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PubMed1981

Isolation and characterization of a low molecular weight complement inhibitor present in normal human serum.

Normal human serum and urine were found to contain a low molecular weight complement inhibitor (LMWI). LMWI was separated from serum by dialysis in membrane tubing or through an Amicon PM10, and then concentrated on an Amicon UM05 membrane. On Bio-Gel P-2 filtration, LMWI was eluted just after the column calibration marker, stachyose hydrate (6666 . 6 daltons), and was estimated to be 500 daltons. Both pathways of complement activation were susceptible to modulation by LMWI. Addition of LMWI reduced the haemolysis of sheep erythrocytes sensitized with antibody, rabbit erythrocytes and guinea-pig erythrocytes bearing human C3 and C4. Formation of EAC142 from EAC14 and guinea-pig C2 was blocked, indicating a failure to generate the classical pathway C3 convertase: however, the lysis of preformed EAC142 was not suppressed. Conversion of factor B and C3 did not occur when LMWI was present during zymosan activation of serum. This indicates that the inhibitor either prevented, or acted at a step prior to, the cleavage of factor B by factor D. LMWI did not prevent formation of erythrocyte C567 intermediates nor their subsequent lysis by C8 and C9. Thus, serum contains a 500-dalton inhibitor which modulates the activities of both complement pathways at an early step in each of the activation sequences. LMWI may serve as a regulator of the inflammatory process by suppressing C3 convertase formation and generation of complement-derived, biologically reactive molecules.

Blood↗

PubMed1983

Inhibition of neutrophil function by fluid phase C3b of complement.

A high-molecular-weight fragment of C3 was isolated from normal human serum by column chromatography, was generated by incubation of serum at 37 degrees C with inulin, and was produced from highly purified C3 by limited digestion with trypsin. This product was shown to inhibit the antibacterial function of neutrophils by using Escherichia coli O75 as the main test organism. The inhibitor reacted with anti-C3b and anti-C3c, but not with anti-C3B (anti-native C3) or anti-C3a. The manner of preparation of the inhibitor, the sodium dodecyl sulfate-polyacrylamide gel electrophoresis pattern, and the amino acid composition of the inhibitor indicated that it was fluid phase C3b. The inhibitor of neutrophil function (fluid phase C3b) was shown to bind to C3b receptors or acceptors on sheep erythrocytes in a model system.

Amino Acids↗

PubMed1990

[Study of the complement system. General principles and perspectives].

Measurement of complement in clinical medicine is traditionally based on the determination of CH50 and immunochemical and/or functional measurement of complement proteins C1q, factor B, C3 and C4. The interpretation of these measurements, as far as complement activation is concerned, can however be difficult as these tests do not allow to discriminate between consumption due to activation, hereditary deficiency, increased rate of synthesis or even hyposynthesis. This explains why their use as markers of evolutivity in diseases where complement activation is occurring has given variable results. New tests for complement activation have been more recently introduced. These are mainly the measurements of the anaphytotoxins, the degradation products of C3 and the membrane attack complex. As these tests reflect more directly complement activation, they may be more reliable markers. The immunochemical and functional measurements of C1-inhibitor are of special interest as they are the tests which allow definitive diagnosis of the hereditary angio-oedema. General principles for the interpretation of the different tests used to evaluate the complement system are presented and discussed.

Anaphylatoxins↗

PubMed2001

Cytolytic complement activity in otitis media with effusion.

