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PubMed1993

Genetic deficiencies of the complement system and association with disease--early components.

Genetic deficiency of one of the early components of the classical pathway of complement (C1q, C1r, C1s, C4 and C2) is often associated with clinical symptoms and immunochemical abnormalities common in idiopathic autoimmune diseases, such as lupus erythematosus, but also with an increased incidence of various, local and generalized infections. These observations are consistent with the current view of the complement system's role in handling immune complexes and combating microbial invasion. However, the absence of absolute correlations in these experiments of nature suggests that genetic defects of the classical pathway act only epistatically to other host factors and the primary etiologies of the associated diseases. In contrast, the strong association of properdin and factor D deficiency with serious infections caused by encapsulated Gram-negative bacteria suggests a more immediate involvement of the alternative pathway in a specific segment of immunity and its pathology. This concept is also supported by the primordial role of the alternative pathway in the evolution of the complement system and the apparent lethality of factor B deficiency. The gene structures of most of these early components have now been elucidated providing the basis for detailed analyses of the defective alleles, the determination of carrier status, and prenatal diagnosis.

Complement C1↗
PubMed2002

C1q, autoimmunity and apoptosis.

Deficiency of classical pathway complement components displays a hierarchical association with the development of systemic lupus erythematosus (SLE). Individuals with deficiency of C1q, the first component of the classical pathway of activation, have the highest prevalence of SLE and the most severe manifestations of the disease. However, complement is also implicated in the effector inflammatory phase of the autoimmune response that characterizes SLE. Complement proteins are deposited in inflamed tissues causing consumption of complement. In addition, autoantibodies to C1q develop as part of the autoantibody response. Understanding how C1q deficiency results in the autoimmune phenotype of SLE may provide valuable clues to the role of the complement system in the maintenance of immune tolerance. In this review firstly we discuss the relationship between C1q deficiency and/or consumption and lupus. Secondly, we consider the links between apoptosis and complement. Finally we review the lessons we have learned from a murine model of C1q deficiency discussing the experimental evidence in support of the hypothesis that C1q may critically influence the immune response to self-antigens contained within the surface blebs generated by apoptotic cells.

Animals↗
PubMed1995

In vitro anticomplementary activity of constituents from Morinda morindoides.

In a screening program for complement classical pathway modulation, an 80% MeOH extract of the leaves of Morinda morindoides showed potent dose-dependent anticomplementary activity. Bioassay-guided chromatographic separation of the active constituents led to the isolation of ten flavonoids of which two were aglycones. The compounds were tested in vitro for their putative complement-inhibiting properties on the classical (CP) and the alternative (AP) pathways of the complement system. The results indicated that quercetin [1], quercetin 3-O-rhamnoside (quercitrin) [5], and quercetin 3-O-rutinoside (rutin) [7] showed similar anticomplementary activities (inhibition) on the CP of complement. A mixture of two kaempferol triglycosides isolated and denoted as M(015), also had a good inhibitory effect. The effects of these compounds were dose-dependent for this pathway. On the AP of complement, quercetin [1] and M(015) had, respectively, more pronounced inhibitory and activatory effects than the other tested flavonoids, but their effects were not dose-dependent for this pathway. The other isolated flavonoids showed weak effects or were inactive for both pathways.

Animals↗
PubMed1979

Staphylococcus aureus opsonization mediated via the classical and alternative complement pathways. A kinetic study using MgEGTA chelated serum and human sera deficient in IgG and complement factors C1s and C2.

Staphylococcus aureus opsonization was studied kinetically by: (1) determination of the uptake of [3H]-thymidine labelled bacteria by human PMN's; (2) fluorescent anti-C3 and anti-IgG staining of opsonized bacteria; and (3) measuring bacterial complement consumption. Maximum opsonization in normal serum occurred within 5 min of incubation. About 80% of staphylococci were then taken up by PMN's, and IgG and C3b could be detected on the bacterial surface. In the absence of a functional classical complement pathway, as in sera deficient in C1s and C2 and in MgEGTA chelated serum, maximal opsonization was only achieved after 30--60 min incubation. Opsonization in IgG deficient serum occurred at a rate similar to that found in C2 deficient or MgEGTA chelated serum. Opsonization was greatly enhanced when sera were reconstituted. It was concluded that in IgG deficient serum Staphylococcus aureus opsonization is mediated via the alternative complement pathway. Dilution of normal serum primarily affected the classical complement pathway, resulting in a decreased rate of opsonization. In normal serum IgG did not appear to be a rate-limiting factor. S. Aureus opsonization was best studied by the phagocytosis assay and the fluorescent-antibody technique. Measuring haemolytic complement consumption was found to be an insensitive indicator of bacterial complement activation and opsonization.

