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PubMed2003

Negligible role of antibodies and C5 in pregnancy loss associated exclusively with C3-dependent mechanisms through complement alternative pathway.

Factors involved in pregnancy failure due to abnormal fetomaternal tolerance are poorly understood. Here we describe distinct defects in placenta formation and subsequent pregnancy loss solely dependent on the activation of the complement alternative pathway and the effector mechanisms provided by the maternal C3. Surprisingly, this effect is independent of other complement activation pathways and of the effector mechanisms provided by other complement components. These findings provide significant insight into the role of the innate immune system in human pregnancy failure, a frequent clinical outcome.

Abortion, Spontaneous↗
PubMed1990

Use of DBA/2N mice in models of systemic candidiasis and pulmonary and systemic aspergillosis.

Mouse models of systemic candidiasis and pulmonary and systemic aspergillosis were established by using DBA/2N mice, which are known to be deficient in the C5 component of complement. In experiments comparing lethality in the respective models in DBA/2N versus outbred CFW mice, results showed that the 50% lethal dose values for the DBA/2N mice were 10- to 1,000-fold lower than those for the outbred mice, depending on the experiment. Additionally, onset of death was somewhat delayed for the DBA/2N mice. In the case of the pulmonary aspergillosis model, administration of cortisone acetate was necessary to ensure lethality after intranasal infection, but only a single dose was necessary.

Animals↗
PubMed2003

Pre-neutralization of C5a-mediated effects by the monoclonal antibody 137-26 reacting with the C5a moiety of native C5 without preventing C5 cleavage.

Complement C5a is aetiologically linked to inflammatory tissue damage in conditions like septicaemia, immune complex diseases and ischaemia-reperfusion injury. We here describe a monoclonal antibody (mAb), 137-26, that binds to the C5a moiety of human C5 and neutralizes the effects of C5a without interfering with C5 cleavage and the subsequent formation of lytic C5b-9 complex. Mouse anti-human C5 mAbs were generated and the reactivity with C5 and C5a was detected by ELISA and surface plasmon resonance. The inhibition of C5a binding to C5a receptor was studied using a radioligand binding assay. The effects of the antibody on C5a functions were examined using isolated neutrophils and a novel human whole blood model of inflammation. Haemolytic assays were used to study the effect on complement-mediated lysis. mAb 137-26 reacted with both solid- and solution-phase C5 and C5a in a dose-dependent manner with high affinity. The antibody competed C5a binding to C5a receptor and inhibited C5a-mediated chemotaxis of neutrophils. Furthermore, the antibody effectively abrogated complement-dependent E. coli-induced CD11b up-regulation and oxidative burst in neutrophils of human whole blood. mAb 137-26 was more potent than a C5a receptor antagonist and a previously described anti-C5a antibody. mAb 137-26 did not inhibit complement-mediated lysis, nor did it activate complement itself. Together, mAb 137-26 binds both the C5a moiety of native C5 and free C5a, thereby effectively neutralizing the biological effects of C5a. The antibody may have therapeutic potential in inflammatory diseases where C5a inhibition combined with an operative lytic pathway of C5b-9 is particularly desired.

Animals↗
PubMed1984

Detection of terminal complement components in experimental immune glomerular injury.

Complement mediates glomerulonephritis by inflammatory cell-dependent and non-inflammatory cell-independent effects on glomerular permeability. The latter may involve terminal components of the complement system. We examined several models of immunologic renal injury in the rat by immunofluorescence (IF) for terminal complement components C5, C6, C7, and C8 in glomeruli using antisera to human C5-8, which cross-react with the analogous rat complement components. Rats with the heterologous and autologous phases of passive Heymann nephritis (PHN) had proteinuria and 1 to 2+ capillary wall deposits of heterologous or rat IgG, rat C3, and C5-8. Complement depletion with cobra venom factor (CVF) significantly decreased proteinuria in both models and prevented deposition of all complement components. Rats with active Heymann nephritis had similar deposits of rat IgG and C5-8. Rats with anti-GBM nephritis and aminonucleoside nephrosis had severe proteinuria which was not affected by CVF treatment and deposits of C5-8 were absent. The presence of terminal complement components in immune deposits in experimental glomerular disease correlates with a functional role for complement in mediating glomerular injury. These data support the hypothesis that the terminal complement pathway may be a major mediator of some types of immune glomerular injury.

