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PubMed1989

Ascorbic acid transport by 3T6 fibroblasts. Regulation by and purification of human serum complement factor.

It was earlier reported (Padh, H., and Aleo, J. J. (1987) Proc. Soc. Exp. Biol. Med. 185, 153-157) that the activation of serum complement by endotoxin or immunocomplexes inhibited ascorbate transport in 3T6 fibroblasts. We show here that the inhibitor of 3T6 fibroblasts. We show here that the inhibitor of ascorbate transport increased the Km for ascorbate without affecting the Vmax, indicating that the inhibitor reduces the affinity of the ascorbate transporter for ascorbate without affecting the process of translocation. Inhibition by serum and endotoxin was reversible, and the generated inhibitor was no longer heat-labile (at 56 degrees C for 30 min) suggesting that the inhibitor of ascorbate transport is likely to be a small protein molecule. Utilization of complement components suggested that C3 was consumed during formation of the inhibitor of ascorbate transport while C5 and factor B were not consumed. These data along with other results indicate that the inhibitor is generated at C3 step of complement activation. The inhibitor was purified from inulin activated human serum and it had an apparent molecular mass of around 9000 daltons. The inhibitory effect of the purified factor was abolished by antiserum to C3a suggesting that the 9000-dalton factor could be related to this fragment of complement protein. These data raise the possibility that tissue supply of ascorbate may be compromised during infection or autoimmune processes when serum complement is activated.

Animals↗

PubMed1985

Involvement of complement in atopic dermatitis.

There is little information about the role of complement in atopic dermatitis (AD). We studied the levels of both normal complement components and activation products in peripheral blood of patients with mild to intermediate disease. 35 patients had not received systemic or topical steroid therapy 6 weeks prior to blood collection. C3, C4 and C1 INA were determined in serum by radioimmunodiffusion. C3a and C5a levels were measured in EDTA plasma by radioimmunoassay. Compared to healthy non-atopic controls C3, C4 and C1 INA were found to be increased significantly. There was a tendency towards increased C3a levels but the difference was not significant. No measurable amounts of C5a were detected. Elevations of C3a were correlated with elevated levels of C3. The results suggest that the complement system participates in the inflammatory process in AD.

Adolescent↗

PubMed1987

Complement activation during hemodialysis: laboratory evaluation of hemodialyzers.

A laboratory method that facilitates delineation of the complement-activating characteristics of various dialyzers under defined conditions has been developed. Results obtained by circulating reconstituted human serum through these devices and measuring time-dependent production of both C3a and C5a antigens are entirely consistent with previous clinical observations. For example, the complement-activating potential of dialyzer membranes could be described as high (cuprammonium cellulose), moderate (cellulose acetate), or low (polycarbonate or polyacrylonitrile). Furthermore, these techniques provided the opportunity to identify membrane characteristics that are not readily defined by clinical studies alone. Specifically, membranes that transported and absorbed C5a antigen were readily identified by these methods. Additionally, laboratory evaluation provided the unique ability to define the efficiency of complement activation taking place on the membrane surface. Results of these investigations are compatible with a hypothetical model that not only describes the properties of a typical dialyzer membrane but may be generally applicable to other biomaterials as well.

Acrylic Resins↗

PubMed1995

Posttransfusion anaphylactic reactions in a patient with severe von Willebrand disease: role of complement and alloantibodies to von Willebrand factor.

