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PubMed1985

Complement profile in a C1 inhibitor deficient family.

Complement components and anaphylatoxins in a C1 inhibitor (C1INH) deficient family were studied. C4a was increased when C1INH was decreased, and C3a was increased in subjects with systemic lupus erythematosus (SLE)-like symptoms and with angioedema attacks. Danazol was effective in controlling the clinical as well as complement abnormalities including low CH50, C1INH and C4, which increased within 10 days after danazol treatment was started. Two-dimensional immunoelectrophoresis of C1INH showed that there was no functionally or electrophoretically abnormal C1INH present before or after danazol treatment. C3a and C4a were considered to play important roles in the pathogenesis of angioedema and associated SLE-like symptoms.

Anaphylatoxins↗
PubMed1990

In vitro phosphorylation of human complement factor C3 by protein kinase A and protein kinase C. Effects on the classical and alternative pathways.

Complement factor C3, recently found to contain covalently bound phosphate, was phosphorylated in vitro by cyclic AMP-dependent protein kinase (protein kinase A) and Ca2(+)-activated, phospholipid-dependent protein kinase (protein kinase C). Both protein kinases phosphorylated the same serine residue(s) located in the C3a portion of the alpha-chain. In addition, protein kinase C phosphorylated the beta-chain to a lesser extent. Protein kinase A gave a maximal incorporation of 1 mol of phosphate/mol of C3 while that value with protein kinase C was 1.5 mol of phosphate/mol of C3. The velocity in pmol of [32P]phosphate/(min x unit kinase) was 20 times higher for protein kinase C than for protein kinase A although a 10 times lower ratio of protein kinase to C3 was used in the former case. The apparent Km for C3 was 2.6 microM when protein kinase C was used. The phosphorylated C3 was found to be more resistant to partial degradation by trypsin than unphosphorylated C3. It was also found that phosphorylation of C3 in the C3a portion of the alpha-chain inhibited both the classical and alternative complement activation pathways on an approximately stoichiometric basis.

Amino Acids↗
PubMed1989

Accentuated complement activation in patient plasma during the adult respiratory distress syndrome: a potential mechanism for pulmonary inflammation.

The adult respiratory distress syndrome (ARDS) represents an acute inflammatory lung disorder, characterized by both refractory hypoxemia and a mortality rate approaching 95%. Researchers have proposed that activation of the complement (C) system may play a role in the development of the pulmonary inflammation associated with ARDS. The purpose of this investigation was to determine whether complement activation occurs to a greater extent in patients with ARDS than in patients without ARDS, thereby providing a potential mechanism for the acute inflammation seen in ARDS. In this study, we assessed plasma complement activation by measuring complement activation by-products: C1rC1s-C1 inhibitor complex and C3b-P complex, generated subsequent to activation of the classical and alternative pathways, respectively, and also the terminal complement complex, formed after activation of either the classical or alternative complement pathway. Multivariate discriminant analysis revealed that these three complement activation complexes could distinguish patients with ARDS from those without ARDS (p less than 0.04). Furthermore, these three complexes provided a more sensitive discriminator of ARDS than did plasma levels of C3a desarginine (p greater than 0.30), C5a desarginine (p greater than 0.41) and total hemolytic complement activity (CH50) (p greater than 0.72). We conclude that a temporal association exists between the complement activation and the development of ARDS. Therefore, we suggest that complement activation by-products be included in the armamentarium for ARDS.

Adult↗
PubMed1980

The pathomechanism of acetylsalicylic acid intolerance. A hypothesis.

In a number of individuals suffering from chronic asthma or chronic urticaria, acetylsalicylic acid and structurally unrelated non-steroidal anti-inflammatory agents and other compounds, e.g. tartrazine, elicit an intolerance syndrome that mimics the signs and symptoms of an immediate-type allergic (anaphylactic) reaction. An immunological basis for this reaction could be excluded. It is assumed that the eliciting agents activate complement and that the intolerant individuals lack plasma carboxypeptidase B, that normally inactivates C3a and C5a in statu nascendi. The anaphylatoxins, if not immediately inactivated, release the endogenous mediators of the anaphylactic reaction from the tissue mast cells.

Aspirin↗
PubMed1990

Assembly of terminal SC5b-9 complement complexes: a new index of blood-membrane interaction.

