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PubMed1984

The influence of electrochemical gradients of Na+ and K+ upon the membrane binding and pore forming activity of the terminal complement proteins.

The hemolytic activity of the terminal complement proteins (C5b-9) towards erythrocytes containing high potassium concentration has been reported to be dramatically increased when extracellular Na+ is substituted isotonically by K+ (Dalmasso, A.P., et al., 1975, J. Immunol. 115:63-68). This phenomenon was now further investigated using resealed human erythrocyte ghosts (ghosts), which can be maintained at a nonlytic osmotic steady state subsequent to C5b-9 binding: (1) The functional state of C5b-9-treated ghosts was studied from their ability to retain trapped [14C]-sucrose or [3H]-inulin when suspended either in the presence of Na+ or K+. A dramatic increase in the permeability of the ghost membrane to both nonelectrolytes - in the absence of significant hemoglobin release - was observed for C5b-9 assembly in the presence of external K+. (2) The physical binding of the individual 125I-labeled terminal complement proteins to ghost membranes was directly measured as a function of intra- and extracellular K+ and Na+. The uptake of 125I-C7, 125I-C8, and 125I-C9 into membrane C5b-9 was unaltered by substitution of Na+ by K+. (3) The binding of the terminal complement proteins to ghosts subjected to a transient membrane potential generated by the K+-ionophore valinomycin (in the presence of K+ concentration gradients) was measured. No significant change in membrane binding of any of the C5b-9 proteins was detected under the influence of both depolarizing and hyperpolarizing membrane potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane Permeability↗
PubMed1987

Interactions of purified Serratia marcescens metalloproteases with fresh human serum and with purified human serum proteins.

Exposure of fresh human serum to two purified metalloproteases of S. marcescens strains SF 178 and SH 186 (both of serotype O6/O14:H12) at 35 degrees C, 3 h, resulted in altered electrophoretic mobility of the protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin, alpha 2-HS-glycoprotein, and complement (C) components C1q, C1s, C3a, C3c, C4, C5, and C9, but not C6, C7, C8, and properdin, as determined with electroimmunoassays (Laurell technique). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the partial degradation of the heavy (H) chain of purified human immunoglobulin IgG by the metalloproteases of S. marcescens strains SF 178 and SV O1 (serotype O13/O19:H1), but not by the metalloproteases of strains SH 186 and SE 182 (serotype O9B:H11) following extended incubation (35 degrees C, 22 h). Human IgA and IgM were refractory. Purified human C components, C3, C4, C5, C6, C7, C8, and C9, as well as purified human alpha 1-antitrypsin, alpha 2-macroglobulin, transferrin, and lactoferrin were attacked by the S. marcescens metalloproteases SF 178 and SH 186 at 35 degrees C for 5 h, as demonstrated with the SDS-PAGE procedure; haptoglobin and C-reactive protein were resistant.

Acute-Phase Proteins↗
PubMed1985

The hereditary and acquired deficiencies of complement.

The identification of hereditary and acquired complement deficiencies in humans has led to a better understanding of the biologic importance of the complement system in immunity and autoimmune disease. Although the understanding of the relevance of complement in the pathogenesis of disease is incomplete, several characteristic clinical syndromes associated with complement deficiencies have been recognized and should be known to the practicing clinician. In allergic diseases, one need recognize the C1 inhibitor deficiency syndromes which can present as severe, recurrent angioedema in childhood or in the adult as recurrent angioedema in association with a lymphoid malignancy or autoimmune disease. Complement analyses allow one to readily diagnose C1 inhibitor deficiency in angioedema. Correct diagnosis is critical because safe effective therapy is available. Chronic urticaria is also uncommonly associated with complement deficiencies, particularly acquired C1q deficiency. Again, effective therapy for hypocomplementemic urticarial vasculitis and C1q deficiency is available and differs significantly from the usual management of chronic urticaria. Homozygous and acquired deficiencies of C3 are associated with severe immune deficiency and recurrent infections with gram-positive and gram-negative bacteria. Recurrent meningococcemia and gonococcemia are being identified frequently in patients with a deficient membrane attack mechanism relating to deficiency of C5, C6, C7, or C8. Nearly one third of the patients developing meningococcemia may have an associated complement deficiency indicating the importance of complement determinations in understanding the treatment and prognosis for these patients. Deficiency of almost every complement component has been reported in association with one or more rheumatic diseases, particularly systemic lupus erythematosus. Extensive studies of C2 deficiency and limited studies of C4 deficiency indicate that these components of the classical pathway of complement are important in preventing the development of SLE or are linked to other genes predisposing to SLE. The clinical presentations of SLE in association with C2 or C4 deficiency are relatively uniform. The patients exhibit typical skin manifestations suggestive of SLE and DLE and often exhibit antibodies to SSA (Ro). The association of complement deficiencies with clinical syndromes is important for today's physician. The syndromes and deficiencies described here are the beginning of an expanding knowledge relating to the pathobiology of complement in human disorders.

