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PubMed1989

Complement activation during an active cytomegalovirus infection after renal transplantation: due to circulating immune complexes or alternative pathway activation?

In 32 patients with a renal allograft, serial determinations after transplantation were made of C3d, the stable conversion product of the complement factor C3, as well as serial measurements of the anaphylatoxin C3a des arg. Furthermore, serial determinations were made on the presence of circulating immune complexes using three different assays (C1q binding assay, polyethylene glycol precipitation test, and indirect granulocyte phagocytosis test). Twenty patients were studied during an active cytomegalovirus (CMV) infection, and 12 patients were studied during allograft rejection or during stable phase after renal transplantation. In 12 patients with a CMV infection serial measurements were made of AP50 (alternative pathway of complement). During an active CMV infection elevated C3d as well as elevated C3a des arg levels were found and not in the control group (P less than 0.01). In 8 out of the 12 patients tested, with CMV infection, a decreased hemolytic activity of the alternative pathway (AP50) was found, together with the elevated levels of C3d and C3a des arg. Serum C4 levels were normal or high during CMV infection. Furthermore, circulating immune complexes were found to be positive in 15 out of the 20 patients with a CMV infection (both primary and secondary infections), and in 2 out of 12 patients of the control group. The complement activation found in the CMV group was not related to the presence of circulating immune complex-like material, since complement activation was present in advance of the appearance of the immune complexes, suggesting that complement activation was not due to classical pathway activation by those complexes. We conclude that our data are consistent with complement activation and the formation of biologically active peptides like C3a des arg in patients with an active CMV infection. The decreased hemolytic activity of the alternative pathway (AP50) together with the normal or high C4 levels suggest involvement of the alternative pathway, although further studies of the alternative pathway of C are warranted to confirm this hypothesis.

Adolescent↗

PubMed1994

Dextran sulfate activates contact system and mediates arterial hypotension via B2 kinin receptors.

To define some of the mechanisms underlying dextran sulfate (DXS)-induced hypotension, we investigated the effects of either the plasma kallikrein inhibitor des-Pro2-[Arg15] aprotinin (BAY x 4620) or the specific bradykinin B2-receptor antagonist Hoe-140 on the hypotensive response to DXS. In the first study, anesthetized miniature pigs were given DXS alone, DXS plus BAY x 4620 in various doses, or saline. As expected, DXS alone produced a profound but transient systemic arterial hypotension with a concomitant reduction in kininogen. Circulating kinin levels, complement fragment des-Arg-C3a, and fibrin monomer were all increased. Treatment with BAY x 4620 produced a dose-dependent attenuation of these effects with complete blockade of the hypotension as well as the observed biochemical changes at the highest dose (360 mg). In a second study, two groups of pigs were given either DXS alone or DXS plus Hoe-140. DXS-induced hypotension was completely blocked by Hoe-140 pretreatment; however, kininogen was again depleted. We conclude, therefore, that DXS-induced hypotension is produced by activation of plasma kallikrein that results in the production of bradykinin and that liberation of bradykinin and its action on B2 receptors in the vasculature are both necessary and sufficient to produce the observed effects on circulatory pressure.

Animals↗

PubMed1987

Interactions of purified Serratia marcescens metalloproteases with fresh human serum and with purified human serum proteins.

Exposure of fresh human serum to two purified metalloproteases of S. marcescens strains SF 178 and SH 186 (both of serotype O6/O14:H12) at 35 degrees C, 3 h, resulted in altered electrophoretic mobility of the protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin, alpha 2-HS-glycoprotein, and complement (C) components C1q, C1s, C3a, C3c, C4, C5, and C9, but not C6, C7, C8, and properdin, as determined with electroimmunoassays (Laurell technique). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the partial degradation of the heavy (H) chain of purified human immunoglobulin IgG by the metalloproteases of S. marcescens strains SF 178 and SV O1 (serotype O13/O19:H1), but not by the metalloproteases of strains SH 186 and SE 182 (serotype O9B:H11) following extended incubation (35 degrees C, 22 h). Human IgA and IgM were refractory. Purified human C components, C3, C4, C5, C6, C7, C8, and C9, as well as purified human alpha 1-antitrypsin, alpha 2-macroglobulin, transferrin, and lactoferrin were attacked by the S. marcescens metalloproteases SF 178 and SH 186 at 35 degrees C for 5 h, as demonstrated with the SDS-PAGE procedure; haptoglobin and C-reactive protein were resistant.

Acute-Phase Proteins↗

PubMed1994

Soluble complement receptor type 1 inhibits complement activation induced by hemodialysis membranes in vitro.

