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PubMed1985

Renal filtration and catabolism of complement protein D.

Complement protein D, a serine protease participating in the formation of the C3 convertase of the alternative complement pathway, has the lowest molecular weight (23,750) and serum concentration of all complement proteins. In normal serum, D is the rate-limiting protease of the alternative pathway of complement activation. We report that the serum concentrations of D in 20 patients with chronic renal failure (mean +/- S.D., 0.42 +/- 0.28 mg per deciliter) and in 16 patients on long-term dialysis (1.53 +/- 0.39 mg per deciliter) were significantly higher (P less than 0.001) than in 22 healthy adults (0.18 +/- 0.04 mg per deciliter). In chronic renal failure the serum concentration of D correlated with that of creatinine (r = 0.75, P less than 0.001). The serum concentrations of D found in patients with renal failure reached and in some cases exceeded those at which the protease is no longer rate-limiting. Thus, enhanced activity of the alternative pathway of complement should be expected in patients with advanced renal failure. Urinary D was undetectable (less than 0.2 micrograms per deciliter) in 17 normal adults and either undetectable or below the concentration expected from the degree of proteinuria in 10 patients with nephrotic syndrome. However, in a patient with Fanconi's syndrome the urinary concentration of D (1.3 mg per deciliter) was an order of magnitude higher than the serum concentration, representing 0.5 per cent of the total protein. The urinary D in this patient had normal hemolytic activity, antigenicity, and size. These results indicate that D is filtered through the glomerular membrane and is probably catabolized in the proximal renal tubules.

Adult↗
PubMed1996

Specific complement inhibition with heparin-coated extracorporeal circuits.

BACKGROUND: Although it is well established that heparin-coated extracorporeal circuits reduce complement activation during cardiac operations, little in vivo information is available on the reduction in alternative and classic pathway activation. METHODS: In a prospective, randomized study involving patients undergoing coronary artery bypass grafting with standard full heparinization, we compared heparin-coated circuits (Duraflo II) (10 patients) with uncoated circuits (10 patients) and assessed the extent of initiation of complement activation by detecting iC3 (C3b-like C3) concentrations, classic pathway activation by C4b/c (C4b, iC4b, C4c) concentrations, terminal pathway activation by soluble C5b-9 concentrations, and C3 activation by C3a (C3a desArg) and C3b/c (C3b, iC3b, C3c) concentrations. RESULTS: Heparin-coated extracorporeal circuits significantly reduced circulating complement activation product C3b/c and soluble C5b-9 concentrations at the end of cardiopulmonary bypass and after protamine sulfate administration compared with the uncoated circuits, but not iC3, C4b/c, or C3a concentrations. CONCLUSIONS: Heparin-coated extracorporeal circuits reduce complement activation through the alternative complement pathway, probably at the C3 convertase level, and, consequently, the terminal pathway. C3b/c seems to be a more sensitive marker than C3a to assess complement activation during cardiac operations.

Aged↗
PubMed1983

Role of the capsule and the O antigen in resistance of O18:K1 Escherichia coli to complement-mediated killing.

Epidemiological data show that O18:K1 Escherichia coli is a common cause of neonatal bacteremia and meningitis. These bacteria were capable of multiplying in the bloodstream of newborn rats and were resistant to the bactericidal effects of complement in the absence of specific antibodies. The roles played by the O antigen and the K antigen in complement resistance were analyzed by comparing the bactericidal effects of normal sera and of sera deficient in various complement components or in immunoglobulins. These sera were tested on O18:K1 bacteria and on mutants lacking either the lipopolysaccharide O antigen or the K1 capsular polysaccharide. In addition, O1:K1 cells, which can cause pyelonephritis but which are rare in newborn meningitis and which do not multiply in the bloodstream of newborn rats, were also examined. Different mechanisms of protection against the alternative and classical pathways were recognized: K1-positive cells were resistant to the bactericidal activity of sera deficient in classical complement pathway components, whereas K1-negative cells were sensitive to these sera. Based on these results and on those from complement fixation assays, the K1 sialic acid polysaccharide impedes the activation of, and thus protects the bacteria against, the alternative complement pathway. Not only the K1-negative mutant cells but also O1:K1 bacteria and mutants lacking the O18 oligosaccharide repeating units of the lipopolysaccharide were sensitive to the classical complement pathway. These bactericidal effects were observed even in the absence of specific antibodies. It is proposed that both the K1 capsule and the O18 oligosaccharide restrict antibody-independent classical pathway activation by shielding deeper structures on the cell membrane that are capable of activating this pathway.

Animals↗
PubMed1988

Developmentally regulated expression by Trypanosoma cruzi of molecules that accelerate the decay of complement C3 convertases.