Previous studies have suggested that activation of the complement system might be a major mechanism for posttransfusion non-immunoglobulin (Ig) E-mediated anaphylactic reactions, but its causative effect has not been clearly demonstrated in human models. Serial plasma samples were collected from a patient with severe von Willebrand disease, IgG alloantibodies against von Willebrand factor (vWF), and a history of posttransfusion anaphylaxis. During an 18-day period the patient was treated with factor VIII-vWF concentrate and with recombinant factor VIII. Complement system activation was assessed from plasma levels of C4a, C3a, cleavage products of complement factor B, soluble terminal complement complex, C1 inhibitor and C4-binding protein, and the contact phase of coagulation was assessed from plasma levels of activated factor XII and cleaved high-molecular-weight kininogen. Plasma levels of antibodies to vWF and complement-fixing IgG-vWF complexes were also evaluated. Symptoms of anaphylaxis and signs of complement activation were present only when IgG antibodies to vWF were measurable during replacement with factor VIII-vWF concentrate (days 1 and 6). IgE, IgA, and IgM antibodies to vWF were not detectable in plasma at any time. Replacement with recombinant factor VIII (days 7 to 18) secured hemostasis and did not elicit anaphylactic reactions, and complement parameters did not significantly change even when antibodies to vWF reached peak plasma levels. This prospective study of a natural clinical model indicates a cause-effect relationship between formation of IgG-vWF complexes and massive complement activation in posttransfusion non-IgE-mediated anaphylactic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1998

Complement activation in patients with sepsis is in part mediated by C-reactive protein.

The involvement of C-reactive protein (CRP) in the activation of complement in patients with sepsis was investigated. In 104 patients with infections of varying severity, circulating levels of CRP-complement complexes, which are specific indicators for CRP-mediated complement activation, were assessed. Complement-CRP complexes were increased in almost all patients and correlated significantly with levels of C3a (r = .59; P < .001) and C-reactive protein (r = .76; P < .001). In addition, they correlated with levels of secretory phospholipase A2 (r = .59; P < .001). Levels of complement-CRP complexes in patients with a pneumococcal type of infection were similar to those in patients with other types of infections. Complement-CRP complexes were significantly higher in patients with shock (P = .01) and in patients who died (P = .03). These results demonstrate that part of the complement activation in patients with sepsis is independent from a direct interaction with microorganisms but rather results from an endogenous mechanism involving CRP.

C-Reactive Protein↗

PubMed2002

CD59 prevents human complement-mediated injuries in isolated guinea pig hearts.

OBJECTIVE: To assess complement-mediated myocardial injury on isolated guinea pig working hearts and cardioprotective effects of CD59. METHODS: Using a modified Langendorff apparatus, isolated guinea-pig working hearts were perfused with a modified Krebs Henseleit buffer containing 3% heat-inactivated human plasma and zymosan (IPZ) (control) (n = 10), 3% normal human plasma and zymosan (NPZ) (n = 10), or 3% normal human plasma and zymosan and 1.5 microg/ml CD59 (NPZC) (n = 10), respectively. Epicardial electrocardiogram (ECG), cardiac output (CO), coronary arterial flow (CF), maximum left ventricular developed pressure (LVP(max)), maximum left ventricular developed pressure increase rate (+ dp/dt(max)), maximum left ventricular developed pressure decrease rate (- dp/dt(max)) and heart rate (HR) were recorded at 0, 15, 30, 45 and 60 min of treatment. After the experiment, immunohistochemical examination was performed to detect the presence of C3a or C5b-9 in the myocardium of the isolated hearts. RESULTS: Compared the IPZ group, hearts treated with NPZ showed a slight depression on ST segments of epicardial ECG at 15 min, a significant elevation between 30 min to 60 min, a decrease in CF, CO, LVP(max), + dp/dt(max) and - dp/dt(max), and an increase in HR at 15 min. The observed alterations in CF, CO, LVP(max), + dp/dt(max) and - dp/dt(max) remained decreased, while the HR remained increased until the end of the protocol. The all above parameters of hearts treated with NPZC were similar to the control group (IPZ) at any given time. Immunohistochemical examination showed positive signals of C3a and C5b-9 in the myocardium of hearts treated with NPZ. C3a was positive in NPZC, and C3a and C5b-9 were negative in IPZ. CONCLUSIONS: Activated human complements directly damage isolated guinea pig working hearts, and CD59 offers a significant protection against the injuries.

