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PubMed1993

Chronic neutropenia associated with C2 and C9 deficiency.

A Japanese male with a deficiency of the second and ninth components of complement associated with chronic idiopathic neutropenia is presented. In this case the second component of complement is totally deficient while the ninth component is approximately half that of normal control. Neutrophil granulocytes are constantly few, but this case shows no evidence of susceptibility to either viral or bacterial infections. His HLA type is different from that of Caucasians, suggesting that the genetic abnormality responsible for the complement deficiency of this Japanese case is different from that seen in Caucasian patients.

Adult↗
PubMed1993

Interaction between apolipoproteins A-I and A-II and the membrane attack complex of complement. Affinity of the apoproteins for polymeric C9.

We have previously observed enhanced binding of HDL and apolipoproteins A-I and A-II to human endothelial cells exposed to activated complement. Induction of these binding sites required complement activation through C9, suggesting a specific role for the C9 component of the C5b-9 complex. We now report that specific and saturable binding sites for apoA-I and -A-II are expressed by C9 polymers (polyC9), whereas little binding was observed to native monomeric C9. These data suggested an interaction of the apoproteins with a site(s) which is exposed only upon C9 polymerization, and also suggested that binding of the apoproteins to this new site might interfere with assembly of C9 into the polyC9 tubule and insertion into the cell membrane. ApoA-I was found to inhibit zinc-catalyzed polymerization of C9 in a concentration-dependent fashion. Formation of SDS-resistant C9 polymers was completely inhibited at apoA-I or -A-II concentrations > or = 5 microM. ApoA-I also produced a concentration-dependent inhibition of C9 incorporation into C5b-9 complexes on endothelial cells, which was accompanied by a corresponding decrease in SDS-resistant C9 polymers associated with the cell membrane. In summary, the ability of the HDL apoproteins A-I and A-II to interact with an activation-dependent conformer(s) of the C9 component of the C5b-9 complex appears to explain the expression of HDL binding sites on endothelial cells exposed to complement. These apoproteins are also inhibitors of C9 polymerization, which may underlie the protective effect of HDL for blood cells exposed to activated complement.

Amino Acid Sequence↗
PubMed1995

Protection of retroviral vector particles in human blood through complement inhibition.

The rapid inactivation of murine-derived retroviral vectors in human or nonhuman primate sera is largely attributed to the activity of complement mediated through the classical pathway. In this study, we have further investigated the relationship between the human complement cascade and retrovirus inactivation. Preincubation in normal human serum effectively inactivated LXSN retroviral vector particles, whereas the vector maintained the ability to transduce cells following incubation in sera deficient in either the C1, C2, C3, C5, C6, C8, or C9 human complement proteins. Preincubation of serum with monoclonal antibodies (mAbs) that functionally block specific complement components, including C5, C6, C8, and C9, successfully protected the LXSN vector from complement-mediated inactivation. Treatment of serum with cobra venom factor, which consumes terminal complement, also effectively protected the vector from inactivation. LXSN vector survival in serum corresponded inversely to the level of complement activity following treatment of serum with anti-C5 mAb as assessed in an erythrocyte hemolytic assay. Additionally, pretreatment of human whole blood with anti-C5 mAb effectively inhibited inactivation of the LXSN vector. Taken together, these data demonstrate that formation of the membrane attack complex (MAC, C5b-9) is required for the inactivation of the murine-based LXSN retroviral vector in human blood and that this process can be abrogated with the use of soluble complement inhibitors.

3T3 Cells↗
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↗
PubMed1985

Enhanced complement-mediated lysis of type III paroxysmal nocturnal hemoglobinuria erythrocytes involves increased C9 binding and polymerization.