Angioedema↗
PubMed1975

Studies of the action of some anti-inflammatory drugs on complement mediated immune haemolysis.

1 The effects of various anti-inflammatory and non-anti-inflammatory drugs on complement mediated haemolysis have been studied. Drugs which were significantly protein bound were found to inhibit this form of immune lysis, but only at greater concentrations than achieved therapeutically. 2 Removal of the drugs by prolonged dialysis resulted in restoration of complement activity with the exceptions of phenylbutazone and warfarin sodium. 3 Reconstitution experiments indicated that C2 and some of the later components especially C7 were affected by the drugs. 4 Intra-articular injections of prednisolone (100 mg) in patients with rheumatoid arthritis, failed to produce significant changes in the synovial fluid complement system. 5 None of the drugs affected the binding of antibody to antigen, or the ability of sensitized sheep cells to fix complement.

Animals↗
PubMed1998

Human heart generates complement proteins that are upregulated and activated after myocardial infarction.

In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.

Adult↗
PubMed1991

Collagenase of Clostridium perfringens type A: degradation of human complement component C1q.

The semipurified collagenases from Clostridium perfringens type A strains 2-Cli and ATCC 13124, both characterized by molecular weights of 79.4 kilodaltons, partially degraded purified human complement (C) component C1q. The following purified human serum proteins were refractory: C components C3, C4, C5, C6, C7, C8, and C9; immunoglobulin (Ig)A (from colostrum), IgG, and IgM; alpha 2-macroglobulin, haptoglobin, and C-reactive protein.

Blotting, Western↗
PubMed1989

Detection of refolding conformers of complement protein C9 during insertion into membranes.

Human complement protein C9 is a hydrophilic serum glycoprotein responsible for efficient expression of the cytotoxic and cytolytic functions of complement. It assembles on the surface of a target cell together with C5, C6, C7 and C8 to form the membrane attack complex (MAC) and therefore has to change structure to become an integral membrane protein. As the protein assumes a stable structure in an aqueous environment, the question arises as to how it can enter the hydrophobic interior of a membrane. During MAC assembly C9 polymerizes into a circular structure, termed poly(C9) (ref. 8), which is responsible for the cylindrical electron microscopic appearance of the MAC. The suggestion has been made that C9 must at least partly unfold in order to enter a membrane and also that polymerization of the molecule is intimately linked to insertion and cytotoxicity. The extent of unfolding and the mechanism of polymerization are not understood, nor is it known precisely which parts of the molecule participate in the proposed structural changes. We have been able to capture refolding C9 conformers during membrane insertion with the help of sequence-specific anti-peptide antibodies. Some of these antibodies inhibit C9-mediated haemolysis but not C9 polymerization, while others have the opposite effect. This suggests that the two processes are independent.