Complement Activation↗
PubMed1989

Complement activation and C3 binding by serum-sensitive and serum-resistant strains of Pseudomonas aeruginosa.

The relationship among complement consumption, C3 deposition, and C3 fragmentation pattern was compared for serum-sensitive (Sers) and serum-resistant (Serr) strains of Pseudomonas aeruginosa. The Sers strains, which were mucoid strains derived from patients with cystic fibrosis, had lipopolysaccharide deficient in O-antigen side chains. These organisms generally activated much less complement per organism than their Serr counterparts, characterized by the presence of lipopolysaccharide with long lipopolysaccharide O side chains. Surprisingly, however, although the Serr strains consumed more total hemolytic complement, less C3 was deposited onto the surface of these strains than onto that of the Sers strains. Maximal C3 binding required the participation of both the classical and alternative complement pathways, although classical complement pathway involvement was more important for Serr strains. Finally, while more than half of the C3 deposited on most Sers strains was in the form of C3b, most of the C3 on the Serr strains was in the form of iC3b, indicating a more rapid and extensive conversion of C3b to iC3b on the surface of these strains. Limited complement activation by Sers mucoid strains of P. aeruginosa may confer a selective survival advantage to these organisms in colonizing the airways of patients with cystic fibrosis.

Adult↗
PubMed1986

Purification and characterization of complement activating-acidic polysaccharide from the root of Lithospermum euchromum Royle.

An extraordinary potent anti-complementary substance was isolated from the root of Lithospermum euchromum Royle (Japanese name: Nan-shikon) which activates the complement system in vitro, and the active principle was shown to be acidic polysaccharide (LR-polysaccharide IIa). LR-polysaccharide IIa was purified by chromatographies on DEAE-Sepharose, Sephadex G-100, concanavalin A-Sepharose, Ricinus communis agglutinin conjugated Sepharose, Sepharose CL-6B and Sepharose CL-2B. LR-polysaccharide IIa was found to be composed of rhamnose, fucose, arabinose, xylose, mannose, galactose and glucose in the molar ratios of 2.0:2.5:3.4:2.8:5.6:9.6:14.4. The polysaccharide also contained 15% of galacturonic acid and 3.8% of protein. The methylation analysis of the polysaccharide showed that rhamnose, arabinofuranose, xylose, glucose and galactose are present as a part of the nonreducing terminal residues. The main chain and side chains are composed of ----3Glc1----,----3Gal1----,----6Man1----,----4Gal1, [corrected] and the branching points consist of (formula; see erratum) These results indicated that LR-polysaccharide IIa has a highly complicated structure. A marked consumption of C4 was observed after the incubation of the serum with LR-polysaccharide IIa in the presence of the Ca++ ion. The anti-complementary activity of LR-polysaccharide IIa was reduced partially in the absence of the Ca++ ion. After the incubation of the serum with LR-polysaccharide IIa in the absence of Ca++ ion, a cleavage of C3 in the serum was found to have occurred through immunoelectrophoresis as well as from the consumption of the complement when rabbit erythrocytes were used in the assay system. These results indicate that the mode of complement activation by LR-polysaccharide IIa is via both the alternative and classical pathways. Complement titer also decreased in guinea pigs upon i.p. injection of LR-polysaccharide IIa.

Animals↗
PubMed1984

Defective binding of the third component of complement (C3) to Streptococcus pneumoniae in multiple myeloma.