The interaction of terminal complement proteins (C5-C9) with normal erythrocytes and type III paroxysmal nocturnal hemoglobinuria erythrocytes (PNH-E) has been compared in terms of binding of the C5-9 complex, C9 polymerization, and C9 insertion into membranes. Complement components C5, C7, and C8 bind equally well to both types of erythrocytes, whereas the binding of C9 to PNH-E is 5-6 times greater than that to normal erythrocytes. The kinetics of C9 binding was compared with the kinetics of lysis for both types of cells under conditions leading to 100% lysis. There was a noticeable lag time between C9 binding and lysis of normal erythrocytes, but the lysis of PNH-E proceeded without a lag and the kinetics of lysis more closely paralleled C9 binding. The efficiency of C9 insertion was similar for both types of cells, but C9 polymerization was significantly enhanced on PNH-E. These data indicate that the enhanced susceptibility of type III PNH-E toward lysis by C5-9 can be correlated with abnormally high C9 binding and increased formation of poly(C9).

Carrier Proteins↗
PubMed1989

Phosphorylcholine acts as a Ca2+-dependent receptor molecule for lymphocyte perforin.

Large granular lymphocytes and cytolytic T-lymphocytes (CTL) contain numerous cytoplasmic granules thought to be responsible, at least in part, for the cytolytic activity of these effector cells. Isolated granules are lytic for a variety of target cells and the granule proteins are specifically released upon target-cell interaction. Major proteins in mouse CTL granules are a family of seven serine proteases designated granzymes A to G, and a pore-forming protein called perforin (cytolysin). Purified perforin is cytolytic in the presence of Ca2+ and shows ultrastructural, immunological and amino-acid sequence similarities to complement component C9. Despite these similarities, perforin and C9 are clearly distinct in their mode of target-cell recognition. Whereas C9 insertion is absolutely dependent on a receptor moiety assembled from the complement proteins C5b, C6, C7, and C8 on the target-cell membrane, no requirement for a receptor molecule has been reported for perforin. Here, we demonstrate that phosphorylcholine acts as a specific, Ca2+-dependent receptor molecule for perforin.

Animals↗
PubMed1975

Extracorporeal immunoadsorption of circulating specific serum factors in cancer patients.

Circulating serum factors have been said to abrogate the effects of immune response in cancer, i.e. "blocking" and "antigenic inhibition". The aim of this investigation was to isolate such specific factors in a purified and native state. F(ab)2 fragments isolated from hypernephroma were insolubilized on the surfaces of an extracorporeal perfusion chamber which was inserted into the circulation by means of an arterio-venous shunt. As a result, 3 proteins not present in normal serum were isolated and eluted for further study. In immunoelectrophoresis the 3 proteins were specifically precipitated by heterolgous (rabbit) antihypernephroma serum but not by anti-serum directed against normal serum components. Moreover C9 components, C3 activator and C3 were isolated in the chamber, the latter complement factor in large concentrations. This further sustained that specific antigen-antibody reactions had occurred in the chamber. One of the 2 patients studied were perfused for 60 h and 40 min. During this period 450 litres of blood were brought into intimate contact with the immunoadsorbent. Proteins in amounts sufficient for immunochemical analysis were isolated within 3 h.

Adenocarcinoma↗
PubMed1978

Differences in the terminal steps of complement lysis of normal and paroxysmal nocturnal hemoglobinuria red cells.

The number of microscopically visible lesions produced on the membrane for a given degree of lysis on normal cells as on PNH cells. Since complement lesions were not formed until C8 or C9 was incorporated into the complement sequence, the results suggest that increased lysis of red cells in PNH is due at least in part to more efficient penetration of the PNH membrane by the terminal lytic sequence of complement. Furthermore, the efficiency of the terminal lytic sequence in the lysis of PNH cells when complement was activated by the alternative pathway and the classical pathway was analyzed. There was no significant difference (p less than 0.01) in the number of lesion present at an equivalent degree of lysis when initiated by antibody, cobra venom factor, or acidification. Thus, the efficiency of the terminal lytic sequence does not vary with different modes of activation.

Complement C8↗
PubMed1997

Potent inhibition of terminal complement assembly by clusterin: characterization of its impact on C9 polymerization.