Complement C9↗
PubMed1982

Hydrophilic-amphiphilic transition of the terminal SC5b-8 complement complex through tryptic modification: biochemical and ultrastructural studies.

the SC5b-8 complex of human complement is a hydrophilic molecule of mol. wt 800,000-850,000 that is seen in the electron microscope as an elongated, straight or curved structure of 50-55 nm total length and 8-9 nm width. Tryptic attack on the fluid-phase complex exposes lipid-binding surfaces on the molecule. The trypsinized complex can be incorporated into liposomal lipid bilayers, and the majority of protein is then viewed as ill-defined, larger tufts projecting exterior to the liposomal membrane. These tufts possibly represent clusters of a unit lesion, which consists of two diverging projections, each approximately 25 nm in length. The two projections are possibly joined to each other to give the membrane-bound complex a shape akin to that of an incomplete funnel. Analyses by SDS-polyacrylamide gel electrophoresis show that the polypeptide subunits C5b, C7 and C8 beta entirely resist tryptic degradation in both SC5b-8 and SC5b-9 complement complexes. Limited proteolysis of C6, C8 alpha gamma and C9, and extensive degradation of the S-protein are effected by trypsin. The results are compatible with the concept that proteolytic cleavage of the S-protein in SC5b-8 and SC5b-9 is the cause of the trypsin-dependent, hydrophilic-amphiphilic transition of the terminal, fluid-phase complement complexes.

Alpha-Globulins↗
PubMed1999

Complement membrane attack complex and protectin (CD59) in liver allografts during acute rejection.

BACKGROUND/AIMS: The complement system is important in the rejection of xenografts, but very little is known about its activation in the rejection of allografts. Complement lysis is induced by the membrane attack complex (MAC), an aggregate of C5b, C6, C7, C8 and C9 molecules. The main defender against MAC is the CD59 molecule, also called protectin. In this study, the aim was to analyze the possible deposition of MAC and the fate of CD59 on distinct cell populations during liver allograft rejection. METHODS: Liver allografts were monitored by frequent fine-needle aspiration biopsies (FNAB) to demonstrate the immunoactivation of rejection. To examine MAC and CD59 in the FNAB, in relation to the activation markers of rejection, IL2-receptor, MHC class II and ICAM-1 expression, specific monoclonal antibodies and immunoperoxidase staining were used. RESULTS: Ten out of 21 consecutive liver transplants underwent a histologically confirmed episode of reversible acute rejection. In the FNAB, a significant increase of the activation markers IL2-receptor, class II and ICAM-1 correlated with the peak of inflammation during the episode. In association with inflammation, a significant deposition of MAC was recorded in neutrophils and lymphocytes infiltrating the graft and in the parenchymal cells. MAC deposition subsided together with the inflammation. A significant decrease in CD59 expression was seen in neutrophils during rejection, but CD59 expression on other inflammatory cells and hepatic tissue cells varied greatly. CONCLUSIONS: Complement activation was seen in association with acute rejection of liver allografts and it led to MAC assembly on leukocytes and tissue cells. A decrease in CD59 expression was less clear-cut, but it may predispose the cells to complement-mediated elimination.

Acute Disease↗
PubMed1992

Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins.

The substantia nigra (SN) in 11 Parkinson's disease (PD) patients and 5 neurologically normal controls was examined immunohistochemically using antibodies to various proteins of the complement system. In PD, but not in control SN, intra- and extraneuronal Lewy bodies and dendritic spheroid bodies were stained with anti-human C3d, C4d, C7 and C9 antibodies, but not with antibodies to C1q, fraction Bb of factor B or properdin. Axonal spheroid bodies in the nigrostriatal tract were not stained by any of the complement antibodies. However, complement-activated oligodendroglia were revealed by anti-C3d and anti-C4d antibodies in the PD substantia nigral area. These data indicate that some pathological structures in PD activate the classical complement pathway.

Aged↗
PubMed1982

Glutathione-catalyzed disulfide-linking of C9 in the membrane attack complex of complement.