Animals↗

PubMed1987

Plasma anaphylatoxin concentrations in inflammatory skin diseases.

To study the possible involvement of the complement system in inflammatory skin disorders, we measured the concentrations of C3a and C4a anaphylatoxins in the peripheral blood of 148 patients with various inflammatory skin disorders and 48 healthy control subjects by radioimmunoassay. Significant increases in mean levels of both C3a and C4a anaphylatoxins were found in 59 patients with psoriasis. Remarkable increases in both C3a and C4a anaphylatoxins were also noted in some patients with leukocytoclastic vasculitis, urticarial vasculitis or unspecified toxic erythema. On the other hand, elevation of C4a alone was noted in a case of systemic lupus erythematosus. In contrast, using the mean of the normal control +/- 2 S.D., no significant anaphylatoxin elevation was found in 16 patients with pustulosis palmaris et plantaris, 7 with pityriasis rosea, 3 with erythema multiforme, and 3 with erythema nodosum or autoimmune bullous dermatoses.

Anaphylatoxins↗

PubMed1991

Post-streptococcal glomerulonephritis: studies on the interaction between nephritis strain-associated protein (NSAP), complement and the glomerulus.

Nephritis strain-associated protein (NSAP), a streptokinase produced by strains of streptococci isolated from patients with acute glomerulonephritis, is believed to be a specific antigen which participates in the production of glomerular injury. In order to investigate the mechanisms by which NSAP induces damage we have examined its potential to activate complement in vitro and to bind to isolated human glomeruli. NSAP, both alone and in combination with specific antibody, caused depletion of complement in normal human serum as measured by total haemolytic complement activity and generation of the complement breakdown products. C3a and C4a. Furthermore, Scatchard analysis showed that NSAP bound tightly to human glomeruli (Ka of 400 +/- 240 x 10(6) M) when compared to non-nephritic streptokinase (Ka of 7.3 +/- 4.1 x 10(6) M) and fully cationized human serum albumin (Ka of 0.6 +/- 0.04 x 10(6) M). These findings are consistent with the hypothesis that the deposition of streptococcal antigens within the glomerulus may precede the fixation of complement and specific antibody.

Bacterial Proteins↗

PubMedDate not supplied

SC5b-9 is the most sensitive marker in assessing disease activity in Brazilian SLE patients.

This study investigated whether increased plasma levels of terminal complement complex (SC5b-9) or split products correlate with disease activity and clinical manifestations in Brazilian systemic lupus erythematosus (SLE) patients. Comparisons with conventional measurements of complement and other inflammatory markers were also performed. Plasma levels of SC5b-9, C3a desArg, C1rs-C1Inhibitor, C3b(Bb)P, C3, C4, erythrocyte sedimentation rate (ESR) and mucoproteins (MP) were measured in 41 patients with SLE of different disease activity: 10 patients with none, 15 patients with mild, and 16 patients with moderate or severe activity. All parameters, with the exception of C3 and C3b(Bb)P, showed a statistically significant correlation with disease activity. Plasma levels of SC5b-9, C3a desArg, C4, CH50, ESR and MP revealed significant differences between the groups of patients without activity and those with moderate or severe disease. Although none of the variables were able to discriminate between patients without and those with mild activity, SC5b-9, C3a desArg, C4, ESR and mucoproteins showed significant differences between the patients with mild and those with moderate or severe disease. Among all the variables, SC5b-9 levels showed the most significant results and correlated well with the severity of the disease (p < 0.0005). Our data suggest that elevated levels of complement activation products, particularly of SC5b-9 are more sensitive markers in assessing disease activity than conventional laboratory diagnosis. Modern complement diagnosis is therefore recommended for monitoring disease progress in SLE patients.

Adolescent↗

PubMed1991

Complement activation in cancer patients undergoing immunotherapy with interleukin-2 (IL-2): binding of complement and C-reactive protein by IL-2-activated lymphocytes.

