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PubMed1990

Complement activation in systemic sclerosis.

The use of a synthetic protease inhibitor, nafamstat mesilate, has enabled reliable estimations of in vivo complement activation to be made in patients with systemic sclerosis. Elevations of C3a and C4a anaphylatoxins were found in 2 and 24 out of 30 patients respectively, indicating that complement activation, predominantly by the classical pathway, is a common occurrence in the disease, even though complement C3 and C4 levels were within the reference range.

Adult↗
PubMed1990

[Hereditary angioneurotic edema. Management in pediatric surgery].

Hereditary angioneurotic oedema is an autosomal dominant disorder associated with serum deficiency of functionally active C1 inhibitor protein (type 1) or normal serum level of functionally deficient C1-inhibitor (type 2). These biochemical abnormalities induce a complement activation which leads to episodic swelling of interstitial tissues usually of the abdominal viscera and of the upper airway with resultant asphyxia. Vasoactive peptides from the degradation of component C2 of the complement along with an activation of basophils by chemotactic substances from the degradation of C3 and C5 are the main mechanisms involved in vasodilatation and swelling. Attacks of angioneurotic oedema, sometimes fatal when involving the upper airway, can occur during any but usually during ear-throat-nose, dental or facial surgery. This article describes the pathophysiology and the main features of the disease in children. It reviews the different treatments used to avoid attacks or to cure an attack of angio-oedema once it has begun, both during planed surgery and during emergency surgery.

Adolescent↗
PubMed1975

Immunoconglutinins and C3 in human saliva.

High titres of immunoconglutinin activity (antibody to bound complement components) have been found in the parotid, sublingual and submandibular saliva of most healthy subjects. The immunoconglutinin (IK) titre in mixed saliva was substantially lower than in the other samples of saliva. C3 was detectable in only three of 164 samples of parotid, submandibular and sublingual saliva but was present in forty-seven of 117 mixed saliva samples. It is suggested that crevicular fluid is the major source of C3 in mixed saliva. A negative correlation was found in mixed saliva between the C3 concentration and the IK titre, and this suggested that C3 was the inhibitor of IK in mixed saliva. Binding of C3 to IK has been demonstrated in mixed saliva by using highly purified salivary IK and C3. Purified C3, C3i, C3c and C3d inhibited the activity of purified IK. It is suggested that salivary IK represents the secretion of a B-lymphocyte population which has evaded the mechanism responsible for inducing B-cell tolerance to autologous serum proteins. The reason for its persistence in the salivary glands, however, is not known at present.

Adolescent↗
PubMed2001

Sodium butyrate enhances complement-mediated cell injury via down-regulation of decay-accelerating factor expression in colonic cancer cells.

Decay-accelerating factor (DAF) expressed on the surface of colonic cancer cells presents a barrier to complement-mediated clearance by contributing to the ineffectiveness of the humoral immune response. In this study, to investigate the mechanisms responsible for the anti-tumor effects of butyrate, we evaluated how butyrate modulates DAF expression in colonic cancer cells. Three colonic cancer cell lines (HT-29, Caco-2, and T84 cells) were studied. DAF protein expression was assessed by western blot, and DAF mRNA expression was evaluated by northern blot. Complement C3 deposition on the surface of colonic cancer cells was determined by enzyme-linked immunosorbent assay (ELISA). The promoter activity of the DAF gene was assessed by a reporter gene-luciferase assay. Butyrate reduced the basal and interleukin-4 (IL-4)- and tumor necrosis factor-alpha (TNF-alpha)-induced expression of DAF protein and mRNA in HT-29 cells. It increased the susceptibility to complement attack and enhanced C3 deposition on HT-29 cells. The inhibitory effect of butyrate on DAF mRNA expression was also observed in T84 and Caco-2 cells. Butyrate decreased basal DAF expression at both transcriptional and post-transcriptional levels. The inhibitory effect of butyrate on IL-4-induced DAF expression was closely associated with a blockade of IL-4-induced DAF mRNA stability. TNF-alpha-induced transcriptional activation and the increased stability of the DAF gene were also blocked by butyrate. Similar but weak effects were induced by trichostatin A, a potent histone deacetylase inhibitor, suggesting that histone acetylation might participate in butyrate activity. These observations indicate that both a down-regulation of DAF expression and the induction of susceptibility to complement attack contribute to the anti-tumor effects of butyrate in colonic cancer.