Patients with multiple myeloma (MM) are at an increased risk for infections with bacteria that require opsonization with complement. Because Streptococcus pneumoniae is the most frequently encountered pathogen in these patients, we investigated the ability of serum from patients with MM to mediate the binding of C3b, the major opsonin of the complement system, to S. pneumoniae. S. pneumoniae types 3, 14, and 25 were chosen for study, since S. pneumoniae type 3 activates primarily the classical complement pathway (CCP), type 25 primarily the alternative complement pathway (ACP), and type 14 both pathways. S. pneumoniae were treated with normal serum or serum from 17 patients with MM, and the bound C3b was quantified with fluorescein-conjugated anti-C3 in a spectrophotofluorometric assay. Despite normal or elevated serum concentrations of C3, total hemolytic complement, and C-reactive protein in all of the MM sera, factor B in 16/17 such sera, and C4 in 14/17 MM sera studied, all 17 sera demonstrated a defect in C3b binding to type 3 (32.7% +/- 6% of normal). In addition, serum from 15/17 patients bound decreased amounts of C3b to types 14 (39.6% +/- 8%) and 25 (52.2% +/- 8%). Mixing normal serum with MM serum restored MM C3b binding activity to all three S. pneumoniae types, suggesting that the defect was related to a deficiency rather than an inhibitor of C3 activation. Although MM patients are unable to produce specific antibodies to bacterial antigens, the addition of anti-S. pneumoniae antibodies to MM serum did not enhance C3b binding to any of the S. pneumoniae types. However, when S. pneumoniae were opsonized in a mixture of MM serum and C3-depleted normal serum, C3b binding was restored to all three S. pneumoniae types, demonstrating that MM C3 functions normally in the presence of other normal serum factors. In the present studies, the MM C3b binding defect appeared to correlate with the incidence of S. pneumoniae infections. Serum from patients with a history of an S. pneumoniae infection bound significantly less C3 (20.5% +/- 4%) than those study patients without a history of an S. pneumoniae infection (55.8% +/- 8%) (p less than 0.0025). Thus, MM serum has a defect in the activation of C3, and this may contribute to the increased susceptibility of MM patients to S. pneumoniae infections.

Complement C3↗
PubMed1986

Bactericidal, bacteriolytic and opsonic activity of human serum against Escherichia coli.

The effect of human serum on Escherichia coli was studied with serum-sensitive and serum-resistant strains. The bactericidal effect of human serum on serum-sensitive strains of E. coli depended on the activation of the classical complement pathway. The role of activation of the alternative pathway was less important. After incubation in sub-bactericidal concentrations of serum these strains were also easily phagocytosed by polymorphonuclear leukocytes (PMNL). Strains of E. coli of certain O-types required not only an intact classical pathway but also the presence of specific antibodies for effective killing by serum and effective phagocytosis by PMNL, despite rapid activation of complement and rapid deposition of C3 on the bacterial surface in the absence of antibody. Capsulate strains O1K1 and O78K80 resisted the bactericidal effect of serum even in the presence of specific antibodies; phagocytosis by PMNL only occurred after opsonisation with specific antibodies.

Antibodies, Bacterial↗
PubMed1986

Effect of EGTA on phagocytosis of Salmonella typhimurium by human neutrophils.

The ingestion of mutant strains of Salmonella typhimurium by human neutrophils was greatly reduced by the presence of ethylene glycol tetra-acetic acid (EGTA) in the reaction mixture. Ingestion of preopsonized bacteria by neutrophils was little affected by Ca++ in the reaction mixture but largely reduced by the presence of EGTA. In addition to chelation of Ca++, EGTA has an adverse effect on neutrophils. In studies of phagocytosis, to avoid this effect, EGTA should not be present in the reaction mixture when it is used to prevent the complement classical pathway activation.

Blood Bactericidal Activity↗
PubMed1986

The interaction of Escherichia coli with normal human serum: the kinetics of serum-mediated lipopolysaccharide release and its dissociation from bacterial killing.

We have examined the killing of E. coli and kinetics of lipopolysaccharide (LPS) release after the exposure of the bacteria to normal human serum (NHS) and sera deficient in complement components, or with inactivated complement components. LPS of the galactose epimerase-deficient strain E. coli J5 were specifically radiolabeled by growing the bacteria in a medium containing [3H]galactose. Exposure of the washed bacteria to NHS resulted in a significant reduction (greater than 99%) in viability within 15 min and the concomitant release of radiolabeled LPS. However, maximal release of LPS was consistently 30% of the total radiolabel incorporated into the LPS molecules. The amount of tritium-labeled LPS released was shown to be directly proportional to the concentration of bacteria exposed to NHS, suggesting that release of LPS was not limited by the availability of some critical serum component(s). The consumption of complement in NHS by incubation with E. coli was demonstrated by decreased alternative and classical pathway-specific hemolytic activity. The use of Factor D-depleted and VEM-treated human sera demonstrated that, with these bacteria, both the alternative and classical pathways of complement contribute to bacterial killing and release of LPS. It is noteworthy that, in VEM-treated and Factor D-depleted sera, the rate of killing and the kinetics of LPS release were somewhat slower as compared to control serum. Bacterial killing in C7-depleted and C9-deficient human sera was minimal. Neither killing nor LPS release occurred in heat-inactivated (56 degrees C, 30 min) human serum. The amount of [3H]LPS released by C9-deficient serum was qualitatively similar to the amount released by the action of NHS. Tritium-labeled LPS was not released in C7-depleted serum. These data indicate that bacterial killing can be dissociated from LPS release, and suggest that, whereas LPS release may be necessary for the bactericidal effects of serum complement, it is probably not sufficient to effect killing. Furthermore, a significant fraction of LPS can be removed from the outer membrane of the bacteria without an apparent affect on viability.

