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PubMed1984

Schistosoma mansoni: escape from complement-mediated parasiticidal mechanisms following percutaneous primary infection.

Schistosomula were recovered from the skin of mice following primary infections. On the surface of such "infecting schistosomula", mouse C3 could not be detected by immunofluorescence. Subsequent incubation in vitro with fresh mouse serum led to the effective deposition of mouse C3 on schistosomula only when they were recovered within a few hours but not after one or two days following infection. In vitro deposited murine C3c was lost from i.v. injected schistosomula in the mouse circulation within one day as was human C3c. Infecting schistosomula exhibited a close to complete resistance to the lytic in vitro activity of human complement. This resistance was complete in older parasites. It existed in spite of the presence of parasite-bound human C9, which was detectable on all developmental stages of schistosomes following incubation in fresh, but not inactivated human serum. Lung schistosomula, 3-week and 6-week-old schistosomes were resistant to cellular cytotoxicity upon incubation with fresh human serum and rat peritoneal exudate cells although cell adherence mediated by human C3b was demonstrated with lung worms. The data suggest that schistosomula may evade in vivo the lytic activity of complement and also complement-mediated cellular cytotoxicity. Depending on the species of serum, this can be demonstrated in vitro by lack of opsonization or by resistance to lytic and cellular attack mechanisms.

Animals↗
PubMed1992

Differences of two Borrelia burgdorferi strains in complement activation and serum resistance.

Complement activation and serum resistance of the Borrelia burgdorferi strains B31 (American strain) and PKo (European strain) were compared. In 25% (v/v) normal human serum (NHS) free of B. burgdorferi-specific antibodies the cells of the PKo strain were high activators of complement as indicated by rapid and strong C9 consumption, by deposition of up to 336763 C9 molecules per cell and by the formation of the terminal complement complex on the cell surface. By comparison, complement activation by the B31 strain was low with 5.4-fold less C9 deposited per cell. The addition of B. burgdorferi-specific antibodies to NHS either as purified IgG or heat-inactivated patient sera, had no influence on the results with both strains. After an incubation period of 2h at 37 degrees C in 25% (v/v) NHS most cells of the PKo strain had lost their viability as indicated by cell immobilization and failure to multiply in subcultures. In addition, extensive cell fragmentation and bleb formation were observed in the electron microscope. In contrast, the B31 strain remained alive and morphologically intact after the same incubation with NHS. We conclude from our results that complement activation and serum resistance are properties which differ considerably between isolated strains of B. burgdorferi.

Antibodies, Bacterial↗
PubMedDate not supplied

Immunologic alterations associated with chronic hemodialysis.

Parameters of humoral immunity were studied in 18 patients with chronic renal failure undergoing hemodialysis. IgG, IgA and IgM serum levels presented no differences compared with healthy donors. High immunoglobulins levels were found in 40 patients with chronic renal failure and conservative treatment. Complement components C1q, C4, C9, were normal, but C3 and C3A were significantly low prior to dialysis. During hemodialysis, the complement system showed an activation by the alternative pathway (AP). The cuprophan membrane was proved to be an important factor in this activation. The circulating immune complexes (CIC) were also high. Seven patients presented autoantibodies, 2 against smooth muscle and 5 against gastric parietal cells. Our results suggested a certain humoral immune alteration during chronic hemodialysis.

Antibody Formation↗
PubMed2006

Deficiency of C4 from donor or recipient mouse fails to prevent renal allograft rejection.

Complement effector products generated in the transplanted kidney are known to mediate transplant rejection, but which of the three main activation pathways of complement trigger this response is unclear. Here we assessed the role of the classical and lectin pathways by studying the common component C4 in mouse kidney transplant rejection. We transplanted wild-type or C4-null H-2(b) donor kidneys into H-2(k) or H-2(d) recipients, or vice-versa, to assess the roles of donor kidney and recipient expression of complement. Intragraft C4 gene expression rose substantially during rejection. However, we found no significant association between graft acceptance and the presence of C4 in either the donor kidney or recipient mouse. At the time of rejection, we found no significant differences in alloantibody response in the different groups. Tubular deposition of C3 to C9 occurred regardless of the absence or presence of C4 in either the donor or recipient mouse, indicating that C4 was dispensable for complement activation at this site. These data suggest that complement activation and renal allograft rejection are independent of the classical and lectin pathways in these models, implying that in the absence of these pathways the alternative pathway is the main trigger for complement-mediated rejection.