Antineoplastic Agents↗
PubMed1981

Synthetic C3a analogs as specific inhibitors of C3a activity.

Various C3a-related C-terminal synthetic oligopeptides were investigated for their ability to induce a release of serotonin from guinea pig platelets. The results confirm earlier findings that expression of biological C3a activity requires the four to five C-terminal amino acids of the C3a primary structure and underlines the essential role of the C-terminal arginine. Besides their ability to induce a specific release reaction, these peptides--after short incubation with the platelets--lead to a specific desensitization of the cells for C3a or C3a-related stimuli. Expression of this inhibitory activity required concentrations of the peptides more than 100-fold lower than those that were necessary to induce secretion. The possibility of using C3a analogs as specific inhibitors for C3a offers a valuable tool for in vivo studies of biological C3a activity.

Amino Acid Sequence↗
PubMed1995

Phospholipase A2 from plasma of patients with septic shock is associated with high-density lipoproteins and C3 anaphylatoxin: some implications for its functional role.

Phospholipase A2 (PLA2) activity was purified 12,544-fold with a 13% yield from the plasma of patients diagnosed of septic shock by the sequential use of heparin-agarose affinity chromatography, gel filtration, and reverse-phase f.p.l.c. Gel-filtration chromatography of plasma omitting high-ionic-strength buffer revealed a molecular mass different from that of purified PLA2 and co-elution with apolipoprotein A-I peaks, which suggests its association with high-density lipoproteins (HDL). N-terminal analysis of the enzyme activity protein band, electroblotted from a SDS-acrylamide gel and with an assessed molecular mass of 19 kDa, showed an identical sequence to that of alpha-chain of human C3 complement component, suggesting the presence in this band of a complex formed by a complement C3-derived anaphylatoxin (C3a)-related fragment and the PLA2 linked side-by-side. Because the preparation of plasma enzyme showed lower activity than the enzyme obtained from fibroblasts transfected with the coding sequence of human group-II PLA2, and because the addition of C3-derived anaphylatoxins from human serum inhibited the activity of this recombinant PLA2, it was considered that C3a-related peptides behave as inhibitors of group-II PLA2. The enzyme showed optimal activity on [14C]oleate-labelled autoclaved E. coli, on synthetic phosphatidylethanolamine, and on [3H]arachidonate-labelled membranes of the monoblast cell line U937, but it did not show any activity on the release of [3H]arachidonate from pre-labelled human polymorphonuclear leukocytes (PMNs). In short, PLA2 from plasma of sepsis patients shows unique associations with other plasma proteins which may influence its functional properties. The association with C3-related peptides shows an inhibitory effect on the enzyme activity, whereas the association with HDL might influence its environment and/or its interaction with cells. The study of the catalytic properties shows a prominent effect on bacterial phospholipids, synthetic phosphatidylethanolamine, and membranes from U937 monoblasts, but not on synthetic phosphatidylcholine or on PMNs, even when these cells were maintained in culture to allow spontaneous apoptosis and became a good substrate for pancreatic type PLA2.

Amino Acid Sequence↗
PubMed1996

Role of complement in the aetiology of Pick's disease?