Plasma samples from cancer patients undergoing immunotherapy with high-dose recombinant interleukin-2 (IL-2) were obtained over a 5-day course of treatment and assayed by radioimmunoassay or enzyme-linked immunosorbent assay for the complement degradation products, C3a, iC3b, Ba, Bb, C4d, and SC5b-9. In the majority of patients, pretreatment C3a, Ba, Bb, and SC5b-9 plasma levels were comparable with those measured in normal donor plasma. However, by the end of the 5-day treatment course, C3a levels had increased 15.6-fold. In several patients, peak concentrations of C3a were as high as those reported in patients with sepsis or burn injury. Plasma levels of alternative pathway components Ba and Bb also increased, 8.0- and 5.0-fold, respectively, during IL-2 treatment. Likewise, levels of one of the terminal complexes, SC5b-9, increased 5.0-fold and the plasma C4d and iC3b concentrations increased 4.8- and 2.9-fold, respectively, by the fifth day of treatment. To determine whether activated lymphocytes participate in IL-2-induced complement activation, peripheral blood mononuclear cells (PBMC) obtained from IL-2 recipients before and 5 days after beginning therapy were reacted with monoclonal antibodies (MoAbs) against C3c and the terminal complement complex SC5b-9. Dual-color cytofluorographic analysis showed that within the CD3(+) population, the percentage of cells binding the anti-C3c and anti-SC5b-9 MoAbs increased 6.2-fold and 5.1-fold, respectively, by day 5. The anti-C3c MoAb also bound to CD3(+) cells stimulated in vitro with IL-2 and then exposed to serum. Moreover, fluid-phase iC3b was generated from purified C3 by PBMC activated in vitro with IL-2, but not by unstimulated cells. Serum levels of C-reactive protein (CRP) are markedly elevated in patients undergoing IL-2 immunotherapy. This hepatic acute phase reactant has been shown to activate the classical pathway when bound to cell surfaces. Because levels of the classical component C4d increase markedly during IL-2 treatment, we sought to determine if CRP became bound to PBMC during IL-2 treatment and found that during therapy, the percentage of CD3(+) cells reactive with an anti-CRP MoAb increased from less than 2% to greater than 18%. When PBMC were activated with IL-2 in vitro and then exposed to exogenous CRP, greater than 20% of the CD3(+) cells reacted with the anti-CRP MoAb.(ABSTRACT TRUNCATED AT 400 WORDS)

C-Reactive Protein↗

PubMed1977

Cell membranes in cytotoxicity.

Silica particles are cytotoxic for macrophages because they damage the membranes around secondary lysosomes in which the particles are engulfed. Hydroxyl groups of silicic acid on the surface of the particles form hydrogen bonds with phosphate ester groups of phospholipids and disrupt a variety of natural and artificial membranes. Asbestos fibers induce secretion of hydrolytic enzymes from cultured macrophages. Magnesium hydroxide groups of chrysotile asbestos interact ionically with ionized sialic acid residues of membrane glycoproteins, increase passive cation flux and produce osmotic lysis. The terminal components of complement (C5b-C9) when inserted into the bilayer structure also increase passive cation flux and produce osmotic lysis. The small complement cleavage product C3a is lytic for several cell types, especially malignant cells. The mechanism by which specifically sensitized thymus-derived (T)-lymphocytes kill tumour cells is discussed. Plasma membranes from effector lymphocytes possess considerable cytolytic potential, which is dependent on the activity of a membrane-associated proteinase.

Animals↗

PubMed1976

Secretion of lysosomal enzymes induced by immune complexes and complement.