Animals↗
PubMed1982

[Hereditary complement deficiencies].

Complement deficiencies of all nine C-components have been observed. Hereditary defects of early components of the classical pathway - C1, C4, C2 - are often associated with diseases of the immuncomplex-type especially with systemic lupus erythematosus, dermatomysitis, vasculitis and nephritis. Deficiencies of C3 and C3b inactivator are linked to severe and recurrent bacterial infections. Patients with hereditary defects of the so-called late components, C5-C9, show increased susceptibility to recurrent disseminated infections by neisseria gonorrhoeae and meningitidis. The most frequent of the defects of the complement system is the hereditary deficiency of C1-inactivator which is associated with hereditary angioneurotic edema. In this paper the C-defects and their genetics are described and possible pathomechanisms are discussed.

Complement Activating Enzymes↗
PubMed1990

Complement, complement activation and anaphylatoxins in human ovarian follicular fluid.

Functionally active complement was sought and detected in human follicular fluids obtained during the pre-ovulatory period. All the functional complement activities tested, including total haemolytic complement, classical pathway activity and alternative pathway activity were present in nine fluids from four different donors with values within the normal serum range. The immunochemical analysis demonstrated the presence of complement factors from C1 to C9, of B and of C1 INH, H, I. Complement anaphylatoxins were found employing RIA techniques in amounts significantly higher than in human plasma, thus demonstrating that follicular fluid complement, at least during the pre-ovulatory period, is partially activated. A possible role for urokinase-like substances in such an activation was indicated by further in vitro experiments. The presence of active complement in follicular fluid can be relevant for the function of the enzymatic multi-factorial mechanism of ovulation.

Anaphylatoxins↗
PubMed1994

The functions of the ninth component of human complement are sustained by disulfide bonds with different susceptibilities to reduction.

Purified C9 with expected hemolytic and polymerizing activities was found to contain approximately 0.2 mol of sulfhydryl groups/mol of C9. By proteolysis of C9 with labeled SH groups, the SH residues on intact C9 were mapped to Cys-359 and Cys-384 which, presumably, form an intra-domain disulfide bond in the intact molecule. The blocking of these sulfhydryl residues by alkylation, however, had minimal influence on the functions of C9. On the other hand, reduction of C9 by 1 mM dithiothreitol (DTT) (6-fold molar excess over Cys residues) followed by alkylation resulted in a complete block of polymerization activity and a 50% loss of C9 hemolytic activity. In contrast, the ability of C9 to bind EAC1-8 remained largely unaffected. The loss of poly-C9 formation activity correlated with the alkylation of approx. 6 liberated sulfhydryl groups. Hemolytic activity was abolished by treatment with > 5 mM DTT which allowed the liberation of approximately 18 sulfhydryl groups. Most of the DTT-susceptible disulfides were within the C9a fragment (an N-terminal peptide derived by thrombin). Thus, three major functions of C9, EAC1-8 binding, polymerization, and hemolytic activity, are sustained by disulfide bond-dependent conformational motifs with different susceptibility to reducing reagents. The maintenance of the N-terminal C9a region is essential for polymerization, but not EAC1-8 binding activity of C9. Taken together, the results of the present study differentiate in molecular terms several of the functional portions of C9, and stress the significance of intra-chain disulfide linkages in maintaining the structural components necessary for the functions of C9.

Animals↗
PubMed1987

Complementary DNA and derived amino acid sequence of the beta subunit of human complement protein C8: identification of a close structural and ancestral relationship to the alpha subunit and C9.