A variety of bioincompatible events that occur during hemodialysis have been attributed to complement activation. However, cause-effect relationships have been based primarily on indirect evidence and the results of in vitro studies, because an acceptable method for inhibiting complement activation during clinical hemodialysis has been unavailable. Methods for inactivating complement in vitro are available, but the most commonly used of these techniques (heat inactivation and chelation of divalent cations) lack specificity. A recombinant, soluble form of human complement receptor type 1 (sCR1) has been developed recently and shown to inhibit complement activation in vivo. Here, we report studies aimed at determining the effects of sCR1 on dialysis-induced complement activation and neutrophil degranulation. In a concentration dependent fashion, sCR1 inhibited plasma complement activation by cuprophan membrane in vitro. Using a maximally inhibitory concentration (30 micrograms/ml), sCR1 blocked generation of C3a(desArg) by cuprophan, cellulose acetate, and polymethylmethacrylate membranes by 90%, 84%, and 84%, respectively. In contrast, elastase release (a measure of neutrophil degranulation) was inhibited by 70%, 70%, and 44%, respectively, suggesting that dialysis-induced neutrophil activation is mediated in part by noncomplement dependent mechanisms. Both heat- and EDTA-treatment of plasma abolished dialysis membrane-induced complement activation, but these treatments also affected noncomplement dependent components of the degranulation process. These observations show that, compared with other commonly used methods for inhibiting dialysis induced complement activation, sCR1 is more specific. An additional advantage of sCR1 is its potential for use in the clinical setting.

Biocompatible Materials↗

PubMed1992

Decreased formation of the complement component C4A in leukocyte-depleted stored whole blood.

As reported earlier, factors of the complement cascade get activated in CPD-A1-stabilized whole blood. While leukocyte depletion inhibited partially the activation of C4, it had no effect on C3a concentrations. Therefore cleavage of C4 during storage of whole blood seems to be partially leukocyte-dependent, whereas the activation of C3 is possibly due to the activation of the alternate pathway of the complement system by contact of blood to plastic surfaces. Even though the radioimmunologically measured C3a might be inactive as an anaphylatoxin, these observations are of clinical importance since the inactivated C3a-desArg still possesses biological activities, like activation of platelets which may lead to hypercoagulability and thrombosis.

Blood Preservation↗

PubMed1985

Blood-membrane interaction: C3a, an indicator of biocompatibility.

An interest in hemodialysis-related patient symptomatology dating back to the beginnings of maintenance hemodialysis (HD) therapy prompted our investigations to determine the etiology of such discomfort. Since the discovery by Craddock et al (1) of the activation of the alternative complement pathway by hemodialyzer membrane, our efforts toward defining the relationship of symptoms to complement activation have been done in collaboration with the Minnesota group. Results of an earlier blinded study, (2) and continuing investigations of HD membranes provide data which support the contention that complement activation, although not necessarily etiologic in the symptoms related to dialysis, serves as an indicator of membrane compatibility. These newer data reveal C3a rises in vivo and in vitro by a Japanese processed cuprammonium membrane for dialysis to be similar to cuprophane. In vivo C3a elevation using Travenol CA-110 hemodialyzers of cellulose acetate are significantly lower and are similar to earlier results obtained by cellulose acetate of CD manufacture.

Cellulose↗

PubMed1994

Endotoxemia, complement, and white blood cell activation in cardiac surgery: a randomized trial of laxatives and pulsatile perfusion.

Endotoxin activates complement and white blood cells and all are implicated in the pathologic effects of cardiopulmonary bypass (CPB). We investigated if reduction in intestinal bacterial load with a laxative and/or pulsatile perfusion to improve bowel circulation during CPB reduced endotoxemia and complement and white blood cell activation. Sixty patients were randomized to four groups in a 2 x 2 factorial structure: group 1 (no laxative, nonpulsatile perfusion); group 2 (laxative, nonpulsatile perfusion); group 3 (no laxative, pulsatile perfusion); and group 4 (laxative, pulsatile perfusion). Plasma concentrations of endotoxin, C3a and C5a, and granulocyte elastase (GE) were measured before anesthesia, skin incision, and heparin administration; during CPB (1, 30, 60, 90, and 120 minutes and after protamine administration); and after CPB at 3, 6, 12, 24, and 48 hours and 7 days. In all groups there was a small increase in the concentration of endotoxin (overall from 6 ng/L before CPB to 11 ng/L at 90 to 120 minutes; p < 0.001) and significant increases in C3a, C5a, and GE levels but no significant differences among the groups. Endotoxin levels did not correlate with activation of complement or white blood cells. There was a weak correlation between duration of CPB and levels of C3a (r = 0.14; p < 0.03) and GE (r = 0.25; p = 0.001) but not endotoxin or C5a. There was a general correlation between levels of C3a and GE but not in individual patients. In conclusion, CPB results in statistically significant increases in endotoxin, C3a, C5a, and GE during CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Surgical Procedures↗

PubMed2001

Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation.