We recently showed that culture-derived metacyclic trypomastigotes (CMT), but not epimastigotes (Epi), of the Miranda 88 strain of Trypanosoma cruzi evade lysis by the human alternative complement pathway because of inefficient binding of factor B to complement component C3b on the parasite surface. These results suggested that CMT and tissue-culture-derived trypomastigotes (TCT), which also activate the alternative pathway poorly, might produce a molecule capable of interfering with factor B binding to C3b. We now demonstrate that CMT and TCT lysates, as well as molecules spontaneously shed from CMT and TCT but not Epi, accelerate decay of 125I-labeled factor Bb from the alternative-pathway C3 convertase (C3bBb) assembled on zymosan or Epi and also accelerate decay of the classical-pathway C3 convertase (C4b2a) on sheep erythrocytes. Parasites metabolically labeled with [35S]methionine spontaneously shed a limited number of radioactive components ranging in molecular mass from 86 to 155 kDa for trypomastigotes and 25 to 80 kDa for Epi. Decay-accelerating activity within supernatants is inactivated by papain and is coeluted with 35S-containing polypeptides on FPLC anion-exchange chromatography, suggesting that the active constituents are protein molecules. Molecules with decay-accelerating activity may explain the developmentally regulated resistance to complement-mediated lysis in infective and vertebrate stages of the T. cruzi life cycle.

Animals↗
PubMed1981

Inhibition of the classical and alternative pathways of human and guinea pig complement by pyran copolymer.

The ability of pyran copolymer to interact with the classical and alternative pathways of complement was assessed in human and C4-deficient guinea pig serum. Pyran induced a dose-dependent inhibition of hemolytic activity in both serum systems. Immuno-electrophoretic analysis of pyran-treated human serum revealed that C3 was not cleaved. Factor B was altered into a more anionic mobility which was not similar to biologically cleaved Ba or Bb fragments. Pyran-treated serum was unable to lyse antibody-coated erythrocytes (EA or EA coated with C1 and C4 and EA coated with C1, C4 and C2. Pretreatment of serum with ethylenediaminetetraacetic acid did not prevent inhibition of hemolytic activity by pyran. Cobra venom factor did not cleave C3 in the presence of pyran. These data indicate that pyran does not activate complement by standard mechanisms but does inhibit one or more of its components.

Animals↗
PubMed1981

Studies on the possible involvement of complement component C3 in the initiation of acid hydrolase secretion by macrophages. I. Correlation between enzyme-releasing and complement-activating capacities of several secretagogues.

A possible relationship between activation of the alternative pathway of complement and acid hydrolase secretion by macrophages has been investigated in vitro by examining the dose--response characteristics of several immunological and non-immunological stimuli of these two processes. Zymosan particles, insoluble immune complexes, methylamine and several other primary aliphatic monoamines were all found to elicit the selective release of lysosomal enzymes from macrophages by a process that correlated well with the ability of these agents to bring about consumption of haemolytically-active components of the alternative complement pathway. By contrast, substances which failed to activate the alternative complement pathway, i.e. soluble aggregated immunoglobulin and several primary aliphatic diamines, were found to be likewise incapable of inducing the selective release of lysosomal glycosidases from macrophages. These observations are interpreted as further evidence for imputing a role for complement C3 in the initiation of lysosomal enzyme release from macrophages.

Animals↗
PubMed1992

Hereditary dysfunction of the third component of complement associated with a systemic lupus erythematosus-like syndrome and meningococcal meningitis.

OBJECTIVE: We describe a dysfunction of C3 in a patient with a systemic lupus erythematosus (SLE)-like syndrome. Alternative pathway complement function was absent, but classical pathway complement function was partially intact. METHODS: We used functional, preparative, and immunochemical techniques in the study. RESULTS: The patient's C3 proved normally susceptible to trypsin proteolysis and partially resistant to classical pathway, but completely resistant to alternative pathway, convertase-dependent cleavage. CONCLUSION: The dysfunction, thus, was caused by a failure of C3 to interact with the C3 convertases, rather than by a lack of a proteinase-sensitive cleavage site in the deficient protein.

Adult↗
PubMed1983

Complement deposition in the skin of patients with herpes-associated erythema multiforme.

Granular staining for C3 by direct immunofluorescence is a frequent finding along the dermoepidermal junction and in papillary blood vessels in the early skin lesions of erythema multiforme. In order to evaluate whether the complement cascade is activated by the classical or alternative pathway, ten biopsies from patients with herpes-associated erythema multiforme, which were positive for granular C3 along the dermoepidermal junction, were stained by an immunofluorescence technic for other complement components. Staining for the components of classical pathway, C1q and C4, were found in none of the ten biopsies. However, in nine of ten biopsies, granular staining for properdin was present along the dermoepidermal junction. These findings suggest complement activation by the alternative complement pathway in herpes-associated erythema multiforme.