A cDNA clone encoding the beta subunit (Mr 64,000) of the eighth component of complement (C8) has been isolated from a human liver cDNA library. This clone has a cDNA insert of 1.95 kilobases (kb) and contains the entire beta sequence [1608 base pairs (bp)]. Analysis of total cellular RNA isolated from the hepatoma cell line HepG2 revealed the mRNA for beta to be approximately 2.5 kb. This is similar to the message size for the alpha subunit of C8 and confirms the existence of different mRNAs for alpha and beta. This finding supports genetic evidence that alpha and beta are encoded at different loci. Analysis of the derived amino acid sequence revealed several membrane surface seeking segments that may facilitate beta interaction with target membranes during complement-mediated cytolysis. Determination of the carbohydrate composition indicated 1 or 2 asparagine-linked but no O-linked oligosaccharide chains. Comparison of the beta sequence to that reported for alpha in the preceding paper [Rao, A. G., Howard, O. M. Z., Ng, S. C., Whitehead, A. S., Colten, H. R. & Sodetz, J. M. (1987) Biochemistry (preceding paper in this issue)] and to that of human C9 revealed a striking homology between all three proteins. For beta and alpha, the overall homology is 33% on the basis of identity and 53% when conserved substitutions are allowed. For beta and C9, the values are 26% and 47%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1976

Deviated lysis: Transfer of complement lytic activity to unsensitized cells II. Generation of the activity by inulin and by antigen antibody complexes.

Deviated lysis (d.l.) activity, i.e. lysis of unsensitized cells by lytic C activity, was generated via the classical pathway of Cactivation (ag ab complexes) and via the alternative pathway (inulin). The activity was observed on the surface of the activating particles and in the fluid phase. The activity was relatively stable at 32 degrees C. Its generation involved the C components C6 through C9 and possibly also C5.

Animals↗
PubMed2001

Complement-mediated lipopolysaccharide release and outer membrane damage in Escherichia coli J5: requirement for C9.

Lipopolysaccharides (LPS) are major antigenic components of the outer membrane of Gram-negative bacteria and can stimulate activation of the complement system. Such activation leads to formation of the complement membrane attack complex (MAC) on the cell walls, LPS release and, in serum-sensitive strains, to cell death. In this study, Escherichia coli J5 strains, which incorporate exogenous galactose exclusively into LPS, were used to generate target strains with different LPS chemotypes, and the LPS of the strains was labelled with tritium (3H-LPS). The ability of normal human serum (NHS) and human complement-deficient sera to release LPS was subsequently monitored. NHS-induced release of 64-95.7% of 3H-LPS within 30 min; overall, no significant difference was observed between release of LPS from E. coli J5 strains with different LPS chemotypes. In functional assays, maximum LPS release had occurred by 30 min and before maximum bacterial killing. Electron microscopy revealed NHS-induced outer-membrane disruption in the form of blebs at 15 min; at this time-point the inner membrane remained intact. Background LPS release and no bactericidal activity were detected in heat-inactivated serum or human sera deficient in C6, C7 or C8. The C9-deficient (C9D) serum had low bactericidal activity and failed to induce LPS release; however, addition of purified human C9 reconstituted its ability to release LPS. This study demonstrated the need for functional C9 molecules for LPS-releasing activities in serum-sensitive E. coli J5 strains.

Blood Bactericidal Activity↗
PubMed1991

Blood dendritic cells carry terminal complement complexes on their cell surface as detected by newly developed neoepitope-specific monoclonal antibodies.

Blood dendritic cells carry the terminal complement complex (TCC) on their surface, as detected by three monoclonal antibodies (mAb). Two of these mAb were generated by immunizing mice with the terminal complement complex, whereas the third was generated by immunizing mice with blood dendritic cells. All three mAb are directed against neoepitopes on the C9 molecule, as assessed by binding and blocking experiments and studies with several forms of denatured C9 and C9-depleted serum. Only one of these mAb binds to soluble polymerized C9. All three mAb allow the quantification of human TCC in sensitive ELISA procedures and could be used as markers for the evaluation of the functions of non-lytic TCC on dendritic cells.

