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PubMed1994

Anti-complement activity of oleanolic acid: an inhibitor of C3-convertase of the classical complement pathway.

Oleanolic acid is a naturally occurring compound, isolated from Luffa cylindrica, which inhibits the in-vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea-pig serum. In further experiments this reduced immunohaemolysis was found to be due to inhibition of the C3-convertase of the classical complement pathway. The threshold concentration for inhibition of C3-convertase was 100 micrograms mL-1. However, higher concentrations of oleanolic acid showed constant inhibitory effects on immunohaemolysis. Oleanolic acid also exhibited weak inhibitory effects on individual components of the complement system.

Animals↗
PubMed1975

Interaction of collagen with serum complement: inhibition of complement-mediated hemolysis.

Collagens from various vertebrate tissues were tested for their ability to consume complement (C) activity upon incubation in human serum or with isolated components of complement. 10 of 12 collagens tested had anticomplementary activity. The heat-denatured form of collagen, gelatin, was found weakly anticomplementary, but elastin was found inactive in the interaction with C. Inactivation of C is a reaction which is dependent on the time of incubation and the collagen concentration and partially dependent on the temperature of incubation. Most collagens depleted C from human serum in presence of cation chelators, EDTA and EGTA, whereas the large part of anticomplementary activity of soluble collagens obtained from rat skin was abolished in presence of EDTA. Evidence is presented that two different principles in collagens play a role in inactivation of C. A factor, contained in insoluble collagens and inhibitable by mild oxidation with periodate, inactivates C1 directly even in presence of chelating agents. Another principle, contained in soluble and insoluble collagen and resistant to periodate treatment, depletes C in serum by utilization of C via the alternate pathway (the C3 shunt).

Animals↗
PubMed1991

Low number of complement C3b/C4b receptors (CR1) on erythrocytes from patients with essential mixed cryoglobulinemia, systemic lupus erythematosus and rheumatoid arthritis: relationship with disease activity, anticardiolipin antibodies, complement activation and therapy.

Our aim was to assess whether the amount of complement C3b/C4b receptors (CR1) on erythrocytes shows a correlation to disease activity in various connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and essential mixed cryoglobulinemia (EMC). Using an anti-CR1 monoclonal antibody, 26 patients with SLE, 34 with RA and 22 patients with EMC were investigated for erythrocyte CR1 expression. The control group consisted of 30 healthy individuals. The mean number of CR1/erythrocyte in the control group was 568 +/- 197 (range 174-1060), significantly higher than studied (EMC:379 +/- 248; p = 0.0005;SLE 147 +/- 56, p less than 0.0001; RA 298 +/- 177, p less than 0.0001). In patients with RA and in SLE, but not in patients with EMC, the number of CR1 numbers and anticardiolipin antibody (aCl) titers (r2 = 0.493; p = 0.034). A statistically significant correlation between CR1 numbers and CH50 values was found in patients with SLE, while in 3 patients with RA 4 months of therapy with cyclosporine A led to a further 30% reduction in CR1 number. Our conclusions are that (a) the decreased expression of erythrocyte CR1 is apparently a common feature of patients with various connective tissue diseases; (b) several acquired factors such as disease activity, complement activation, aCl and drugs may contribute to the loss of CR1 from erythrocytes; (c) in patients with RA and SLE, but not in patients with EMC, CR1 enumeration on erythrocytes may serve as a variable for clinical monitoring.

Adult↗
PubMed1996

Complement-fixing islet cell antibodies in type-1 diabetes can trigger the assembly of the terminal complement complex on human islet cells and are potentially cytotoxic.

Forty-one sera of patients with IDDM (insulin-dependent diabetes mellitus) containing complement-fixing islet cell antibodies were analyzed for their ability to activate TCC (terminal complement complex). Eighteen sera were found to promote deposition of TCC on human islets of pancreatic cryostat sections with a nonhomogeneous pattern of distribution corresponding to that of insulin. Activation of TCC by IDDM serum and binding of this complex to islet cells was confirmed using purified islets. Flow cytometric analysis of islet cell treated with a TCC+ IDDM serum showed IgG binding to the cell surface. The same serum had a cytotoxic effect on islet cells in the presence of human C. These results obtained with a homologous system of C activation by IDDM sera suggest that TCC may contribute, at least in part, to the pancreatic beta cell damage.

Autoantibodies↗
PubMed1987

Intrathecal complement activation in neurological diseases evaluated by analysis of the terminal complement complex.