The complement system is an important inflammatory mediator during procedures such as cardiopulmonary bypass and hemodialysis when blood is exposed to large areas of biomaterial surface. This contact between blood and the biomaterials of implants and extracorporeal circuits leads to an inflammatory response mediated by the complement system. The aim of this study was to assess the ability of a complement regulator (factor H) immobilised on a biomaterial surface to inhibit complement cascade mediated inflammatory responses. The cross-linker N-succinimidyl 3-(2-pyridyldithio) propionate was used to immobilise factor H on a model biomaterial surface without affecting the biological activity of the inhibitor. Binding of factor H was then characterised using quartz crystal microbalance-dissipation (QCM-D) and enzyme immunoassays for products of complement activation: bound C3 fragments and soluble C3a, sC5b-9, and C1s-C1INA. Immobilised factor H reduced the amount C3 fragments deposited on the biomaterial surface after incubation with serum, plasma. or whole blood. In addition, lower levels of soluble C3a and sC5b-9 were generated after incubation with whole blood. In summary, we have demonstrated that complement activation on a highly activating model surface can be inhibited by immobilised factor H and have defined prerequisites for the preparation of future biomaterial surfaces with immobilised regulators of complement activation.

Biocompatible Materials↗

PubMed1976

Serum and glomerular complement in 205 cases of glomerulonephritis.

In 205 cases of GN the glomerular deposits of C3, C1q, C4, and C3A and the serum levels of the same complement components at the time of biopsy were studied. Alterations of serum complement profile were found only in acute GN, membranoproliferative GN and lupus nephritis, while glomerular deposition was observed with a different incidence and intensity in all nephropathies. A strict correlation between the intensity of deposits and the degree of hypocomplementaemia was found only in early acute GN and in active lupus nephritis.

Complement C1↗

PubMed1991

Neuroimmunopharmacologic effects of drugs of abuse.

Direct studies linking drugs of abuse with changes in neurotransmitters and subsequent effects on the immune system are not abundant. One can, however, hypothesize that an indirect effect can occur since a variety of neurotransmitters known to be acted on by various drugs of abuse can, in turn, be correlated with changes in immunity. These changes most likely are mediated via alterations in the autonomic nervous system or the ratio of hormones regulated by the pituitary gland. In addition, there is sound evidence to suspect that the immune system might be capable of altering either the induction of tolerance or the severity of withdrawal symptoms. An increasing body of evidence indicates that IL-1, IFN-alpha, as well as C3a and C5a of the complement cascade, are capable of acting on central catecholamines within the brain. The possibility that immune system peptides are capable of regulating neurotransmitters is further suggested by the evidence of neuropsychiatric side effects during the course of clinical trials. Since a variety of drugs of abuse can directly alter immunocompetence as evidenced by the results of in vitro protocols described elsewhere in this volume, one could speculate that certain behavioral manifestations of drug addiction may be modulated, in part, by immunologic status.

Animals↗

PubMed1986

Cyclophosphamide treatment in polyarteritis nodosa.

Five male patients with polyarteritis nodosa were treated with cyclophosphamide as follows: 3 mg/Kg/die i.v. up to maximum of 3 g.; subsequently, 200 mg/die per os for two weeks, then 100 mg per os every other day for three months; finally, 100 mg every fourth day until the 18th month. One patient, who also had fever, received 25 mg/die of prednisone for the initial three weeks of treatment. Before treatment ESR, WBC, and circulating immune-complexes were increased, while C3a, C3c and C4 serum complement components levels were normal. Skin ulcers healed within 4 months. A progressive marked improvement of visceral damages in the first months of therapy have been noted (e.g. blood pressure values in normal range after suspension of concomitant antihypertensive treatment, regression of peripheral neuropathy, etc. etc.). No further ischemic lesions occurred during treatment. Significant decreases of ESR and serum immune-complexes levels were detected. No untoward effects due to cyclophosphamide were observed. These findings support the effectiveness of this drug in polyarteritis. The possibility of association with glucocorticoids during the acute phase of disease is also discussed.

Adult↗

PubMed2005

Expression of the anaphylatoxin receptors C3aR and C5aR is increased in fatal asthma.

