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PubMed1983

Interaction of human beta-endorphin with nonopiate binding sites on the terminal SC5b-9 complex of human complement. Significance of COOH-terminal beta H-endorphin fragments.

We have characterized the binding of 125I-labeled human beta-endorphin (125I-beta H-endorphin) to sites present on the terminal fluid-phase complex of human complement, consisting of complement components C5b, C6, C7, C8, C9, and the S-protein (SC5b-9 complex). Specific binding exhibited saturability, reversibility, structural specificity, temperature dependence, and absence of negative cooperative effects. Binding was maximal at 4 degrees C and pH 7.0; it was diminished by monovalent and divalent cations as well as by increasing concentrations of urea and Triton X-100 and apparently required intact disulfide groups. Binding was not inhibited by a number of opioid peptides sharing common sequences with the NH2 terminus of beta H-endorphin. In contrast, binding was inhibited by beta H-endorphin, N-acetyl-beta H-endorphin, and a series of COOH-terminal beta H-endorphin fragments, where of the COOH-terminal dipeptide Gly-Glu represented the minimal effective structure. Stepwise extension towards the NH2 terminus led to an increased binding affinity of the respective fragment. Computer resolution of competition curves yielded one binding component for several shorter COOH-terminal beta H-endorphin fragments and for beta H-endorphin (1-5) + (16-31), whereas two distinct binding components were obtained when beta H-endorphin (27-31), beta H-endorphin (6-31), N-acetyl-beta H-endorphin or beta H-endorphin were used as inhibitors. This study presents detailed data on the binding of COOH-terminal beta H-endorphin fragments to specific nonopiate binding sites present on the terminal SC5b-9 complex of human complement. We suggest that through this interaction, beta H-endorphin may modulate certain functions within the immune system.

Binding Sites↗
PubMed1992

A 41.7 kDa serine protease from Clostridium perfringens type A: degradation of purified human serum proteins.

Two clinical isolates of Clostridium perfringens type A produced a novel caseinolytic serine protease. Both enzymes had a molecular weight of 41.7 kilodaltons and an isoelectric point of 9.1. The two enzymes were immunogenic for rabbits and closely related serologically. Both enzymes partially degraded the heavy chains of human immunoglobulins (Ig) G and IgM, but not IgA. Purified human complement (C) components C3, C5, C8, and C9 were attacked; C1q was refractory. Both enzymes were active against human transferrin, alpha 1-antitrypsin, alpha 2-macroglobulin, haptoglobin, type III fibrinogen, and fibronectin. C-reactive protein was refractory.

Blood Proteins↗
PubMed1990

[Meningococcal infection and arthritis].

Arthritic manifestations in patients with meningococcal disease are of varied pathogenesis. Four different pathogenic mechanisms may be involved. Direct bacterial invasion of the synovium and multiplication within the joint (septic arthritis); hypersensitivity reaction or allergic arthritis; intra- or periarticular hemorrhage (hemarthrosis) and iatrogen causes, i.e. reaction to antimicrobial agents, serum therapy etc. Four distinct clinical forms have been described: The septic, culture-positive polyarthritis is seen early in the course of the disease. The sterile "non-infectious" or allergic mono- or oligo arthritis are seen later in the course. Primary meningococcal arthritis. Arthritis may be seen in relation to chronic meningococcemia. Treatment consists primarily of specific antimeningococcal chemotherapy, viz penicillin and non-steroid-anti-inflammatory drugs. The prognosis of meningococcal arthritis is excellent and joint sequelae are rare. Predisposing factors in relation to meningococcal disease are reviewed. The most important are socioeconomic conditions, acute respiratory illness, particularly in relation to age as children less than two years are most susceptible, passive smoking, IgA blocking antibodies, the concentration of complement factors C3, C6, C7, C8, and IgG2-defects.

Arthritis, Infectious↗
PubMed1988

Molecular mechanisms of lymphocyte-mediated killing.