Otitis media with effusion (OME) is a chronic inflammation persisting in the middle ear cavity of at least 8 weeks duration. Middle ear effusion (MEE; n = 38), samples from children suffering from OME were investigated for their direct cytolytic activity or an ability to enhance complement lysis of unsensitized bystander cells. Thirteen of the 38 MEEs had direct endogenous haemolytic activity and 27 samples had an ability to enhance serum-initiated lysis. Using an enzyme immunoassay, high levels of terminal complement complexes (TCC) were detected in the MEE samples (mean 34.1 microg/ml, range 5--89 microg/ml). This indicated strong local complement activation that had progressed to the terminal stage. As one potential factor promoting complement activation we identified both monomeric and trimeric properdin in MEE by Western blotting. By stabilizing C3 and C5 convertases properdin accelerates the alternative and terminal pathways of complement. On the other hand, the membrane attack complex (MAC) inhibitor CD59, which was found to be extensively shed into the MEE in a functionally active form, may control excessive cytotoxicity of the MEE. In conclusion, intense complement activation, up to the terminal level, maintains ongoing inflammation in the middle ear cavity and can pose a threat to the local epithelium.

CD59 Antigens↗

PubMed2006

Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion.

Ischemia/reperfusion (I/R) of several organs results in complement activation, but the kidney is unique in that activation after I/R occurs only via the alternative pathway. We hypothesized that selective activation of this pathway after renal I/R could occur either because of a loss of complement inhibition or from increased local synthesis of complement factors. We examined the relationship between renal complement activation after I/R and the levels and localization of intrinsic membrane complement inhibitors. We found that loss of polarity of complement receptor 1-related protein y (Crry) in the tubular epithelium preceded activation of the alternative pathway along the basolateral aspect of the tubular cells. Heterozygous gene-targeted mice that expressed lower amounts of Crry were more sensitive to ischemic injury. Furthermore, inhibition of Crry expressed by proximal tubular epithelial cells in vitro resulted in alternative pathway-mediated injury to the cells. Thus, altered expression of a complement inhibitor within the tubular epithelium appears to be a critical factor permitting activation of the alternative pathway of complement after I/R. Increased C3 mRNA and decreased factor H mRNA were also detected in the outer medulla after I/R, suggesting that altered synthesis of these factors might further contribute to complement activation in this location.

Animals↗

PubMed1983

Selective complete Clq deficiency associated with systemic lupus erythematosus.

We report a case of systemic lupus erythematosus (SLE) and recurrent infections associated with isolated Clq deficiency. A 17-year-old girl from Saudi Arabia was hospitalized with seizures, fever, arthralgia, hair loss, oral ulceration and skin rash. Clinical and laboratory findings fulfilled the ARA preliminary criteria for the classification of SLE. Nonlesional skin contained immunoglobulins and C3 at the dermal-epidermal junction. She did not have antibodies to DNA or low C3 or C4. Total serum hemolytic complement activity was absent due to a total selective absence of Clq. There was no circulating inhibitor of Clq activity. The published experience of isolated selective complete Clq deficiency associated with clinical disease is reviewed.

Adolescent↗

PubMed1995

Production of the third component of complement (C3) by peripheral polymorphonuclear neutrophils of the patients with rheumatoid arthritis.

Normal human polymorphonuclear neutrophils (PMN) can spontaneously produce the third component of complement (C3) in in vitro culture as detected by ELISA. This C3-producing capacity of PMN can be augmented by TNF-alpha (20 ng/ml) and bacterial lipopolysaccharide (100 ng/ml), but not by IL-1 beta or IL-8. The C3 production by PMN was found to be temperature dependent and was suppressed by the addition of protein inhibitor. The C3 mRNA in PMN could be detected by reverse transcription assisted polymerase chain reaction (RT-PCR) after TNF-alpha or LPS stimulation for 6 hours. To further understand C3 production by peripheral blood PMN in rheumatoid arthritis (RA), spontaneous and TNF-alpha stimulated production of C3 by peripheral PMN were compared in 15 cases of active RA, 15 inactive RA and 15 normal individuals. We failed to find any significant difference among the three groups. We conclude that PMN plays a negligible role in C3 hypercomplementemia in patients with active RA.

Arthritis, Rheumatoid↗

PubMed2004

Synthetic small-molecule complement inhibitors.

