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PubMed1986

Effect of beta-propiolactone--an inhibitor of HTLV III/LAV activity--on immunological analyses.

beta-Propiolactone (BPL) inactivates LAV/HTLV III, the retrovirus associated with acquired immune deficiency syndrome (AIDS). Addition to specimens from patients with suspected AIDS or antibodies to LAV/HTLV III could reduce any occupational risk to laboratory staff. This study demonstrates that BPL treatment does not significantly affect the immunological analyses commonly required on these patients, namely measurements of serum immunoglobulins, complement components C3 and C4 and other serum proteins, detection of autoantibodies and estimations of T lymphocyte subpopulations.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Terminal complement complex (C5b-9) in children with recurrent hemolytic uremic syndrome.

Recurrent hemolytic uremic syndrome (recHUS) is a heterogeneous group of disorders. The pathogenesis of recHUS is not fully understood. recHUS has a high risk of development of terminal renal insufficiency and other sequelae. Abnormalities in complement factor H or in membrane-bound complement inhibitors with consecutive complement activation can be found in approximately 30 to 50% of the patients. Starting in 2001, we evaluated 42 patients with recHUS from five European countries (Germany, Austria, Hungary, Switzerland, and the Czech Republic). We measured the terminal complement complex (TCC) by an enzyme-linked immunosorbent assay using a neoepitope-specific anti-C9 antibody in 17 patients in plasma (native complement activation), serum (after coagulation), and zymosan-activated serum (Z-serum; after stimulation of coagulation). We compared the results to those of 16 healthy persons. In patients with recHUS (eight males, nine females) with a median age of 10.8 years, the TCC values were higher in plasma (0.57 versus 0.48 microg/mL; P = 0.04) and serum (3.1 versus 2.2 microg/mL) than in those of the control group, with a median age of 28.6 years (six males, 10 females) The TCC values in patients with low C3 compared with patients with normal C3 levels were even higher in plasma and serum, and the ratio was much lower. Children with recHUS have higher concentrations of TCC in plasma and serum. The ratio of Z-serum to serum showed significantly lower values in children with recHUS (96.01 versus 150.3; P = 0.01). These findings indicate a higher grade of complement activation and consumption in recHUS, suggesting that TCC may mediate cell toxicity. This may play an important role in the inferior outcome of these patients. The isolated substitution of factor H, or other complement inhibitors to block TCC formation, may represent useful therapies for these patients.

Adolescent↗

PubMed1988

Studies on phagocytosis of unopsonized rabbit erythrocytes by human monocytes.

Monolayers of freshly isolated human monocytes are known to ingest particulate activators of the human alternative complement pathway. The ingestion of rabbit erythrocytes, ER, by human monocytes in serum-free medium was studied. The process is Mg2+-dependent and optimum phagocytic activity was obtained at approximately 20 mM MgCl2. Preincubation of mononuclear leukocytes increased the number of monocytes ingesting ER by at least twofold and this involved de novo protein synthesis, as evidenced by inhibition with cycloheximide. However, preincubation of the mononuclear leukocytes for longer periods (greater than 4 hr) caused a decrease in the percentage of ingesting monocytes. No inhibition of ingestion of ER was observed by cobra venom factor (CVF) or F(ab')2 rabbit anti-human C3 of F(ab')2 murine monoclonal anti-human Bb, known to inhibit C3 convertase activity. The ingestion was also not inhibited by (a) rabbit anti-human CR1, (b) OKM1 or anti-MO1, two monoclonal anti-CR3 antibodies, (c) goat anti-human IgG Fc receptor, or (d) mannan, a competitive inhibitor of ligand uptake by the mannosyl-fucosyl receptor (MFR). In contrast, ingestion was inhibited by glucan particles of yeast.

Animals↗

PubMed2005

Ascitic complement system in ovarian cancer.

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised.

Adenocarcinoma↗

PubMed1990

Aspergillus fumigatus complement inhibitor: production, characterization, and purification by hydrophobic interaction and thin-layer chromatography.