The terminal complement complex (TCC) was determined in plasma and cerebrospinal fluid (CSF) from 208 neurological patients. Elevated CSF TCC levels were observed in higher frequencies in patients with infectious diseases (80%), radiculoneuritis (62%), multiple sclerosis (30%), and miscellaneous autoimmune diseases (27%) than in patients with miscellaneous non-inflammatory diseases (2-13%). The plasma level of TCC was significantly increased only in the infectious group. No positive correlation was observed between the plasma and the CSF TCC concentration in the whole patient population nor in subgroups divided according to blood-brain barrier function. Furthermore, the CSF TCC concentration did not correlate with the serum/CSF albumin ratio or with CSF total protein concentration when this was below 1.0 g/l. It is concluded that an elevated TCC concentration in CSF reflects intrathecal complement activation and that quantification of TCC in CSF may be a valuable supplement in the examination of neurological diseases.

Blood-Brain Barrier↗
PubMed1990

Hormonal regulation of complement biosynthesis in human cell lines--II. Upregulation of the biosynthesis of complement components C3, factor B and C1 inhibitor by interleukin-6 and interleukin-1 in human hepatoma cell line.

The effect of interleukin (IL)-6 and IL-1 on the biosynthesis of complement components C3, factor B, C2, C4 and C1 inhibitor (C1 inh), as well as that of albumin, was studied in vitro in human hepatoma-derived cell line, HepG2. Measuring the amounts of secreted complement proteins we detected a significant upregulation of C3 by both hormones. The enhancement of the factor B and especially that of C1 inh production was predominant by IL-6. In our experimental system neither IL-1 nor IL-6 affected the biosynthesis of C2 and C4. Albumin secretion was significantly decreased only in the simultaneous presence of IL-1 and IL-6. Detection of the changes in the amounts of C3- and factor B-specific mRNA of HepG2 cells suggests a pretranslational regulation by these cytokines. The secretion of C3 and factor B was markedly potentiated when IL-1 and IL-6 were added together. However only the gene expression of factor B, but not of C3, was found to reveal synergism. IL-6 enhanced the in vitro production of C3 in mouse hepatocytes as well. This effect was greatly potentiated in the presence of histamine.

Carcinoma, Hepatocellular↗
PubMed1983

Effects of immunological adjuvants on the mouse complement system. I. The inability of the polyanion heparin to act as an adjuvant is paralleled by inefficient alternative complement pathway inhibition.

Interference with hemolytic complement activity by polyanionic substances was studied in relation to the ability of these compounds to act as an adjuvant for a dead listeria vaccine. Heparin appeared a poor inhibitor of the mouse alternative pathway not only in contrast to its effects on the mouse classical and the human classical and alternative pathways, but also when compared to two polyanions with known adjuvant activity: dextran sulfate and suramin. For the three polyanions mentioned a correlation between adjuvant activity and mouse alternative pathway inhibition was observed. These findings suggest a possible causal relationship between interference with alternative complement pathway activation and adjuvant activity.

Adjuvants, Immunologic↗
PubMed1986

Lipopolysaccharides as complement inhibitors by complex formation with the purified third complement component (C3).

Lipopolysaccharides (LPS) from different bacteria in smooth or rough form (Y. enterocolitica, Y. pseudotuberculosis, E. coli, S. typhimurium, S. marcescens) strongly inhibited hemolytic C3 in incubation mixtures with purified C3. LPS from a core deficient mutant was still reactive, whereas lipid A no longer affected C3 activity. The physical state of LPS was critical for its effect on C3. Strand-like LPS structures formed by Ca++-induced aggregation of solubilized LPS, as shown by electron microscopy, demonstrated the highest reactivity with C3. Inhibition of hemolytic C3 was found to be due to complex formation between LPS and C3 by a hydrophobic reaction. The binding capacity of 1 microgram LPS-R and LPS-S was as high as 125 ng C3 and 56 ng C3, respectively. The C3b fragment required different reaction conditions for maximal binding. The strong binding capacity of LPS for the complement component C3 raises the possibility that LPS act as inhibitors of complement by interruption of the reaction cascade at local infectious sites with gram-negative bacteria.

Centrifugation, Density Gradient↗
PubMed1996

Role of a disulfide-bonded peptide loop within human complement C9 in the species-selectivity of complement inhibitor CD59.