Animals↗
PubMed1980

Role of complement activation in a model of adult respiratory distress syndrome.

The adult respiratory distress syndrome is characterized by arterial hypoxemia as a result of increased alveolar capillary permeability to serum proteins in the setting of normal capillary hydrostatic pressures. Because bacterial sepsis is prominent among the various diverse conditions associated with altered alveolar capillary permeability, we studied the effect of bacteremia with attendant complement activation on the sequestration of microorganisms and the leakage of albumin in the lungs of guinea pigs. Pneumococci were injected intravenously into guinea pigs and their localization was studied. Unlike normal guinea pigs, complement-depleted guinea pigs did not localize injected bacteria to the lungs. Preopsonization of organisms did not correct this defect in pulmonary localization of bacteria in complement-depleted animals, suggesting that a fluid-phase component of complement activation was required. Genetically C5-deficient mice showed no pulmonary localization of bacteria. C5-sufficient mice demonstrated the usual pulmonary localization, thus further suggesting that the activation of C5 might be important in this localization. The infusion of activated C5 increased alveolar capillary permeability to serum proteins as assayed by the amount of radioactive albumin sequestered in the lung. Neutropenic animals did not develop altered capillary permeability after challenge with activated C5. Thus, complement activation through C5, in the presence of neutrophils, induces alterations in pulmonary alveolar capillary permeability and causes localization of bacteria to the pulmonary parenchyma. Complement activation in other disease states could potentially result in similar clinical manifestations.

Capillary Permeability↗
PubMed1980

Genetic control of susceptibility to Cryptococcus neoformans in mice.

Inbred mice injected intravenously with 5 x 10(6) cells of Cryptococcus neoformans showed two patterns of survival: sensitive (A/WySn, A.BY, A/J, DBA/2J, NZB/B1NJ, and SWR/J) and resistant [C57BL/10Sn, B10.A, B10.A (2R), B10.S (7R),C57BR/cdJ, C58/J, C3H/HeJ, BALB/c, DBA/1J, and SJL/J]. Relative susceptibility based on survival time was shown to correspond to differences obtained for 50% lethal dose values. Either decreasing the dose of organisms or changing to the intraperitoneal route of inoculation resulted in prolonged survival times, but neither change affected the observed patterns of survival. F1 hybrids between different sensitive strains were also sensitive, whereas F1 hybrids between sensitive and resistant strains were resistant, indicating a dominant mode of inheritance. Sensitivity and resistance were shown to be under single gene control by segregation analysis in F2 progeny produced by inbreeding (B10.A x A/WySn)F1 hybrids and in (F1 x A/WySn) backcross progeny. Blood obtained from parental strains, F1, F2, and backcross hybrids was tested for the presence or absence of hemolytic complement. Mice lacking hemolytic complement activity in their sera are homozygous for the Hc(0) allele at the Hc locus on chromosome 2 and are deficient in the complement component C5. A 1:1 correspondence was found between C5 deficiency and sensitivity to C. neoformans. Resistance was shown to cosegregate with the presence of hemolytic complement in the F2 and the backcross progenies.

Animals↗
PubMed1996

Complement proteins are present in developing endochondral bone and may mediate cartilage cell death and vascularization.

Normal endochondral bone formation follows a temporal sequence: immature or resting chondrocytes move away from the resting zone, proliferate, flatten, become arranged into columns, and finally become hypertrophic, disintegrate, and are replaced by bone. The mechanisms that guide this process are incompletely understood, but they include programmed cell death, a stage important in development and some disease processes. Using immunofluorescence we have studied the distribution of various complement proteins to examine the hypothesis that this sequence of events, particularly cell disintegration and matrix dissolution, are complement mediated. The results of these studies show that complement proteins C3 and Factor B are distributed uniformly in the resting and proliferating zones. Properdin is localized in the resting and hypertrophic zone but not in the proliferating zone. Complement proteins C5 and C9 are localized exclusively in the hypertrophic zones. This anatomically segregated pattern of distribution suggests that complement proteins may be important in cartilage-bone transformation and that the alternate pathway is involved.

Animals↗
PubMed1981

Delayed hypersensitivity reactions to Listeria monocytogenes in rats decomplemented with cobra factor and in C5-deficient mice.