Aspergillus fumigatus has previously been shown to produce a soluble extracellular inhibitor of the alternative complement pathway, called Aspergillus complement inhibitor, or CI. We now report an efficient method for production of CI which relies on the fact that poorly conidiating cultures yielded CI activity with approximately sevenfold-higher potency than CI produced by conidiating cultures. CI from poorly conidiating cultures provided 50% inhibition of alternative pathway-mediated binding of 125I-labeled complement component C3 to cryptococcal blastoconidia at a mean concentration of 60 micrograms/ml. The ability of crude CI to inhibit the alternative complement pathway seemed to be independent of intact protein or polysaccharide structure, as evidenced by resistance of inhibitory activity to digestion by proteases, including subtilisin, alpha-chymotrypsin, papain, and pepsin as well as endoglycosidases F and H. Separation of the active inhibitory component of CI from contaminating materials contained in crude CI preparations was achieved by using Phenylsuperose hydrophobic interaction chromatography in a fast protein liquid chromatography system. The active material proved to be extremely hydrophobic, desorbing from the column only during elution with ethanol; it contained only 15% protein and 5% polysaccharide. Furthermore, results from preparative thin-layer chromatography indicated that lipids which comigrated with phosphatidylserine/phosphatidylinositol and phosphatidylethanolamine possessed significant complement-inhibitory activity. Taken together, these data suggested that phospholipids from A. fumigatus contributed to the functional activity of CI.

Aspergillus fumigatus↗

PubMed1984

Prevention of immune precipitation by purified classical pathway complement components.

The role of the classical pathway of complement in the prevention of immune precipitation has been investigated using purified complement components and immune complexes (IC) consisting of rabbit anti-BSA and BSA. C1 reduced the rate of immune precipitation. As C1q, EDTA treated C1 or C1-inhibitor treated C1 were unable to retard the precipitation of IC, it was concluded that the intact C1 molecule was required for this function. Use of phenylmethylsulphonyl fluoride and benzamidine showed that the enzymatic site on C1 was not required for this activity. C4 and C2 did not affect immune precipitation significantly when C1 was present at the concentrations present in serum. When C3 was added to C1, C4 and C2 precipitation of IC did not occur. These data demonstrate that classical pathway activation alone is sufficient for the prevention of immune precipitation.

Antigen-Antibody Complex↗

PubMedDate not supplied

Prospective analysis of C1 dissociation and complement activation in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the results of complement analysis for assessment of disease activity and severity, and prediction of flares in systemic lupus erythematosus (SLE). METHODS: Patients with mild extra-renal flares, severe extra-renal flares or flares of lupus glomerulonephritis were followed for eight months, with investigations being performed every second month. Findings in initial samples four months before the flares were compared with findings in a control group with stable disease. C-reactive protein, and circulating C1q, C4 and C3 were determined together with two types of complexes containing C1 inhibitor (C1 INH), C1 INH-C1r-C1s and C1 INH-C1r-C1s-C1 INH, and the C3 breakdown product C3d. RESULTS: Enhanced formation of C1 INH-C1r-C1s appeared to be a marker of low specificity and was mainly seen in patients with extra-renal disease. Concentrations of C1 INH-C1r-C1s-C1 INH, C3d, C1q and C3 clearly varied according to disease activity in patients with severe disease. Interestingly, high C1 INH-C1r-C1s-C1 INH values were found four months before the flares in all but one patient with lupus glomerulonephritis. Assessment of the relative predictivity for a subsequent flare indicated low C1q to be the most reliable marker, the predictivity of the complexes being: low C1q > high C1 INH-C1r-C1s-C1 INH > low C3 > high C3d > low C4. CONCLUSION: The importance of C1q and C1-related events in SLE may be underestimated. In addition, our results demonstrate the relevance of serial complement analysis for the assessment of disease activity and severity.

Adolescent↗

PubMed1975

Modulation of human neutrophil polymorphonuclear leucocyte migration by human plasma alpha-globulin inhibitors and synthetic esterase inhibitors.

The exposure of isolated washed human neutrophils to purified human alpha1-antitrypsin resulted in a transient 2-fold enhancement of random migration and concomitant 70-90 per cent inhibition of chemotactic responsiveness to C5a or C3a, while treatment with alpha2-macroglobulin gave a less pronounced brief enhancement of random migration and prolonged 40-60 per cent suppression of chemotaxis. Peak effects occurred with concentrations of 1 mug/ml of alpha1-antitrypsin and 10 mug/ml of alpha2-macroglobulin. In contrast, the inhibitor of the activated first component of complement, at the highest concentration studied of 100/mug/ml, slightly enhanced chemotactic migration in response to C5a without influencing random migration. Preincubation of neutrophils with either L-1-tosylamide-2-phenylethyl-chloromethyl ketone (TPCK) or N-alpha-p-tosyl-L-lysine-chloromethyl ketone (TLCK) at concentrations of 10-8-10-4M suppressed chemotaxis with concomitant inhibition of random migration by TPCK and enhancement of random migration by TLCK. All agents worked directly and irreversibly on the cells but caused only slight stimulation of the activity of the hexose monophosphate shunt of layers of adherent neutrophils. The results suggest that interaction of the plasma alpha-globulins or synthetic esterase inhibitors with surface receptors on neutrophils can influence both the random migration and responsiveness to chemotactic factors of these cells.