The membrane attack complex of complement (the dimeric C5b-9 complex) is a multimolecular assemblage of five proteins (C5b, C6, C7, C8, and C9) which are held together by noncovalent forces. We found that C9 molecules in the complex can be covalently crosslinked (disulfide-linked) by glutathione. In this experiment, the tetramolecular C5b-8 complex bound to phospholipid vesicles was first prepared from purified C5b-6, incubated (37 degrees C, 20 min) with an excess of 131I-C9 in the presence of 1 mM glutathione; an average of 5.3 molecules of C9 per C5b-8 were bound and the C5b-9 complex formed was predominantly a dimeric C5b-9 complex. About one-third of C9 in this C5b-9 complex was found to be in a disulfide-linked dimeric form. The C5b-9 complex, having only an average of 0.9 molecules of C9 per C5b-8, was also prepared in the presence of glutathione; this C5b-9 preparation contained both monomeric and dimeric C5b-9 complexes, and about one-fifth of the C9 subunits was in a cross-linked dimeric form. By contrast, C9 in the absence of the C5b-8 complex was not significantly cross-linked by glutathione. These results indicate that C9 has a unique property to associate with itself upon reaction with the C5b-8 complex.

Centrifugation, Density Gradient↗
PubMed1986

C7 radiculopathy: importance of scapular winging in clinical diagnosis.

Lesions of the seventh cervical (C7) root are common and cause a readily recognised neurological syndrome. Recognition of this pattern is essential in differentiating C7 root lesions from lesions of the brachial plexus or peripheral nerves. Serratus anterior weakness is not generally included in this syndrome. We report six verified cases of C7 radiculopathy in which weakness of the serratus anterior was present in addition to the usual findings. This was manifest as winging of the scapula, when pushing forward against a wall, either with the hands at shoulder level or, in some cases, only when the hands were lowered to waist level. This latter method of testing places the muscle at a mechanical disadvantage and reveals partial paralysis. Analysis of this clinical finding complements anatomical evidence suggesting that the powerful lower digitations of the muscle may be primarily supplied by the C7 root in some cases. Scapular winging, apparent either in the usual position or the modified position described here, should be recognised as consistent with a diagnosis of C7 radiculopathy. When present, this sign serves to differentiate C7 radiculopathy from lesions of the brachial plexus or radial nerve.

Adult↗
PubMed1996

S-protein/vitronectin interaction with the C5b and the C8 of the complement membrane attack complex.

S-protein/vitronectin participates in the regulation of complement-mediated lysis by incorporating into the membrane attack complex C5b-9. Subsequently, soluble SC5b-7 and SC5b-9 macromolecules are not inserted into the membrane lipid bilayer nor induce lytic pore formation. Using a dot blot binding assay, it was determined that soluble S-protein/vitronectin interacted with immobilized C5b and C8 among the five separately immobilized components (C5b, C6, C7, C8, C9) of the membrane attack complex. Those interactions imply a new model of the formation of the complement membrane attack complex and its regulation by S-protein/vitronectin.

Animals↗
PubMedDate not supplied

Interaction of human beta-endorphin with the terminal SC5b-9 and "preterminal" SC5b-7 and SC5b-8 complexes of human complement.

Human beta-endorphin (beta H-EP) is demonstrated to bind to the "preterminal" SC5b-7 and SC5b-8 complexes and to the terminal SC5b-9 complex of human complement. Detailed binding studies revealed saturability, reversibility and structural specificity of the beta H-EP interaction with high or low affinity non-opiate binding sites on SC5b-7 and SC5b-9 complexes. The high affinity binding sites seem to be located predominantly on C5b, C6 or C7 subunits of the complexes.

Alpha-Globulins↗
PubMed1994

Complement and antibody in neutrophil-mediated killing of type V group B streptococcus.

