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Results for “Complement Pathway, Classical”

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PubMed1980

The critical role of complement in experimental pneumococcal sepsis.

Using a guinea pig model fo bacteremia due to Streptococcus pneumoniae serotype 7, opsonization by the classical and alternative pathways of complement activation was studied in immune and nonimmune animals. Depletion of the alternative complement pathway and complement components C3-C9 resulted in a significant, lethal defect of intravascular clearance in both normal and immune animals. Preopsonization corrected the initial clearance defect in complement-depleted animals. Maximal rates of clearance of bacteremia occurred in immune, normal animals, Immune, C4-deficient animals had clearance curves similar to normal, nonimmune animals. Thus, optimal clearance of pneumococcal bacteremia requires an intact alternative an classical pathway of complement activation. In the nonimmune animal, the alternative pathway provides the primary host defense against infection, whereas after immunization, optimal clearance of bacteremia requires an intact classical pathway of complement activation. However, immunization does not alter the lethal clearance defect in complement-depleted animals.

Animals↗

PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗

PubMed1997

Effect of whole and fractionated intravenous immunoglobulin on complement in vitro.

Intravenous immunoglobulins (IVIG) are increasingly used for treatment of inflammatory diseases, and the modulation of complement may contribute to some of its beneficial effects. IVIG may bind C1q and activated C3 and C4, and enhance inactivation of C3b. We have previously shown that IVIG inhibited complement-mediated lysis solely via its Fc part through interaction with the classical pathway. In the present study we have investigated whole IVIG (Octagam, and Sandoglobulin) and the monomer, dimer and multimer fractions of Octagam with respect to complement activation in serum and inhibition of complement lysis of red cells. The isolated fractions were found to be stable, homogeneous (monomer, dimer or multimer) and pure (virtually only IgG). Both whole IVIG and its fractions significantly activated complement in serum and inhibited hemolysis compared with human albumin. These effects were most pronounced in the monomer, less in the multimer and least in the dimer fraction. The complement activation was shown to be mediated through the classical pathway since formation of C1rs-C1inh complexes and C4bc were increased, in contrast to Bb. Surprisingly, heat aggregation of Octagam was not followed by a corresponding increase in complement activation, as would be expected, unless it was dialysed before heating, suggesting that it is stabilized to avoid excess activation. In conclusion, the results support the hypothesis that IVIG causes a mild activation of complement in vitro. We suggest that this effect may contribute to the complement inhibitory properties of IVIG by diverting complement deposition from the target to the fluid phase.

Animals↗

PubMed2002

Complement interaction with trypanosomatid promastigotes in normal human serum.

In normal human serum (NHS), axenic promastigotes of Crithidia, Phytomonas, and Leishmania trigger complement activation, and from 1.2 to 1.8 x 10(5) C3 molecules are deposited per promastigote within 2.5 min. In Leishmania, promastigote C3 binding capacity remains constant during in vitro metacyclogenesis. C3 deposition on promastigotes activated through the classical complement pathway reaches a 50% maximum after similar50 s, and represents >85% of total C3 bound. In C1q- and C2-deficient human sera, promastigotes cannot activate the classical pathway (CP) unless purified C1q or C2 factors, respectively, are supplemented, demonstrating a requirement for CP factor in promastigote C3 opsonization. NHS depleted of natural anti-Leishmania antibodies cannot trigger promastigote CP activation, but IgM addition restores C3 binding. Furthermore, Leishmania binds natural antibodies in ethylenediaminetetracetic acid (EDTA)-treated NHS; after EDTA removal, promastigote-bound IgM triggers C3 deposition in natural antibody-depleted NHS. Serum collectins and pentraxins thus do not participate significantly in NHS promastigote C3 opsonization. Real-time kinetic analysis of promastigote CP-mediated lysis indicates that between 85--95% of parasites are killed within 2.5 min of serum contact. These data indicate that successful Leishmania infection in man must immediately follow promastigote transmission, and that Leishmania evasion strategies are shaped by the selective pressure exerted by complement.

