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PubMed1990

Persistent low C3 levels associated with meningococcal meningitis and membranoproliferative glomerulonephritis.

Recurrent meningococcal meningitis is usually related to terminal complement factor deficiencies (C5-C8); however it is not frequent with isolated primary C3 deficiency. Similarly, membranoproliferative glomerulonephritis has been described in association with primary C3 deficiencies and the presence of C3 nephritic factor. We present a case of an 18-year-old woman with relapsing meningococcal meningitis in whom membranoproliferative glomerulonephritis and persistent low serum C3 levels were found. A detailed immunological study was performed, but no other abnormalities in the complement components were found. C3 Nef was also negative. Moreover, the familiar complement studies showed an asymptomatic C4 deficiency in her mother and borderline C3 levels in her sister. The presence of persistent low serum C3 levels in the absence of other immunological abnormalities suggests that this is the cause of the relapsing meningococcal infections and the glomerular disease of this patient. We suggest that a complement deficiency, including isolated C3 deficiency, should be ruled out in all cases of relapsing meningitis. Further, the possibility of glomerular disease should be carefully considered in these patients.

Adolescent↗

PubMed1992

Serum SC5b-9 (terminal complement complex) level, a sensitive indicator of disease activity in patients with Henoch-Schönlein purpura.

The concentration of the terminal complement complex (TCC), SC5b-9, was determined by enzyme immunoassay using 95 serum samples from 30 patients with Henoch-Schönlein purpura (HSP), 27 with other forms of inflammatory skin disease and 20 normal healthy donors. Twenty-five patients with HSP showed significantly increased TCC concentration in the active phase of the disease, during which newly formed urticarial or purpuric macules/papules could be seen. Skin biopsy specimens of skin lesions from patients with elevated TCC levels in nearly all cases contained the membrane attack complex of complement and consisted of C5b, C6, C7, C8, C9 without S protein on the vessel walls. Systemic and local activation of complement may thus possibly occur in HSP. Three patients with various manifestations of the disease were followed over a period of several years during which the active and inactive phases were scanned. TCC elevation in all cases was correlated with exacerbation of the disease. In contrast, C3, C4 and CH50 levels either remained normal or increased and thus were not reliable indicators of disease activity. Measurement of TCC should thus prove quite useful for monitoring the activity of HSP in patients in whom there is complement activation and also serve to facilitate clarification of the functions of complement in the pathogenesis of the disease.

Acute Disease↗

PubMed1994

The membrane attack complex of complement. Assembly, structure and cytotoxic activity.

The membrane attack complex of complement is formed by the molecular fusion of the five terminal complement proteins, C5, C6, C7, C8, and C9. While the assembly process on a target membrane and its modulation by restriction factors present on host cells is now quite well understood the molecular details of the architecture of the complex still need much further clarification. This is especially true for the interaction of the last acting protein C9, which provides the cytotoxic action of the complex, with the precursor C5b-8 complex. Because of this lack of structural details the molecular mechanisms that lead to complement-mediated cell death remain cryptic, however, it is hoped that recent advances in controlling the assembly process and in site-specific modification of the terminal complement proteins by recombinant DNA techniques should change this predicament quickly.

Bacteria↗

PubMed1979

Genetic control of the eighth component of complement.

Using isoelectric focusing in polyacrylamide gel and a hemolytic assay for development of patterns, extensive, structural polymorphism in human C8 has been delineated. Two alleles, C8A and C8B, have been identified in orientals, with gene frequencies of 0.655 and 0.345. In blacks, what appears to be a third common allele was found, so that frequencies were 0.692, 0.259, and 0.049 for C8A, C8B, and C8A1. In whites, C8A1 was rare with a frequency of 0.003, and frequencies for C8A and C8B were 0.649 and 0.349. Inheritance was autosomal codominant in family studies and the distribution of types in random unrelated populations fit the Hardy-Weinberg equilibrium in all groups. C8 allotypes have been determined for two previously studied families, each with a homozygous C8-deficient propositus. This study suggests that C8 deficiency is a silent or null allele of the C8 structural locus, and that half normal levels of C8 cannot be used as a single criterion for the establishment of heterozygous C8 deficiency. C8 allotypes, as well as 18 other autosomal markers, were also determined for 24 families. The C8 structural locus is not closely linked to these markers, including the human histocompatibility loci complex.