During the past few years, several large molecular-weight compounds with complement-inhibitory activities have entered clinical trials for a wide variety of acute and chronic inflammatory conditions. Various small synthetic compounds that offer several advantages over the larger complement inhibitors are also being discovered at a rapid pace. In this review, the focus will be on three of these small molecules, a C3-binding peptide, compstatin; a synthetic peptidic antagonist of the C5a anaphylatoxin receptor, 3D53; and a non-peptidergic antagonist of the C3a anaphylatoxin receptor, SB-290157. In recent years, compstatin has undergone a series of optimizations that have led to more active and stable analogs, while 3D53 and SB-290157 have been more extensively tested in animal models of various human inflammatory diseases. These compounds have been shown to be effective and display little or no toxicity, and as such may be promising new candidates for further therapeutic development.

Animals↗

PubMed2001

Cryoprecipitate of patients with cryoglobulinemic glomerulonephritis contains molecules of the lectin complement pathway.

Serological and histological studies were carried out to explore the role of the lectin complement pathway in the pathogenesis of cryoglobulinemic glomerulonephritis. Sixteen patients with mixed cryoglobulinemia type II with glomerulonephritis (GN) were enrolled. All cases had hepatitis C virus (HCV) infection. The serum concentration of mannose-binding lectin (MBL) was significantly higher in the GN patients than in the normal controls according to ELISA (P < 0.01). IgG, IgM, C1q, C4d, HCV envelope antigen, MBL, and MBL-associated serine protease-1 (MASP-1) could be visualized in the cryoprecipitate of the 16 patients by Dot blot assay. Renal biopsy specimens obtained from 3 patients were examined by immunohistochemistry, and the glomeruli strongly stained for IgG, IgM, MBL, MASP-1, C4d, C3c, and C3d in a fringe-like pattern. The pattern of HCV constituent deposition was partially fringe-like. The complement profiles of the 16 cases were distinctive; briefly, the serum levels of C1q, C2, and C3 were reduced, although the levels of circulating regulatory proteins (C1-inhibitor, factor H, and factor I) were in the normal range. The serum C4 level was significantly reduced. These results indicate that immune complex formation involves molecules of the lectin pathway and leads to organ damage in cryoglobulinemic glomerulonephritis.

Adolescent↗

PubMed2003

CCP1-4 of the C4b-binding protein alpha-chain are required for factor I mediated cleavage of complement factor C3b.

C4b-binding protein (C4BP) is a potent regulator of the complement system because it strongly inhibits the classical pathway of complement. Furthermore, C4BP serves as a cofactor to factor I (FI) in the cleavage of fluid phase C3b and can, therefore, influence the alternative pathway of complement. The major form of C4BP in plasma consists of seven identical alpha-chains and one beta-chain. Both types of subunits are composed of complement control protein (CCP) domains, eight such domains make up one alpha-chain. To elucidate the structural requirements for the interaction between C3b and the alpha-chain, nineteen recombinant C4BP variants were used: six truncated monomeric variants, nine polymeric variants in which individual CCPs were deleted, and finally four variants in which double alanine residues were introduced between CCPs. We found that C4BP requires all four N-terminal CCPs of the alpha-chain, with CCP2 and 3 being the most important, to act as a cofactor in the cleavage of C3b. Also, a cluster of positively charged amino acids on the interface between CCP1 and 2 is involved in the binding. Compared to the interaction with C4b, we conclude that binding of C3b to C4BP requires larger molecular surface on C4BP. We found that C4BP was able to act as cofactor in degradation of surface bound C3b and to accelerate decay of alternative C3-convertase. However, in both cases 1,000-fold molar excess of C4BP over factor H (FH), well known inhibitor of the alternative pathway, was required to obtain the same effect.

Amino Acid Substitution↗

PubMedDate not supplied

Protective effect of nafamostat mesilate on injury of porcine hepatocytes by human plasma.