Lymphocytes kill tumor cells and other target cells by a contact-dependent mechanism. Killer lymphocytes acquire cytoplasmic granules upon lymphokine stimulation and these granules in turn contain potent cytotoxic mediators, some of which have been characterized recently. These include (i) a pore-forming protein (perforin) of 70 kDa that polymerizes into transmembrane tubules in the presence of calcium and that is structurally related to the terminal components (C5b-6, C7, C8 and C9) of the complement cascade, (ii) a cytokine related to tumor necrosis factor and lymphotoxin that causes DNA fragmentation in target cells, and (iii) a family of serine esterases presently without any known function. The relevance of these mediators in lymphocyte-mediated killing is currently being investigated. The identification and characterization of additional putative mediators of cytotoxicity in the future will undoubtedly provide us with a better understanding of the molecular basis of cell-mediated killing.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1993

Meningococcal disease in patients with late complement component deficiency: studies in the U.S.S.R.

The purpose of this study was to examine the occurrence of late complement component deficiency (LCCD) states in the USSR. Thirty deficient individuals were detected: 27 with C8 beta and 3 with C7 deficiency. Among individuals with a first episode of meningococcal infection, about 1% had LCCD, whereas among patients with recurrent bacterial meningitis the prevalence of LCCD rose to approximately 50%. This corresponds to a prevalence for LCCD of approximately 12 per 100,000 in the general population. The individuals with LCCD identified in this study experienced about 77 episodes of meningococcal disease and acute bacterial meningitis. Mathematical analysis of the morbidity from meningococcal disease in individuals with LCCD demonstrated that the probability of disease did not change with the age of the patient and was not affected by prior episodes of infection. This finding suggest that in contrast to the situation in the general population, prior infection fails to protect the deficient individual from recurrent disease. In comparison to complement-sufficient persons, the course of disease in individuals with LCCD is less severe, as shown by a reduction in the number of episodes of endotoxic shock and mortality as well as their more rapid recovery. These findings suggest that exuberant complement activation and concomitant formation of membrane attack complexes during meningococcal infection in complement-sufficient patients plays an important role in the activation and injury of peripheral blood cells and endothelial cells during endotoxic shock.

Adolescent↗
PubMed1985

Complement-mediated serum cytotoxicity for Leishmania major amastigotes: killing by serum deficient in early components of the membrane attack complex.

Leishmania major, the agent of Oriental sore, is an obligate intracellular parasite of macrophages in mammalian hosts. Man's immune defense against this organism requires participation of specifically sensitized lymphocytes and activated macrophages. Recent studies, however, have demonstrated that as little as 1/120 concentration of normal human serum is highly cytotoxic for the amastigote form of L. major. Initiation of the lethal process occurs rapidly, requiring only 30 sec of parasite exposure to serum, and is mediated by antibody-independent activation of the alternate complement pathway. The molecular mechanism of cytotoxicity is not known, but may require participation of the membrane attack complex, C5b-9. We investigated this possibility by treating amastigotes with human sera genetically deficient in complement components C5, 6, 7, 8, or 9. We then measured viability of treated parasites by amastigote-promastigote conversion. Our results were quite unexpected: not only did C9-deficient serum kill organisms, but sera singly deficient in each of the preceding components C6 to C8 were also cytotoxic. The degree of cytotoxicity was related both to serum concentration and to the point in the complement cascade at which deficiency occurred. Sera lacking C6 or C7 were less cytotoxic than those deficient in C8, which were less toxic than those deficient in C9. Cytoxicity of deficient sera was abolished by heating serum to 56 degrees C for 30 min. These findings indicate that an incomplete membrane attack complex may mediate cytotoxicity for L. major amastigotes. Moreover, our results raise important questions regarding the mechanism by which the complex is assembled on the surface of a living, unicellular eukaryotic organism.

Animals↗
PubMed1992

Early complement components enhance neutralization of Chlamydia trachomatis infectivity by human sera.

Immunoglobulin G in human serum neutralizes chlamydial infectivity in vitro. Complement-intact, C5-depleted, and C8-depleted human serum all have significantly more neutralizing activity than serum heated to inactivate early components of complement. Cobra venom factor, an analog of human C3b, enhances neutralization of antichlamydial immunoglobulin G in the absence of early complement components.

Blood Bactericidal Activity↗
PubMed1993

[Complement deficiencies and meningococcal disease in The Netherlands].