Animals↗

PubMed1985

The modulation of immune complex aggregation by classical pathway-mediated reactions.

Classical pathway (CP)-triggered reactions of complement-modulated immune complex (IC) aggregation (tetanus toxoid/human anti-tetanus toxoid-IgG; ICs of equivalence) were investigated turbidimetrically during the early stages of reaction. Monospecific Fab'- or Fab-fragments (rabbit) directed against certain complement components were used to block the complement function in normal human serum (NHS). Additionally, parts of the reactions were studied using purified complement components. C1q in serum generated by the addition of EDTA as well as purified C1q were found to increase the IC aggregation. In contrast to C1q, macromolecular C1 is able to inhibit IC aggregation, whereas additional participation of C-1 INH reversed this process. The cooperation of the remaining CP proteins (C4, C2, C4bp, and I) reconstituted the inhibition capacity of the complement. Whereas C3 supported significantly inhibition, a significant influence of other effector pathway (EP) components (C5-C9) was not detectable turbidimetrically.

Antigen-Antibody Complex↗

PubMed2000

Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis.

This study investigated the capacity of neurons and astrocytes to spontaneously activate the complement system and control activation by expressing complement regulators. Human fetal neurons spontaneously activated complement through the classical pathway in normal and immunoglobulin-deficient serum and C1q binding was noted on neurons but not on astrocytes. A strong staining for C4, C3b, iC3b neoepitope and C9 neoepitope was also found on neurons. More than 40% of human fetal neurons were lysed when exposed to normal human serum in the presence of a CD59-blocking antibody, whereas astrocytes were unaffected. Significant reduction in neuronal cell lysis was observed after the addition of soluble complement receptor 1 at 10 microg/ml. Fetal neurons were stained for CD59 and CD46 and were negative for CD55 and CD35. In contrast, fetal astrocytes were strongly stained for CD59, CD46, CD55, and were negative for CD35. This study demonstrates that human fetal neurons activate spontaneously the classical pathway of complement in an antibody-independent manner to assemble the cytolytic membrane attack complex on their membranes, whereas astrocytes are unaffected. One reason for the susceptibility of neurons to complement-mediated damage in vivo may reside in their poor capacity to control complement activation.

Antibodies, Blocking↗

PubMed1990

Serum haemolytic classical and alternative pathways of complement in infancy: age-related changes.

The haemolytic activity of complement was evaluated in the serum of healthy children from birth to 2 years of age using the kinetic method for the determination of the time needed to lyse 50% of target red cells (t 1/2). No sex-linked differences were observed in any of the age groups studied and the lowest lytic activity levels for both complement pathways were detected in neonates. The two pathways, however, showed different maturation patterns, i.e., lytic activity levels similar to those of adults were reached between the 1st and 3rd month of life (classical pathway) and around the 13th month (alternative pathway). In the age group of 7 to 24 months, the lytic activity of the classical pathway was higher than in adults. The present data permitted us to establish normal ranges of t 1/2 values for the classical and alternative pathways in serum of healthy neonates and children aged 1 to 24 months.

Age Factors↗

PubMed1994

K1, K5 and O antigens of Escherichia coli in relation to serum killing via the classical and alternative complement pathways.

The sensitivity of Escherichia coli strains to 80% normal human serum (NHS) and the relative importance of the classical and alternative complement pathways was assessed in relation to K1, K5, and O antigen carriage. Strains of each of the common O-serogroups, O1, O2, O4, O6, O7, O9, O18 and O75, smooth strains not typable (NT) with these antisera and auto-agglutinable (AA) strains were studied. Of the 166 strains studied, 37 carried the K1 antigen and 45 the K5 antigen. The variation in sensitivity to NHS between different O-serogroups reported previously was confirmed. Although carriage of the K1 and K5 antigens varied with O-serogroup, this did not explain the differences either between or within O-serogroups. Strains with the K1 or K5 antigen were significantly more resistant to the alternative complement pathway than strains without these antigens. However, this appeared to be more related to the O-serogroups with which they were associated; 37 of 50 O2, O4, O6 and AA strains were affected by complement through both pathways but 20 of 30 O7, O18 and O75 strains were affected by the classical pathway alone and 16 of 20 O9 and NT strains were affected by the alternative pathway alone.

