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PubMed1987

Antibody-independent activation of C1. II. Evidence for two classes of nonimmune activators of the classical pathway of complement.

Nonimmune activation of the first component of complement (C1) by cardiolipin (CL) vesicles present specific features which were not demonstrated on immune complexes. CL vesicles which activate C1 in the presence of C1-inhibitor (C1-INH) were found to bind C1s in the absence of C1r, and to induce a specific C1r-independent cleavage of C1q-bound C1s. Therefore, several known natural nonimmune activators were analyzed by comparing their ability to activate C1 in the presence of C1-INH and to mediate a C1r-independent cleavage of C1s. Freshly isolated human heart mitochondria (HHM) activated C1 only in the absence of C1-INH. However, mitoplasts derived from HHM (HHMP) activated C1 regardless of the presence of C1-INH, and induced a specific cleavage of C1q-bound C1s. The same pattern was observed in the case of smooth E. coli and a semi-rough E. coli strain. DNA, known to activate C1 only in the absence of C1-INH, does not induce C1s cleavage in the absence of C1r. Thus, nonimmune activators can be classified into two distinct categories. "Strong" activators, such as CL vesicles, HHMP, or the semi-rough E. coli strain J5 can activate C1 in the presence of C1-INH. By using C1qs2 as a probe, they exhibit a specific, C1r-independent cleavage of C1s. C1s-binding to C1q is a critical factor for the activation process in this group. In the case of "weak" activators, such as E. coli smooth strains, DNA, or HHM, no C1s-binding to activator-bound C1q was detected, and C1r-independent C1s cleavage and C1 activation in the presence of C1-INH were not observed. As in the case of immune complexes, C1r activation appears to play a key role in the C1 activation by "weak" activators.

Calcium↗
PubMed1979

Activation of the classical pathway of complement by the C3NeF-stabilized cell-bound amplification convertase.

C3 nephritic factor (C3NeF) has been shown to be composed of two heavy and two light chains, like IgG; in addition it shares antigenic determinants with IgG. C3NeF, purified from the sera of eight patients by incorporation of C3NeF into the stabilized fluid phase amplification C3 convertase, C3bBb(C3NeF), followed by its release after decay of convertase function, was investigated for its ability to bind 125I-C1q and to activate 125I-C1. It was found that although fluid phase C3b,Bb(C3NeF) is fully capable of binding 125I-C1q, it is not able to activate 125I-C1 even at concentrations of 1.3 x 10(12) C3bBb(C3NeF) complexs/ml. On the other hand, cell-bound C3bBb(C3NeF) is capable of both binding 125I-C1q and activating 125I-C1. This discrepancy between fluid phase and cell-bound, C3bBb(C3NeF) was found for C3NeF preparations from eight different patients and therefore seems to apply to all C3NeF preparations.

Binding Sites↗
PubMed1980

Alternate and classical pathway components of complement in the normal cornea.

Activation of complement by either the classical or alternate pathway may be involved in corneal inflammation. This study was undertaken to determine whether the normal human cornea contains components for both classical and alternate pathway activation of complement. Direct immunofluorescence of corneas from human donors using fluorescein-labeled antiserums was used to demonstrate C1q, C3, C4, and C5. The C1q component (the recognition unit of the classical pathway and largest complement component) was found in the periphery of the cornea. Normal donor corneas were also eluted in phosphate-buffered saline at 4 degrees C for one to four days. Ouchterlony plates, in which the corneal eluate was reacted against antiserums to complement components, disclosed the presence of C1q, C3, C4, C5, properdin, and properdin factor B. Plasminogen was also found. Radial immunodiffusion was used to obtain estimates of the concentrations of C3, C4, and C5 in the cornea.

Aged↗
PubMed1984

Activity of classical and alternative pathways of complement in preterm and small for gestational age infants.

