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PubMed1989

Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis in the rat.

Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis from other forms of experimental glomerulonephritis in the rat. In the passive Heymann nephritis (PHN) model of membranous nephropathy (MN) subepithelial deposits form from anti-Fx1A antibody reacting with antigen expressed on the glomerular epithelial cell membrane followed by membrane patching and shedding of immune complexes. Immune complex deposits are accompanied by deposits of C5b-9 which is required for the mediation of proteinuria. We tested the hypothesis that C5b-9 assembly on the epithelial cell membrane might result in C5b-9 excretion in the urine, which would distinguish this autoimmune mechanism of MN from other processes that result in subepithelial immune complex deposits. Using monoclonal antibodies developed to rat C6 and a rat C5b-9 neoantigen, in a sensitive ELISA assay, elevated urinary excretion of rat C5b-9 was documented in PHN associated with on-going glomerular immune deposit formation. No urinary C5b-9 was detectable in MN induced by an exogenous antigen (cationized IgG) despite equivalent glomerular C5b-9 deposits, or in models of nephrotoxic nephritis, subendothelial immune complex nephritis, anti-mesangial cell membrane antibody-induced nephritis or two non-immune nephropathies. Infusion of preformed C5b-9 in proteinuric animals excluded glomerular filtration of C5b-9 as a contributing mechanism to urinary C5b-9 excretion. We conclude that in the rat, increased urinary excretion of C5b-9 is a marker of MN induced by antibody to a glomerular epithelial cell antigen. Urine C5b-9 excretion reflects active glomerular immune deposit formation and distinguishes MN induced by this mechanism from other forms of MN as well as from other glomerular diseases with equivalent glomerular C5b-9 deposits.

Animals↗
PubMed1999

[A study of plasma terminal SC5b-9 complement complex in patients with pregnancy induced hypertension].

OBJECTIVE: To study the relationship between complement SC5b-9 complex and damage of vascular endothelial in pregnancy induced hypertension (PIH). METHODS: Plasma SC5b-9, Serum circulate immunocomplex (CIC), fibronectin (Fn) levels were determined with ELISA in 47 cases of PIH (study group 1) and 15 cases with potential risk factors of PIH (study group 2) and 40 cases of normal pregnancies (control group). RESULTS: SC5b-9 level increased and CIC level decreased significantly in study group 1 and study group 2 than that in control group (P < 0.01). The Fn level increased in moderate and severe PIH cases than that of mild PIH and control group (P < 0.01). The positive rates of SC5b-9 in study group 1 and study group 2 were significantly higher than those of the control group (P < 0.01). The positive rate of Fn in moderate and severe PIH cases significantly higher than those of mild PIH cases and control group (P < 0.01). CONCLUSION: Complement was activated by classical pathway. Terminal SC5b-9 complement complex play an important roles in the pathogenesis of PIH and has close relationship with vascular endthelial damage.

Adult↗
PubMed1990

[Evaluation of the bactericidal effect of the membrane attack complex of serum complement].

The bactericidal activity of serum complement and particularly of the membrane attack complex (MAC-C5b-C9) was studied on E. coli C600 with a simple functional test. The test evaluates the in vitro kinetics of the bactericidal effect and the subsequent counting of surviving germs. Homozygous deficiency of a particular membrane attack complex protein was easily detected from a total loss of bactericidal activity. These results were confirmed on Neisseriae meningitidis A and C, but in this case a more complex protocol was required. Deficits of proteins of the membrane attack complex sequence of complement are often found in sera of patients suffering from recurrent Neisseriae infections. This simple test, adapted to family studies, appears, thus, as a valuable basis for a detection of relatives at risk.

Blood Bactericidal Activity↗
PubMed1999

Membrane attack complex of complement and neutrophils mediate the injury of acid aspiration.

A significant role for the alternative complement pathway in acid aspiration has been demonstrated by the observation that C3 genetic knockout mice are protected from injury. Utilizing C5-deficient mice, we now test the role of the terminal complement components in mediating injury. Lung permeability in C5-deficient mice was 64% less than in wild-type animals and was similar to wild-type mice treated with soluble complement receptor type 1, which gave a 67% protection. Injury was fully restored in C5-deficient mice reconstituted with wild-type serum. The role of neutrophils was established in immunodepleted wild-type animals that showed a 58% protection. Injury was further reduced (90%) with the addition of soluble complement receptor type 1, indicating an additive effect of neutrophils and complement. Similarly, an additional protection was noted in C5-deficient neutropenic mice, indicating that neutrophil-mediated injury does not require C5a. Thus acid aspiration injury is mediated by the membrane attack complex and neutrophils. Neutrophil activity is independent of C5a.