Antigens, Bacterial↗

PubMed1999

A novel assay for serum complement activity: C42 generation assay.

BACKGROUND: In most clinics, laboratory tests for serum complement are limited to immunochemical determinations of C3 and C4 and are occasionally extended to the hemolytic titration of total complement functional activity (CH50). However, these tests are often not sufficient for the analysis of low CH50 serum. METHODS: A novel assay for serum complement activity, the C42 generation assay, has been developed. The principle of this assay is based on the hemolysis of sensitized sheep erythrocytes (EA) by complement components in two sera: C42 (the classical pathway C3 convertase) is generated on EA by C1, C4 and C2 in the first serum, followed by a second reaction leading to hemolysis by C3-C9 supplied by the addition of the second serum in the presence of EDTA. RESULTS: This methodology permits the evaluation of two distinct serum complement activities of a test serum. The combined activity of C1, C4 and C2, as well as the combined activity of C3-C9, can be estimated from the observed degrees of hemolysis. Information obtained from this assay is helpful for the analysis of test serum determined to have decreased CH50. Several clinical cases are presented in which this assay was utilized. CONCLUSIONS: The C42 generation assay is another functional assay of serum complement which can provide information beyond that obtained from the typical serum CH50 assay. Since intermediate cells or isolated complement components are not necessary, this assay can be employed rapidly and economically in a clinical setting.

Animals↗

PubMed1984

Heterogeneity, polypeptide chain composition and antigenic reactivity of autoantibodies (F-42) that are directed against the classical pathway C3 convertase of complement and isolated from sera of patients with systemic lupus erythematosus.

F-42, an autoantibody found in the sera of some patients with systemic lupus erythematosus, was isolated from sera of seven different patients. By binding of the autoantibodies to cell bound C42, the autoantibodies were purified to homogeneity and radiolabelled with 125I. Purified preparations of 125I-F-42 were bound for at least 96% by 10(9) erythrocytes bearing C4bhuC2hu. Analysis of all 125I-F-42 preparations by SDS-PAGE demonstrated apparent mol. wts of approximately 150,000. After reduction in the presence of 8 M urea each 125I-F-42 preparation yielded heavy and light chains. The heavy chains in some instances were slightly heavier than the heavy chain of normal human IgG. The reaction of 125I-F-42 from the seven patients was positive with Sepharose bound antisera to IgG, kappa, lambda, gamma 1, gamma 2, gamma 3 and in one case to gamma 4. These studies indicate that F-42 is an autoantibody directed against antigens expressed by the classical C3 convertase, C42.

Autoantibodies↗

PubMed1984

[A new low molecular-weight protein effector of human complement from the venom of the Central Asian cobra Naja naja oxiana].

Six protein effectors of human complement were isolated from the whole venom of the Central Asian cobra Naja naja oxiana. Three of them have acidic properties and molecular weights of 61 000, 5000 and 3000, and the rest are basic proteins with molecular weights of 54 000, 9000 and 7000. Two low molecular weight basic proteins CFB-II and CFB-III are isolated in as high amounts as 115 and 85 mg per g of dry venom. All the effectors inhibit the classical pathway of complement activation and, with the exception of CFB-II and CFB-III, the alternative pathway. The latter, on the contrary, enhances the alternative pathway of activation. N-Terminal sequence determination for CFB-III demonstrated its identity to the earlier characterized cytotoxin II. The action of CFB-III on the classical pathway of complement activation consists in the component C4 inactivation. A mechanism for the CFB-III activation of the alternative pathway is proposed implying the CFB-III induced transformation of the C3 component into a C3b-like one producing a soluble C3 convertase.

Chromatography, Gel↗

PubMed1981

The role of complement and IgG on zymosan opsonization.