Complement activity was compared in 50 low birth weight infants divided into appropriate and small for gestational age groups; the influence of birth weight and gestational age on complement development was also investigated. CH50 and kinetics (tH50) of both classical and alternative pathway activity of complement, C3, and Factor B levels were significantly higher in small for gestational age infants (classical pathway CH50, 630 HU/ml +/- 184 SD; CP tH50, 77 min +/- 47; aternative pathway CH50, 44.8 HU/ml +/- 11.3; AP tH50, 56 min +/- 43; C3, 73.98 mg/dl +/- 12.68; and Factor B, 13.17 mg/dl +/- 3.67) than in weight-matched appropriate for gestational age infants (CP CH50, 523 HU/ml +/- 152; CP tH50, 105 min +/- 49; AP CH50, 38.8 HU/ml +/- 13; AP tH50, 90 min +/- 53; C3, 58.14 mg/dl +/- 9.43; and Factor B, 9.32 mg/dl +/- 1.73). Complement values were lower in low birth weight infants than in adult controls (P less than 0.001 in all cases). All complement parameters were mainly correlated with gestational age; CH50 values of the classical and alternative pathways were also highly correlated with each other (r = 0.64; P less than 0.001). Low birth weight infants, especially preterm infants, have an important defect of complement activity. Complement factors increase gradually during gestation and intrauterine growth retardation does not affect complement development. Classical and alternative complement pathway activities have a similar development pattern.

Complement Activation↗
PubMed1987

Role of the fourth complement component (C4) in the regulation of contact sensitivity. I. Analysis in mice with high and low C4 levels.

Lymph node cells collected from CBA/J mice 4 days after painting the skin with picryl chloride are able to immunize naive recipients by hapten-IgM immuno complexes. These cells ("4-day" cells) activate the early components of the classical pathway of complement from mice of the H-2 Sd haplotype (high-C4), but fail to activate the classical pathway of complement from mice of the H-2 Sk haplotype (low-C4). Incubation of "4-day" cells in complement from mice with high-C4 levels abolishes the induction of contact sensitivity, probably as a consequence of the solubilization of membrane-bound immuno complexes caused by complement activation. The presence of "4-day" cells is determined by the levels of C4. In fact, using strains of mice which differ only at the S region of the H-2 complex, we found that mice of the H-2 Sd (and perhaps H-2 Sb) haplotype (high-C4 levels) lack "4-day" cells in their lymph nodes and this is due to the activation of the early components of the classical complement pathway which occurs in vivo in these mice during sensitization with picryl chloride. The finding that contact sensitivity reaction to picryl chloride in H-2 Sk mice lasts about 21 days, whereas H-2 Sd mice show a contact sensitivity reaction until 7 days after sensitization, strongly suggests that the S region, and in particular C4 levels, controls the persistence of "4-day" immunogenic cells, and so play a role in the duration of the contact sensitivity reaction to picryl chloride in the mouse.

Animals↗
PubMed1982

Immunological aspects of adverse reactions to althesin.

Sequential plasma samples from 30 patients showing clinical signs of hypersensitivity to Althesin were investigated to determine if a specific immune response to the drug was present (as measured by classical complement pathway activation) or if a non-antibody-dependent alternative complement pathway activation was taking place. The patients were classified as those reacting on first exposure to Althesin and those who reacted adversely only on a second exposure. The alternative complement pathway, but not the classical pathway, was activated in five of the 13 first-time reactors, while in the remaining eight no complement activation was detected. In contrast, classical complement pathway activation was demonstrated in the blood samples of all 17 patients reacting on repeat exposure. Severe reactions occurred in nine of the 17 previously exposed patients compared with only one of the 13 reacting on first exposure to Althesin.

Adolescent↗
PubMedDate not supplied

Immunomodulatory activity of three Sri-Lankan medicinal plants used in hepatic disorders.

The effects of aqueous extracts of Osbeckia octandra whole plant, Melothria maderaspatana whole plant and Phyllanthus debelis leaves on the human immune system were investigated. The extracts showed strong anticomplement effects on both the classical and alternate pathways of the human complement system in vitro. The effects were dose-dependent and most pronounced in the classical complement pathway assay. The extracts also exhibited a direct dose-dependent inhibition of luminol-induced chemiluminescence of human polymorphonuclear leukocytes upon stimulation with zymosan.

