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PubMed1978

Activation of the classical and alternative pathways of complement fixation by immune complexes containing normal and tryptophan-modified immunoglobulin G.

Koshland's reagent (2-hydroxy-5-nitrobenzyl bromide (NBB)) has been shown to modify tryptophanyl residues in anti-ovalbumin IgG. As little as 2 moles NBB/mole IgG antibody are sufficient to block the classical pathway of complement activation when the antibody is complexed to antigen (ovalbumin). In contrast, immune complexes containing antibody with the same degree of tryptophanyl substitution will activate the alternative pathway of complement fixation. Immune complexes containing F(ab')2 fragments derived from anti-ovalbumin IgG do not activate the classical pathway. When measuring the percentage activation of C3 using the method of Laurell, NBB does not affect the alternative pathway of the complement system up to a molar ratio of 2 NBB/F(ab')2. The above findings, provide a means to evaluate the relative contribution of complement activation by the different pathways.

Animals↗

PubMed2006

Modulation of complement activity in vitro and in vivo by Yersinia wild and mutant strains.

The ability of released proteins (Yops) and surface lipopolysaccharides (LPS) from the wild-type strain Yersinia enterocolitica 8081-L2, serotype 0:8 to influence the complement activity was determined. Yops and LPS from wild-type and mutant strains showed different ability to affect the classical pathway (CP) functional complement activity in vitro. The serum CP activity was inhibited during the infection induced with six Y. enterocolitica and three Y. pseudotuberculosis strains in rabbits. The changed complement activity might be of importance for the course of Yersinia infections.

Animals↗

PubMed1990

Increased amounts of C4-containing immune complexes and inefficient activation of C3 and the terminal complement pathway in a patient with homozygous C2 deficiency and systemic lupus erythematosus.

Plasma and serum samples from a patient with homozygous C2 deficiency and severe systemic lupus erythematosus who responded with full clinical remission after plasma infusions were examined for immune complexes (IC), C3 activation products, and the terminal complement complex (TCC). Plasma contained large amounts of C4-containing IC but no C3-containing IC or complement activation products. Classical pathway activation in vitro did not lead to C3 activation or TCC formation as seen in normal serum, but a very efficient binding of C1q and C4 was found. No disturbances in alternative pathway activation were observed. The results indicate an impaired formation of C3-containing IC and an inefficient clearance of C4-containing IC, supporting the idea of a causal relationship between the dysfunctional classical pathway, pathophysiology, and clinical manifestations in this patient.

Antigen-Antibody Complex↗

PubMedDate not supplied

Evidence that immunoglobulin-positive neurons in Alzheimer's disease are dying via the classical antibody-dependent complement pathway.

A recent study provided evidence that immunoglobulins (Igs) are not only present in Alzheimer's disease (AD) brains, but are also immunohistochemically detected in and/or on a particular population of pyramidal neurons that appeared morphologically degenerative in contrast to neighboring normal-appearing Ig-negative neurons. Because little has been reported about these Ig-positive neurons, the objectives of this study were to characterize the inflammatory profile of these neurons in the AD brain by determining if they possess complement components and are associated with reactive microglia. The data showed that the Ig-positive neurons had complement C1q and C5b-9 proteins and appeared degenerative. Furthermore, D-related human leukocyte antigen (HLA-DR)-positive fibers of reactive microglia were spatially closer (p < 0.001) and often in contact with the Ig-positive neurons than the Ig-negative neurons. Collectively, these data suggest that the Ig-positive neurons detected in AD brains are dying from the processes of the antibody-induced classical complement pathway.

Alzheimer Disease↗

PubMed1978

Complement activation during subsequent stages of canine endotoxin shock.

Changes in total haemolytic complement and levels of C3, C4 and C6 were studied during subsequent stages of lethal endotoxin shock in dogs. Substantial decreases of all parameters were observed. C4 and C6 decreases showed a very similar pattern, indicating activation of complement by the classical pathway in addition to the activation of the alternative pathway known to occur in this pathological condition. The findings emphasize the role of the complement system in the pathophysiology of endotoxin shock and are consistent with the concept that complement activation has prognostic value during endotoxaemia.

Animals↗

PubMed1983

[Role of immunoglobulins in the activation of complement].