Zymosan particles require opsonization for optimal interaction with granulocytes and activation of their respiratory burst. In the present study we evaluated the serum factors necessary for zymosan opsonization. First, zymosan was treated with either normal serum or hypogammaglobulinemic serum (HGS), which is deficient in immunoglobulins (Ig) but has a normal concentration of complement components. Using granulocyte chemiluminescence to assay opsonization, the activity of particles treated with HGS was 66 +/- 1.9% (mean +/- SEM) of that with normal serum (p less than 0.001), suggesting a role of Ig. HGS opsonic activity was restored to normal when the particles were also treated with IgG; however, neither heat-inactivated normal serum (56 degrees C, 30 min) nor pure human IgG alone had opsonic activity. The roles of the classical (CCP) and alternative (ACP) pathways of the complement system were also investigated. ACP activity seemed essential, since inactivation of the ACP (50 degrees C, 30 min) eliminated the activity of normal serum. However, when the ACP was intact, CCP action appeared to participate in opsonization, since selective CCP inactivation with EGTA and MgCl2 reduced the opsonic activity of normal serum by 26 +/- 3.3% (p less than 0.005). Thus, it is concluded that the ACP, CCP, and IgG all participate in zymosan opsonization.

Agammaglobulinemia↗

PubMed1983

The relative importance of the classical and alternative complement pathways in serum bactericidal activity against Escherichia coli.

The relative importance of the classical and alternative complement pathways in serum bactericidal activity against Escherichia coli strains of the common urinary O-serogroups has been assessed with strains that differ widely in their sensitivity to normal human serum. With most promptly serum-sensitive strains, rapid killing occurred, mediated by the classical pathway and, when this pathway was eliminated, delayed killing by alternative-pathway activity occurred. However, one strain of serogroup O1 was affected by the classical pathway only and a strain of serogroup O9 was killed rapidly by the alternative pathway. Strains with delayed sensitivity to normal human serum were largely, and in some cases exclusively, affected by the classical pathway. When added to heat-inactivated serum, some strains showed no significant growth whereas the viable numbers of other test strains increased more than 50-fold in 3 h. Whether this variation is due to differences in nutritional requirements or sensitivity to some non-complement-dependent bacteriostatic mechanism remains to be determined.

Complement System Proteins↗

PubMed2006

Involvement of complement pathways in patients with bacterial septicemia.

The complement system is a major humoral portion of the innate immune system, playing a significant role in host defence against microorganisms. The biological importance of this system is underlined by the fact that at least three different pathways for its activation exist, the classical, the MBL and the alternative pathway. To elucidate the involvement of the classical and/or the MBL pathway during bacterial septicemia, 32 patients with gram-positive and 30 patients with gram-negative bacterial infections were investigated. In patients with gram-positive bacteria, a significant consumption of C1q (p=0.005) but not of mannose-binding lectin (MBL) (p=0.2) was found during the acute phase of infection. In contrast, in patients with gram-negative bacterial infections, a significant reduction of MBL (p=0.002) and only a moderate, less significant reduction of C1q (p=0.03) were observed. As a model for the binding of MBL to gram-negative bacteria, Salmonella strains with defined mutations in their lipopolysaccharide (LPS) structure were used. The comparison of the binding of MBL to these Salmonella strains with that of the corresponding isolated LPS forms bound to microtiter plates revealed a similar binding pattern, supporting the interpretation that LPS on the surface of gram-negative bacteria is the major acceptor molecule for MBL on these bacteria, which according to our results obviously also takes place during gram-negative bacterial septicaemia. Furthermore, we were able to demonstrate that MBL bound to LPS was able to initiate activation of the complement cascade as measured by the occurrence of the cleavage product C4c.

Bacteremia↗

PubMed1981

Involvement of membrane-associated sialic acid in the resistance of sheep erythrocytes to lysis by mouse complement.