OBJECTIVE: To determine the prevalence of complement system deficiencies in patients who have survived a Neisseria meningitidis infection. DESIGN: Retrospective. SETTING: Reference laboratory for bacterial meningitis of the University of Amsterdam and the National Institute of Public Health and Environmental Protection. METHOD: Out of the files of the laboratory 187 patients who had experienced a meningococcal infection in the Netherlands between 1959-1990 were selected in two groups according to the infecting bacterial strain: 97 patients with a serogroup X, Y, Z, W135, 29E, or non-groupable strains and 90 patients with an infection due to serogroup A or C. The patients were asked for their cooperation by their family doctor and one of us visited the patients at home to take blood samples. The complement activity was studied with a haemolysis in gel test and with an assay of haemolytic activity in free solution. RESULTS: Complement deficiency was present in 18% of the 187 patients who had experienced a meningococcal infection. The highest prevalence was found in patients older than 10 years who had developed infections due to serogroups X, Y, W135, or non-groupable strains (45%). Of the patients with a serogroup A or C infection, 3% had an complement deficiency. Of the complement deficiencies, 42% concerned a component of the alternative pathway, 12% a deficiency of C3, and 46% a component of the terminal route. The most commonly found deficiencies were properdin deficiency (39%) and C8 deficiency (18%). 30% of the complement deficient patients reported other family members having experienced meningitis. Recurrent meningitis was only observed in patients with terminal route deficiencies. CONCLUSION: We recommend that patients with a meningococcal infection due to serogroups X, Y, W135 or non-groupable strains should be screened for complement deficiency.

Adolescent↗
PubMed1995

A novel type of X-ray-sensitive Chinese hamster cell mutant with radioresistant DNA synthesis and hampered DNA double-strand break repair.

It has been shown that the Chinese hamster cell mutant V-C8 is sensitive to different DNA damaging agents, such as mitomycin C (MMC), alkylating agents, UV light, and X-rays. We found that V-C8 is also sensitive to the following radiomimetic agents: bleomycin (approximately 2-fold, based on D10 values), H2O2 (approximately 2-fold), streptonigrin (approximately 11-fold), and etoposide (approximately 8-fold). Two independent spontaneous MMC-resistant revertants isolated from V-C8 cells show a level of cell killing by X-rays, EMS, and UV light which is similar to that of wild-type cells, suggesting that the observed pattern of cross-sensitivity of V-C8 cells to a wide spectrum of DNA damaging agents results from a single mutation. V-C8 cells also display radioresistant DNA synthesis following gamma-irradiation which, however, remained almost unchanged in the V-C8 revertants. The measurement of the level and rate of repair of DNA single- and double-strand breaks (SSBs and DSBs, respectively) by the DNA elution technique showed that the V-C8 mutant has a slower repair of DSBs induced by gamma-rays. The described unique phenotype of V-C8 cells suggested that V-C8 represents a novel type of mutant amongst X-ray-sensitive hamster cell mutants. To confirm this, complementation analysis with other X-ray-sensitive mutants was performed. V-C8 cells were fused with EM9, XR-1, xrs5, sxi-1, V-3, V-E5, irs3, and BLM2 mutant cells, representing different complementation groups. All the obtained hybrids regained X-ray resistance (or bleomycin resistance in the case of V-C8/BLM2 hybrids) similar to that of wild-type cells, indicating that V-C8 represents a new complementation group. The results presented indicate that V-C8 is defective in a gene involved in a pathway operating in the responses to different DNA damaging agents in mammalian cells.

Animals↗
PubMed1985

Cyanine dye fluorescence used to measure membrane potential changes due to the assembly of complement proteins C5b-9.