Serious infections caused by type V group B streptococci (GBS) are increasing. The requirements for antibody, complement, and neutrophil receptors in the killing of 12 clinical type V GBS isolates were investigated. When tested at concentrations of 33%, 5% and 1%, a human serum pool promoted neutrophil-mediated killing of the 12 isolates at a mean of 83% +/- 9%, 77% +/- 17%, and 14% +/- 28%, respectively. Addition of heated immune rabbit serum to the 5% or 1% pool increased killing significantly (97% +/- 2% or 80% +/- 15%, respectively, P < .01). With hypogammaglobulinemic serum, complement-mediated killing ranged from 74% +/- 2% for a strain designated resistant to 98% +/- 1% for a strain designated sensitive. Neutrophil-mediated killing was not altered by use of human sera deficient in C4 or C7 but was reduced significantly with C3-deficient serum (P < .05). Maximal inhibition of neutrophil-mediated killing was observed by monoclonal antibody blockade of complement receptor (CR) 3 alone or in combination with CR1 or Fc receptor III. Thus, C3 is required and specific antibody promotes neutrophil-mediated killing of type V GBS. Neutrophil CR3 and either CR1 or Fc receptor III optimize phagocytosis. A number of host responses function in concert to effect optimal neutrophil-mediated killing of clinical isolates of type V GBS.

Animals↗
PubMed1977

On the mechanism of cell membrane damage by complement: evidence on insertion of polypeptide chains from C8 and C9 into the lipid bilayer of erythrocytes.

The preceding paper (Hammer, C.H., A. Nicholson, and M. M. Mayer, 1975, Proc. Natl. Acad. Sci., 72:5076) presented evidence on insertion of polypeptide chains from the C5b and C7 subunits of C5b, 6, 7 complex into the phospholipid bilayer of erythrocyte membranes. In the present study, EAC1-8 and EAC1-9 (sheep erythrocytes carrying rabbit antibody and complement proteins C1 through C8 or C9, respectively), prepared with either 125I-C8 or 125I-C9, were incubated with trypsin or chymotrypsin and the release of 125I was measured. Only 9 to 19% of the specifically bound radioactivity was released. In addition, elution experiments were performed with 0.02 M EDTA-1.0 M NaCl. This solution did not elute C9 from EAC1-9. By contrast cellbound C9 was recovered from erythrocyte membranes with sodium dodecyl sulfate (SDS). Thus, enzymatic stripping and elution experiments indicate that cellbound C9 behaves like an integral membrane protein, presumably due to insertion into the lipid bilayer. EAC1-9 membranes that had been subjected to extended digestion with trypsin or chymotrypsin were extracted with SDS to recover the enzyme-resistant part of the C9 molecule from the membrane. Even though this domain of C9 carried 90% of the radioiodine associated with native C9, its m.w. was found to be only 18,000 daltons by analysis on SDS-PAGE. This represents one-quarter of the native C9 molecule.

Animals↗
PubMed1987

Terminal complement complex in plasma from patients with systemic lupus erythematosus and other glomerular diseases.

To evaluate terminal complement pathway activation in plasma from patients with systemic lupus erythematosus (SLE) and primary glomerular diseases, we developed an enzyme-linked immunosorbent assay (ELISA) for measuring the terminal complement complexes (TCC). The method is based on a sandwich technique using rabbit antibodies against native human C5, C7 and C9. To avoid interference by native components, we equilibrated plasma specimens with 5% polyethylene glycol buffer. The precipitates were measured by ELISA. TCC was detectable in all 14 normal controls (0.48 +/- 0.06 AU/ml; mean +/- s.e.m.). TCC levels were elevated in 18 of 54 patients with SLE (0.89 +/- 0.07 AU/ml; P less than 0.01) and in eight of 11 patients with membranoproliferative glomerulonephritis (MPGN) (3.15 +/- 0.62 AU/ml; P less than 0.01). However, only one of six patients with membranous nephropathy and none of 13 with mesangial proliferative glomerulonephritis showed high values. In SLE, TCC was correlated with circulating immune complexes and inversely with CH50, C3, C4, C5 and alternative complement pathway activity (AH50), and showed significantly high values even in normal CH50 cases (n = 34; P less than 0.01). In MPGN, TCC was inversely correlated with CH50, AH50, C3, C5 and C9. These results suggest that the classical pathway plays an important role for TCC generation in SLE and that the alternative pathway does in MPGN.

Adolescent↗