Activation of the complement system during the course of hemodialysis was recognized more than 20 years ago and since then the generation of C3a and C5a desarg has been used as parameters of blood-membrane interaction. More recently, determination of terminal C5b-9 complement complexes has become feasible. In the present study we determined plasma concentrations of C5b-9 complexes during hemodialysis using Cuprophan or Hemophan membranes. As early as 10 min into dialysis, Cuprophan membranes led to higher arterial plasma concentrations of C5b-9 complexes in comparison to Hemophan-containing devices. With Cuprophan, systemic arterial peak values of 237 +/- 27 U/ml were reached 45 min after the onset of dialysis, while corresponding peak values using Hemophan were only 58 +/- 16 U/ml. Venous concentrations of C5b-9 complexes, measured at the outlet of the dialyzer, were 489 +/- 102 U/ml with Cuprophan and 77 +/- 19 U/ml with Hemophan dialyzers. As an index of red cell lysis, plasma levels of free hemoglobin were evaluated. There was hemolysis with both membranes. Free hemoglobin levels increased threefold with Cuprophan and only twofold with Hemophan membranes. Taken together, plasma concentrations of C5b-9 complexes clearly discern between dialysis membranes of high or low compatibility. The fact that there is simultaneous lysis of red cells might indicate that deposition of C5b-9 complexes on innocent cells occurs which would lead subsequently to an array of diverse pathophysiological reactions.

Adult↗
PubMed2006

Complement inhibitors selectively attenuate injury following administration of cobra venom factor to rats.

Systemic activation of complement is a pathophysiological response common to severe disturbances such as hemorrhagic shock, major burn injury and sepsis. Intravenous infusion of cobra venom factor (CVF) has been used as an animal model of acute respiratory distress syndrome (ARDS), and reliably and selectively induces rapid intravascular activation of the complement system, leading to acute organ damage. In the present study, we have used different complement inhibitors to investigate the roles of complement products in CVF-induced responses in the rat. Rats were treated with either a C5a receptor antagonist (C5aRA, AcF-[OP(d-Cha)WR], 1 mg/kg i.v. or 10 mg/kg p.o.), a C3a receptor antagonist (C3aRA, N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine, 0.1 mg/kg i.v.) or a convertase inhibitor, rosmarinic acid (RMA, 10 mg/kg i.v.), prior to CVF-induced complement challenge. Intravenous CVF resulted in hallmark events evident in the development of ARDS, including systemic neutropenia followed by neutrophil migration to the lung and bronchoalveolar vascular leakage, blood pressure alterations, and an increase in TNFalpha levels in both serum and bronchoalveolar lavage fluid. These hemodynamic changes were differentially inhibited by antagonism of C5a receptors, C3a receptors or by inhibition of the entire complement cascade using RMA. This evidence strongly implicates complement factors in the development of lung injury associated with systemic complement activation and identifies complement inhibition as a potential therapeutic target for acute syndromes such as ARDS and other severe systemic shock states mediated by activation of complement.

Administration, Oral↗
PubMed1977

Chemical evidence for common genetic ancestry of complement components C3 and C5.

Sequence studies reveal a marked similarity between the partial primary structures of human C3a and C5a anaphylatoxins. Eight of the first 25 residues are identical when threonine at position 1 in C5a is aligned with glutamine at position 3 in C3a and one gap is inserted in the C3a sequence. A unique cysteinyl-cysteine sequence is conserved in the 2 molecules, which further suggests a genetic relatedness. Computer-generated alignment scores from comparison of the NH2-terminal portions of human C3a and C5a exceeded by 4 standard deviations the score from random permutations of these same sequences. This sequence similarity between the two anaphylatoxins suggests that the respective precursors, C3 and C5, had a common genetic ancestry. The proposed genetic relationship between C3 and C5 may express itself functionally through a similar molecular behavior in complement-dependent cytolysis.

Amino Acid Sequence↗
PubMed2006

Methylation of the phosphate oxygen moiety of phospholipid-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production.