CD59 antigen is a membrane glycoprotein that inhibits the activity of the C9 component of the C5b-9 membrane attack complex (MAC), thereby protecting human cells from lysis by human complement. The complement-inhibitory activity of CD59 is species-selective, and is most effective toward C9 derived from human or other primate plasma. The species-selective activity of CD59 was recently used to map the segment of human C9 that is recognized by this MAC inhibitor, using recombinant rabbit/human C9 chimeras that retain lytic function within the MAC [Husler, T., Lockert, D. H., Kaufman, K. M., Sodetz, J. M., & Sims, P. J. (1995) J. Biol. Chem. 270,3483-3486]. These experiments suggested that the CD59 recognition domain was contained between residues 334 and 415 in human C9. By analyzing the species-selective lytic activity of recombinant C9 with chimeric substitutions internal to this segment, we now demonstrate that the site in human C9 uniquely recognized by CD59 is centered on those residues contained between C9 Cys359/Cys384, with an additional contribution by residues C-terminal to this segment. Consistent with its role as a CD59 recognition domain, CD59 specifically bound a human C9-derived peptide corresponding to residues 359-384, and antibody (Fab) raised against this C9-derived peptide inhibited the lytic activity of human MAC. Mutant human C9 in which Ala was substituted for Cys359/384 was found to express normal lytic activity and to be fully inhibited by CD59. This suggests that the intrachain Cys359/Cys384 disulfide bond within C9 is not required to maintain the conformation of this segment of C9 for interaction with CD59.

Amino Acid Sequence↗
PubMed1992

Limited tryptic cleavage of complement factor H abrogates recognition of sialic acid-containing surfaces by the alternative pathway of complement.

The potency of complement factor H (H) in accelerating the decay of the alternative pathway C3 convertase, C3b,Bb (decay-accelerating activity), was used as a measure of the affinity of native versus trypsin-treated H for the complement protein C3b bound to surfaces. When about 99% of H was cleaved at the primary tryptic cleavage site 34 kDa from the N-terminus, its decay-accelerating activity on C3b,Bb on sheep erythrocytes fell about 60-fold, whereas the trypsin-treated H was only 3-4 times less potent than native H in dissociating C3b,Bb on Sepharose 4B. The residual decay-accelerating activity, remaining after the primary cleavage, was not affected by secondary cleavage at a site 120 kDa from the N-terminus, as shown with H preparations cleaved to different degrees. Because cell surface sialic acid is known to be responsible for the high affinity of H for C3b bound on sheep erythrocytes, the results strongly suggest that the integrity of the primary tryptic cleavage site of H is essential for the recognition of sialic acid-containing surfaces by the C3b-H complex.

Animals↗
PubMed2000

Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2.

The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.

Animals↗
PubMed2003

The B cell receptor itself can activate complement to provide the complement receptor 1/2 ligand required to enhance B cell immune responses in vivo.

B cells express complement receptors (CRs) that bind activated fragments of C3 and C4. Immunized CR knockout (KO) mice have lower antibody titers and smaller germinal centers (GCs), demonstrating the importance of CR signals for the humoral immune response. CR ligands were thought to be generated via complement fixation mediated by preexisting "natural" IgM or early Ab from inefficiently activated B cells. This concept was recently challenged by a transgenic (Tg) mouse model that lacks circulating antibody but still retains membrane IgM (mIgM) and mounts normal immune responses. To test whether CR ligands could be generated by the B cell receptor (BCR) itself, we generated similar mice carrying a mutated mIgM that was defective in C1q binding. We found that B cells from such mutant mice do not deposit C3 on B cells upon BCR ligation, in contrast to B cells from mIgM mice. This has implications for the immune response: the mutant mice have smaller GCs than mIgM mice, and they are particularly deficient in the maintenance of the GC response. These results demonstrate a new BCR-dependent pathway that is sufficient and perhaps necessary to provide a CR1/2 ligand that promotes efficient B cell activation.

Animals↗
PubMed1979

Complement activation in acne vulgaris: consumption of complement by comedones.

Comedones, the contents of acne lesions, were shown to consume scomplement hemolytic activity in normal serum. This consumption was stimulated by the addition of serum from patients with inflammatory acne. Absorption of acne serum with Propionibacterium acnes cells removed all stimulating activity. Immunoelectrophoretic analysis of serum incubated with comedones revealed the conversion of C3 and factor B in normal serum. The addition of acne serum resulted in cleavage of C4. In serum treated with ethylene glycol-bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, only C3 and factor B were converted. This indicates that comedones may activate complement by either the classical or the alternative pathway. It is suggested that P. acnes cells in comedonal material are responsible for the complement activation.

Acne Vulgaris↗
PubMed2002

Attenuation of experimental allergic encephalomyelitis in complement component 6-deficient rats is associated with reduced complement C9 deposition, P-selectin expression, and cellular infiltrate in spinal cords.