The sensitivity of the murine complement system to regulation by membrane-associated sialic acid was investigated. Therefore the C-mediated lysis of sialic acid-rich sheep erythrocytes, sialic acid-poor rabbit erythrocytes and enzymatically desialylated sheep erythrocytes was studied. Mouse complement differed from human and guinea pig complement in that besides the alternative, also the classical pathway appeared sensitive to regulation by surface sialic acid. The possible reaction mechanisms behind the selective sensitivity of the murine classical pathway to membrane-linked sialic acid are discussed and will be subject of further study.

Animals↗

PubMed1984

Activation of the alternative complement pathway by isolated human glomerular basement membrane.

The capacity of isolated human glomerular basement membrane (GBM) to initiate surface activation of the human alternative complement pathway was defined by the deposition of C3b under circumstances in which the classical complement pathway was inoperative. The deposition of C3b from normal or C2-deficient serum was time- and magnesium-dependent, implying a role for the alternative pathway. Normal human serum rendered deficient in D did not sustain C3b deposition until its reconstitution with D, indicating an absolute requirement for a protein unique to the alternative pathway and essential to the cleavage activation of the C3 amplification convertase of that pathway. The capacity of the excess control proteins H and I to prevent C3b deposition onto GBM incubated in C2-deficient serum provided further evidence for the direct activation of the alternative pathway in this system. The use of radiolabeled monoclonal antibody to localize the deposited C3b afforded specificity and quantitation of about 100 ng of C3b/mg of GBM. Immunohistochemical analysis with a monoclonal antibody to detect C3b demonstrated its deposition to be confined to the epithelial surface of the GBM.

Antibodies, Monoclonal↗

PubMed1983

C1 inactivator-C1s complexes in inflammatory joint disease.

A newly developed enzyme linked immunosorbent assay for the quantitation of C1 inhibitor (C1In)-C1s complexes was used to study activation of the classical pathway of complement in inflammatory joint diseases. Synovial fluid (SF) specimens were obtained from patients with rheumatoid arthritis (RA), other arthritides and non-inflammatory joint effusions. Paired serum (S) samples were obtained in 17 cases. Immune complexes (IC) were measured by the staphylococcal binding assay. C1In-C1s were higher in RA SF samples than in paired RAS samples (P less than 0.01). IC were higher in RA SF than non-RA SF. There was a significant inverse correlation between SF C1In-C1s complexes and SF total haemolytic complement. For all SF samples there was a correlation between IC and C1In-C1s complexes, but for RA SF alone there was no significant correlation between these parameters. There was no correlation between titre of rheumatoid factor and C1In-C1s complexes. These results demonstrate that activation of the classical pathway of complement is the hallmark of rheumatoid synovitis, yet also suggest functional heterogeneity of both circulating and intra-articular IC.

Antigen-Antibody Complex↗

PubMed2004

Serum haemolytic complement activities in 11 different MHC (B) typed chicken lines.

To study the relation between serum complement levels and the chicken MHC (B) complex, complement haemolytic activity was measured in sera from hens from seven pure-bred B-typed White and one Brown Leghorn lines, and three ISA-Warren lines that had been divergently selected for antibody responses to sheep red blood cells (SRBC). Significant differences occurred in the serum haemolytic complement activities, both belonging to the classic (CPW) and the alternative (APW) pathways, among the 11 different haplotyped chicken lines. Hens with high CPW and high APW titres predominantly displayed the B2 or B21 haplotypes. Chickens with low CPW and APW were found in B14 and B15 haplotypes. Haplotype B14 appears to be different in complement levels when present into the pure-bred lines or into the ISA-Warren line selected for low antibody responses to SRBC. Otherwise, the presence of B21 in ISA-Warren line selected for high antibody responses to SRBC does not differ with the B21 in the inbred lines (except in the NL-line for CPW values). In general the haplotypes B2 and B21 are found in chicken lines with enhanced disease resistance, and the B15 haplotype has been connected with enhanced disease susceptibility. Our results suggest that levels of haemolytic complement activity, either from the classical or from the alternative pathways, may underlie part of the immunocompetence ascribed to the MHC (B) complex in chickens.

Animals↗