathogenesis of arteriosclerosis].

Immunological factors seem to play an important role in the pathogenesis of atherosclerosis, which is a multifactorial chronic disease. It was demonstrated on animals that antibodies, immune complexes and cells may be the reason why the immunological damage in the vascular wall appears and may lead in consequence to the development of atherosclerotic changes. Immunological mechanisms of atherosclerosis are discussed.

Animals↗
PubMed1990

C3, C4, and the terminal complement complex differ from C1q by binding predominantly to the antigenic part of solid phase immune complexes.

The binding of the C components C1q, C4, C3, the terminal C5b-9 complement complex (TCC) and S protein to immune complexes was studied. The hapten 5-iodo-4-hydroxy-3-nitrophenacetyl (NIP) conjugated to BSA was adsorbed to polystyrene plates and reacted with a human IgG3-mouse chimeric anti-NIP antibody. After addition of serum a dose-dependent binding of C1q, C4, C3, and TCC to the immune complexes was found. An increase in the amount of NIP-BSA was associated with an increase in the binding of TCC and a decrease in the binding of S-protein. After addition of soluble NIP only 4 to 6% of the anti-NIP antibody remained bound to the Ag. C1q showed diminished binding after addition of NIP, whereas C4, C3, and TCC quantitatively remained bound to the Ag. Binding of TCC to the immune complexes was also found in an alternative assay, in which the anti-NIP antibody was adsorbed to the solid phase before NIP-BSA and an additional layer of anti-NIP antibody were added. The supernatants from the solid phase assay were tested for C3 activation and formation of the fluid phase TCC (SC5b-9). Activation of the C3 was reflected in the fluid phase by a dose-dependent increase in C3 activation products. This was not seen for TCC despite increased binding to the solid phase.

Animals↗
PubMed2003

Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors.

Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.

Antigens, CD↗
PubMed2023

Genome-wide screen in human plasma identifies multifaceted complement evasion of Pseudomonas aeruginosa.

Pseudomonas aeruginosa, an opportunistic Gram-negative pathogen, is a leading cause of bacteremia with a high mortality rate. We recently reported that P. aeruginosa forms a persister-like sub-population of evaders in human plasma. Here, using a gain-of-function transposon sequencing (Tn-seq) screen in plasma, we identified and validated previously unknown factors affecting bacterial persistence in plasma. Among them, we identified a small periplasmic protein, named SrgA, whose expression leads to up to a 100-fold increase in resistance to killing. Additionally, mutants in pur and bio genes displayed higher tolerance and persistence, respectively. Analysis of several steps of the complement cascade and exposure to an outer-membrane-impermeable drug, nisin, suggested that the mutants impede membrane attack complex (MAC) activity per se. Electron microscopy combined with energy-dispersive X-ray spectroscopy (EDX) revealed the formation of polyphosphate (polyP) granules upon incubation in plasma of different size in purD and wild-type strains, implying the bacterial response to a stress signal. Indeed, inactivation of ppk genes encoding polyP-generating enzymes lead to significant elimination of persisting bacteria from plasma. Through this study, we shed light on a complex P. aeruginosa response to the plasma conditions and discovered the multifactorial origin of bacterial resilience to MAC-induced killing.

Humans↗
PubMed1984

Complement channels in membranes: inhibition with a monoclonal antibody to a neoantigen of polymerized C9.

The channels produced by complement in red cell membranes are heterogeneous, with diameters of approximately 0.5 to approximately 12.0 nm. We investigated the relationship of the components of the membrane attack complex, C5b through C9, to the functional transmembrane channels greater than 3 nm in diameter. Radiolabelled macromolecules were incorporated into resealed red cell membrane ghosts which were then treated with complement. A monoclonal antibody to a neoantigen in polymerized C9 inhibited macromolecule diffusion through the complement channels. There was also inhibition with polyclonal antisera to C9 but not with antisera to any of the other components of the membrane attack complex. The results demonstrate a functional correlation of the larger complement lesions with the previously described poly C9 tubular structures.

Animals↗
PubMed1989

Complement activation in human lymphoid germinal centres.

The presence of complement activation products has been studied in morphologically normal human lymphatic tissue from tonsil, spleen and lymph node. Newly established monoclonal antibodies (mAbs) with reactivity against the C4 cleavage fragments C4a, C4b, C4c and C4d were applied on cyrostat sections in the indirect immunoperoxidase staining technique. Irrespective of organ type, C4d activation product could be detected in germinal centres of all secondary lymphoid follicles. To substantiate this finding, the complete sequence of complement activation products was investigated by a series of mono- and polyclonal antibodies to the complement proteins C1, C2, C3, factor B, C5, C9 to C5b-9 neoantigens and to the regulatory complement proteins C4 binding protein (C4bp), factor I, factor H and properdin. Similar to C4d, all secondary follicles exhibited a strong staining reaction for C3d antigens restricted to germinal centres. At the same site, albeit with distinctly weaker intensity, components of the membrane attack complex (MAC) C5b-9 were found. The simultaneous deposition of C1, C4b and C4bp in certain germinal centres indicates that complement activation is induced via the classical pathway. Concomitant deposition of IgM suggests IgM-antigen complexes that have been trapped on follicular dendritic cells (FDC) during normal immune response as the most likely candidates for activators of the classical pathway. Our data demonstrate that human lymphoid germinal centres as important sites of immune regulation closely interrelate with the complete cascade of complement-activation products, including the membrane attack complex (MAC).