Methoxy(polyethylene glycol), mPEG, -grafted liposomes are known to exhibit prolonged circulation time in the blood, but their infusion into a substantial percentage of human subjects triggers immediate non-IgE-mediated hypersensitivity reactions. These reactions are strongly believed to arise from anaphylatoxin production through complement activation. Despite the general view that vesicle surface camouflaging with mPEG should dramatically suppress complement activation, here we show that bilayer enrichment of noncomplement activating liposomes [dipalmitoylphosphatidylcholine (DPPC) vesicles] with phospholipid-mPEG conjugate induces complement activation resulting in vesicle recognition by macrophage complement receptors. The extent of vesicle uptake, however, is dependent on surface mPEG density. We have delineated the likely structural features of phospholipid-mPEG conjugate responsible for PEGylated liposome-induced complement activation in normal as well as C1q-deficient human sera, using DPPC vesicles bearing the classical as well as newly synthesized lipid-mPEG conjugates. With PEGylated DPPC vesicles, the net anionic charge on the phosphate moiety of phospholipid-mPEG conjugate played a key role in activation of both classical and alternative pathways of complement and anaphylatoxin production (reflected in significant rises in SC5b-9, C4d, and C3a-desarg levels in normal human sera as well as SC5b-9 in EGTA-chelated/Mg2+ supplemented serum), since methylation of the phosphate oxygen of phospholipid-mPEG conjugate, and hence the removal of the negative charge, totally prevented complement activation. To further corroborate on the role of the negative charge in complement activation, vesicles bearing anionic phospholipid-mPEG conjugates, but not the methylated phospholipid-mPEG, were shown to significantly decrease serum hemolytic activity and increase plasma thromboxane B2 levels in rats. In contrast to liposomes, phospholipid-mPEG micelles had no effect on complement activation, thus suggesting a possible role for vesicular zwitterionic phospholipid head-groups as an additional factor contributing to PEGylated liposome-mediated complement activation. Our findings provide a rational conceptual basis for development of safer vesicles for site-specific drug delivery and controlled release at pathological sites.

Anaphylatoxins↗
PubMed1987

Psychopharmacological activity of immune complexes in rat brain is complement dependent.

Sprague-Dawley male rats implanted with chronic indwelling cannulae at the perifornical hypothalamus eat excessively during the sixth hour following administration of exogenous immune-complexing reactants to the brain site. Rabbit anti-HSA was injected, followed in 30 min by a 20-fold excess of antigen. Anaphylatoxin C5a has also been shown to induce excessive intake, an effect similar to that of norepinephrine at this brain site. If the anaphylatoxins or other byproducts or consequence of the complement cascade were responsible for the immune complex effect, interference with the initiation of the cascade or with the conversion of C3 to C3a and C3b should abolish the behavioral response. These experiments demonstrate that immune complexes formed with the non-complement-fixing F(ab')2 fragment of the rabbit anti-HSA do not induce eating, and that normally active IgG antibody complexes do not induce eating if the site has been pretreated with goat anti-rat C3. This latter treatment had no effect, however, on the ability of the animals to respond to norepinephrine or to C5a. We conclude that the immune complex effect is complement dependent.

Animals↗
PubMed2001

Interactions of IgM ABO antibodies and complement with methoxy-PEG-modified human RBCs.

BACKGROUND: RBCs modified with cyanuric chloride activated methoxy-PEG (CmPEG; 5000 Da) are less immunogenic than untreated RBCs, and their use thus may reduce the risk of alloimmunization in chronically transfused patients. STUDY DESIGN AND METHODS: To further examine the potential utility of CmPEG-RBCs, the effects of derivatization on an arm of the immune system that plays an important role in transfusion rejection-the complement system--were determined. RESULTS: When CmPEG-RBCs were incubated in autologous or heterologous ABO-matched serum, no classical or alternative pathway consumption was found, no C3a was generated, no cell-bound C3b or C9 was detected, and no cell lysis occurred. Cell-bound complement regulation was normal for CmPEG-RBCs, as determined by acidified serum or reactive lysis assays. CmPEG-RBCs differed from control RBCs only when incubated in ABO-mismatched serum. In that case, CmPEG modification failed to protect against ABO antibody-dependent complement-mediated lysis. Indeed, cell lysis was actually enhanced at CmPEG concentrations >1.0 mM. CONCLUSION: The enhanced lysis of CmPEG-RBCs in ABO-mismatched serum correlated with increased IgM binding and C3a generation and elevated C3b and C9 membrane deposition. While PEG modification effectively blocks non-ABO antigens, these data show that ABO matching is still required. Once ABO-matched, these modified RBCs retain great potential for the prevention of alloimmunization.

ABO Blood-Group System↗
PubMed1989

[Complement activation during cardiopulmonary bypass: mechanism and prevention].