Depending on their class and sub-class, immunoglobulins may activate the complement by the classical pathway or by the alternative pathway. This activating property depends on how immunoglobulins are associated. Activation by the classical pathway implies binding to, and activation of C1. Binding is essentially an ion type interaction between C1q and--in the case of human IgG's for instance--the C gamma 2 domain. It has recently been investigated in depth by various techniques, such as inhibition of the C1q--IgG interaction by chemical compounds or by peptides isolated from C gamma 2. Activation of C1 seems to involve some elements of C gamma 3. In addition to initiating the classical pathway, immunoglobulins may act as acceptors of the classical C3-convertase (C4b C2a); a structure accepting the newly formed C4b is present in the Fab portion of IgG. It would appear that optimal functioning of the complement system is achieved when the C1 activating site and the C3-convertase forming site are close together on the IgG molecule, since the newly born peptidic fragments have a very short life. Immunoglobulins may activate the alternative pathway via their Fab portion. This property is directly related to the ability of Ig's to accept nascent C3b, which probably includes that of accepting nascent C4b as described above. In the alternative pathway C3-convertase may form when structural conditions around IgG-bound C3b encourage binding of B to C3b rather than the intervention of I and H factors which degrade C3b. The Ig-C3b interaction responsible for activation of the alternative pathway may also be directly involved in solubilization of immune complexes during activation of complement.

Animals↗

PubMed1983

Analysis of chemotactic factor generation in C1q-deficient sera.

The roles of the classical and alternative complement pathways in the formation of chemotactic factors in normal human serum and in sera from patients with an inherited selective deficiency of C1q were studied. Monocytic chemotaxis was evaluated in serum activated by zymosan, endotoxin, cobra venom factor, aggregated human IgG and immune complexes. Chemotactic activity was only impaired when the C1q-deficient serum concentration was low or the period of exposure to zymosan, endotoxin or immune complexes was short. No effect was demonstrated when cobra venom factor and aggregated human IgG were used as activating agents even at limited serum concentrations. Chemotactic activity was also impaired when deficient sera were chelated with EGTA and activated with immune complexes during 7 and 60 min. The addition of normal human serum or purified human C1q to the assay resulted in improvement or normalization of the chemotactic function. The observation that the formation of chemotactic factors via the alternative pathway requires a higher serum concentration and/or longer activation time, points out the necessity for an intact classical pathway in order to achieve optimal activation of the alternative pathway.

Antigen-Antibody Complex↗

PubMed1985

Immunological evaluation in children with juvenile chronic arthritis treated with auranofin.

An immunological evaluation was performed before therapy and every four months during the first year of treatment with auranofin in 6 children with juvenile chronic arthritis. The immunological tests included: IgG, IgA, IgM, IgE and "natural" antibody serum levels, CH50 of the classical and alternative complement pathways, PWM-induced IgM production in vitro, and polymorphonuclear neutrophil functions. A reduction of the in vitro IgM synthesis and in the CH50 of the classical pathway of complement, and a normalization of impaired chemotaxis, occurred in patients who presented a clinically significant improvement during auranofin treatment.

Antibody Formation↗

PubMed1990

The mechanism of carbohydrate-mediated complement activation by the serum mannan-binding protein.

Serum mannan-binding protein (S-MBP), a lectin specific for mannose and N-acetylglucosamine, was documented to activate complement through the classical pathway. In this study, we examined the mechanism that initiates this activation. By a passive hemolysis test using sheep erythrocytes coated with yeast mannan, the activation of complement by human S-MBP was shown to proceed in the absence of C1q. The following binding studies using 125I-labeled C1r2s2 and C1s indicated that the activated form of C1r2s2 bound to S-MBP located on the surface of the cells with high affinity. The binding of C1s to the cell-bound S-MBP require the presence of C1r, suggesting that C1r2s2 binds to S-MBP through C1r. The activation of C1s from a proenzyme to a protease was mediated by cell-bound S-MBP in the presence of C1r and the activated protease remained associated with the cells and was not released into the medium. The activation of complement with S-MBP was a solid phase event and did not proceed in a fluid phase. On the basis of these results, it was concluded that S-MBP is responsible for the initiation of carbohydrate-mediated complement activation as C1q does in immune complex-mediated complement activation.

Animals↗

PubMed1999

Functional definition of a B cell epitope, KGEQGEPGA, on C1q the Fc-binding subunit of the first component of complement.