Adjuvants, Immunologic↗
PubMed1973

Interactions of the classical and alternate complement pathway with endotoxin lipopolysaccharide. Effect on platelets and blood coagulation.

The contributions of the classical and alternate pathways of complement activation to the biological effects of endotoxin have been examined in the guinea pig, with particular reference to thrombocytopenia, leukopenia, and the development of the hypercoagulable state. Injection of endotoxin into normal guinea pigs led to a 95% fall in the level of circulating platelets within 15 min as well as a fall in circulating granulocytes. C4-deficient guinea pigs, known to have a complete block in the activity of the classical complement pathway, but with the alternate pathway intact, sustained no fall in platelets. The development of granulocytopenia proceeded normally. Endotoxin did activate the alternate complement pathway in C4D guinea pigs, as evidenced by the fall in C3-9 titers. With restoration of serum C4 levels, endotoxin-induced thrombocytopenia was observed in C4D animals. Thus, function of the classical complement pathway was an absolute requirement for the development of thrombocytopenia. Experiments performed in cobra venom factor (CVF)-treated normal guinea pigs, with normal levels of C1, C4, and C2, but with less than 1% of serum C3-9 demonstrated the importance of the late components in the development of thrombocytopenia but not leukopenia.C4-deficient guinea pigs had normal clotting times demonstrating that C4 was not required for normal clotting. In addition, development of the hypercoagulable state, evidenced by a marked shortening of the clotting time, was not observed on injection of endotoxin into C4D animals. Therefore, development of the hypercoagulable state paralleled the development of thrombocytopenia and required function of the classical complement pathway. Again, the importance of the late components of complement was emphasized by the failure of CVF-treated normal animals to develop hypercoagulability. These results demonstrate that endotoxin is capable of activating both the classical and alternate complement pathways in guinea pigs but that function of the classical pathway is an absolute requirement for the development of thrombocytopenia and the hypercoagulable state.

Animals↗
PubMed1983

Interaction of desialated guinea pig erythrocytes with the classical and alternative pathways of guinea pig complement in vivo and in vitro.

We examined the fate of desialated autologous erythrocytes injected intravenously into guinea pigs (GP). Desialated GP erythrocytes (E) were lysed directly or cleared by the reticuloendothelial system in normal GP (NIH-GP) and cleared by the reticuloendothelial system in GP genetically deficient in the classical complement pathway component C4 (C4D-GP), which activate complement only via the alternative pathway. Desialated E were also cleared in cobra venom factor-treated GP (CVF-GP), which had less than 1% of normal C3 levels, but were not cleared at all in C4D-CVF-GP. Preinjection of asialoorosomucoid (ASOR) and ovalbumin (OVA) had no effect on the rate of E clearance. These in vivo studies indicated that complement activation is essential for clearance of desialated E and that clearance is unaffected by blockade of galactose or mannose receptors. Inhibition of complement-mediated clearance required blockade of both classical and alternative complement pathways. In vitro studies showed that lysis of desialated E could occur in NIH-GP serum (GPS) but not in C4D-GPS. Surprisingly, CVF-GPS also caused lysis of desialated E. Lysis was dependent on both natural antibody to desialated E and classical pathway activation; natural antibody was of both the IgG and IgM classes. C3 uptake studies demonstrated that almost 10 times as many C3 molecules/E were deposited by NIH-GPS as by C4D-GPS or CVF-GPS onto desialated E. Approximately equal numbers of C3 molecules were deposited by CVF-GPS, which did lyse desialated E, and by C4D-GPS, which did not. We suggest that the molecular mechanism of in vivo clearance and in vitro lysis of desialated E by CVF-GP is via classical pathway deposition of C3b into sites on the erythrocyte surface protected from inactivation by H (beta 1H) and I (C4b/3b inactivator). Deposition of C3b into these sites by alternative pathway activation is sufficient to cause clearance but not lysis of desialated E. CVF-GPS may not represent an adequate reagent for testing the complement dependence of various biologic phenomena, particularly if the question involves surfaces that can provide protected sites for C3b molecules.

Animals↗
PubMed1987

The classical and alternate pathways of complement in oral contraceptive users.