Animals↗
PubMed1987

Localization of S protein and its relationship to the membrane attack complex of complement in renal tissue.

The S protein (S) binds to the attack complex of complement (C5b-9) in plasma preventing cytolysis. Using immunofluorescence microscopy, the authors determined the distribution of S in human renal tissue and its relationship to C5b-9, immunoglobulins, C3, albumin, and fibronectin. They examined normal and diseased human kidney tissue from patients with several forms of glomerulonephritis, diabetic nephropathy, and arterionephrosclerosis. S and C5b-9 were found in all diseased tissues; their amounts and distribution directly correlated with severity and location of injury. S and C5b-9 were colocalized in all immune deposits and in all injured glomeruli, tubular basement membranes, and vessel walls. Other than within immune deposits, S and C5b-9 were usually not colocalized with C3. This study demonstrates that S is deposited in areas of tissue injury and thus may participate in the pathogenesis of renal damage. Because in tissue S and C5b-9 are always associated, the attack complex in tissue must either be derived from the circulation as SC5b-9 or it must be capable of binding S after the formation in situ of C5b-9.

Anions↗
PubMed1981

Assembly of the functional membrane attack complex of human complement: formation of disulfide-linked C9 dimers.

The 158,000 Mr protein, previously designated C5c, present in fully assembled complement (C) membrane attack complexes (MC5b-9) has been identified as a disulfide-bonded dimer of C9. This conclusion was based on the observations that: (i) a portion of the 125I-radiolabeled precursor C9 incorporated into MC5b-9 complexes comigrated with the 158,000 Mr protein band in NaDodSO4/polyacrylamide slab gels; (ii) monospecific antisera produced against native C9 and the 158,000 Mr protein immunologically crossreacted with monomeric native C9 by double immunodiffusion and with monomeric C9 and the 158,000 Mr protein on immunoreplication procedures; and (iii) two-dimensional NaDodSO4/polyacrylamide slab gel electrophoresis, in which the second dimension was conducted under reducing conditions, revealed that the 158,000 Mr protein contained two identical 71,000 Mr subunits which comigrated with monomeric C9. Molar ratio estimates indicated that 1 mol of C5b, C9 dimer, C6, C7, and C8 and 3-4 mol of C9 monomer were present per MC5b-9 complex. Each fully assembled membrane-bound MC5b-9 complex would therefore have a calculated Mr of 982,000. The presence of C9 dimers in the hemolytically active 29S dimeric form of the MC5b-9 complex and the absence of C9 dimers in the hemolytically inactive 23S monomeric form of the fluid phase SC5b-9 complex strongly suggest an important role for C9 dimer formation in MC5b-9 complex structure and function. The most probable function of C9 dimers would be the formation of intercomplex disulfide crosslinks which would provide a mechanism to stabilize the assembly of MC5b-9 into aggregates of increasing size on the target membrane surface which would thus be responsible for the observed pore size heterogeneity of functional C lesions.

Animals↗
PubMed2006

Cloning of a CD59-like gene in rainbow trout. Expression and phylogenetic analysis of two isoforms.

CD59, the major inhibitor of the complement membrane attack complex, is an 18-20 kDa glycoprotein, linked to the membrane via a glycosylphosphatidylinositol (GPI)-anchor. It restricts binding of C9 to the C5b-8 complex, preventing the formation of the complement membrane attack complex C5b-9. In this study we report the cloning of a second CD59-like gene in the rainbow trout, Oncorhynchus mykiss (referred to as CD59-2 and the previously deposited trout CD59-like gene as CD59-1). Trout CD59-2 is 56% identical to CD59-1 at the amino acid level. Both of trout CD59s show the highest identity score (54%) with putative CD59-like molecules from other teleost, and the overall identity with their mammalian orthologs is less than 30%. Trout CD59s are expressed in brain, heart, intestine, kidney, liver and spleen. Particularly, CD59-2 is abundant in trout brain, while CD59-1 seems to be absent in the trout spleen. Moreover, both of trout CD59 genes seems to be present as a single copy in trout genome.

Amino Acid Sequence↗
PubMed1987

Killing of human melanoma cells by the membrane attack complex of human complement as a function of its molecular composition.