BACKGROUND: The mechanisms leading to death from asthma are not completely understood. Recent studies suggest the involvement of the anaphylatoxins C3a and C5a, generated during complement activation, and their receptors C3aR and C5aR in the pathogenesis of asthma. OBJECTIVE: The aim of our study was to investigate the expression of C3aR and C5aR in fatal asthma. METHODS: We analyzed lung tissue from 14 subjects who died of asthma (fatal asthma; FA) and 14 subjects who died of nonpulmonary causes (controls) and bronchial biopsy specimens from 16 subjects with mild intermittent asthma (MIA). C3aR and C5aR expression was evaluated by immunohistochemistry, and a semiquantitative analysis of the intensity of staining was performed according to a visual analogue scale (score, 0-3). RESULTS: C3aR was expressed on airway epithelium, smooth muscle, submucosal, and parenchymal vessels. C5aR was expressed on myeloid cells infiltrating the submucosa and on airway epithelium. Statistical analysis demonstrated higher expression of C3aR on submucosal vessels in FA compared with controls and MIA (median [minimum-maximum], controls, 0.24 [0-1.48]; MIA, 0.0 [0-1.00]; FA, 1.56 [0.13-3]; P = .002). C3aR was also increased on parenchymal vessels in FA (controls, 0.56 [0-2.00]; FA, 1.81 [0.5-3]; P = .0004). C5aR expression on airway epithelium was increased in FA compared with controls and MIA (controls, 1.25 [0.25-3]; MIA, 1.00 [0-2.00]; FA, 3.00 [1.13-3.00]; P = .001). CONCLUSION: The results of our study suggest a role of complement in FA.

Adult↗

PubMed1997

Anaphylatoxin C5a receptor mRNA is strongly expressed in Kupffer and stellate cells and weakly in sinusoidal endothelial cells but not in hepatocytes of normal rat liver.

Anaphylatoxins (C5a and C3a), which are generated during complement activation, have recently been shown to increase glucose output from hepatocytes (HC) in perfused rat liver. They did not act directly on HC but indirectly by prostanoid release from non-parenchymal cells (NPC), probably Kupffer cells (KC). In order to corroborate this mechanism, the distribution of anaphylatoxin receptors in the different cell types of rat liver was determined by quantitative RT-PCR with primers specific for the rat C5a receptor (rC5aR) using RNA isolated from KC, sinusoidal endothelial cells (SEC), hepatic stellate cells (HSC) and HC. In line with functional data, C5aR mRNA was detected in freshly isolated NPC but not in HC of rat liver. Mainly KC but also HSC clearly expressed C5aR mRNA, while SEC did so only weakly. KC expressed up to 10-fold more C5aR mRNA than HSC and these in turn up to 10-fold more than SEC. These results support the proposed indirect action of anaphylatoxins on HC.

Animals↗

PubMed2006

Discovery and identification of potential biomarkers in a prospective study of chronic lymphoid malignancies using SELDI-TOF-MS.

The accurate diagnosis of the different forms of chronic mature B-cell lymphocytic malignancies is of primary importance to determine an appropriate and efficient treatment. Usually, the diagnosis is achieved by morphology and immunophenotyping. Nevertheless, the diagnostic tools available are not able to discriminate pathologies with variable evolution, or to classify some of them. To discover new biomarkers, we used peptide and protein profiling SELDI-TOF-MS, to analyze 39 chronic B-cell malignancies and 20 control serum samples. Markers of interest were subsequently identified and characterized. In the obtained SELDI-MS profiles, most of the differences were observed in three mass ranges (m/z = 13 000; m/z = 9000; m/z < 2000). Identification of these biomarkers was achieved either by direct enrichment on the ProteinChip arrays followed by on-chip-MS/MS or by chromatographic fractionation, 1D-gel followed by nanoLC-MS/MS analysis. An increase of a sulfite form of transthyretin (13,841 Da) was observed in the patient group. A second set of markers at 8.6 and 8.9 kDa was identified as complement related fragment proteins, the C3a and C4a anaphylatoxins. In the low mass range, several peptides originating from N-terminal and C-terminal processing of the C3 alpha and C4 alpha chains were specifically observed in 38% of the patient sera, but in none of the control sera. This study emphasizes the usefulness of mass spectrometry studies in such malignancies.

Amino Acid Sequence↗

PubMed2006

An unexpected role for the anaphylatoxin C5a receptor in allergic sensitization.