Immune complexes react with neutrophils and macrophages by way of surface membrane Fc receptors. Alternatively, after fixation of complement, interaction may be with membrane C3b receptors. As a result, phagocytosis is induced. A consequence of this process is the liberation to the extracellular medium of lysosomal constituents. In neutrophils, fusion of granules with phagocytic vacuoles liberates the contents to the outside because some of the vacuoles, for various reasons, are inefficiently closed off. Alternatively, reaction of neutrophils in vitro or in vivo with immune complexes and/or activated complement components (C3b, C3a, C5a, C567) on surfaces too large to be phagocytosed, induces direct exocytosis of granules with consequent release of constituents. In both cases the liberation of lysosomal constituents is a secretory process, does not involve cell lysis, and resembles closely the secretory reactions of other widely differing cell types.

Adenosine Triphosphate↗

PubMed1994

The synthesis of a water soluble complement activating polyacrylic acid-IgG polymer.

Polyacrylic acid-IgG polymer (PAA-IgG) activates the classical and alternative pathway of complement as shown by specific Clq-(IgG-PAA) interaction and the generation of C4d, Bb, C3b, C3a and C5a. This water soluble and stable PAA-IgG polymer represents a model substance for the study of humoral and cellular inflammatory mechanisms, mediated by the complement system.

Acrylic Resins↗

PubMed2002

Marked activation of complement and leukocytes and an increase in the concentrations of soluble endothelial adhesion molecules during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans.

OBJECTIVE: Animal studies have demonstrated that reperfusion disorders occurring after cardiac arrest affect outcome. Reperfusion injury can be caused by activation of complement, polymorphonuclear leukocytes (PMN), and PMN-endothelial interaction. We studied different specific markers of these processes during and after cardiopulmonary resuscitation in humans. DESIGN: Prospective clinical trial. SETTING: University hospital. PATIENTS: A total of 55 patients who underwent out-of-hospital cardiopulmonary resuscitation for nontraumatic causes. INTERVENTIONS: Blood samples were drawn immediately, 15 mins, and 30 mins after initiation of cardiopulmonary resuscitation. In the case of restoration of spontaneous circulation, additional blood samples were taken at serial time points until 7 days after cardiac arrest. MEASUREMENTS AND MAIN RESULTS: A marked activation of complement and PMN was found in all patients investigated. Serum concentrations of specific activation markers of the complement system, anaphylatoxin C3a and the soluble membrane attack complex SC5b-9, and PMN elastase were increased during cardiopulmonary resuscitation and for </=48 hrs after restoration of spontaneous circulation. Compared with controls at 30 mins after initiation of cardiac massage, concentrations of C3a, SC5b-9, and PMN elastase were increased in patients without and in those with restoration of spontaneous circulation. PMN elastase concentrations were significantly greater in patients without restoration of spontaneous circulation than in those who could be stabilized. In addition, the plasma concentrations of the soluble P-selectin were significantly increased between 15 mins and 24 hrs after the start of cardiopulmonary resuscitation. The concentrations of soluble intercellular adhesion molecule-1 were increased between 2 hrs and 72 hrs. CONCLUSIONS: Our data clearly demonstrate a marked activation of complement and PMN and an increased PMN-endothelial interaction during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans. These changes are known to induce reperfusion disorders and tissue injury and point to new therapeutic options to improve outcome after cardiac arrest.

Aged↗

PubMed1993

Anaphylatoxins in dilated cardiomyopathy.

OBJECTS: The aim of the study was to investigate the possible relationship between activation of complement system and thromboembolic complications in dilated cardiomyopathy (DCMP). METHODS: The plasma C3a and C5a concentrations were determined by radioimmunoassay measurement (Amersham International, UK) in 23 patients with DCMP, 9 with hypertrophic cardiomyopathy (HCMP) and 11 healthy volunteers. RESULTS: The mean C3a concentration was significantly higher in DCMP patients (572 +/- 55 ng ml-1) compared with hypertrophic cardiomyopathy (344 +/- 30 ng ml-1) and with healthy controls (294 +/- 43 ng ml-1) (P < 0.001). There were no significant correlations for C5a concentrations in this group. Mean C3a concentration in DCMP patients with thromboembolic complications (736 +/- 95 ng ml-1) was also significantly higher compared with DCMP patients without these complications (344 +/- 14 ng ml-1) (P < 0.001). CONCLUSIONS: We conclude that anaphylatoxins may play a role in the pathogenesis of thromboembolic complications.