Nafamostat mesilate (NM), a protease inhibitor, possesses a cytoprotective effect and inhibits the activation of complement. The present study investigated whether NM has any protective effect against injury of porcine hepatocytes by human plasma in a bioartificial liver support system. Porcine hepatocytes were harvested and seeded at a density of 2 x 10(5) cells on a 35-mm collagen-coated plate in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum. Twenty-four hours later, the medium was replaced with human plasma with three concentrations of NM between 3.8 x 10(-5) and 3.8 x 10(-4) M and then cultured for 6 h. The viability of porcine hepatocytes, lactate dehydrogenase (LDH) levels, lidocaine clearance, porcine albumin production, and changes in complement (C3) levels were measured. The viability of porcine hepatocytes in human plasma decreased significantly to 37.7 +/- 11.4% of that in DMEM. NM improved the viability of the hepatocytes, lowered the levels of LDH, and increased lidocaine clearance and albumin production in a concentration-dependent manner. The concentrations of C3, the marker of xenogeneic reactions, did not change significantly, indicating that no hyperacute xenogeneic reaction occurred in our series. Together, our results suggested that NM exerts favorable effects on porcine hepatocytes in human plasma through direct effect such as prevention of protease activity in the plasma membrane of porcine hepatocytes rather than inhibition of complement-dependent immunoreactions.

Albumins↗

PubMed2003

Membrane-bound complement regulatory proteins inhibit complement activation by an immunotherapeutic mAb in a syngeneic rat colorectal cancer model.

MAb-mediated immunotherapy offers a potential tool for destroying metastasizing colorectal tumor cells. Promising results have been obtained by using xenograft models. However, overexpression of membrane-bound complement regulatory proteins (mCRP) impedes complement-mediated destruction of tumor cells in vitro. mCRP operate in a species selective manner. Therefore a syngeneic animal model is needed to investigate the contribution of mCRP in mAb-mediated immunotherapy. Here we present a syngeneic rat colorectal carcinoma model, which fulfills the conditions necessary to investigate the effect of mCRP expression on mAb-mediated immunotherapy of metastases of solid tumors.CC531 rat colorectal cancer cells were injected subcapsularly into the liver of syngeneic WAG/Rij rats. Four mAb (MG1(IgG2a), MG2(IgG2a), MG3(IgG3) and MG4(2a)(IgG2a)) directed against CC531 cells, were tested for their complement activating abilities in vitro and tumor homing capacities in vivo. Only MG4(2a) was found to activate complement in vitro and home to the tumor cells in vivo. This mAb induced C3-deposition and C-mediated lysis of CC531 cells in vitro when the effects of the C-inhibitors Crry/p65 and CD59 were neutralized. This implies an important role for these mCRP in restricting the effector functions of tumor-associated mAb on these cells. Although C activation could be induced by MG4(2a) in situ on tumor tissue sections, no deposition of C3 could be found on the tumor cells positive for MG4(2a) in vivo. This suggests that complement activation in vivo was inhibited by mCRP. The results indicate the suitability of this syngeneic animal model for studying the effects of mAb immunotherapy. However, the effect of mCRP on tumor cells need to be overcome, e.g. by the use of mAb against tumor antigens and mCRP.

Animals↗

PubMed1992

Complement regulatory proteins at the feto-maternal interface during human placental development: distribution of CD59 by comparison with membrane cofactor protein (CD46) and decay accelerating factor (CD55).