The anaphylatoxins complement component 3a and 5a (C3a and C5a, respectively) are classically seen as proinflammatory mediators of allergic asthma that recruit inflammatory cells, induce edema, and cause bronchoconstriction. A few years ago, controversy arose when it was shown that C5-deficient mice were more susceptible to experimental asthma compared with C5-sufficient mice. In a study by Köhl et al. in this issue of the JCI, it is shown in a series of truly "complementary" experiments that C5a receptor (C5aR) blockade promotes Th2 sensitization upon first exposure to inhaled allergen, whereas C5aR blockade during established inflammation suppresses the cardinal features of asthma (see the related article beginning on page 783). Blockade of C5aR alters the function of airway DCs, crucial for inducing and maintaining Th2 responses in the lung. Targeting C5aR as a treatment for established asthma could be beneficial, but might be accompanied by sensitization to novel antigens.

Allergens↗

PubMedDate not supplied

Immunologic alterations associated with chronic hemodialysis.

Parameters of humoral immunity were studied in 18 patients with chronic renal failure undergoing hemodialysis. IgG, IgA and IgM serum levels presented no differences compared with healthy donors. High immunoglobulins levels were found in 40 patients with chronic renal failure and conservative treatment. Complement components C1q, C4, C9, were normal, but C3 and C3A were significantly low prior to dialysis. During hemodialysis, the complement system showed an activation by the alternative pathway (AP). The cuprophan membrane was proved to be an important factor in this activation. The circulating immune complexes (CIC) were also high. Seven patients presented autoantibodies, 2 against smooth muscle and 5 against gastric parietal cells. Our results suggested a certain humoral immune alteration during chronic hemodialysis.

Antibody Formation↗

PubMed1992

Relative contribution of contact and complement activation to inflammatory reactions in arthritic joints.

Although both the complement and contact system are thought to contribute to the inflammatory reaction in arthritic joints, only activation of complement has so far been well established, whereas contact activation and its contribution to arthritis has not been systematically explored. Complement and contact activation were assessed in 71 patients with inflammatory arthropathies and 11 with osteoarthritis using sensitive assays for C3a, and C1-inhibitor (C1INH)-kallikrein and C1INH-factor XIIa complexes respectively. Increased plasma concentrations of kallikrein-and factor XIIa-C1INH complexes were found in two and seven of the 71 patients with inflammatory arthropathies, respectively, and in none of the patients with osteoarthritis. Increased synovial fluid concentrations of kallikrein and factor XIIa complexes occurred in 13 and 15 patients with inflammatory joint diseases respectively, and in two patients with osteoarthritis. Contact system parameters did not correlate with clinical symptoms, local activity, or neutrophil activation. In contrast, synovial fluid concentrations of C3a and C1INH-C1 complexes were increased in all patients and in 20 patients with inflammatory arthropathies respectively, and were higher in patients with a higher local activity score. Synovial fluid C3a correlated with parameters of neutrophil activation such as lactoferrin. Increased plasma concentrations of C3a and C1INH-C1 complexes occurred in 13 and 11 patients with inflammatory joint diseases, and in one and two patients with osteoarthritis respectively. Plasma concentrations of C3a correlated with the number of painful joints. Thus contact activation occurs only sporadically in patients with arthritis and contributes little if anything to the local inflammatory reaction and neutrophil activation. These latter events are significantly related to the extent of complement activation.

Adolescent↗

PubMed2006

[Complement activation and inflammation].

The complement system not only plays an important role in the defense system, but also contributes to the amplification of inflammation if activated in excess or inappropriately controlled. Complement activation through one of three pathways is tightly controlled by various regulators of complement activation (RCA) which are constitutively expressed on various cells in order to restrict excessive activation. Complement activation may generate polypeptides, so-called anaphylatoxins, and membrane attack complex (MAC) with large molecular mass. Anaphylatoxins (C3a, C4a, and C5a) produced by activation of the complement is considered to bridge innate and acquired immunity. Considering that C5a is more potent than C3a, but the serum concentration of C3 is 10 times higher than that of C5, the overall effects of C3a may be comparative with those of C5a. Since both anaphylatoxins are considered to exert their actions through rhodopsin-typed receptors, their receptor antagonists are targets for the discovery of anti-inflammatory and immune-modulating drugs. Complement activation may be related to the pathophysiology of various refractory disorders including ARDS, asthma, septic syndrome, SLE, rheumatoid arthritis, ischemia-reperfusion injury, and psoriasis etc. Pharmacological manipulation of the complement system may consist of various strategies including (1) inhibitors of complement activation at various levels, (2) receptor antagonists of anaphylatoxins, C3a and C5a, and (3) inhibitors of C5a including monoclonal antibody. Candidate agents concerning the above-mentioned manipulations have being produced and some are now in progress toward clinical trials in patients with certain diseases.

Animals↗