Antigen-Antibody Complex↗
PubMed1990

TraT lipoprotein, a plasmid-specified mediator of interactions between gram-negative bacteria and their environment.

The TraT protein is a cell-surface-exposed, outer membrane lipoprotein specified by large, usually conjugative, F-like plasmids. Two biological activities have been associated with the protein: (i) prevention of self-mating of cells carrying identical or closely related conjugative plasmids, by blocking the formation of stable mating aggregates; and (ii) resistance to the bactericidal activities of serum, possibly by inhibiting the correct assembly or efficient functioning of the terminal membrane attack complex of complement. The protein therefore interacts not only with components of the outer membrane but also with specific external agents. In conjugative plasmids the traT gene lies within the region necessary for the conjugal transfer of DNA (tra), although its expression is not necessarily dependent on the expression of other tra genes. Recently, however, the gene has been discovered in isolation from other tra genes in nonconjugative virulence-associated plasmids, providing further evidence that the TraT protein may have a role in pathogenesis. The nucleotide sequences of several traT genes have been determined, and comparison of the corresponding amino acid sequences suggests that a central region of five amino acid residues flanked by hydrophobic domains determines the specificity of the protein in surface exclusion. Additionally, studies of mutants with different amino acid alterations within the hydrophobic domains have shown that insertion of charged residues disrupts normal outer membrane integrity. This review considers our current knowledge of the distribution, structure, and biological role(s) of the protein. Recent applications of the protein in studies of the unusual permeability properties of the outer membrane and for the transport of foreign antigenic determinants to the bacterial cell surface are also discussed.

Amino Acid Sequence↗
PubMed1991

Complement in inflammation: induction of nephritides and progress to chronicity.

The C5b-9 complex has a dual role as a factor involved in the initiation of nephritides and in the progress to chronicity and sclerosis. The unique pathophysiology of the membrane attack complex, distinct from other mediators, is its independence from specific receptors. It inserted in any membrane lipid bilayer tested so far.

Animals↗
PubMed1994

Defective regulation of complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation.

A prominent clinical manifestation of sickle cell disease (SCD) is hemolytic anemia. Although complement activation can lead to intravascular hemolysis, its role in the hemolysis of SCD is not known. Because normal red blood cells induced to vesiculate by treatment with calcium and ionophore become sensitive to damage by activated complement and because sickle cells release microvesicles as they circulate, we postulated that sickle cells might also be unusually sensitive to complement-dependent hemolysis. Complement activation is tightly regulated on the membrane of the normal erythrocyte; therefore, defective complement regulation by the sickle cell would be necessary for complement-dependent hemolysis to occur. These studies show a defect in the regulation of membrane attack complex (C5b-9) formation in sickle erythrocytes, particularly in the most dense cells. The defect is characterized by increased binding of C5b-7 and of C9 to denser sickle cells and results in increased susceptibility of sickle cells to C5b-9-mediated (reactive) lysis initiated by either C5b6 or activated cobra venom factor. Among the densest sickle cells, irreversibly sickled cells are especially sensitive to reactive lysis. The similarity of this defect to that previously described in a patient with paroxysmal nocturnal hemoglobinuria suggests that complement-mediated hemolysis could play a role in the anemia of SCD.

Adenosine Triphosphate↗
PubMed1992

Complement receptors in atherosclerotic lesions.

Accumulation of cholesterol in the tunica intima of arteries is a feature of atherosclerotic development. Recently, the demonstration of oxidized LDL in atherosclerotic lesions considerably strengthened the possibility of its role in the atherogenesis in vivo. However, the mechanism of lipid accumulation in monocyte-derived macrophages has not yet been clarified. It has been reported that the complement system may be related to atherosclerosis. In this report, complement receptors in the atherosclerotic lesions obtained from autopsy sample were investigated. Initially C3b receptors were detected using sheep erythrocytes bearing human C3b (EAC1423b cells). EAC1423b cells adherent to only aortic sections showing intimal thickening, but not to intact artery. Second, immunostaining of consecutive aortic sections was performed. Apo B and C5b-9 complex were stained using the indirect immunoperoxidase method, and macrophage, C3b receptor (CR1) and C3bi receptor (CR3) were stained using monoclonal antibody in the alkaliphosphatase anti-alkaliphosphatase method. In the intact artery of 3 month old patient, antigen- specific staining were not observed. In intimal thickening and atheroma of older patients, consecutive sections suggested that complement receptor-expressing cells were macrophages. Staining for apo B antigen existed at extracellular site in the intima, and C5b-9 complex was observed in intima and partially in the media. The above data showed that macrophage complement receptors were expressed in the atherosclerotic lesions when the complement system was activated. We conclude that these data suggest that the complement system and complement receptors may be related to the uptake of LDL by macrophages.