Adult↗

PubMed1984

Complement-induced expression of cryptic receptors on the neutrophil surface: a mechanism for regulation of acute inflammation in trauma.

We explored the hypothesis that identified changes in neutrophil function in patients with acute injury result from in vivo exposure to C5a. To evaluate this hypothesis, we performed a battery of tests on 26 trauma patients (14 with blunt injury, 12 with penetrating injury). Measured were plasma levels of the complement activation products C3a and C5a; neutrophil chemotaxis to C5a and N-formyl-methionyl-leucyl-phenylalanine (FMLP); neutrophil receptors for FMLP and C3b; and superoxide response to FMLP and serum-opsonized zymosan. Patient responses measured within 48 hours of admission were divided into two groups based on neutrophil migratory response to C5a. Patients unresponsive to C5a (but responsive to FMLP) showed elevated plasma C3a levels (248 +/- 6 ng/ml) compared with patients with normal C5a migratory response (104 +/- 8 ng/ml). FMLP receptor number was markedly increased in the chemotactically deactivated group (group I: 155,680 +/- 100; group II: 51,200 +/- 200) and receptor affinity was diminished. Binding activity of C3b increased in the C5a-unresponsive cells to 126% that of controls versus 94% for normally responsive patient cells. Superoxide production was found to be significantly increased in patient cells with increased receptor numbers. These results support the concept that a subgroup of trauma patients manifest plasma and neutrophil changes compatible with complement activation. The neutrophil changes identified demonstrate a state of cellular activation. The clinical significance of these results may reside in a risk of pulmonary microvascular injury if activated cells are marginated and then subsequently stimulated.

Chemotaxis, Leukocyte↗

PubMed1978

A leukotactic factor in the stratum corneum of pustulosis palmaris et plantaris: a possible mechanism for the formation of intra-epidermal sterile pustules.

Previous studies on the chemotactic properties of soluble substances from psoriatic scales demonstrated the presence of complement-derived chemotactic factors (anaphylatoxins) that seem to play a crucial role in the production of typical psoriasiform tissue changes. The crude extract from the stratum corneum of lesions of pustulosis palmaris et plantaris (PPP) was also noted to contain highly chemotactic components for polymorphonuclear leukocytes (PMN's) as compared with a crude callus extract in the present study. The leukotactic factors contained in the major chemotactic fractions isolated by Sephadex G-75 chromatography revealed in vitro characteristics and in vivo biological activities very similar to those of the leukotactic factor derived from psoriasis scale reported in earlier work, i.e. complement cleavage products (C3a and C5a). On the basis of these findings we have reason to believe that pustule formation in PPP occurs through a mechanism that has a strong resemblance to that in pustular psoriasis. We hypothesize further that similar mechanism may be operative in other dermatoses in which the formation of sterile subcorneal pustules is a characteristic feature.

Acrodermatitis↗

PubMed1989

The complement system in the acute phase of myocardial infarction.

Although some studies suggest that complement activation is involved in the development of acute myocardial infarction, there has been little convincing evidence of a change in the complement system in patients suffering from myocardial infarction. In this study circulating levels of C3a, C3, C4 and the total hemolytic complement titer (CH50) were serially measured in 12 patients with acute myocardial infarction up to 10 days after an attack. The plasma C3a level was greatly elevated throughout the post-attack observation period. The C3, C4 and CH50 levels were significantly increased above those controls on days 8, 9 and 10 after infarction. These findings indicate that there is complement activation in patients with acute myocardial infarction, and suggest a pathogenetic role for complement activation in the development of myocardial damage after infarction.

Acute-Phase Reaction↗