The efficiency of the membrane attack complex (MAC) in killing M21 melanoma cells was determined varying the molar ratio of cell-bound C9:C8. It was found that C5b-8 produced functional channels as evidenced by 86Rb release and propidium iodide uptake; cell killing occurred in the absence of C9 with greater than 5 X 10(5) C5b-8/cell; the maximal molar ratio of C9:C8 was 6.6:1; using nonlytic numbers of C5b-8 (4.7 X 10(5)/cell), greater than 90% killing ensued at a C9:C8 molar ratio of 2.8:1 at which approximately 9,000 poly C9/cell were formed, and 50% killing at a ratio of 1:1; (e) when the MAC was assembled on cells at 0 degree C, consisting of C5b-8(1)9(1), and unbound C9 was removed before incubation at 37 degrees C, killing was similar to that observed when poly C9 formation was allowed to occur. Thus, MAC lytic efficiency toward M21 cells may be enhanced by but does not depend on poly C9 formation.

Cell Line↗
PubMed1993

Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells.

The membrane attack complex of complement (MAC) can induce reversible changes in cell membrane permeability resulting in significant but transient intracellular ionic changes in the absence of cell lysis. Because ion fluxes and cytosolic ionic changes are integral steps in the signaling cascade initiated when growth factors bind to their receptors, we hypothesized that the MAC-induced reversible changes in membrane permeability could stimulate cell proliferation. Using purified terminal complement components we have documented a mitogenic effect of the MAC for quiescent murine 3T3 cells. The MAC enhances the mitogenic effects of serum and PDGF, and also stimulates cell proliferation in the absence of other exogenous growth factors. MAC-induced mitogenesis represents a novel effect of the terminal complement complex that could contribute to focal tissue repair or pathological cell proliferation locally at sites of complement activation.

3T3 Cells↗
PubMed1985

The cobra complement system: II. The membrane attack complex.

Rabbit erythrocytes are lysed by cobra plasma. The membranes of the lysed rabbit erythrocytes exhibited typical ultrastructural complement lesions with an inner diameter of 72 A. Structures similar to human C5b-8 complexes were also visualized. The proteins found in membranes lysed by cobra plasma resembled closely the proteins of the human membrane attack complex in number and molecular weight. Cobra poly C9 that is resistant to reduction and boiling in SDS could also be demonstrated. These results indicate that the membrane attack complex of cobra complement is very similar to its mammalian counterpart.

Animals↗
PubMed1993

Membrane signaling by complement C5b-9, the membrane attack complex.

The terminal complement complexes C5b-7, C5b-8 and C5b-9 are able to generate nonlethal cell signals. One universal consequence of a cell being targeted by C5b-8 or C5b-9 is an influx of Ca2+. In addition, other second messengers, including cAMP, inositol phosphate intermediates and arachidonate metabolites, are generated by the terminal complement complexes in specific cell types. In vivo, terminal complement complexes have been found in a wide variety of inflammatory processes in humans and in experimental animal models. Some of these models of inflammation putatively induced by terminal complement complexes have been tested in complement-deficient animals, and indeed no inflammation results, which supports the critical role of the terminal complement complexes in the pathogenesis of the lesion.

Animals↗
PubMed1986

Membrane attack complex of complement in rheumatoid synovial tissue demonstrated by immunofluorescent microscopy.

Rheumatoid and osteoarthritic synovial membranes were examined for evidence of terminal complement pathway activation. Using antiserum highly specific for C9 neoantigen, immunofluorescent microscopy was employed to study synovial membrane specimens from 4 patients with rheumatoid arthritis, one patient with psoriatic arthritis, and 5 patients with osteoarthritis. C9 neoantigen was detected in 3 of the 4 rheumatoid membranes, the one psoriatic membrane, and one of the 5 osteoarthritic membranes. Activation of the terminal pathway of complement through C9 should be added to the spectrum of immunologic events known to occur in some rheumatoid synovial membranes.

Adult↗
PubMed1991

Formation of ion-conducting channels by the membrane attack complex proteins of complement.