Adolescent↗
PubMed1995

Perforin: structure and function.

Perforin is a cytolytic mediator produced by killer lymphocytes, and is stored in and released by cytoplasmic granules. The protein is partially homologous to the terminal components of the membrane attack complex of complement and produces pores of up to 20 nm in diameter on target membranes. Its genomic and protein structures have recently been unraveled, and its function elucidated through the availability of genetically engineered, perforin-deficient mice. Here Chau-Ching Liu, Craig M. Walsh and John Ding-E Young briefly outline certain biochemical and molecular features of perforin, and discuss the still-evolving issues concerning the relevance of perforin and Fas in cell killing.

Animals↗
PubMed2002

Involvement of dipeptidyl peptidase IV in immune complex-mediated glomerulonephritis.

Dipeptidyl peptidase IV (DPPIV) is widely expressed in many tissues; however, its precise biological function is poorly understood. One of its possible physiologic roles is an involvement in the immune system, which plays a pivotal role in the pathogenesis of glomerulonephritis. The present study focused on the involvement of DPPIV in immune complex-mediated glomerulonephritis. Experimental nephritis was induced by anti-Thy-1.1 monoclonal antibody E30 using Wistar or F344 rats. The application of a new monoclonal antibody against DPPIV, F16, completely suppressed E30-induced proteinuria and mesangial proliferation in Wistar rats, whereas these preventive effects of F16 were not observed in F344 rats, which spontaneously lack DPPIV protein. Treatment with F16 inhibited glomerular deposition of complement C3 and complement C4 after the binding of E30 to the mesangial cell surface. Because the preventive effect of F16 was attributable to suppression of the complement cascade, we examined its influences on complement-dependent mesangial cell lysis in vitro. We discovered that the complement cascade was markedly inactivated in F16-treated Wistar rat serum but not in F16-treated F344 rats. These results indicate that DPPIV may play a somewhat crucial role in regulating the complement cascade and that inhibition of DPPIV may serve as a new target for preventing complement-dependent tissue injury.

Animals↗
PubMed1982

Interaction of rabbit spermatozoa and serum complement components.

Unheated rabbit and human sera were found to induce acrosomal loss in rabbit spermatozoa, while similar concentrations of heated sera did not. In addition, human serum did not induce acrosomal loss when pretreated with antiserum to complement component C8, suggesting that acrosomal loss in unheated serum is caused by the membrane attack complex of complement. Human serum complement anaphylatoxins did not induce acrosomal loss, although they are known to induce exocytosis of secretory granules in other cell types. When incubated directly in human or rabbit sera, rabbit spermatozoa fixed complement; i.e., reduced the potential hemolytic activity of the sera. Fixation was suppressed by adding EGTA to reduce free calcium. This indicates that rabbit spermatozoa fix complement by initiating the classical pathway to complement activation. Initiation requires the presence of cell-bound immunoglobulins and the subsequent binding of complement component C1q. Immunoglobulins were detected in detergent extracts of washed ejaculated spermatozoa by a solid-phase radioimmunoassay, and the binding of 125 I-human C1q was detected on samples of living ejaculated spermatozoa. Seminal plasma was found to inhibit complement-induced hemolysis of erythrocytes. These results suggest that, in the absence of seminal plasma, spermatozoa may activate complement where it is present in the male or female tract.

Acrosome↗
PubMedDate not supplied

Complement receptors and regulatory proteins in human atherosclerotic lesions.

Complement activation in human atherosclerotic lesions is indicated by the presence of C5b-9 terminal complexes. By using monoclonal antibodies to the complement C3b receptor (CR1) and the iC3b receptor (CR3), it was observed that approximately 20% of the cells in complicated human carotid lesions express CR1 and CR3 antigens. One to five percent of complement receptor-positive cells stained for smooth muscle cell-specific myosin, and the remainder were determined to be predominantly macrophages, based on their reactivity to anti-LeuM3 (CD14) monoclonal antibody. No C3dg receptor (CR2)-positive cells were observed in any of the eight lesions examined. The complement regulatory glycoprotein decay accelerating factor (DAF) was widely distributed extracellularly, in addition to being present on 20% to 60% of the total cell population. Factor H, a plasma protein that regulates alternative pathway C3 convertase formation, was observed extracellularly in 70% of the lesions examined. C1 inhibitor was present in a few plaque specimens, was relatively sparse, and appeared largely cell associated. Terminal C5b-9 complement complexes were pervasive in all lesions. Both the complement regulatory proteins and the activation products were limited to the area of lesion involvement and were absent from normal arterial wall. The results demonstrate that molecules involved in complement regulation and complement ligand binding are present in atherosclerotic lesions, where they may function to modulate the activities of complement.

Arteriosclerosis↗