A synthetic peptide representing the C1q epitope KGEQGEPGA has been shown to suppress or delay the onset of CII-induced arthritis when applied intravenously (i.v.) prior to an intradermal (i.d.) challenge, in a mouse model; the phenomenon being associated with the development of immunoglobulin (Ig)M antibodies specific for the KGEQGEPGA epitope. Here we show that this amino acid sequence provides an immunodominant B cell epitope that is recognised by autoantibodies present in the sera of patients with chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, two diseases associated with an immune response to C1q. The peptide's ability to produce peptide specific IgM when applied i.v. in both normal and athymic mice but not in mice exhibiting the x-linked B-cell associated Bruton's tyrosine kinase defect permits classification of the KGEQGEPGA peptide as a T-cell independent antigen type-2 (TI-2). IgM monoclonal antibodies raised against the peptide are able to functionally block activation of the complement cascade by C1q, via a mechanism that inhibits the C4 consumption. Antibodies to this immunodominant epitope may therefore modulate inflammatory processes by interfering with the activation of the classical pathway of the complement.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed1989

Effect of immune globulin intravenous on opsonization of bacteria by classic and alternative complement pathways in premature serum.

The mechanisms involved in the effect of immune globulin intravenous (IGIV) on bacterial opsonization by both complement pathways in premature serum were elucidated in this study. Of the bacteria used, Staphylococcus aureus and Salmonella enteritidis were nonencapsulated while Streptococcus pyogenes and Escherichia coli 07 K1 were encapsulated. As demonstrated by indirect immunofluorescence, IGIV showed specific antibody titers of 1:32 for S. aureus and S. enteritidis and of 1:8 for S. pyogenes and E. coli 07 K1. IGIV alone had no direct opsonic activity against these organisms. Addition of IGIV did not alter the opsonic activity of normal adult serum against these organisms. In contrast, addition of IGIV promoted the opsonic activity of premature serum against the nonencapsulated bacteria to levels matching that in normal adult serum. The IGIV preparation significantly improved the opsonization of bacteria by the classic (from 39 to 68% of that in adult serum) and alternative (from 22 to 97% of that in adult serum) complement pathways in premature serum. IGIV also markedly augmented C3 deposition on the bacteria by both complement pathways. These studies suggest that IGIV containing high titers of specific antibodies promote opsonization of bacteria by the enhancement of complement pathway activation, especially the alternative pathway, in premature serum.

Complement System Proteins↗

PubMed1976

The serine protease nature of the C3 and C5 convertases of the classical and alternative complement pathways.

Activated Factor B, incorporated into the cobra venom factor (CVF)-dependent C3/C5 convertase, was inactivated by diisopropylfluorophosphate (DFP). Inactivation was time- and dose-dependent and was enhanced by the presence of substrate. Treatment of the zymogen of Factor B with DFP effected significant inactivation. Incorporation of [3H]diisopropylphosphate into the zymogen and into the activated form of Factor B was demonstrated after [3H]DFP treatment and subsequent electrophoresis of the proteins on polyacrylamide gels containing sodium dodecyl sulfate. Inactivation of activated C2 incorporated into the classical C5 convertase was observed on DFP treatment of the enzyme. DFP also reduced the activity of the C2 zymogen. The description of their serine proteinase nature further emphasizes the close structural and functional relationship of C2 and Factor B.

Complement C2↗

PubMed1985

Hyaluronic acid-complement interactions--I. Reversible heat-induced anticomplementary activity.

The in vitro interaction of hyaluronic acid (HA) with complement (C) classical-pathway activity has been investigated. It was found that native HA, even at a high concn (greater than 3 mg/ml), has a relatively weak anticomplementary activity. However, we report here that native HA can be reversibly altered by heat treatment such that C-inhibitory properties are manifested. We have determined in this study that a potent C-inhibitory activity can be obtained if HA solutions are thermally treated (100 degrees C), and stabilized by prompt freezing with prompt thawing just prior to the interaction with human serum complement. Several investigators have proposed that the intermolecular-associated strands of HA undergo a reversible decoupling upon thermal treatment and this decoupled state of HA can be semi-stabilized by quickly cooling the sample. This heat-treated HA strongly inhibits C1 as well as classical-pathway-mediated C3 conversion. However, if heat-treated HA samples are not stabilized but, rather, slowly cooled after heating or if heated HA samples are snapfrozen and then slowly thawed, the anticomplementary activity is gradually lost. Interestingly, the activity for this same sample can be regenerated by retreatment of the same sample with heat followed by low-temp stabilization, indicating the reversibility of the physical state of HA responsible for the anticomplementary effect. Since no detectable molecular degradation of thermally-treated HA was found, it was assumed that a heat-induced physical transition of HA (decoupled state) was responsible for the C-inhibitory effect.