The mechanism of complement activation during cardiopulmonary bypass was studied for the prevention. In ten patients undergoing open-heart procedures, the serum levels of complement fractions (C3, C4, and C3 activator) were measured by a single radial immune diffusion method. In four of ten patients, the plasma levels of C3a, C4a, and C5a fractions were studied by the radioimmunoassay 2 antibodies method. The serum levels of C3, C4, and C3 activator decreased after cardiopulmonary bypass. The plasma levels of C3a, C4a, and C5a increased after bypass. The lower level of C3 activator shows that C3 activator was not excessively produced during cardiopulmonary bypass. Therefore it can be thought that much C4b2a from classical pathway as well as C3a over-production localizing extra-corporeal circuits and little inhibitors on alternative pathway resulted in increased complement activation. The prevention should be done from these etiologies.

Adult↗
PubMed1998

Extracorporeal ("ex vivo") connection of pig kidneys to humans. III. Studies of plasma complement activation and complement deposition in the kidney tissue.

The complement system is one of the important factors involved in the hyperacute rejection of xenografts. This report deals with the activation of the complement system in a clinical trial where pig kidneys were extracorporeally connected to two volunteer dialysis patients who were pretreated with plasmapheresis in order to substantially reduce anti-pig xenoantibodies. The clinical data of the perfusion experiments and the patients humoral immune response to pig xenoantigens have been reported in detail (Xenotransplantation 1996; 3:328-339, 340-353). Three consecutive daily plasmapheresis treatments of the patients reduced the plasma complement protein (C3, C4, and C5) concentrations to 8-27% of the baseline values. The perfusion of the pig kidney connected to patient 1 was terminated at 65 min due to graft rejection and this patient was not hemodynamically affected by the experiment. The second experiment was terminated at 15 min due to an anaphylactic like reaction of the patient. In patient 1 a slight reduction of plasma C3, C4, and C5 and an increase of C5a and SC5b-9 occurred, while C3a decreased during the perfusion. Patient 2 had an increase of all complement parameters, most prominent for C4d and SC5b-9, which occurred concomitant with the appearance of the anaphylactic like side effects. In general, plasma levels of PMN elastase, IL6 and IL8 increased in both patients during the perfusion. Immunohistochemical investigation of the kidney tissues revealed deposition of human complement factors C1q, C4c, and C3c in a congruent pattern with the vasculature of the kidney in patient 1. In kidney 2 only trace amounts of C1q and C3c were found. Both kidneys were negative for properdin. Therefore, in this experimental set up with extracorporeal connection of pig kidneys to the human circulation the human complement cascade is activated mainly through the classical pathway.

Adult↗
PubMed2006

OxLDL immune complexes activate complement and induce cytokine production by MonoMac 6 cells and human macrophages.

Oxidized low density lipoprotein (OxLDL) is immunogenic and induces autoimmune responses in humans. OxLDL antibodies are predominantly of the proinflammatory IgG1 and IgG3 isotypes. We tested the capacity of immune complexes prepared with copper-oxidized human LDL and affinity chromatography-purified human OxLDL antibodies [OxLDL-immune complexes (ICs)] to activate complement and to induce cytokine release by MonoMac 6 (MM6) cells and by primary human macrophages. The levels of C4d and C3a were significantly higher in human serum incubated with OxLDL-ICs than after incubation with OxLDL or OxLDL antibody, indicating complement activation by the classical pathway. MM6 cells and primary human macrophages were incubated with OxLDL-ICs, with or without prior conditioning with interferon-gamma. After 18 h of incubation, both MM6 cells and primary human macrophages released significantly higher levels of proinflammatory cytokines after incubation with OxLDL-ICs than after incubation with OxLDL or with OxLDL antibody, both in primed and unprimed cells. OxLDL-ICs were more potent activators of MM6 cells than keyhole limpet hemocyanin-ICs. Blocking Fc gamma receptor I (FcgammaRI) with monomeric IgG1 significantly depressed the response of MM6 cells to OxLDL-ICs. In conclusion, human OxLDL-ICs have proinflammatory properties, as reflected by their capacity to activate the classical pathway of complement and to induce proinflammatory cytokine release from MM6 cells and primary human macrophages.

Antibodies↗
PubMed1995

In vitro complement activation by ragweed allergen extract in the sera of ragweed allergic and non-allergic persons.