Alpha-Globulins↗

PubMed1995

Inhibition of complement-mediated red cell lysis by immunoglobulins is dependent on the IG isotype and its C1 binding properties.

We have investigated the effect on complement activation of human immunoglobulins (Ig) using several therapeutic Ig preparations including two for intravenous use (IVIG), and various purified myeloma proteins. Ig inhibited lysis in a dose-dependent manner in the classical pathway assay whereas no alternative pathway inhibition was observed. The Fc part of the molecule was responsible for all the inhibitory effect. Purified IgG3 myeloma proteins were potent inhibitors whereas IgG1 inhibited to a lesser extent and IgG2 and IgG4 did not inhibit at all. Inhibition was obtained both when Ig was added to the solution and when it was coated onto a solid matrix. Analysis of the soluble and solid phase Ig after incubation revealed binding of C1q and activated C4 and C3 to the isotypes which inhibited lysis. Using selectively depleted sera and reconstitution with their respective purified components, efficient inhibition of lysis was seen when Ig was added prior to serum (C1), some inhibition was seen at the C4 level, whereas no effect was seen when Ig was added at the C9 level. We conclude that the complement-modulatory effect of Ig in vitro is isotype specific and dependent mainly on competitive C1 binding by the Ig molecule in the absence of antigen.

Animals↗

PubMed1987

Ixodes dammini: salivary anti-complement activity.

Saliva of the tick Ixodes dammini prevents hemolysis of rabbit erythrocytes by the human alternative pathway of complement. Deposition of C3b to activating surfaces and concomitant C3a release are inhibited. C3b deposition to activating surfaces is inhibited regardless the origin (humans, rat, mouse, guinea pig, and hamster) of the serum. The inhibitor elutes as a single peak upon gel filtration, with an apparent molecular weight of 49,000. Salivary anti-complement may contribute to successful feeding of I. dammini in their natural hosts.

Animals↗

PubMedDate not supplied

The complement system in human reproduction.

Regulation of the complement system in reproduction is unique inasmuch as reproductive tissues represent the only condition where allogeneic interactions occur naturally. Both allogeneic extraembryonic membranes and semen that contact and interact with maternal cells and tissues must avert complement-mediated damage to ensure reproductive success. Several regulators of complement activation exist. Membrane cofactor protein (MCP) and decay accelerating factor (DAF) inactivate C3 and C5 convertases on cell surfaces. In addition, CD59 inhibits the membrane attack complex (MAC) of the complement cascade. Strong expression of these membrane glycoproteins by trophoblast and amniotic epithelium has been observed. MCP, DAF, and CD59 likely safeguard extraembryonic tissues from complement damage originating from maternal and fetal blood or amniotic fluid. Different reproductive tract fluids vary in complement levels. With the exception of ovarian follicular fluid, these levels are generally much less than those in blood. Endometrial and cervical content of C3 appear to be regulated by hormones. These observations suggest that the effects of complement activation may vary in reproductive tissues. MCP is absent from the surfaces of oocytes. Sperm express MCP and DAF in discrete areas that would not be associated with the known complement-regulatory functions of these proteins. Seminal plasma contains MCP and the MAC inhibitor SP-40,40 but not DAF.SP-40,40 may exemplify how complement-regulatory proteins perform alternative functions as it interacts with molecules other than complement components. We have reviewed aspects of the complement system that relate to allogeneic interactions in reproduction and that suggest fruitful areas for further research.

Antigens, CD↗

PubMed1986

[Inhibition of the binding and activation of the first component of human complement. The effect of synthetic peptides, immunoglobulin fragments and various proteins].