The interactions of the heterodimeric apolipoprotein and complement inhibitor, clusterin (CL, 80 kDa), with actively assembling terminal complement proteins were characterized. Clusterin inhibited at three sites and by two modes of action. Clusterin inhibited C9 assembly on C5b-8 and C5b-9 and also bound to C5b-7 to prevent membrane attachment. The impact on C5b-9 assembly was the most potent. C9 assembly was monitored by assembly-induced fluorescence changes of C9 labeled with fluorescein isothiocyanate (FITC-C9). Assembly of monomeric FITC-C9 with C5b-8 or C5b-9(1) produced a substantial decrease in fluorescence intensity due to changes in the environment of the probe. Addition of the next subunit of unlabeled C9 produced a further small change. One equivalent of FITC-C9 bound to C5b-8 at low temperatures, but the fluorescence change and addition of more C9 did not occur until the temperaure was increased. Kinetic analysis of the fluorescence change suggested an irreversible, first-order process with an activation energy of 29 kcal/mol (k = 0.12 s(-1) at 25 degrees C). The kinetic properties differed for C9 addition to C5b-9(1) (0.27 s(-1) at 25 degrees C, 21 kcal/mol), indicating that C9 activation occurred at a different or altered site. Clusterin binding to C5b-8-(FITC-C9)1 caused fluorescence quenching similar to that of unlabeled C9, indicating that it bound to the C9 binding site. Clusterin binding to C5b-8 and C5b-9(1) was reversible with affinities that were 2 and 15 times that of C9 for the C5b-8 and C5b-9(1) complexes, respectively. The results suggested that the presence of <10% of the circulating clusterin in its heterodimeric, active form could reduce the rate of complement cytolysis of nucleated cells by 10-fold, and under some conditions by 100-fold or more. This would provide a high level of protection for certain cells and may allow time for action by other inhibitors of complement.

Clusterin↗
PubMed1983

Molecular composition of the terminal membrane and fluid-phase C5b-9 complexes of rabbit complement. Absence of disulphide-bonded C9 dimers in the membrane complex.

The terminal membrane C5b-9(m) and fluid-phase SC5b-9 complexes of rabbit complement were isolated from target sheep erythrocyte membranes and from inulin-activated rabbit serum respectively. In the electron microscope, rabbit C5b-9(m) was observed as a hollow protein cylinder, a structure identical with that of human C5b-9(m). Monodispersed rabbit C5b-9(m) exhibited an apparent sedimentation coefficient of 29 S in deoxycholate-containing sucrose density gradients, corresponding to a composite protein-detergent molecular-weight of approx. 1.4 X 10(6). Protein subunits corresponding to human C5b-C9 were found on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. By densitometry, there were consistently six molecules of monomeric C9 present for each monomeric C5b-8 complex. Fluid-phase rabbit SC5b-9 was a hydrophilic 23 S ma macromolecule that differed in subunit composition from its membrane counterpart in that it contained S-protein and only two to three molecules of C9 per monomer complex. The data are in accord with the previous report on human C5b-9 that C5b-9(m) contains more C9 molecules than SC5b-9 [Ware & Kolb (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 6426-6430]. They corroborate the previous molecular-weight estimate of approx. 10(6) for C5b-9(m) and thus support the concept that the fully assembled, unit lesion of complement is a C5b-9 monomer [Bhakdi & Tranum-Jensen (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 1818-1822]. They also show that C9 dimer formation is not required for assembly of the rabbit C5b-9(m) protein cylinder, or for expression of its membrane-damaging function.

Animals↗
PubMed1996

Complement proteins are present in developing endochondral bone and may mediate cartilage cell death and vascularization.