Alleles↗

PubMed1994

[Homozygote CB deficiency revealed by recurrent Neisseria meningitidis infections in an adolescent].

BACKGROUND: Meningococcal infections associated with late complement component deficiency are rarely severe and usually occur during adolescence and adulthood. We report severe manifestations in a boy in whom the first episode appeared early. CASE REPORT: A 14 year-old gypsy boy was admitted because of a febrile meningococcal meningitis that was complicated by a rapidly extensive and necrotic purpura, obnubilation and clotting abnormalities without hemodynamic anomalies. The patient was given symptomatic therapy and a 12-day course of antibiotics that resulted in rapid and complete recovery. Medical history of this patient showed that he had been admitted at the age of 3 years for a severe febrile purpura with septic shock and clotting abnormalities followed by rapid and complete recovery after symptomatic and antibiotic therapy. No germ had been then isolated. The complement system was studied 3 weeks after the second hospitalization: total hemolytic complement activity could not be detected and C2, C3 and C4 were normal. Examination of the terminal pathway-revealed total C8 deficiency. The patient received meningococcal vaccine and was discharged on oral penicillin prophylaxis. He remained healthy during the ensuing 4 years. CONCLUSIONS: Meningococcal infections associated with late complement component deficiency are generally uncomplicated but they remain potentially severe. Early screening for this late complement component deficiency should be considered after severe clinical manifestations.

Adolescent↗

PubMed1973

The complement system in bullous pemphigoid. I. Complement and component levels in sera and blister fluids.

Compared with other serum and blister fluid proteins, total hemolytic complement was reduced in the blister fluid of six serologically positive bullous pemphigold patients while four serologically negative cases had blister fluid complement levels closely approaching the serum levels. Except for pemphigus vulgaris blisters. blister fluids from most patients with other bullous diseases and experimentally induced blisters had blister fluid complement levels more closely approaching the serum levels. With the exception of the two terminal components. C8 and C9, individual components of the complement sequence were also reduced in the blister fluids of the six bullous pemphigold patients with circulating basement membrane zone antibodies. On the other hand, transferrin and IgG levels of these same six serologically positive blister fluids closely approached the corresponding serum levels. Conversion of C3 proactivator was also demonstrable in the serologically positive bullous pemphigoid blister fluids, but not in the corresponding sera. Our studies, therefore, are suggestive of local activation of the complement sequence, by both the classical and alternate pathways, in blisters of serologically positive bullous pemphigold patients.

Basement Membrane↗

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↗

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↗

PubMed2005

Emission of membrane vesicles: roles in complement resistance, immunity and cancer.

Complement-mediated cell death is caused by C5b-9, the membrane attack complex (MAC) composed of the five complement proteins C5b, C6, C7, C8, and C9. Assembly of the C5b-9 complex initiates oligomerization of C9 and production of a transmembrane protein channel that inflicts damage to target cells. For protection, cells eliminate the MAC from their surface either by ectocytosis (direct emission of membrane vesicles) or by endocytosis (internalization). The process of ectosome release is rapid and involves cytosolic Ca(2+) and activation of protein kinases, such as protein kinase C (PKC) and extracellular signal-regulated protein kinase (ERK). Recently, the involvement of mortalin (also known as GRP75 and mitochondrial hsp70) in MAC elimination has been suggested. Extracellular application of antibodies directed to mortalin increases cell sensitivity to MAC-mediated lysis. Release of membrane vesicles is ubiquitous and enhanced in apoptotic or tumor cells and upon cell activation. Composition of the ectosomes (also often referred to as microparticles) membrane proteins and lipids appears to be different from those of the original plasma membrane, indicating involvement of a selective sorting process during ectosome formation. Exosomes (unlike ectosomes) are membrane vesicles generated by endocytosis, endosome sorting into perinuclear multivesicular bodies (MVB) and exocytosis of MVBs. Exosomes appear to be different in size and composition from ectosomes. Exosome-associated MAC has also been described. Although research on ectosomes and exosomes is still limited, physiological roles in coagulation, vascular functions, angiogenesis, wound healing and development have been attributed to these shed membrane vesicles. On the other hand, there are indications that elevated levels of ectosomes and exosomes may predispose to morbidity. Membrane vesicles released by cells exposed to complement MAC may play roles in health and disease beyond protection from cell death.

Animals↗

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↗