Complement in the postmortem brains of 15 cases of Pick's disease has been widely analyzed immunohistochemically and, in 2 cases, by immunoelectron microscopy. Astrocytes and the Pick bodies and cytoplasm of ballooned neurons were immunoreactive with antibodies to classical pathway components C1, C1q, C4, C2 and C3 and the terminal complex components C5, C6 and C8. In almost all cases, no immunostaining was obtained with antibodies against C9 and neoepitopes in the membrane attack complex (MAC), the complement complex responsible for cytotoxicity. However, unequivocal staining with antibodies to two soluble complement regulatory proteins, S-protein and clusterin, and to the membrane complement inhibitor CD59 was found, although three other membrane inhibitors, CR1(CD35), DAF (CD55), and MCP (CD46), were not detected. The complement immunoreactivity of astrocytes and neurons could be the result of complement biosynthesis or attack. Complement attack will be restricted by the expressed regulatory proteins. However, neurons may be the victims of attack since they show pathological change. The internalization of complement-attacked membrane, perhaps involving the genesis of Pick bodies and ballooning, may explain the intracellular immunolocalization of complement in damaged neurons. Immunoglobulins, as a possible source of complement activation, were observed in only two cases, leaving unresolved the trigger for complement activation in the other cases.

Aged↗
PubMedDate not supplied

Coagulopathy in hemorrhagic fever with renal syndrome (Korean hemorrhagic fever).

The pathophysiology of bleeding manifestations in hemorrhagic fever with renal syndrome (HFRS) was elucidated by serially evaluating coagulation and fibrinolytic profiles and complement alterations in patients with HFRS. In the early stage of the disease, platelet counts, platelet survival time, and platelet aggregation in vitro decreased. Prolongation of bleeding time, prothrombin time, and activated partial thromboplastin time was noted, with decreases in coagulation factors II, V, VIII, IX, and X. Levels of fibrinogen were decreased, and those of fibrinogen-fibrin degradation products in serum and urine were increased. Concentrations of plasminogen, alpha 2-plasmin inhibitor, and antithrombin III in plasma were depressed. Procoagulant activity was present in plasma. Circulating immune complexes were found, whereas serum levels of C3 were decreased. In the early stage of HFRS, thrombocytopenia, defects in platelet function, and disseminated intravascular coagulation may play central roles in the pathogenesis of bleeding manifestations. Vasculopathy and immunologic aberrations also may play a role.

Antigen-Antibody Complex↗
PubMed1979

Soluble proteins in the human atherosclerotic plaque. With spectral reference to immunoglobulins, C3-complement component, alpha 1-antitrypsin and alpha 2-macroglobulin.

A number of soluble proteins contained in human aortic intimal tissue was extracted into buffered saline (pH 7.4) and identified and quantitated by immunoelectrophoresis and immunodiffusion. The proteins included IgA, IgG, IgM, B1C (C3), alpha 1-antitrypsin, alpha 2-macroglobulin, fibrinogen, albumin, LDL, HDL, alpha 1-acid glycoprotein, beta 2-glycoprotein, transferrin and ceruloplasmin. The concentration of soluble proteins was significantly higher in the atherosclerotic intima than in the normal intima. The diseased intima also contained a small amount of tissue-bound IgG, IgA and B1C which was extractable with citrate buffer at pH 3.2. The vascular band IgG, and B1C were shown by enzymatic and immunohistochemical studies to be closely associated with the collagenous tissue of the plaque. The Ig contained in the atherosclerotic plaque may be derived in part from the biosynthesis of Ig by the artery, since the incorporation of 14C-labeled leucine into IgG by the atheromatous plaque was demonstrable by radioimmunoelectrophoresis. In contrast to the diseased artery, the normal artery did not synthesize IgG and did not contain vascular bound IgG or complement. However, the normal artery was capable of fixing IgG and B1C eluted from the diseased artery. The present studies suggested that the IgG contained and synthesized by the plaque might represent an immune response to an endogenous or exogenous antigen closely associated with plaque collagen. IgG and B1C either alone or in the form of an immune complex also may play an important role in phagocytosis in the plaque and thereby influence the course of atherosclerosis. The proteolytic inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin, found in relatively high concentrations in the plaque, could enhance fibrosis of the lesion because of thier known inhibitory effects on collagenase and elastase.