Adult↗
PubMed2003

Synthesis of low molecular weight compounds with complement inhibition activity.

An attempt was made to synthesize a series of non-cytotoxic low molecular weight meta-substituted aromatic ethers (2-4, 5-7) and some of their bioisosteres (14-16) and to evaluate their activity on the activation of human complement (classical pathway) and their intrinsic hemolytic activity. The in vitro assay results of the inhibition of complement-mediated hemolysis by these analogues indicate that the aldehydic meta substituted aromatic ethers show inhibitory potency, while carboxylic acid meta substituted aromatic ethers show hemolytic activity. Some of the bioisosteres exhibit both inhibitory as well as hemolytic property.

Complement Inactivator Proteins↗
PubMed1987

A complement-resistant HeLa cell line (T638) is blocked at the step of C3 deposition.

A complement-resistant line of HeLa cells (T638) was derived by serial passage of complement-susceptible HeLa cells in anti-beta 2-microglobulin (b2m) antiserum and complement. The T638 line maintained stable complement resistance when passed for an additional 1500 generations in the absence of antiserum and complement. T638 cells expressed equivalent levels of cell-associated b2m as did the parent HeLa cell line. Furthermore, T638 cells were resistant to killing by complement and anti-HeLa antiserum with specificity for molecules other than b2m. These results indicate that the resistance of T638 cells does not simply reflect loss of anti-b2m binding antigens. We next investigated the mechanism of resistance of T638 cells to complement-mediated killing. Antibody-sensitized HeLa and T638 cells both consumed CH50 activity completely from normal human serum; cytotoxicity was not mediated via the alternative complement pathway. HeLa and T638 cells caused equivalent utilization of C4 from normal human serum in the presence of antibody. Consumption of C2, greater with T638 than with HeLa cells during incubation in serum, was complete when cells bearing purified C1 and limited C4 were incubated with C2. T638 cells bound more 3H-C4 than HeLa cells during incubation in serum, but binding of 3H-C3 by T638 cells was fourfold to fivefold less than by HeLa cells. Finally, we investigated the rate of decay in the capacity of C142 on HeLa and T638 to cleave and deposit 3H-C3. The T1/2 for decay of C142-mediated binding of 3H-C3 on HeLa was 3.9 min, whereas minimal C3 deposition was detected on T638 cells at all time points. These results show that T638 cells evade complement-mediated lysis despite activating early components of the classical complement pathway. The mechanism of resistance is a failure to form an effective C3 convertase.

Antibodies↗
PubMed1981

Complement-inhibiting and anti-inflammatory properties of chlorazole fast pink 2BL.

Chlorazole fast pink 2BL inhibited the classical complement pathway in rat serum both in vivo and in vitro. The in vitro potency of chlorazole fast pink against the alternative pathway could not be assessed accurately but it was clearly less than that against the classical pathway. The compound appears to bind strongly to albumin with a resulting decrease in potency in undiluted as compared to diluted serum. Anti-inflammatory activity was observed in models of inflammation known to be highly complement-dependent (direct passive Arthus, zymosan oedema) but not in models in which complement is not involved (dextran oedema) or plays a minor role (carrageenan oedema).

Animals↗
PubMed1997

Structure and assembly of the catalytic region of human complement protease C1r: a three-dimensional model based on chemical cross-linking and homology modeling.