The complement (C) regulatory proteins decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), which control C3 convertases, together with CD59, an inhibitor of the membrane attack complex (MAC), were found to be present in the developing human placenta from at least 6 weeks of gestation until term. Immunostaining revealed differences in the distribution of these proteins on the fetally derived trophoblast epithelium, especially in early placentae which contain trophoblast populations of diverse proliferative potential and differentiation status. Expression of all three proteins occurred on the terminally differentiated syncytiotrophoblast epithelium covering chorionic villi and which is in direct contact with maternal blood. CD59 was also expressed on the underlying villous cytotrophoblast cells and on their extra-villous derivatives. These two populations showed differential expression of the C3 convertase regulators. Villous cytotrophoblast cells expressed MCP but were largely devoid of DAF. Proliferation of this population to generate extra-villous cytotrophoblast cell columns was associated with both an increase in DAF expression and a decrease in MCP expression. Throughout placental development, expression of DAF appeared to be lower than that of MCP and CD59 as assessed by solid-phase binding assays on isolated trophoblast membranes. Early placentae were also found to contain both DAF+ and DAF- chorionic villi. Conversely, expression of CD59 appeared comparatively high and transcripts for CD59 were found to be much more abundant than those for DAF in purified trophoblast cells. C regulatory proteins appear to play an important role throughout gestation in protecting the fetally derived human conceptus from maternal C. The differential expression patterns of the proteins on trophoblast may reflect differences in requirement for specific functional activities at different locations within the placenta.

Antigens, CD↗

PubMed2003

Effect of hybrid complement regulatory proteins on xenogeneic cells.

To suppress C3 fragment deposition in the classical pathway complement activation on xenogeneic membranes, decay accelerating factor (DAF) was the most effective molecule among the complement regulatory proteins (CRPs) used in the present study. C3 fragment deposition was closely related to subsequent xenogeneic cell lysis. However, other molecules were also very effective in different ways and include phosphatidylinositol (PI)-anchored short consensus repeat (SCR) 2-4 of membrane cofactor protein (MCP-PI), PI-anchored C1 esterase inhibitor (C1-INH-PI), and PI-anchored SCR8-11 of complement receptor type 1 (CR1-PI). On the other hand, regarding a strategy for downregulating C4 fragment deposition, the use of only C1-INH-PI and PI-anchored SCR1-3 of the C4b-binding protein (C4bp-PI) was found to be effective.

Animals↗

PubMed1987

The role of ion channels and protein kinase C activation in the stimulation of complement protein synthesis.

Monocyte C2 synthesis is stimulated by antigen-antibody complexes (IC), carbamylcholine (C-Ch), phenylephrine (PE) and gamma-interferon. Tetrodotoxin or nifedipine abrogated the effects of IC, C-Ch and PE but did not influence the effect of gamma-interferon on C2 synthesis. Thus stimulation of C2 synthesis by IC, C-Ch and PE is dependent upon activation of Na+/K+ and Ca2+ channels, whereas gamma-interferon operates independently of these ion channels. Calcium channel agonists (CG28392 and BK8644) stimulated C2 synthesis, and this effect was prevented by nifedipine but not by tetrodotoxin. Thus Na+/K+ channels are activated prior to Ca2+ channels. Stimulation of C2 synthesis occurred when phospholipase C or phorbol myristate acetate (PMA) were added to the monocyte cultures, suggesting that PI cycle turnover and protein kinase-C (PK-C) activation are involved in the stimulation of C2 synthesis in monocytes. PMA, an activator of PK-C, stimulated the synthesis of C2, C3, B, P and C1-inhibitor approximately two-fold. In contrast gamma-interferon reduced synthesis of C3 and P by 44% and 22% respectively, and stimulated C1-inhibitor synthesis twelve-fold. These data suggest that the action of gamma-interferon complement synthesis is, at least partially, independent of PK-C activation. The effects of IC, C-Ch, PE, PI, CG28392, BK8644 and gamma-interferon were inhibited by trifluoperazine implying that calmodulin and/or other calcium binding proteins play a role in the modulation of complement protein production.

Calcium Channel Agonists↗

PubMed1995

Disparity in blood activation by two different heparin-coated cardiopulmonary bypass systems.