The fluorescent potentiometric indicator diS-C3-(5) has been used to investigate changes in membrane potential due to assembly of the C5b-9 membrane attack complex of the complement system. EAC1-7 human red blood cells and resealed erythrocyte ghosts--bearing membrane-assembled C5b67 complexes--were generated by immune activation in C8-deficient human serum. Studies performed with these cellular intermediates revealed that the membrane potential of EAC1-7 red cells and ghosts is unchanged from control red cells (-7 mV) and ghosts (O mV), respectively. Addition of complement proteins C8 and C9 to EAC1-7 red cells results in a dose-dependent depolarization of membrane potential which precedes hemolysis. This prelytic depolarization of membrane potential--and the consequent onset of hemolysis--is accelerated by raising external [K+], suggesting that the diffusional equilibration of transmembrane cation gradients is rate limiting to the cytolytic event. In the case of EAC1-7 resealed ghosts suspended at either high external [K+] or [Na+], no change in membrane potential (from O mV) could be detected after C8/C9 additions. When the membrane potential of the EAC1-7 ghost was displaced from O mV by selectively increasing the K+ conductance with valinomycin, a dose-dependent depolarization of the membrane was observed upon addition of C8 and C9. In these experiments, lytic breakdown of the ghost membranes was less than 5%. Conclusions derived from this study include: (i) measured prelytic depolarization of the red cell Donnan potential directly confirms the colloid-osmotic theory of immune cytolysis. (ii) The diffusional transmembrane equilibration of Na+ and K+ through the C5b-9 pore results in a dose-dependent depolarization of the membrane potential (Em) which appears to be rate-limiting to cytolytic rupture of the target erythrocyte. (iii) Enhanced immune hemolysis observed in high K+ media cannot be attributed to cation-selective conductance across the C5b-9 pore, and is probably related to the near-equilibrium condition of potassium-containing red cells when suspended at high external K+. These experiments demonstrate that carbocyanine dye fluorescent indicators can be used to monitor electrochemical changes arising from immune damage to the plasma membrane under both cytolytic and noncytolytic conditions. Potential application of this method to the detection of sublytic pathophysiological changes in the plasma membrane of complement-damaged cells are discussed.

Complement Membrane Attack Complex↗
PubMed1976

Bactericidal and opsonic activity against Neisseria gonorrhoeae in sera from patients with disseminated gonococcal infection.

Bactericidal and opsonic activities in convalescent-phase sera from patients with disseminated gonococcal infection (DGI) were analyzed with use of the patients' infecting strains and other strains of Neisseria gonorrhoeae. Serum from a patients with C8 deficiency was opsonic for her first DGI isolate grown on solid medium or in chick embryos; with added complement the serum was bactericidal (at a dilution of 1:320). Her serum was not bactericidal for nine other isolates from patients with DGI. Only one of the other patients with DGI had detectable serum bactericidal activity (dilution, 1:2,5) against her own isolate; this patient's serum was also active against one other DGI isolate. Opsonization was detectable only in sera that were potentially bactericidal and could be distinguished from bactericidal activity only with C8-deficient serum. The isolates from patients with DGI were of an auxotype different from that of most other gonococci, and most of the isolates tested were not killed by sera from patients with uncomplicated gonorrhea, even though these wera killed other gonococci. Thus, isolates from patients with DGI appeared to be significantly different from other gonococcal isolates.

Antibodies, Bacterial↗
PubMed1975

Phylogeny of complement components in non-human primates.

The antigenic properties and functional activities of complement components were analyzed in primates to determine their relative evolutionary development. The sera of eight different sub-human primate species were examined by double diffusion in agar and compared to a pool of human serum with rabbit and goat antisera to human complement components Clq, Cls, C4, C2 C3, C5, C6, C8, C9, properdin, factor B (B), and C1 inhibitor. There are no apparent antigenic differences in complement proteins between man and the apes except for C1q. Old world monkeys are antigenically deficient in Clq,C1s, C9, and variably deficient in C4, C3, and C8. New World monkeys are antigenically deficient in all components (measured) except C5, C6, and properdin factor B. Prosimians are antigenically deficient in all components. Functional analyses of complement components showed similar levels in man and primates, except in prosimians. There is a dissociation between hemolytic assays and antigenic analyses, suggesting that functional sites may be separate from antigenic sites.

Absorption↗
PubMed1989

Paroxysmal nocturnal hemoglobinuria. A complement-mediated disease.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic disease characterized by an increased sensitivity of erythrocytes to the hemolytic action of complement. Two membrane proteins, the decay-accelerating factor and the C8-binding protein, which protect normal erythrocytes from the hemolytic action of complement, are deficient on the abnormal blood cells from patients with PNH. Other membrane proteins unrelated to complement regulation, but which share with the decay-accelerating factor and the C8-binding protein a common post-translational modification, namely a glycan-phosphatidylinositol linkage to the cell membrane, are also missing from PNH cells. In the present review, clinical, biological, and molecular aspects of PNH are discussed. In addition, diagnostic tests in clinical use are discussed, and new tests using indirect immunofluorescent assays are proposed.