Chromatography, Gel↗

PubMed1984

Role of protease--protease-inhibitor complexes in inflammation.

Neutrophils accumulate and release proteolytic enzymes at the site of acute inflammation. These proteases cause tissue damage but are inactivated by protease-inhibitors which have been thought to finish their activity. We paid attention to these protease--protease-inhibitor complexes and examined their roles. Trypsin was used as a proteolytic enzyme and was mixed with an excess of purified alpha 1-antitrypsin (alpha 1AT). The trypsin-alpha 1AT complex was separated from native alpha 1AT by column chromatography. Then the complex was incubated with human neutrophils and lysosomal enzyme release was examined. Significant enzyme release was observed when neutrophils were incubated with the complex, but the amount of enzyme release from the cells was not obvious when neutrophils were incubated with alpha 1AT or trypsin alone. The amount of lysosomal enzyme release was proportional to the amount of the complex added. Further study revealed that the complex did not have much influence on neutrophil chemotaxis or superoxide radical generation, but could activate complement by the classical pathway. These facts indicate that protease--protease-inhibitor complexes play a role in prolonging inflammation.

Adult↗

PubMed2003

Complement-inhibiting iridoids from Morinda morindoides.

Morinda morindoides (Baker) Milne-Redhead (syn. Gaertnera morindoides Bak.) is one of the most popular medicinal plants in the Democratic Republic of Congo. In relation to its traditional use against rheumatic pains, fractionation of both the EtOAc- and the n-BuOH-soluble fraction of the 80% MeOH extract of the leaves, guided by the anticomplementary activity on the classical activation pathway, yielded eight novel iridoids (1-8), all containing a spirolactone functionality. Their structure was elucidated using spectroscopic methods. Gaertneroside 1, acetylgaertneroside 2, and gaertneric acid 5 were found to inhibit the activation of the classical pathway of the complement system, with IC(50) values between 58 and 69 microM. In addition to the biologically active flavonoids reported before from the same plant, these complement-inhibiting iridoids may contribute at least in part to the traditional use against rheumatic pains.

Complement Inactivator Proteins↗

PubMed1979

Factor XII deficiency with systemic lupus erythematosus. Biological implications.

A patient with Factor XII (Hageman) deficiency and fulminant systemic lupus erythematosus is presented. The Factor XII deficiency was noted prior to the onset of clinical systemic lupus erythematosus and persisted throughout the patient's course without associated hemorrhagic manifestations. There was no evidence for a circulating anticoagulant. The patient had a rapidly progressive fatal course unresponsive to corticosteroid therapy. Factor XII levels did not increase during therapy with steroids. Despite absence of Hageman factor, evidence for activation of complement by the classic pathway and thromboembolic phenomenon was observed. The role of Factor XII in coagulation and inflammatory pathways and the influence of the factor deficiency on the course of the patient's illness are discussed.

Adolescent↗

PubMed2003

[Anticomplement activity of saponins from Cynara cardunculus L].

Triterpene saponins of ursane and oleane type isolated from the involucral bracts of Cynara cardunculus L. (Asteraceae) were investigated in in vitro assays for their activity on the complement system. The anticomplementary activity of bidesmosidic saponins on the classical pathway activation of the complement was higher than the activity of monodesmosidic saponins, but esterification of the carboxylic group of glucuronic acid in the sugar residue resulted in a significant decrease in anticomplementary activity.

Animals↗

PubMed1978

'In vitro' study of a reaction between the complement system and cellular DNA.

A direct reaction between the complement system and DNA in nuclei was demonstrated in vitro by an indirect immunofluorescence technique using cryostat-cut sections of rat liver as a substrate. This reaction occurred at physiological conditions of pH and molarity and was abolished by pre-treatment of the tissue sections by DNase. It begins by the fixation of C1q and involves the fixation and probably the activation of apparently all the components of the classical pathway of the complement system. The pattern of fluorescence given by this reaction was similar to the pattern given by anti-DNA antibodies present in sera from systemic lupus erythematosus (SLE) patients.

Animals↗