Ragweed allergen (RWA)-induced complement activation in sera of 40 RW allergic patients and of 40 non-allergic controls was investigated. After treatment of the sera with RWA, levels of C3a, C5a, C3bBbP, C1rC1sClinh, SC5b-9 and granulocyte-aggregating activity were determined. Concentration of RW-specific IgG was also measured. After RWA treatment dose-dependent complement activation was detected in sera of RW allergic and non-allergic persons. C3a generation was observed mostly in the sera of RW allergic individuals, while levels of C3bBbP and of RW-specific IgG were significantly higher in sera of allergics, and a strong correlation was found between these two parameters. In a prospective clinical study, a significant positive correlation was observed between the extent of RWA-induced alternative pathway (AP) activation and the severity of symptoms of allergic rhinoconjunctivitis that were developed in a 4-week period subsequent to blood sampling. These observations suggest that complement activation has a role in the development of the symptoms of RW allergy.

Complement Activation↗
PubMed2004

Complement-induced impairment of the innate immune system during sepsis.

The complement system is an integral part of innate immunity and is chiefly responsible for controlling bacterial infections, especially those involving gram- negative organisms. To accomplish this task, serum proteins engage in a series of enzymatic cascades. The cleaved proteins assemble pores on membranous structures, which lead to cell lysis. During this process, powerful inflammatory mediators are produced, including the anaphylatoxins, C5a, C3a, and the membrane attack complex (MAC). Under systemic inflammatory conditions, an overactive complement system may compromise the effectiveness of innate immunity. We review the detrimental effects that are caused by uncontrolled complement activation during sepsis.

Anaphylatoxins↗
PubMed2005

Complement-induced Impairment of the Innate Immune System During Sepsis.

The complement system is an integral part of innate immunity and is chiefly responsible for controlling bacterial infections, especially those involving gram- negative organisms. To accomplish this task, serum proteins engage in a series of enzymatic cascades. The cleaved proteins assemble pores on membranous structures, which lead to cell lysis. During this process, powerful inflammatory mediators are produced, including the anaphylatoxins, C5a, C3a, and the membrane attack complex (MAC). Under systemic inflammatory conditions, an overactive complement system may compromise the effectiveness of innate immunity. We review the detrimental effects that are caused by uncontrolled complement activation during sepsis.

Journal Article↗
PubMed1993

Disulfide bridges in human complement component C3b.

The disulfide bridges of human complement component C3b, derived from C3 by removal of the 77-residue C3a, have been determined. The 10 bridges are Cys537-Cys794, Cys605-Cys640, Cys851-Cys1491, Cys1079-Cys1136, Cys1336-Cys1467, Cys1367-Cys1436, Cys1484-Cys1489, Cys1496-Cys1568, Cys1515-Cys1639, and Cys1615-Cys1624. Including the 3 bridges in C3a (Cys670-Cys698, Cys672-Cys705, and Cys685-Cys706) previously determined by high-resolution X-ray crystallography [Hoppe-Seyler's Z. Physiol. Chem. 361 (1980) 1389-1399] all disulfide bridges of C3 are localized. C3 and the strongly related C4 and C5 are members of the alpha 2-macroglobulin superfamily. The predicted bridge patterns of C4 and C5 are discussed and compared with that of alpha 2-macroglobulin.

Amino Acid Sequence↗
PubMed1997

Effect of body weight and caloric restriction on serum complement proteins, including Factor D/adipsin: studies in anorexia nervosa and obesity.

Complement plays important roles in host immune defences, and recent studies suggest that adipose tissue is an important site of production for some complement proteins. Starvation has been associated with low complement levels, but studied populations have usually had concomitant opportunistic infections or other conditions which might affect complement levels. To determine the impact of body weight and changes in body weight on serum complement, we investigated levels of complement proteins in otherwise healthy patients with a wide range of body weights, including patients with anorexia nervosa before and after treatment, obese dieters before and after weight loss, and normal weight controls. We found that complement proteins of the alternative pathway (C3, B, and D), alternative pathway haemolytic activity (AP50) and the inhibitors H and I were low in starving anorectics and normalized with weight gain. C3a levels were comparable in anorectics at low weight and after weight gain, indicating that low serum complement levels were attributable to hypoproduction and not complement cascade activation with consumption. Further, levels of C3, B, AP50, H and I, but not D, were higher than controls in obese patients and decreased toward normal after weight loss. Overall, percentage of ideal body weight, changes in body weight, and serum transferrin were each highly correlated with serum levels of complement proteins. We conclude that levels of alternative pathway complement components are determined in part by factors that influence body weight and by weight changes, possibly due to changes in production in adipose tissue or at other sites.

Adult↗