Complement System Proteins↗
PubMed1993

Complement component C5 modulates the systemic tumor necrosis factor response in murine endotoxic shock.

Patients with disseminated Neisseria meningitidis infections (meningococcemia) suffer from a fulminant shock syndrome that is accompanied by extraordinarily high concentrations in serum of tumor necrosis factor (TNF). People with homozygous deficiencies of late complement components (C5, C6, C7, and C8) experience a high incidence of disseminated neisserial infections yet suffer from an attenuated form of the disease. The mechanisms that account for this disparity in host response are unclear, but they may in part be related to differences in the systemic TNF response that are modulated by terminal complement components (C5 to C9). The role of C5 in the modulation of the systemic endotoxin-induced TNF response was studied with matched strains of C5-deficient (B10 D2/Osn) and complement-sufficient (B10 D2/Nsn) mice. Following lipopolysaccharide (LPS) administration, complement-sufficient mice exhibited more rapid increases in pulmonary and hepatic vascular permeabilities than did C5-deficient controls. Complement-sufficient mice developed acute passive hepatic congestion, they appeared more ill than C5-deficient mice, and they exhibited a twofold greater rise in serum TNF activity compared with that by C5-deficient mice. C5-deficient mice reconstituted with normal serum before an LPS injection exhibited pulmonary and hepatic vascular permeability increases and serum TNF levels approaching those observed in complement-sufficient mice. Alveolar and peritoneal macrophages isolated from complement-sufficient and C5-deficient mice and incubated in heat-inactivated serum did not exhibit differences in TNF mRNA expression or secreted TNF activity following stimulation with LPS. However, incubation of macrophages in complement-sufficient mouse serum (before LPS stimulation) resulted in increased TNF mRNA expression and TNF activity compared with those in cells incubated in C5-deficient serum. In vitro studies employing human complement components and peripheral blood monocytes revealed that recombinant C5a, in the presence or absence of LPS, can induce increased concentrations of TNF and that C5b to C9 had no additional modulatory effect on the TNF response. These data suggest that C5 modulates the endotoxin-triggered TNF response. The role of complement components distal to C5 (i.e., C5b to C9) in the endotoxin-triggered TNF response remains unclear.

Animals↗
PubMed1979

Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency.

We summarize data from 24 previously described or newly diagnosed cases of homozygous deficiency of the sixth, seventh, or eighth components of complement. Thirteen of 24 patients had at least one episode, and usually two or more episodes of Neisseria meningitidis or Neisseria gonorrhoeae bacteremia, or both. Deficiency of C6, C7, or C8 is a meaningful risk factor for repeated neisserial bacteremia; conversely, hemolytic complement studies are indicated in patients who develop recurrent neisserial infections. When a person with C6, C7, or C8 deficiency is identified, family members should also be studied.

Adolescent↗
PubMed1983

Neoantigen of the polymerized ninth component of complement. Characterization of a monoclonal antibody and immunohistochemical localization in renal disease.