The effects of sequential additions of purified human complement proteins C5b-6, C7, C8, and C9 to assemble the C5b-9 membrane attack complex (MAC) of complement on electrical properties of planar lipid bilayers have been analyzed. The high resistance state of such membranes was impaired after assembly of large numbers of C5b-8 complexes as indicated by the appearance of rapidly fluctuating membrane currents. The C5b-8 induced conductance was voltage dependent and rectifying at higher voltages. Addition of C9 to membranes with very few C5b-8 complexes caused appearance of few discrete single channels of low conductance (5-25 pS) but after some time very large (greater than 0.5 nS) jumps in conductance could be monitored. This high macroscopic conductance state was dominated by 125-pS channels having a lifetime of approximately 1 s. The high conductance state was not stable and declined again after a period of 1-3 h. Incorporation of MAC extracted from complement-lysed erythrocytes into liposomes and subsequent transformation of such complexes into planar bilayers via an intermediate monolayer state resulted in channels with characteristics similar to the ones produced by sequential assembly of C5b-9. Comparison of the high-conductance C5b-9 channel characteristics (lifetime, ion preference, ionic-strength dependence) with those produced by poly(C9) (the circular or tubular aggregation product of C9) as published by Young, J.D.-E., Z.A. Cohn, and E.R. Podack. (1986. Science [Wash. DC]. 233:184-190.) indicates that the two are significantly different.

Animals↗
PubMed2004

Cell signals transduced by complement.

The complement system is composed of soluble blood plasma proteins and cell membrane proteins. A major function of the soluble complement proteins is to bind to and destroy invading pathogens. The membrane proteins of the complement system are divided into complement receptors and complement regulatory proteins. Complement receptors on phagocytic cells promote binding and engulfment of pathogens coated with complement opsonins, whereas complement regulatory proteins protect healthy tissues from accidental damage by the soluble complement proteins. Upon binding of complement proteins or protein fragments that are generated during complement activation, these receptors and regulatory proteins transduce various signals into cells bearing them. The complement membrane attack complex C5b-9 binds to cell membranes, independent of any receptor, and also activates multiple signaling pathways. The receptor-dependent and -independent signals transduced by complement components are of great consequence to health and disease. Complement plays an important role in immunoregulation by activating B and T lymphocytes. It may also exert pro- or anti-apoptotic effects on various cell types. At sublytic doses, the complement membrane attack complex has wide-range effects on many cell types leading to cellular responses, such as secretion, adherence, aggregation, chemotaxis and even cell division. Sublytic complement also induces increased cell resistance to lytic doses of complement. Finally, certain pathogens take advantage of complement membrane proteins to gain entry into cells. The emerging data on these complement-related signaling pathways is hereby described.

Animals↗
PubMed1991

Amplified gene expression in CD59-transfected Chinese hamster ovary cells confers protection against the membrane attack complex of human complement.

Protection against the pore-forming activity of the human C5b-9 proteins was conferred on a nonprimate cell by transfection with cDNA encoding the human complement regulatory protein CD59. CD59 was stably expressed in Chinese hamster ovary cells using the pFRSV mammalian expression vector. After cloning and selection, the transfected cells were maintained in media containing various concentrations of methotrexate, which induced surface expression of up to 4.2 x 10(6) molecules of CD59/cell. Phosphatidylinositol-specific phospholipase C removed greater than 95% of surface-expressed CD59 antigen, confirming that recombinant CD59 was tethered to the Chinese hamster ovary plasma membrane by a lipid anchor. The recombinant protein exhibited an apparent molecular mass of 21-24 kDa (versus 18-21 kDa for human erythrocyte CD59). After N-glycanase digestion, recombinant and erythrocyte CD59 comigrated with apparent molecular masses of 12-14 kDa, suggesting altered structure of asparagine-linked carbohydrate in recombinant versus erythrocyte CD59. The function of the recombinant protein was evaluated by changes in the sensitivity of the CD59 transfectants to the pore-forming activity of human C5b-9. Induction of cell-surface expression of CD59 antigen inhibited C5b-9 pore formation in a dose-dependent fashion. CD59 transfectants expressing greater than or equal to 1.2 x 10(6) molecules of CD59/cell were completely resistant to human serum complement. By contrast, CD59 transfectants remained sensitive to the pore-forming activity of guinea pig C8 and C9 (bound to human C5b67). Functionally blocking antibody against erythrocyte CD59 abolished the human complement resistance observed for the CD59-transfected Chinese hamster ovary cells. These results confirm that the C5b-9 inhibitory function of the human erythrocyte membrane is provided by CD59 and suggest that the gene for this protein can be expressed in xenotypic cells to confer protection against human serum complement.

Animals↗