Normal endochondral bone formation follows a temporal sequence: immature or resting chondrocytes move away from the resting zone, proliferate, flatten, become arranged into columns, and finally become hypertrophic, disintegrate, and are replaced by bone. The mechanisms that guide this process are incompletely understood, but they include programmed cell death, a stage important in development and some disease processes. Using immunofluorescence we have studied the distribution of various complement proteins to examine the hypothesis that this sequence of events, particularly cell disintegration and matrix dissolution, are complement mediated. The results of these studies show that complement proteins C3 and Factor B are distributed uniformly in the resting and proliferating zones. Properdin is localized in the resting and hypertrophic zone but not in the proliferating zone. Complement proteins C5 and C9 are localized exclusively in the hypertrophic zones. This anatomically segregated pattern of distribution suggests that complement proteins may be important in cartilage-bone transformation and that the alternate pathway is involved.

Animals↗
PubMed1985

The membrane attack complex of complement: C5b-8 complex as accelerator of C9 polymerization.

Polymerization of C9 occurs spontaneously or can be induced by the tetramolecular complex C5b-8. Spontaneous C9 (0.15 mg/ml) polymerization required more than 3 days at 37 degrees C. In the presence of C5b-8, C9 polymerization was complete within 10 min. The molar C9:C5b-8 ratio determined the extent of tubular poly C9 formation by C5b-8-bearing phospholipid vesicles. When this ratio was 9:1 or 12:1, 72% of complex-bound C9 was present as SDS resistant tubular poly C9 (Mr = 1.1 X 10(6]. At lower C9:C5b-8 ratios, poly C9 was bound primarily in nontubular form. Tubular poly C9, as part of C5b-9, could also be generated on rabbit erythrocytes by using whole human serum as a complement source. At limiting serum concentration (molar C9 to C8 ratio approximately 2), no SDS-resistant tubular poly C9 was detected. At high serum concentration or when using serum that was supplemented with C9, up to 40% of the C9 was SDS-resistant tubular poly C9, and the rest was poly C9, which was incompletely polymerized. It is suggested that the C5b-8 complex acts as an accelerator of C9 polymerization, and that its relative concentration to C9 determines the ultrastructure of the C5b-9 complex.

Animals↗
PubMed1990

Synthesis of C3, C5, C6, C7, C8, and C9 by human fibroblasts.

We investigated the ability of human fibroblasts to produce the components of the final common pathway (C3-C9) of complement in vitro by co-culturing an alternative complement activator (agarose beads) with the cells. The test system involved incubation of beads with anti-complement antibodies followed by radioactive-labelled anti-Ig detection antibodies. Subsequently, the beads were examined in a radioimmunoassay. Our results indicate that human fibroblasts produce C3, C5, C6, C7, C8, and C9. A neoepitope selectively expressed on activated C9 was detected, indicating assembly of the terminal complement complex and thus formation of a functional terminal complement pathway by the fibroblasts.

Antibodies, Monoclonal↗
PubMed1990

Deposition of C3, C9 neoantigen and vitronectin (S-protein of complement) in lichen planus pemphigoides.

We have compared the distribution of C3, C9 neoantigen (C9n) and vitronectin at the dermoepidermal junction in lichen planus pemphigoides with that in bullous pemphigoid. Eight out of 30 biopsies from patients with lichenoid lesions had linear C3 deposition at the basement membrane zone (BMZ); four of these patients had bullae and fulfilled the criteria for lichen planus pemphigoides. C9n immunoreactivity was detected as a linear or an intermittent linear/granular band at the BMZ only in these four patients, suggesting a role for the membrane attack complex of complement (MAC) in the pathogenesis of blister formation in lichen planus pemphigoides. Faint linear deposition of vitronectin, in addition to C9n, at the BMZ was seen in two of the four cases of lichen planus pemphigoides and three of six cases of bullous pemphigoid. This suggests that vitronectin may be deposited in association with C9n not only as part of the non-lytic SC5b-9 complex, but also as a regulatory step following the lytic action of MAC. A regulatory function for vitronectin in limiting tissue damage following activation of MAC is supported by our finding of a heavy deposition of vitronectin in association with C9n in a lichen planus pemphigoides patient in whom bulla formation had ceased.

Adult↗
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↗