Aorta↗
PubMed2002

Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy.

Diabetic retinal microangiopathy is characterized by increased permeability, leukostasis, microthrombosis, and apoptosis of capillary cells, all of which could be caused or compounded by activation of complement. In this study, we observed deposition of C5b-9, the terminal product of complement activation, in the wall of retinal vessels of human eye donors with 9 +/- 3 years of type 2 diabetes, but not in the vessels of age-matched nondiabetic donors. C5b-9 often colocalized with von Willebrand factor in luminal endothelium. C1q and C4, the complement components unique to the classical pathway, were not detected in the diabetic retinas, suggesting that C5b-9 was generated via the alternative pathway, the spontaneous activation of which is regulated by complement inhibitors. The diabetic donors showed a prominent reduction in the retinal levels of CD55 and CD59, the two complement inhibitors linked to the plasma membrane by glycosylphosphatidylinositol anchors, but not in the levels of transmembrane CD46. Similar complement activation in retinal vessels and selective reduction in the levels of retinal CD55 and CD59 were observed in rats with a 10-week duration of streptozotocin-induced diabetes. Thus, diabetes causes defective regulation of complement inhibitors and complement activation that precede most other manifestations of diabetic retinal microangiopathy. These are novel clues for probing how diabetes affects and damages vascular cells.

Aged↗
PubMed1993

The possible role of membrane complement regulators in vasculitis.

Potentially, damage to endothelial cells of small vessel walls may be induced by the deposition of immune complexes and subsequent complement activation. The degree of deposition of C3b onto the endothelial cell surface under normal conditions is regulated by a number of membrane-bound regulators. Under inflammatory conditions various cytokines could potentially deregulate the expression and function of the membrane-bound complement inhibitors. Such a process could potentially increase the susceptibility of the endothelial cell layer to complement-mediated attack and provoke a vascular lesion.

Animals↗
PubMed1976

In vitro synthesis of factor B of the alternative pathway of complement activation by mouse peritoneal macrophages.

Factor B of the alternative pathway of complement activation was shown to be synthesized and secreted by unstimulated mouse peritoneal macrophages. The activity of B in the culture supernatants from macrophage monolayers was detected by consumption of C3 in reaction mixtures containing supernatant and guinea pig factors C3, D and insoluble C3b. Using a monospecific antiserum, factor B in concentrated culture supernatants was shown by immunodiffusion and immunoelectrophoresis to be identical to factor B in mouse plasma and to form a characteristic complex with cobra venom factor in the presence of D. A steady rate of factor B secretion was observed for 4 days providing the medium was changed every 24 h. Cycloheximide (0.5 mug/ml), an inhibitor of protein synthesis, caused inhibition (90%) of factor B production. Incubation of culture medium containing 14C-labeled amino acids with the macrophage monolayer resulted in incorporation of radioactivity into factor B as detected by autoradiography of precipitation lines formed with anti-B antiserum; This indicated that synthesis of factor B had occurred. In the same culture supernatants the presence of newly synthesized C3 was also demonstrated.

Animals↗
PubMed1992

Analysis of the effects of activation of the alternative pathway of complement on erythrocytes with an isolated deficiency of decay accelerating factor.