Animals↗
PubMed1989

Complement binding on serum-sensitive and serum-resistant transformants of Neisseria gonorrhoeae: effect of presensitization with a non-bactericidal monoclonal antibody.

The binding of C3 and C9 on serum sensitive (FA635) and serum resistant (FA638) transformants of serum sensitive Neisseria gonorrhoeae strain F62 was examined. Previous studies showed that these transformants have Protein IAs which are minimally different by proteinase K cleavage and primary structural and peptide mapping and bear LPS which vary slightly on SDS-PAGE. Binding of C3 and C9 on FA635 exceeded binding on FA638 in NHS and in adsorbed NHS. Monoclonal antibody 4G5, which binds to PI on FA638 but not FA635, increases C9 binding on FA638 to levels 3-3.5 fold greater than on FA635 but does not result in killing. The majority of additional 125IC9 deposited on FA638 following presensitization with 4G5 is released from the bacterial surface by trypsin. These results extend our earlier results with N. gonorrhoeae by showing that, although PI monoclonals can lead to substantial deposition of non-bactericidal C5b-9, this C5b-9 is not fully inserted into the gonococcal outer membrane.

Antibodies, Bacterial↗
PubMed1979

Complement and coagulation: causative considerations in contrast catastrophies.

Earlier studies suggest that adverse reactions to injected radiographic contrast media are idiosyncratic. In an attempt to gain a better understanding of pathophysiologic events underlying these reactions, rabbit models injected with lethal dose ranges of a cholangiographic contrast material were studied. These animals showed activation of both the complement and coagulation systems. Externally applied heat potentiated complement consumption and increased mortality. Depleting complement components C3-C9 by cobra venom factor did not prevent activation of coagulation or diminish mortality. However, depleting fibrinogen diminished complement activation and markedly diminished mortality. Heparin, administered at several hourly intervals after contrast challenge, also diminished mortality. These studies suggest that the adverse effects of contrast media in this model system are mediated chiefly by the coagulation system, and that complement, if it participates deleteriously, must involve components up to, but not including, C3. A logical role for the inhibitor of C1 esterase in adverse contrast reactions is considered.

Ancrod↗
PubMed1987

Immunohistochemical detection of the membrane and fluid-phase terminal complement complexes C5b-9(m) and SC5b-9. Consequences for interpretation and terminology.

Activation of the terminal pathway of complement on a membrane results in the generation of the membrane-damaging terminal C5b-9(m) complement complex, whereas the non-lytic water-soluble SC5b-9 complex is formed when complement is activated in the fluid phase. Both forms of the terminal complement complex (TCC) can be immunohistochemically detected, but not distinguished, by antibodies recognizing neoantigens in the complexes. By means of monoclonal antibodies against C9 neoantigens and against the S-protein, it was demonstrated that deposits of the TCC in tissue sections may be either in the form of C5b-9(m) or SC5b-9. The consequences of this for the interpretation of the histochemical data and the terminology of the two complexes are discussed.

Adult↗
PubMed1987

Deposits of immunoglobulins, complement, and immune complexes in inflamed human gingiva.

Gingival biopsy specimens from 20 patients with moderate to advanced periodontitis were obtained from inflamed sites with pockets of 5 mm or more. Sections were studied by an immunofluorescence technique, using polyclonal rabbit or goat anti-IgG, anti-IgM, anti-C1q, anti-C3a, and anti-C3c and mouse monoclonal anti-C9. Prewashed ethanol-fixed and nonwashed ethanol-fixed or frozen specimens showed many plasma cells staining for IgG or C3a, suggesting the possible occurrence of a receptor for C3a in plasma cells. Plasma cells containing IgM were also seen. Deposits of IgG and IgM with C1q, C3a, and C3c, suggesting immune complexes, were demonstrated by a double staining technique, combining fluorescein (FITC) or rhodamine (TRITC)-labeled anti-immunoglobulins with TRITC- or FITC-conjugated antibody to C3a, C3c, and C1q. The complexes were located mainly within or around vessel walls. Deposits of C3a and C1q were found in vessel walls, in the basement membrane zone of oral gingival epithelium, or diffusely distributed in the tissues. Deposits of C3c were found to a lesser extent and only in vessel walls. Mouse monoclonal anti-C9, visualized with FITC-labeled rabbit anti-mouse and swine anti-rabbit antiserum, showed granular deposits of C9, mainly in the basement membrane zone of oral gingival epithelium. The study indicates the involvement of immune complex vasculitis in inflammatory periodontal lesions. Also, our observations of the occurrence of deposits of complement factors support the hypothesis that complement factors play an important role in the immunopathology of the periodontal lesion.