Biopsy↗
PubMed1991

Evolution of the complement system.

The ancestral form of the alternative pathway of complement activation probably originated as a primitive independent immune system. Subsequent evolution of an adaptive immune response drove the specialization of the classical pathway to connect antibody-mediated nonself recognition to the complement-dependent effector mechanisms. In this article Timothy Farries and John Atkinson consider how the contemporary complexity arose by a succession of credible alterations at the genetic level, and the selective advantages provided at each step.

Biological Evolution↗
PubMed1979

Effect of calcium and factor D depletion on C3 conversion by rat intestinal glycoprotein.

These studies demonstrate that a rat intestinal glycoprotein fraction may activate C3 in normal human serum by the alternative complement pathway alone and by the classical pathway alone. Conversion of C3 by the rat intestinal glycoprotein fraction amounted to 55% when both the classical and the alternative pathways were intact, to 21% when the classical pathway was blocked by ethyleneglycol-bis-(beta-aminoethyl ether)N,N'-tetraacetic acid, and to 21% in Factor-D-depleted serum. Comparable figures for zymosan were 58%, 44%, and 12%, and for sheep erythrocytes sensitized with anti-sheep haemolysin, 27%, less than 1% and 21%, respectively.

Animals↗
PubMed1982

Activation of the alternative pathway of human complement by the extracellular slime glycolipoprotein of Pseudomonas aeruginosa.

The capability of the extracellular slime glycolipoprotein (GLP) of Pseudomonas aeruginosa to activate human complement was investigated. When slime GLP was added to type AB human serum, C3 and factor B were converted to their respective major cleavage fragments, C3b and Bb. This activation also occurred when slime GLP was incubated with serum-ethylene glycol bis(trichloroacetate)-Mg++, a result which indicates that the alternative complement pathway is involved. Additional support for the hypothesis of alternative pathway activation was provided by the fact that when serum-ethylene glycol bis(trichloroacetate)-Mg++ was preheated to inactivate factor B, slime GLP did not induce conversion of C3. The activation of the alternative pathway of human complement by slime GLP may represent an early nonimmune defense against P. aeruginosa infection.

Animals↗
PubMed1994

Effect of gamma-interferon on the synthesis of the functional alternative and terminal complement pathways by human umbilical vein endothelial cells in vitro.

The cytokine gamma-interferon (gIFN) has been reported to modulate synthesis by endothelial cells (EC) of alternative pathway complement factors (H, I, and B). However, the net effect of gIFN on the synthesis and expression of the functional alternative and terminal pathways has not yet been reported. EC cultured under serum-free conditions were treated with different concentrations of gIFN and simultaneously co-incubated with agarose beads, which activate the alternative pathway. C3b and the terminal complement complex (TCC) bound to co-incubated beads were measured by radioimmunoassay using anti-human C3c and TCC antibodies. gIFN in concentrations 500-4000 U/ml increasingly reduced the amount of C3b and TCC detected on the beads. The down-regulating effect of gIFN on EC complement biosynthesis may be physiologically relevant by locally controlling complement activation.

Antibody Specificity↗
PubMed1989

Ba and Bb fragments of factor B activation: fragment production, biological activities, neoepitope expression and quantitation in clinical samples.

Factor B is a centrally important component of the alternative complement pathway. Alternative pathway activation results in factor B cleavage and production of the amino-terminal Ba and the carboxyl-terminal Bb fragments which have molecular weights of approximately 30,000 and 63,000 daltons, respectively. Both Ba and Bb fragments have been reported to express a variety of biological activities in vitro. Thus, binding of Ba and Bb fragments to specific B lymphocyte surface receptors modulates proliferation of prestimulated B cells. In addition, the enzymatically active Bb fragment induces activation and spreading of human and murine macrophages and monocytes as well as regulates C5a des Arg chemotactic activity. The fractional catabolic rate and metabolism of factor B in vivo is similar to that of C3, C4 and C5 complement proteins, which are among the most metabolically active plasma proteins in the circulatory system. Factor B hyperconsumption and increased catabolism, concomitant with factor B fragment production, occurs in a wide variety of diseases, including gram-negative sepsis, autoimmune diseases and burns. Measurement of alternative pathway activation in vivo has been attempted utilized a number of different techniques to quantitate factor B fragments in biological fluids. However, the recent development of enzyme immunoassays (EIA) employing monoclonal antibodies (MoAbs) reactive with factor B fragment neoepitopes provides the best approach currently available for the quantitation of factor B activation fragments. Results obtained using these new MoAb-based EIAs have indicated that factor B fragment concentrations were elevated, as compared with normal donor levels, in EDTA plasma samples obtained from patients with rheumatoid arthritis and systemic lupus erythematosus (SLE). Plasma concentrations of factor B fragments, especially Ba fragment levels, in these patients showed a positive correlation with disease activity scores. One of the highest disease activity correlations was obtained with Ba fragment measurements in SLE plasma samples. In fact, the results strongly suggested that quantitation of Ba fragment levels in SLE plasma samples more accurately reflected disease activity and was a more sensitive predictor of impending flare in these patients than any other test(s) currently available.