A monoclonal antibody to a neoantigen of the C9 portion of the membrane attack complex (MAC) of human complement has been developed and characterized. The distribution of this neoantigen was assessed by indirect immunofluorescence microscopy in nephritic and nonnephritic renal diseases. The antibody (Poly C9-MA) reacted on enzyme-linked immunosorbent assay (ELISA) with a determinant in complement-activated serum that was undetectable in normal human serum (NHS). Zymosan particles incubated in NHS had positive immunofluorescent staining with Poly C9-MA; however, binding of Poly C9-MA was not observed with zymosan particles incubated in sera deficient in individual complement components C3, C5, C6, C7, C8, or C9. Reconstitution of C9-deficient sera with purified C9 restored the fluorescence with Poly C9-MA. Poly C9-MA reacted positively by ELISA in a dose-dependent manner with purified MC5b-9 solubilized from membranes of antibody-coated sheep erythrocytes treated with NHS but not with intermediate complement complexes. Poly C9-MA also reacted in a dose-dependent manner on ELISA and in a radioimmunoassay with polymerized C9 (37 degrees C, 64 h) (poly C9) but not with monomeric C9. Increasing amounts of either unlabeled poly C9 or purified MC5b-9 inhibited the 125I-poly C9 RIA in an identical manner. These studies demonstrate that Poly C9-MA recognizes a neoantigen of C9 common to both the MAC and to poly C9. By immunofluorescence, Poly C9-MA reacted minimally with normal kidney tissue in juxtaglomerular loci, the mesangial stalk, and vessel walls. Poly C9-MA stained kidney tissue from patients with glomerulonephritis in a pattern similar to that seen with polyclonal anti-human C3. In tissue from patients with nonnephritic renal disease--diabetes, hypertension, and obstructive uropathy--Poly C9-MA was strongly reactive in the mesangial stalk and juxtaglomerular regions, tubular basement membranes, and vascular walls. Poly C9-MA binding was especially prominent in areas of advanced tissue injury. Poly C9-MA frequently stained loci where C3 was either minimally present or absent. These studies provide strong evidence for complement activation not only in nephritic but also in nonnephritic renal diseases.

Adult↗
PubMed1983

Evidence of direct insertion of terminal complement proteins into cell membrane bilayers during cytolysis. Labeling by a photosensitive membrane probe reveals a major role for the eighth and ninth components.

Radioiodinated hexanoyldiiodo-N-(4-azido-2-nitrophenyl)tyramine (HNT) was employed as a photosensitive membrane-restricted probe to establish whether terminal complement proteins insert into membrane bilayers during cytolysis. The system studied consisted of natural membranes carrying intermediate (C5b-8) or fully assembled (C5b-9) cytolytic complexes of human complement prepared by two different methods. In one method, C5b-8 and C5b-9 were assembled on membranes de novo by incubating rabbit erythrocytes with C9-depleted or whole human serum, respectively. The probe was partitioned into lipid bilayers of the resulting MC5b-8 and MC5b-9 membranes by post-addition of HNT. Membranes were irradiated and photolabeled C5b-8 and C5b-9 were extracted, purified, and analyzed on polyacrylamide gels. Those constituents labeled by HNT within each complex were identified by autoradiography. The second method involved pre-addition of HNT to membranes carrying the precursive C5b-7 complex and subsequent conversion to MC5b-8 and MC5b-9 by addition of exogenous C8 and C9. After irradiation, C5b-8 and C5b-9 were again purified and analyzed for the presence of photolabel. Results from both methods were similar and indicated all constituents of each complex are labeled to a measurable extent. However, the C8 alpha subunit was predominantly labeled in C5b-8 and both C8 alpha and C9 were predominantly labeled in C5b-9. Because labeling by HNT is specific for intramembrane structural domains of proteins, these results provide direct evidence that constituents of terminal complement complexes insert into the lipid bilayer of cell membranes during lysis. Further, we conclude that in these complexes, C8 alpha and C9 are the primary contributors of inserted peptide domains.

Animals↗
PubMed1990

Neutralization of human immunodeficiency virus type 1 by complement occurs by viral lysis.

The ability of complement to inactivate human immunodeficiency virus (HIV) in the presence of specific antibody was evaluated. HIV was treated with complement and/or antibody, and then its titer was determined on the CD4+ H9 cell line. While complement alone had no effect on the HIV titer, complement plus subneutralizing levels of antibody resulted in titer reductions. Complement sources deficient in membrane attack component C5 or C8 did not inactivate antibody-treated HIV, suggesting that neutralization occurred via lysis. This possibility was investigated by assessing release of reverse transcriptase (RT) from the virion. Antibody plus complement, but neither reagent alone, released RT from HIV in a dose-dependent manner. Release of RT did not occur with C5- or C8-deficient sera, also indicating a requirement for membrane attack components. These studies show that complement can neutralize HIV via the classical complement pathway and that this neutralization occurs via C5b-9-mediated viral lysis. Thus, complement may play a major role in resistance to disease by lysing HIV and preventing infection of Fc- and complement receptor-positive cells, as well as CD4+ cells.

Antibody Formation↗