Antigen-Antibody Complex↗
PubMed1986

C5b-9 assembly: average binding of one C9 molecule to C5b-8 without poly-C9 formation generates a stable transmembrane pore.

Membrane attack by serum complement normally results in the formation of C5b-9 complexes that are heterogeneous with respect to their C9 content. We here report that an apparently homogeneous population of C5b-9 complexes can be generated through treatment of C5b-7-laden sheep erythrocytes with C8 and C9 for 60 min at 0 degree C. Experiments performed by using radioiodinated C8 and C9 components have indicated that binding of C8 to these target cells is essentially temperature independent. In contrast, when a surplus of C9 molecules is offered to C5b-8 cells, an approximately fourfold to 4.5-fold higher number of C9 molecules become cell bound at 37 degrees C as opposed to 0 degree C. C5b-9 complexes isolated from target membranes treated with C9 at 0 degree C contain no polymerized C9 and do not exhibit the ring structure characteristic of the classical complement lesion. Nevertheless, these complexes generate stable transmembrane channels and cause hemolysis at 37 degrees C. The pores have been sized to 1 to 3 nm effective diameter by osmotic protection experiments. SDS-PAGE of the isolated complexes indicates an average stoichiometry of only one molecule C9 bound per C5b-8 complex. The results show that oligomerization of C9 with formation of ring lesions is not a basic requirement for the generation of stable transmembrane complement pores in sheep erythrocytes. They indirectly support the contention that terminal complement components other than C9 contribute to the intramembrane domains of C5b-9 pores.

Animals↗
PubMed1985

Radioimmunoassay of the attack complex of complement in serum from patients with systemic lupus erythematosus.

We developed a radioimmunoassay to measure the attack complex of complement (SC5b-9) in serum from patients with systemic lupus erythematosus. The radioimmunoassay used a monoclonal antibody to an antigen of C9, which is absent from native C9 but present on SC5b-9. SC5b-9 was detectable in 13 of 63 normal subjects, with a mean value of 0.5 unit (range, 0 to 4.8), and elevated in 13 of 14 patients with active lupus. Analysis of 108 samples from the patients with lupus revealed a mean value of 10.1 units (range, 0 to 35) when the disease was active and 1.0 unit (range, 0 to 433) when it was clinically stable. SC5b-9 was a more sensitive measure of disease activity than C3, C4, or CH50; its specificity was equivalent to that of C3 and C4. SC5b-9 was elevated in serum from 6 of 49 patients with other forms of glomerulonephritis. Our study documents the presence of SC5b-9 in abnormal serum and correlates its elevation with clinical disease activity in patients with active systemic lupus erythematosus.

Adolescent↗
PubMed1994

Blocking antibodies specific for human albumin interfere with the hemolytic activity of the membrane attack complex of complement.

Earlier, we showed that antibodies specific for human serum albumin are able to bind to erythrocyte-associated albumin and inhibit complement mediated hemolysis. In the present study we determine if inhibition is occurring at the membrane attack phase of complement activation or at an earlier step. We show that although cell-bound anti-albumin antibodies do not inhibit binding and activation of C3 or uptake of C9, they do appear to cause cells to become refractory to lysis by the membrane attack complex as they inhibit both the kinetics and the extent of hemolysis in a reactive lysis system which employs preformed C5b6 plus C7, C8, and C9. We believe that this is the first report of inhibition of the hemolytic activity of the membrane attack complex by antibodies bound to an erythrocyte surface antigen.

Animals↗