The role of Ab deposition and complement activation, especially the membrane attack complex (MAC), in the mediation of injury in experimental allergic encephalomyelitis (EAE) is not resolved. The course of active EAE in normal PVG rats was compared with that in PVG rats deficient in the C6 component of complement (PVG/C6(-)) that are unable to form MAC. Following immunization with myelin basic protein, PVG/C6(-) rats developed significantly milder EAE than PVG/C rats. The anti-myelin basic protein response was similar in both strains, as was deposition of C3 in spinal cord. C9 was detected in PVG/C rats but not in PVG/C6(-), consistent with their lack of C6 and inability to form MAC. In PVG/C6(-) rats, the T cell and macrophage infiltrate in the spinal cord was also significantly less than in normal PVG/C rats. There was also reduced expression of P-selectin on endothelial cells, which may have contributed to the reduced cellular infiltrate by limiting migration from the circulation. Assay of cytokine mRNA by RT-PCR in the spinal cords showed no differences in the profile of Th1 or Th2 cytokines between PVG/C and PVG/C6(-) rats. PVG/C rats also had a greater increase in peripheral blood white blood cell, neutrophil, and basophil counts than was observed in the PVG/C6(-). These findings suggest that the MAC may have a role in the pathogenesis of EAE, not only by Ig-activated MAC injury but also via induction of P-selectin on vascular endothelium to promote infiltration of T cells and macrophages into the spinal cord.

Animals↗
PubMed2003

Prevention of collagen-induced arthritis in mice transgenic for the complement inhibitor complement receptor 1-related gene/protein y.

The objective of these studies was to examine collagen-induced arthritis (CIA) in C57BL/6 mice transgenic for the rodent complement regulatory protein complement receptor 1-related gene/protein y (Crry) (Crry-Tg), a C3 convertase inhibitor. The scores for clinical disease activity and for histological damage in the joints were both significantly decreased in Crry-Tg mice in comparison to wild-type (WT) littermates. The production of both IgG1 and IgG2a anti-collagen Abs was reduced in the Crry-Tg mice, although spleen cell proliferation in response to collagen type II was not altered. The production of IFN-gamma, TNF-alpha, and IL-1beta by LPS-stimulated spleen cells was decreased, and IL-10 was increased, in cells from Crry-Tg mice in comparison to WT. The steady-state mRNA levels for IFN-gamma, TNF-alpha, and IL-1beta were all decreased in the joints of Crry-Tg mice in comparison to WT. The synovium from Crry-Tg mice without CIA contained the mRNA for the Crry transgene, by RT-PCR, and the synovium from transgenic mice with CIA exhibited little deposition of C3 protein by immunohistological analysis. These results suggest that suppression of CIA in Crry-Tg mice may be due to enhanced synthesis of Crry locally in the joint with decreased production of proinflammatory cytokines.

Animals↗
PubMed1999

Regulation of complement activation by C-reactive protein: targeting the complement inhibitory activity of factor H by an interaction with short consensus repeat domains 7 and 8-11.

C-reactive protein (CRP) is a major acute phase protein whose functions are not totally clear. In this study, we examined the interaction of CRP with factor H (FH), a key regulator of the alternative pathway (AP) of complement. Using the surface plasmon resonance technique and a panel of recombinantly expressed FH constructs, we observed that CRP binds to two closely located regions on short consensus repeat (SCR) domains 7 and 8-11 of FH. Also FH-like protein 1 (FHL-1), an alternatively spliced product of the FH gene, bound to CRP with its most C-terminal domain (SCR 7). The binding reactions were calcium-dependent and partially inhibited by heparin. In accordance with the finding that CRP binding sites on FH were distinct from the C3b binding sites, CRP preserved the ability of FH to promote factor I-mediated cleavage of C3b. We propose that the function of CRP is to target functionally active FH and FHL-1 to injured self tissues. Thereby, CRP could restrict excessive complement attack in tissues while allowing a temporarily enhanced AP activity against invading microbes in blood.

Binding Sites↗
PubMed1975

Studies on rat complement. II. Complement level in experimental tumor in rats.

In the course of methylcholanthrene induced carcinogenesis in rats, CIA50, C4 and C3 increased as compared with control and correlation of tumor size with increase in CIA50, C4 and C3 was observed. In the course of dimethylaminoazobenzen carcinogenesis of rats, complement level and C3 level decreased but in splenectomized rats fed by dimethylaminoazobenzen showed elevated level of complement system. After Corynebacterium infection, CIA50 and C3 of rats increased. This phenomenon is considered to be one of the essential factors to induce high resistance against tumor inoculation.

Animals↗
PubMed1991

Complement activation and bioincompatibility. The terminal complement complex for evaluation and surface modification with heparin for improvement of biomaterials.

The degree of biocompatibility of biomaterials can be evaluated using various assay systems detecting activation of the blood cascade systems, leukocytes or platelets. Activation of complement is one mechanism associated with adverse effects observed when bioincompatible materials are used. We present data showing that the terminal complement complex, an indicator of terminal pathway activation, is suitable for evaluation of biocompatibility of biomaterials such as cardiopulmonary bypass devices. Furthermore, our results suggest that bioincompatibility is improved when artificial surfaces are modified with end point attached functionally active heparin.

Complement Activation↗