BACKGROUND: Several studies have indicated reduced "blood activation" in heparin-coated cardiopulmonary bypass systems. The present study compares the effect of two different heparin coatings on different blood activation indices. METHODS: Low-risk patients (n = 40) were randomized to coronary artery bypass grafting using cardiopulmonary bypass with surfaces coated entirely by either the Duraflo II heparin coat or the Carmeda Biological Active Surface, or with identical uncoated equipment. In all cases, a standard systemic heparin dosage was used. Complement activation (C3 activation products C3bc and C3a and formation of fluid phase terminal SC5b-9 complement complex), neutrophil activation (lactoferrin and myeloperoxidase), and lytic inhibitors (vitronectin and clusterin) were quantified during cardiopulmonary bypass and 6 hours postoperatively. RESULTS: Heparin coating by either method reduced the formation of terminal SC5b-9 complement complex and the release of lactoferrin and myeloperoxidase compared with uncoated systems. Lactoferrin and myeloperoxidase levels increased significantly during cardiopulmonary bypass in the Duraflo II group, whereas no significant increase was observed in the Carmeda Biological Active Surface group. The least formation of terminal SC5b-9 complement complex and neutrophil activation was observed with the Maxima Carmeda Biological Active Surface-coated equipment. The vitronectin and clusterin concentrations were significantly less reduced in the Duraflo II compared with the control group. This study underlines the importance of terminal SC5b-9 complement complex as a suitable marker in the evaluation of complement activation during cardiopulmonary bypass. CONCLUSIONS: Both heparin coatings reduce blood activation, probably more so with Carmeda Biological Active Surface than with Duraflo II.

Anticoagulants↗

PubMed1988

The esterase-like activity of covalently bound human third complement protein.

The acyl ester bond between the third complement protein, C3, and a variety of molecules is hydrolyzed spontaneously at neutral pH (Venkatesh et al., 1984). Modification of the free, single sulfhydryl group of bound C3 by thiol reagents suggested that a functional group other than the -SH acts as a "catalytic" group in this intramolecular hydrolytic reaction. Complete inhibition of the esterase-like activity is observed with stoichiometric amounts of mercuric chloride, palladium chloride, and the bifunctional organic mercurial, 3,6-bis-(acetoxymercuri)-o-toluidine [BAMT]. Since alkyl and aryl mercuric ions do not inhibit the esterase-like activity of C3-[3H]glycerol, it is conjectured that divalent mercury, palladium, and BAMT will form a complex with the -SH group and an atom of the "catalytic" group X having a lone pair of electrons. The structural features of C3 that are essential for the esterase-like activity remain intact after subjecting C3-[3H]glycerol to covalent chromatography on organomercurial agarose. Based on the observed effects of chemical reagents and the kinetic deuterium solvent isotope effect on the esterase-like activity, a general-base mechanism is proposed for the intramolecular hydrolysis of the acyl ester bond in covalently bound C3. The "catalytic" group X is located in the C3d region (residues 317-632 of the alpha chain), since C3d-[3H]glycerol also has esterase-like activity. A general-base mechanism mediated by the same "catalytic" group X may also apply to the formation of acyl ester bonds following the hydrolysis of the internal thiolester bond in native C3.

Chemical Phenomena↗

PubMed1988

Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant.

We reviewed the histopathologic findings in 28 specimens from 25 patients who had skin lesions associated with lupus anticoagulant. The clinical lesions were ulcers, gangrene, thrombophlebitis, hemorrhage, and cutaneous necrosis. Noninflammatory thrombosis of small dermal vessels was observed in all 8 biopsy specimens from gangrene lesions, 10 of 13 specimens from ulcer lesions, and 2 of 5 specimens from thrombophlebitis lesions. Necrotizing vasculitis was not significant in these biopsy specimens. Immunofluorescence findings included a positive lupus band test in lupus erythematosus-associated disease and nonspecific deposits in occasional cases. Focal noninflammatory intravascular coagulation is responsible for the microscopic and clinical skin lesions in these patients.

Blood Coagulation Factors↗