Whole complement (CH50), C3, C4, the alternate pathway activity of complement (APH50) and factor B were measured in 159 women currently taking oral contraceptives and in 186 women who were not taking the pill. The mean levels of all components of the complement, except APH50, were found to be elevated in current users compared to non-users. The elevation in serum levels was seen in the first year after initiation of oral contraceptive use. Thereafter, levels changed little with duration of use. Among women who stopped using oral contraceptives, complement levels were similar to those of women who had never used the pill. Results appeared to be similar irrespective of the type of progestagen included in the oral contraceptive. These data provide support for the view that oral contraceptives have no adverse effect on the classical and the alternate pathways of complement.

Adolescent↗
PubMedDate not supplied

Complement pathway activity in serum from patients with classical dengue fever.

Complement activity in 125 cases of classical dengue fever was examined through the measurement of haemolytic activity. During the first 3 d of fever, the classical complement pathway activity (CCPA) was not altered in 109 cases. After 4 d of fever, 9 of 16 patients in the viraemic period had CCPA decreased by 45% (995 +/- 119 units/ml) and serum complement component C4 decreased by 40% (10.4 +/- 0.9 mg/dl). The alternative complement pathway activity was not affected in any case tested throughout both viraemic and convalescent stages. Both CCPA and C4 persistently decreased in 3 of these 9 patients at the convalescent stage. A decrease in serum C3 was also observed in these 3 patients only, and circulating immune complexes (CIC) levels were particularly high in these 3 patients. These results indicate that there is little evidence of complement activation on days 1-3 of viraemia but that complement activation may occur subsequently. It is concluded that both CIC and other unknown factors not related to CIC may contribute to complement activation in some cases (9/125) of classical dengue fever.

Adult↗
PubMed1979

Classical and alternate complement pathway activities in paired dairy cow--newborn calf sera.

Hemolytic assays were used to compare alternate and classical C pathway activities in sera obtained from clinically normal newborn dairy calves and their mothers at the time of delivery. Mean alternate and classical CH50 concentrations in sera from newborn calves were both significantly lower than in their dams (P less than 0.001). The titer of alternate C pathway activity, expressed as CH50 units/ml, in sera from 17 calves was 12.9 +/- 5.5, whereas for the cows it was 25.8 +/- 6.2. The ratio of cow: calf serum alternate CH50 titers averaged 2.25 +/- 0.80 and ranged from 0.88 to 4.14. Classical CH50 titers were 78.0 +/- 42.7 units/ml in calf sera and 246.0 +/- 44.5 in cow sera. The ratio of cow: calf serum classical CH50 titers averaged 3.71 +/- 1.49 and ranged from 1.19 to 6.87. The wide range of values, noted for both the alternate and classical C pathways, within maternal and neonatal groups was assumed to reflect the biologic variability of complement levels in bovine serum. The possible relationships between deficient levels of alternate and classical CH50 activity in newborn calves and their susceptibility to infections is discussed.

Animals↗
PubMed1985

Relation between serum opsonic activity for Streptococcus pneumoniae and complement function in sickle cell disease.

Opsonic activity for Streptococcus pneumoniae mediated by the alternative and classic complement pathways and concomitant binding of activated C3 to the bacteria were measured in sera from children with sickle cell disease and normal siblings of similar age. Uptake of radiolabeled serotypes 7F, 10A, 15B, and 24F by normal human polymorphonuclear leukocytes and intracellular killing were the parameters used to assess opsonization. C3 fixation was quantitated by radioimmunoassay under conditions identical to those used for opsonic measurements. Both classic and alternative pathway-mediated opsonic activities were significantly reduced in a subset of patients. These alterations were associated with reduction in C3 fixation by way of the classic pathway and normal C3 fixation by way of the alternative pathway. The data implicate auxiliary serum factors rather than an intrinsic defect in the complement system in the opsonic alterations. Retrospective data were suggestive of an increased incidence of pneumococcal bacteremia occurring in association with reduction in opsonic activity.

Adolescent↗
PubMed1978

Possible mechanisms of the first step of the classical complement activation pathway: binding and activation of C1.