Antibodies, Monoclonal↗
PubMed1987

Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia.

A nine-year-old white boy with recurrent pneumococcal bacteremia is described. His serum had no hemolytic activity in either the classic or alternative complement pathways. Absence of classic pathway activity was secondary to a homozygous deficiency of C2. The parents had half-normal levels of C2, compatible with an autosomal recessive mode of inheritance. Measurement of serum properdin levels by radial immunodiffusion and enzyme-linked immunoabsorbent assay revealed a profound deficiency in the patient, normal levels in the father, and half-normal levels in the mother, suggesting X-linked inheritance of the deficiency. Addition of purified properdin to the patient's serum fully reconstituted the alternative pathway function. This patient's unique combination of inherited deficiencies of properdin and C2 is a likely explanation for his susceptibility to bacterial infection.

Child↗
PubMed2005

Common variable immunodeficiency and the complement system; low mannose-binding lectin levels are associated with bronchiectasis.

The importance of the innate immune system, including mannose-binding lectin and the complement system, in common variable immunodeficiency is unclear. The objective of this study was to evaluate mannose-binding lectin and the complement system in relation to clinical and immunological parameters in patients with common variable immunodeficiency. Circulating levels of mannose-binding lectin, complement components, complement activation products and functional capacity of complement pathways were correlated to clinical features within 71 patients and compared with 30 healthy controls. The main findings were; the patients had signs of increased complement activation significantly associated with signs of autoimmunity and immunological hyperactivity; there were no signs of deficiencies of the classical and alternative complement pathways in the patient group; the prevalence of lectin pathway deficiency was the same in patients and controls, but patients with increased frequency of lower respiratory tract infections or bronchiectasis had lower capacity of the lectin pathway than patients without these features (P = 0.002 and 0.004, respectively); the serum concentration of mannose-binding lectin was inversely correlated to the frequency of lower respiratory tract infections (P = 0.002) and bronchiectasis (P = 0.01). We conclude that patients with common variable immunodeficiency have no increased frequency of complement deficiencies but signs of increased complement activation. Our findings suggest that mannose-binding lectin and the lectin complement pathway may protect against lower respiratory tract infection and bronhiectasis in patients with common variable immunodeficiency.

Adult↗
PubMed1983

Species-specific inhibition by glycophorins of complement activation via the alternative pathway.

Glycophorin, one of the major glycoproteins of erythrocytes (E), was extracted from human E (glycophorin-Hu) and guinea pig E (glycophorin-GP) and adsorbed to rabbit-E. The adsorption of glycophorin-Hu and glycophorin-GP to rabbit-E made the E resistant to hemolysis by human serum and guinea pig serum, respectively, via the alternative complement pathway (ACP). However, it did not make the rabbit-E resistant to hemolysis by serum heterologous to the glycophorin adsorbed. This species-specific inhibition by glycophorin of ACP activation should play a role in restricting ACP activation on self cell membranes. By recognizing the self-cell surface as the place where the complement reaction must be prevented, ACP will be able to accomplish the discrimination of non-self constituents without diversity of recognition sites for a variety of foreign substances.

Animals↗
PubMed1992

Legionella pneumophila lipopolysaccharide activates the classical complement pathway.

Legionella pneumophila is a gram-negative bacterium capable of entering and growing in alveolar macrophages and monocytes. Complement and complement receptors are important in the uptake of L. pneumophila by human mononuclear phagocytes. The surface molecules of L. pneumophila that activate the complement system are unknown. To identify these factors, we investigated the effects of L. pneumophila lipopolysaccharide (LPS) on the classical and alternative complement pathways of normal human serum by functional hemolytic assays. Although incubation of LPS in normal human serum at 37 degrees C resulted in the activation of both pathways, complement activation proceeded primarily through the classical pathway. Activation of the classical pathway by LPS was dependent on natural antibodies of the immunoglobulin M class that were present in various quantities in sera from different normal individuals but were absent in an immunoglobulin-deficient serum obtained from an agammaglobulinemic patient. Additional studies using sheep erythrocytes coated with LPS suggested that the antibodies recognized antigenic sites in the carbohydrate portion of LPS. The ability of LPS to interact with the complement system suggests a role for LPS in the uptake of L. pneumophila by mononuclear phagocytes.

Complement C1↗