E from individuals with the Inab blood group phenotype have an isolated deficiency of decay accelerating factor (DAF, CD55). DAF is a glycosyl phosphatidylinositol anchored membrane protein that inhibits activation of both the classical and alternative pathways of complement. Deficiency of DAF from the E of paroxysmal nocturnal hemoglobinuria (PNH) is thought to contribute to their greater sensitivity to complement-mediated lysis. Unlike PNH E, however, Inab cells are not susceptible to acidified serum lysis, a process that is mediated through activation of the alternative pathway. This observation led us to hypothesize that membrane constituents other than DAF control susceptibility to acidified serum lysis. To investigate this hypothesis, Inab E were incubated in acidified serum, and hemolysis and C3 deposition (as a measure of alternative pathway activation) were quantitated. C3 deposition of Inab cells was approximately 20 times greater than normal, however, hemolysis was not observed. Inab E expressed a normal amount of membrane inhibitor of reactive lysis (MIRL, CD59), a glycosyl phosphatidylinositol anchored protein that is also deficient in PNH. When MIRL function was blocked with antibody, C3 deposition markedly increased, and 100% of the Inab cells hemolyzed in acidified serum. These studies demonstrate that susceptibility to acidified serum lysis is controlled primarily by MIRL, and that in addition to its regulatory affect on the membrane attack complex, MIRL also modulates the activity of the C3 convertase of the alternative pathway by a mechanism that remains to be determined.

Animals↗
PubMed2000

Inhibition of complement alternative pathway function with anti-properdin monoclonal antibodies.

Complement activation products appear to contribute to the pathology of several acute and chronic inflammatory conditions. The relative contributions of the classical and alternative complement pathways to these pathologies have, in large part, been undefined. Considerable progress has been made recently in identifying inhibitors of complement activation and demonstrating that such molecules can attenuate inflammation in various models of disease. However, most of these complement inhibitors affect aspects of both the classical and alternative pathways. In an effort to better define the role of the alternative complement pathway in complement-mediated inflammatory conditions, we have developed monoclonal antibodies that specifically inhibit alternative pathway function. These blocking antibodies bind human properdin with high avidity and prevent its interaction with the alternative pathway C3 convertase. This results in a cessation of alternative pathway function in several in vitro assay systems. When tested in a model of cardiopulmonary bypass, in which human blood passes through tubing, a selected antiproperdin antibody caused nearly complete inhibition of the C3a and C5b-9 formation that was seen in untreated blood. Moreover, the anti-properdin agent resulted in a dramatic reduction of neutrophil and platelet activation in the bypass model. Surprisingly, the monoclonal antibody also caused a significant inhibition of C5b-9 generation when classical pathway activators, such as heparin-protamine or immune complexes, were added to human blood. These latter data suggest that the alternative pathway contributes significantly to the formation of complement activation products in blood when the classical pathway is initially triggered.

Antibodies, Monoclonal↗
PubMed1991

Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum.

When incubated in acidified serum, the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) are hemolyzed through activation of the alternative pathway of complement (APC), but normal erythrocytes are resistant to this process. PNH cells are deficient in decay-accelerating factor (DAF), a complement regulatory protein that inhibits the activity of both the classical and the alternative pathways. However, deficiency of DAF alone does not account entirely for the aberrant effects of acidified serum on PNH cells. Recently, we have shown that PNH erythrocytes are also deficient in another complement control protein called membrane inhibitor of reactive lysis (MIRL) that restricts complement-mediated lysis by blocking formation of the membrane attack complex (MAC). To determine the effects of the DAF and MIRL on susceptibility to acidified serum lysis, PNH cells were repleted with the purified proteins. DAF partially inhibited acidified serum lysis by blocking the activity of the amplification C3 convertase. MIRL inhibited acidified serum lysis both by blocking the activity of the MAC and by inhibiting the activity the C3 convertase. When DAF function was blocked with antibody, normal erythrocytes became partially susceptible to acidified serum lysis. By blocking MIRL, cells were made completely susceptible to lysis, and control of C3 convertase activity was partially lost. When both DAF and MIRL were blocked, the capacity of normal erythrocytes to control the activity of the APC and the MAC was destroyed, and the cells hemolyzed even in unacidified serum. These studies demonstrate that DAF and MIRL act in concert to control susceptibility to acidified serum lysis; of the two proteins, MIRL is the more important. In addition to its regulatory effects on the MAC, MIRL also influences the activity of the C3 convertase of the APC. Further, in the absence of DAF and MIRL, the plasma regulators (factor H and factor I) lack the capacity to control membrane-associated activation of the APC.

Animals↗
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↗