C1r is the modular serine protease responsible for autocatalytic activation of C1, the first component of the complement classical pathway. Its catalytic region is a noncovalent homodimer of two gamma-B monomers, each comprising two contiguous complement control protein (CCP) modules, IV and V [also known as short consensus repeats (SCRs)], a 15-residue intermediary segment, and the serine protease B domain. With a view to gain insight into domain-domain interactions within this region, fragment C1r (gamma-B)2, obtained by autolytic proteolysis of the active protease, was cross-linked with the water-soluble reagent 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. Cross-linked species gamma-B intra and gamma-B inter, containing intra- and intermonomer cross-links, respectively, were isolated and then fragmented by CNBr cleavage and trypsin digestion. N-Terminal sequence and mass spectrometry analyses of the resulting cross-linked peptides allowed us to identify one intramonomer cross-link between Lys426 of module V and the C-terminal Asp688 of the serine protease B domain and one intermonomer cross-link between the N-terminal Gly280 of fragment gamma and Glu493 of the B domain. Three-dimensional homology modeling of the CCP modules IV and V and of the B domain was also performed. The complementary information provided by chemical cross-linking and homology modeling studies was used to construct a three-dimensional model of the gamma-B monomer, in which module V interacts with the serine protease on the side opposite to both the active site and the Arg446-Ile447 activation site. Also, a tentative three-dimensional model of the (gamma-B)2 dimer was built, indicating a loose "head to tail" association of the monomers, with the active sites facing opposite directions toward the outside of the dimer. The latter model is compared with available low-resolution structural data, and its functional implications are discussed in terms of the conformational changes occurring during C1r activation.

Amino Acid Sequence↗
PubMed1992

Mechanisms of oligodendrocyte interaction with normal human serum--defining the role of complement.

The interaction of human serum with oligodendroglia was investigated in vitro using purified cultured neonatal rat oligodendrocytes. Previous evidence for antibody independent classical pathway complement activation was confirmed; the results also showed a deficit in the protection of rat oligodendrocytes from complement attack suggesting a deficiency in the expression of terminal regulatory proteins of the complement cascade. Thus, rat oligodendrocytes are selectively sensitive to normal serum due both to complement activation and impaired protection from terminal complement attack.

Animals↗
PubMed1986

Alternative complement pathway activation by C4b deposited during classical pathway activation.

Sheep erythrocytes (E) sensitized with anti-E antibody (A) were reacted with guinea pig C1 (C1gp) and human C4 (C4hu) or guinea pig C4 (C4gp) to prepare EAC1, 4b. Treatment of the EAC1, 4b with a buffer containing EDTA removes C1rgp and C1sgp, resulting in the formation of EAC4b. EAC4b prepared in this way were found to be lysed by human or guinea pig serum in a gelatin Veronal-buffered saline containing 2 mM MgCl2 and 8 mM EGTA (Mg-EGTA-GVB). In the hemolytic sensitivity of EAC4bhu, essentially no difference was noted whether IgG or IgM antibodies were used for preparation of EAC4bhu. The extent of the hemolysis of EAC4bhu was dependent on the dose of C4bhu. Because EAC4bhu were lysed even by C2-deficient human serum, C3 convertase of the classical complement pathway would not be involved in the hemolysis of EAC4bhu. Furthermore, the reactivity of EAC4bhu with serum in Mg-EGTA-GVB remained even after treatment of the intermediate cells with 1 mM PMSF, indicating that any remaining C1gp was not responsible for the hemolysis. Therefore, the hemolysis of EAC4b by sera in Mg-EGTA-GVB was considered to be mediated via activation of the alternative complement pathway (ACP). Pretreatment of EAC4bhu with anti-C4hu antibody or C4-binding protein suppressed the hemolysis of EAC4bhu via the ACP activation. Furthermore, EAC4bhu were more sensitive to hemolysis by the reaction with a mixture of C3, B, D, and H followed by rat serum in EDTA-GVB than EAC1qgp were. These results indicate that C4b molecules on the cell membrane participate in the activation of ACP.

Animals↗
PubMed2000

Apoptosis and autoimmunity: complement deficiency and systemic lupus erythematosus revisited.

Apoptosis may have a dual role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. First, this process may be integral in the clonal deletion of self-reactive lymphocytes and maintenance of peripheral tolerance. Second, apoptosis generates altered self-antigens with the potential for breaking self-tolerance. This review will discuss these two aspects of apoptosis and autoimmunity, and explore the potential role of the classical complement pathway in this context.

Apoptosis↗