The in vivo effect of cobra factor (CoF), the complement-activating protein of cobra (Naja naja) venom, was investigated, using quantifiable assays for localization of labelled donor lymphoblasts and of host macrophages in intraperitoneal and subcutaneous sites of injection of antigens from Listeria monocytogenes. Both commercially available (Cordis) and highly purified CoF impaired these inflammatory responses, suggesting that the complement-activating protein was itself responsible rather than lymphocytotoxic or other contaminants. CoF had no measurable effect on lymphoblast localization during the first 7 hr, and only a slight effect at 24 hr, whereas macrophage accumulation was reduced by about 50% at 24 hr. This suggests that CoF treatment affected non-specific components of the early inflammatory reaction but had little or no effect on the subsequent immunospecific reaction. The effect of CoF on macrophages may be direct, or via depletion of complement components acting on macrophages, such as factor B and/or C3 or fragments thereof. It does not seem to involve the terminal complement components, C5--C9, since neither delayed-type hypersensitivity (DTH) nor cellular resistance to Listeria was reduced in C5-deficient mice when compared with C5-sufficient congenic controls.

Animals↗
PubMed1977

Enhancement of C56-initiated lysis by cell-bound C3 fragments: evidence for a mechanism independent of the prior binding of C56 to C3b.

Cell-bound C3b can reversibly bind C56, the activated complex of the fifth (C5) and sixth (C6) components of complement, and in this way potentiate C56-initiated lysis by favoring the formation of C567 at the cell surface. We report here another way in which cell-bound C3 fragments can enhance C56-initiated lysis, which involves C567 generated in the fluid phase rather than at the cell surface. Evidence for the involvement of fluid phase C567 was obtained by use of dextran sulfate, which is known to inhibit the hemolysis of E mediated by fluid phase C567. Dextran sulfate strongly inhibited the formation of C567 sites on cells bearing C4b and C3b (EAC4b3b) as well as on unmodified E when C56 and C7 were added simultaneously to the cells. By contrast, dextran sulfate had virtually no effect on the reaction sequence involving the prior binding of C56 to C3b and subsequent formation of C567 at the cell surface. Treatment of EAC4b3b with either anti-C3 Fab' fragments or the C3b inactivator reduced but did not eliminate the enhancement of hemolysis, raising the possibilities that a C3 fragment(s) other than C3b also can enhance C56-initiated lysis and/or that the enhancement is indirect without a requirement for an interaction between C567 and the cell-bound C3 fragment itself.

Complement C3↗
PubMed1976

Complement-mediated release of histamine from human basophils. II. Biochemical characterization of the reaction.

Release of histamine from human basophils was induced by activation of complement using zymosan. The histamine-releasing factor resembled C5a on the basis of m.w. (15,000) as well as previous studies showing inactivation by anti-C5. Complement-induced release of histamine was compared with allergic release of histamine which is mediated through appropriate allergens and reaginic IgE. Previously we demonstrated that the former reaction occurred more quickly. Both reactions were inhibited by drugs which increase intracellular concentrations of cAMP3 (theophylline, prostaglandin E1, and histamine) or which mimic the action of cAMP (its dibutyrly derivative). Calcium was required for complement-mediated release of histamine and an increasing response was observed up to physiologic concentrations (2 mM). Magnesium (0 to 1 mM) did not affect the amount of histamine released. Also, glycolysis was probably required for optimal release by complement, since both 2-deoxyglucose and iodoacetamide were inhibitory. When basophils were partly enriched by depletion of neutrophils and eosinophils, the percentage of histamine released by complement was unchanged. Finally, it was shown that activated complement desensitized basophils from responding to a second challenge by the same stimulus. Cross-desensitization was not observed between complement and pollen allergens.

Basophils↗
PubMedDate not supplied

The role of complement in anti-bacterial defence.