A study has been carried out on the inhibition of the subcomponent Clq binding to sensitized sheep erythrocytes (EA) by the following synthetic peptides mimicking the structure of a putative complement binding site of immunoglobulin G: Boc-Trp-Tyr, Boc-Tyr-Trp, Trp-Tyr, Boc-Trp-Phe, Boc-D-Trp-D-Tyr, Boc-D-Tyr-D-Trp, Boc-Leu-Leu, Ac-Phe-Tyr, and commercial Thr-Lys-Pro-Arg (tuftsin). Boc-Trp-Tyr was found to be the most potent inhibitor of Clq binding to EA (Ki 2.86 X 10(-4) M), tuftsin ranking second with Ki 6 X 10(-4) M. The D,D-dipeptides failed to inhibit the Clq binding at the investigated concentrations. Insoluble Z-Trp-Tyr-OMe activated a classical pathway of complement system, as monitored by consumption of C4, C2 and C3 components. Synthetic octapeptide Boc-Glu-Val-Asp-Leu-Leu-Lys-Asp-Glu-OMe (corresponding to the sequence 36-43 of beta 2-microglobulin) inhibited the Clq binding with Ki 4.7 X 10(-4) M, which gave grounds for localizing the complement binding site in beta 2-microglobulin. The finding in the Clq structure of the peptide sequence homologous to than of the pepsin active site, as well as the close similarity in the specificity of these proteins towards hydrophobic amino acid residues justified the assumption on the same structural bases of their specificity. The results of the present study, along with the literature data, underlie the hypothesis on the involvement in the complement binding of the following IgG residues: Trp277, Tyr278, Lys320, Lys322, Glu318 and Lys290. The enlisted residues are closely located in the three-dimensional structure of the CH2 domain of IgG. Lysozyme and lactalbumin having the sequences homologous to Trp277-Tyr278 of IgG inhibited Clq binding to EA with Ki 3 and 1.5 microM respectively.

Amino Acid Sequence↗

PubMed1987

Regulation of the activity of platelet-bound C3 convertase of the alternative pathway of complement by platelet factor H.

The alternative pathway of complement is regulated on the surface of homologous blood cells at the C3 amplification step by the membrane protein decay-accelerating factor, as well as by the plasma protein factor H. We have reported elsewhere that platelets from patients with paroxysmal nocturnal hemoglobinuria regulate the activity of the C3 convertase C3bBb, even though they lack decay-accelerating factor. We now report that normal human platelets contain factor H, which was released from the platelet in response to complement deposition or thrombin stimulation. Factor H was localized to the platelet alpha granules by immunocytochemical techniques. As determined by a solid-phase radioimmunoassay, thrombin-stimulated platelets released approximately equal to 54 ng of factor H per 10(8) platelets. The release of factor H in response to complement or thrombin was inhibited by treating the platelets with metabolic inhibitors. Such inhibition resulted in a 3-fold increase in the activity of C3bBb. Platelets that released factor H bound only half as many molecules of radiolabeled factor B to platelet-bound C3b than platelets that could not release factor H. Treatment of platelets with anti-decay-accelerating factor antibody had no effect on the activity of C3bBb unless the release of factor H was blocked. Therefore, so far as we know, human platelets have a unique mechanism for the regulation of the alternative pathway of complement.

Complement Activating Enzymes↗

PubMed2002

[C1 inhibitor deficiency. Heredity and acquired forms. Symptoms, diagnostic and therapeutic problems].

C1 inhibitor deficiency can be hereditary (Type I and II) or acquired (Type I and II). Clinically it is manifested by recurrent attacks of angioedema which may involve skin, airways and digestive tract. The acquired form of C1 inhibitor deficiency is associated with lymphoproliferative or connective tissue disorders as well as with autoimmunization. Clinical symptoms are similar in all forms of C1 inhibitor deficiencies and they are connected with low serum level of C4 as well as with decreased activity of C1 inhibitor. In acquired angioedema additionally they are also decreased C1 and C1q and in type II C3 serum concentration is diminished. The drugs of choice are anabolics (danazol, stanazolol). Antifibrinolitic drugs are also used, especially in acquired forms of C1 inhibitor deficiency. The infusion of C1 inhibitor concentrate is used in acute emergency treatment.

Angioedema↗

PubMed1989

Factor J: isolation and characterization of a new polypeptide inhibitor of complement C1.

An Mr 20,000 protein inhibitor of C1, the first component of complement, has been purified from human urine and characterized. This inhibitor, tentatively designated factor J, is apparently distinct from known complement inhibitors. During purification on QAE-Sephadex, Mono Q, and heparin-Sepharose, factor J was detected by its ability to inhibit the complement-mediated lysis of sheep erythrocytes bearing antibody, C1, and activated C4 (EAC14). The purity of factor J was documented by the concordant elution from a hydroxylapatite column of functional activity and the UV absorbance as measured at three different wavelengths (220, 254, and 280 nm). The relative Mr of 20,000 was determined by sodium dodecyl sulfate-slab gel electrophoresis of radioiodinated protein. Amino acid analysis indicated a high cysteine content and allowed calculations of a specific activity of 7 functional units/pmol. The target of factor J inhibitory activity on the lysis of EAC14 was localized to C1 by the following criteria: factor J inhibited C1 in a C1 transfer assay, but had no effect on C42 activity or decay, and had no effect on the efficiency of isolated C2 or C3-C9 as provided in serum-EDTA. Factor J inhibition was rapid and not significantly influenced by temperature. In a second functional assay, factor J inhibited the association of the tetrameric complex C1r2s2 with 125I-C1q, and the results, when analyzed graphically by a reciprocal plot, were consistent with noncompetitive inhibition (Ki = 529-760 pM range). Functional and/or antigenic data indicated that factor J is distinct from the other known inhibitors of C1, namely the C1 inhibitor and the C1q inhibitor. Antihuman serum precipitated radioiodinated factor J, indicating that an antigen identical or cross-reacting with factor J exists in serum. In summary, factor J is a newly described potent inhibitor of C1 function.