Different immunoglobulin preparations of human monoclonal IgM, normal human and rat IgG, as well as purified rabbit antibodies were treated by various methods, fragmentation, aggregation and complexing with antigen. The ability of the treated and untreated preparations to fix isolated human C1, to activate the classical complement pathway (to consume C4 in normal human serum) were compared. It was found that the different methods affected the conformation of the immunoglobulin molecules in different ways and induced changes to a greater or lesser extent in the two capacities of the preparations tested. In the case of the monoclonal IgM preparation a strong C1-fixation was observed without measurable complement activation. Other preparations, interfacially aggregated human IgG, BSA-anti-BSA and OA-anti-OA immune complexes had a very weak C1-fixing but a marked complement activating capacity. Some preparations, e.g. heat-aggregated IgG, both fixed and activated C1 effectively, aggregates with a complement-activating capacity without C1-fixing effect were separated by gel-filtration. It was demonstrated further, that at a given time only a part of the activated C1 molecules could be found fixed to the immunoglobulins, the other part was released into the fluid phase after activation. On the basis of the results of this and previous studies a hypothesis is proposed suggesting three possible results of the interaction between C1 and the different preparations: (1) firm fixation and activation; (2) binding not followed by activation and (3) a transient binding leading to activation. The possible application of this hypothesis for the interpretation of the results of the different methods for detecting immune complexes is discussed.

Angioedema↗
PubMed1979

Deficient alternative complement pathway activity in newborn sera.

Neonatal susceptibility to overwhelming bacterial infection is commonly attributed to a relative deficiency in serum opsonic activity. However, few studies have compared the functional capacity of the classical complement pathway with that of the alternative complement pathway in the neonate. The opsonic activity of nine maternal infant serum pairs were studied by determining percent uptake of radiolabeled Escherichia coli. Seven mother-infant paired sera were studied using E. coli strains known to be opsonized via the alternative complement pathway: the mean percent uptake of E. coli opsonized in neonatal sera was 16.8%; of those opsonized in maternal sera, 54%; and of those opsonized in control sera, 45% (P less than 0.005). Two E. coli strains requiring the classical complement pathway for opsonization were phagocytized equally well in maternal and infant sera of seven mother-infant pairs. Determination of anti-O hemagglutination inhibition (HI) antibody titers in six maternal sera for one classical complement pathway activating and one alternative complement pathway strain showed no correlation between percent phagocytosis and HI antibody titer. These data would suggest that serum levels of classical pathway components are probably adequate for opsonization of E. coli via the classical pathway, but that low alternative complement pathway activity in neonatal sera may contribute to the newborn's increased susceptibility to bacterial sepsis.

Complement Activation↗
PubMed1988

Interactions of a nonneutralizing IgM antibody and complement in parainfluenza virus neutralization.

While many viruses activate the complement cascade directly, this is generally not a neutralizing event in the absence of antibody. We used a nonneutralizing IgM monoclonal antibody to parainfluenza virus type 3 (PIV3) hemagglutinin-neuraminidase (HN) to explore the role of antibody in complement-dependent neutralization of PIV3. Neither the antibody nor nonimmune guinea pig serum (GPS) neutralized PIV3 significantly, but a more than 100-fold reduction in titer was found when antibody and GPS were combined. Heat-inactivated GPS or GPS lacking either of two different complement proteins were all inactive with or without antibody. Specific repletion of the deficient sera with highly purified complement proteins restored neutralizing activity, indicating an absolute requirement for the classical pathway of complement activation and lytic terminal complement components, and viral lysis was confirmed by electron microscopy. The presence of antibody before complement activation was essential; later addition had no effect. Spontaneous complement activation by PIV3 occurred via the classical pathway in the absence of antibody. Addition of antibody did not alter the overall rate or extent of complement component C3 binding to PIV3 in these experiments. We conclude that certain nonneutralizing antibodies may support complement-dependent PIV3 neutralization by facilitating viral lysis. This process does not, however, involve enhanced activation through the C3 step. Lysis may require antibody-dependent localization of the membrane attack complex or reorganization of the viral envelope structures to facilitate attack complex insertion and lysis.

Antibodies, Monoclonal↗