The complement system consists of several proteins present in human serum interacting among themselves and with the other compounds of the immune system in the host defence process. In particular, late complement component (C5, C6, C7, and C8) deficiencies (LCCD) are closely associated with Neisseria, mainly meningitidis, infections. The aim of our study was to verify this association in an Italian population by analyzing the complement profile in survivors of meningococcal meningitis. Ten out of the 59 (17%) subjects studied had homozygous LCCD (6 C8, 3 C7 and 1 C6). The meningococcal C strain was the most widely diffused (68%) and had infected all homozygous LCCD subjects. In addition meningococcal serogroup C seemed to be the least immunogenic when compared to serogroups A and B. These data confirm the close association between homozygous LCCD and meningococcal infections from common serogroups (A, B and C) in the Italian population. Anti-meningococcal vaccination is usually recommended for LCCD subjects because it increases, both quantitatively and qualitatively, the antibody component of anti-meningococcal immune defence. We therefore analyzed the levels of anti-polysaccharide (PS) A and PSC antibodies in the members of 4 families including normal subjects and subjects with homozygous and heterozygous C7, C8 or factor H defects, before and after vaccination with only PSA+C. Surprisingly, we found the highest levels of antibodies before vaccination in homozygous subjects, followed by heterozygous and normal controls, whereas, after vaccination, homozygous subjects showed the lowest increase of specific antibodies, indicating their relative incapacity to respond to meningococcal PS alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

C5 convertase of the alternative complement pathway: covalent linkage between two C3b molecules within the trimolecular complex enzyme.

C5 convertase of the alternative C pathway is a complex enzyme consisting of three C fragments--one molecule of a major fragment of factor B (Bb) and two molecules of a major fragment of C3 (C3b). Within this C3bBbC3b complex, the first C3b binds covalently to the target surface, and Bb, which bears a catalytic site, binds noncovalently to the first C3b. In the present investigation, we studied the nature of the convertase that is assembled on E surfaces and obtained evidence that the second C3b binds directly to the alpha'-chain of the first through an ester bond rather than to the target surface. Thus, the alternative pathway C5 convertase could be described as a trimolecular complex in which Bb binds noncovalently to a covalently linked C3b dimer. We also obtained evidence that not only the second C3b but also the first C3b participates in binding C5, that is, covalently-linked C3b dimer acts as a substrate-binding site. Because of this two-site binding, the convertase has a much higher affinity for C5 than the surrounding monomeric C3b molecules. Based on this evidence, a new model of the alternative pathway C5 convertase is proposed. Covalent association of two subunits and the bivalent binding of the substrate are then common properties of the alternative and classical pathway C5 convertases.

Animals↗
PubMed1976

Abnormalities of complement and its components in patients with acute leukemia, Hodgkin's disease, and sarcoma.

Whole complement and component titers were measured in patients with acute leukemia, Hodgkin's disease, and sarcoma. Serum samples were obtained from 42 consecutive patients and 11 healthy control subjects. Sera were frozen and maintained at -70 degrees until analyzed by hemolytic assay. Titers were normalized using a titer obtained from a single source of pooled human serum analyzed simultaneously with each patient sample to correct for day-to-day variation inherent in the assay technique. Significant elevations (p less than or equal to 0.05) of whole complement and C5, C8, and C9 were observed for each patient category, compared to controls. Forty-one of 42 patients had C9 titers greater than or equal to 2 S.D. above the mean titer for controls. Mean C3 and C7 titers were not elevated or depressed in any group. No clinical factors that correlated with abnormal complement or component titers were identified.

Adolescent↗
PubMed2003

Effects of membrane attack complex of complement on apoptosis in experimental autoimmune encephalomyelitis.

Complement activation is involved in the initiation of inflammation and antibody-mediated demyelination in experimental autoimmune encephalomyelitis (EAE). We investigated the role of MAC in apoptosis in myelin-induced EAE in complement C5-deficient (C5-d) and C5-sufficient (C5-s) mice. The number of apoptotic cells assessed by TUNEL assay was significantly increased in C5-d mice during clinical recovery as compared with C5-s mice. Most of the apoptotic cells were lymphocytes, monocytes, and oligodendrocytes. DNA microarray was performed using total RNA extracted from spinal cords. Genes expressed higher in C5-s included members of the caspase (caspase 6, 7), TNF and TNFR families (CD27, FasL, lymphotoxin-beta R) and survivin. These results indicate that C5 and possibly MAC may be required for the limitation of inflammatory response within the central nervous system.

Animals↗
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↗
PubMed2003

Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab's. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab's. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab's or peptides that block C5a-C5a receptor interactions prevent pregnancy complications. The fact that F(ab)'2 fragments of aPL Ab's do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B-deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating Fc gamma Rs do not play an important role in mediating aPL Ab-induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.

Abortion, Spontaneous↗