Animals↗

PubMed2004

Human complement factor I does not require cofactors for cleavage of synthetic substrates.

Complement factor I (fI) plays a major role in the regulation of the complement system. It circulates in an active form and has very restricted specificity, cleaving only C3b or C4b in the presence of a cofactor such as factor H (fH), complement receptor type 1, membrane cofactor protein, or C4-binding protein. Using peptide-7-amino-4-methylcoumarin derivatives, we investigated the substrate specificity of fI. There is no previous report of synthetic substrate cleavage by fI, but five substrates were found in this study. A survey of 15 substrates and a range of inhibitors showed that fI has specificity similar to that of thrombin, but with much lower catalytic activity than that of thrombin. fI amidolytic activity has a pH optimum of 8.25, typical of serine proteases and is insensitive to ionic strength. This is in contrast to its proteolytic activity within the fI-C3b-fH reaction, in which the pH optimum for C3b cleavage is <5.5 and the reaction rate is highly dependent on ionic strength. The rate of cleavage of tripeptide 7-amino-4-methylcoumarins by fI is unaffected by the presence of fH or C3(NH(3)). The amidolytic activity is inhibited by the synthetic thrombin inhibitor Z-D-Phe-Pro-methoxypropylboroglycinepinanediol ester, consistent with previous reports, and by benzenesulfonyl fluorides such as Pefabloc SC. Suramin inhibits fI directly at concentration of 1 mM. Within a range of metal ions tested, only Cr(2+) and Fe(3+) were found to inhibit both the proteolytic and amidolytic activity of fI.

Complement Factor I↗

PubMed1982

The pathogenic mechanisms of blister formation in bullous pemphigoid.

Normal human skin was cultured with sera, IgG fractions, and blister fluids (BF) from patients with bullous pemphigoid. Antibody binding (IgG) was observed by immunofluorescence techniques at the dermal-epidermal junction of all skin explants culture with sera, IgG fractions, and BF. Dermal-epidermal separation was observed only in the skin explants cultured with BF. Dermal-epidermal separation was observed in 19 out of 20 explants cultured with BF obtained from fresh bullae. In addition, dermal-epidermal separation can be produced in vivo 6 hr after the injection of BF into the dorsal skin of Hartley guinea pigs. Dermal-epidermal separation was not observed in skin explants cultured with heat-inactivated (56 degrees, C 30 min) BF, although antibody binding was observed. In addition, dermal-epidermal separation did not occur when the BF were preincubated with rabbit antihuman C1, C3, C4, and C5 antibodies. These observations suggested that both antibody and complement were essential for the production of dermal-epidermal separation. Since patient sera failed to produce dermal-epidermal separation, other factor(s) present in BF but absent from serum might be necessary for the production of dermal-epidermal separation. The addition of the proteinase inhibitors, pepstatin, EDTA, and soy bean trypsin inhibitor, did not inhibit the formation of dermal-epidermal separation. In contrast, the presence of alpha 2-macroglobulin inhibited dermal-epidermal separation.

Animals↗

PubMed1991

Alpha 1-antitrypsin deficiency, complement activation, and chronic liver disease.

Activation of the complement system, the main humoral mediator of inflammation, is restrained by the action of enzyme inhibitors including alpha 1-antitrypsin. Deficiency leads to chronic liver disease in about one in five children with this genetic defect. Complement activation was investigated in 34 children with alpha 1 AT deficiency (12 with minimal, 10 with moderate, and 12 with severe liver disease) and in 38 sex and age matched normal children by measuring the complement parent molecules C3, C4, the C3d fragment and by calculating the C3d:C3 ratio. C3 and C4 were lower in children with severe liver disease compared with controls, indicating impairment of hepatic protein synthesis or complement consumption. The C3d activation fragment was higher in all the patient groups when compared with controls while the C3d:C3 ratio, a measure of activation independent of the concentrations of the parent molecule, was higher in patients than in controls and increased with the degree of disease severity. These results suggest that complement may have a role in the pathogenesis of the chronic liver disease associated with alpha 1AT deficiency.

Adolescent↗