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PubMed1985

Human C3a-mediated suppression of the immune response. II. Suppression of human in vitro polyclonal antibody responses occurs through the generation of nonspecific OKT8+ suppressor T cells.

C3a-mediated suppression of Ig secretion in human PBL cultures occurs through the activation of suppressor T cells. Incubation of T cell-enriched populations derived from peripheral blood or tonsil results in the activation of nonspecific OKT3+8+ suppressor T cells capable of inhibiting Fc fragment-induced Ig secretion in fresh autologous PBL cultures. Generation of OKT8+ suppressor T cells by C3a requires the interaction of T cells, adherent cells, and C3a. Activation of the suppressor-T-cell pathway is initiated early in culture. Incubation of the T-cell-enriched populations with C3a for 0.5 hr results in functional, transferable suppressor cells. Maximum suppression was achieved when C3a was allowed to interact with the cell population for 1-2 hr.

Antibody Formation↗

PubMed1983

Psychopharmacological activity of anaphylatoxin C3a in rat hypothalamus.

C3a anaphylatoxin injected into the perifornical hypothalamic region of sated rats increased the eating response to norepinephrine and the drinking response to carbamyl choline but had no effect on food or water intake in sated, saline control animals. This potentiation of drug-stimulated intakes was reversible by intrahypothalamic injection of catecholamine receptor antagonists haloperidol and phentolamine. We propose that C3a acts as a catecholamine agonist in the central nervous system. The results suggest that C3a may play a role in mediating the neuropsychiatric manifestations associated with immune complex formation or deposition in the central nervous system.

Animals↗

PubMed1983

Suppression of humoral immune responses by synthetic C3a peptides.

Synthetic oligopeptides based on the COOH-terminal sequence of native human C3a were examined for the ability to suppress antigen-specific and polyclonal antibody responses. The synthetic peptides were found to qualitatively mimic the suppressive actions of human C3a, but proved to be less active on a molar basis. Comparison of the activity of the peptides with native C3a indicates that the most potent peptide is C3a 57-77 with C3a 65-77, C3a 70-77, C3a[Ala 71,72]70-77, and C3a 73-77 being less active, respectively. These results indicate that the region of the C3a molecule responsible for immunosuppression is located in the COOH region.

Anaphylatoxins↗

PubMed2004

Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a.

Human mast cells (huMC) increase surface expression of FcgammaRI (CD64) in response to IFNgamma. Subsequent receptor aggregation of FcgammaR1 using CD64-specific F(ab')(2) or antibody directed against FcgammaR1-bound IgG results in cell activation. Human mast cells may be observed degranulating in inflammation associated with autoimmune disease and where IFNgamma is produced. We sought to determine if human mast cells cultured in IFNgamma would degranulate in response to aggregated IgG, what mediators might be generated (i.e., cytokines and eicosanoids), and whether C3a might enhance such activation. Activation of IFNgamma-treated huMC sensitized with 1 microg/ml aggregated IgG(1) resulted in 15-30% degranulation (beta-hexosaminidase release), which was half-maximal by 7.5 min; no degranulation was observed using heat-generated aggregates of IgG(2), IgG(3), or IgG(4). Activation using aggregated IgG(1) led to PGD(2) and LTC(4) generation as well as enhanced IL-3, IL-13, GM-CSF, and TNFalpha production. Preincubation of cells with F(ab')(2) from CD64-specific clone 10.1 reduced aggregated IgG(1)-mediated beta-hexosaminidase release by 38% while degranulation was unaffected by blocking FcgammaRII with F(ab')(2)-specific antibody (clone 7.3). Simultaneous activation of huMC via aggregated IgG and C3a led to additive degranulation. These data support a mechanism by which mast cells may contribute to the inflammatory component in fibrosis, vasculitis, and arthritis.

Cell Degranulation↗

PubMed1986

Degradation of human anaphylatoxin C3a by rat peritoneal mast cells: a role for the secretory granule enzyme chymase and heparin proteoglycan.

Purified human C3a was iodinated (125I-C3a) and used to study the interaction of labeled peptide with rat peritoneal mast cells (RMC). Cellular binding of 125I-C3a occurred within 30 sec, followed by a rapid dissociation from the cell. Both the binding of 125I-C3a and the rate of dissociation from the cell were temperature dependent. At 0 degrees C, the binding of 125I-C3a was increased and the rate of dissociation reduced, as compared with 37 degrees C. Once 125I-C3a was exposed to RMC, it lost the ability to rebind to a second batch of RMC. Analysis of the supernatants by trichloroacetic acid (TCA) precipitation and electrophoresis in sodium dodecyl sulfate polyacrylamide gels (SDS PAGE) revealed a decrease in the fraction of 125I precipitable by TCA and the appearance of 125I-C3a cleavage fragments. Pretreatment of RMC with enzyme inhibitors specific for chymotrypsin, but not trypsin, abrogated the degradation of 125I-C3a. Treatment of RMC bearing 125I-C3a with bis (sulfosuccinimidyl) suberate (BS3) covalently cross-linked the 125I-C3a to chymase, the predominant enzyme found in the secretory granules. Antiserum directed against chymase precipitated 125I-C3a from extracts of RMC treated with BS3. Indirect immunofluorescence of RMC by using the IgG fraction of goat anti-rat chymase showed that chymase is present on the surface of unstimulated cells. Neither purified chymase nor heparin proteoglycan alone had any appreciable effect on 125I-C3a, but together they resulted in prompt degradation of the 125I-C3a. Immunoabsorption of RMC sonicates with specific antibody for chymase completely abrogated the ability of these sonicates to degrade 125I-C3a. The results indicate that 125I-C3a binds to RMC and is promptly degraded by chymase in the presence of heparin proteoglycan.

Anaphylatoxins↗

PubMed2005

In vitro and in vivo evaluation of Adacolumn cytapheresis in healthy subjects.

Adacolumn is a medical device for adsorptive cytapheresis. It has been developed for selective adsorption of granulocytes and monocytes from peripheral blood of patients with immune disorders, such as autoimmune diseases and chronic inflammatory diseases. A double blind sham-controlled crossover study design was used in order to evaluate in vivo biological responses of leukocytes as well as biocompatibility during and after Adacolumn cytapheresis in healthy volunteers. In addition, experiments were undertaken to further evaluate leukocyte reactions to Adacolumn carrier (G-1: cellulose diacetate) beads in vitro. Six healthy volunteers, 4 males and 2 females, with a mean age of 26.7 years were randomly assigned to one of the two treatment arms in a crossover fashion. Three subjects received a single Adacolumn treatment, followed by a single sham treatment at an interval of 7 days. The other three subjects received the two treatments in reverse order. All subjects were followed up 7 days after the last treatment. Additionally, in vitro investigations were carried out using blood from the healthy donors to examine the effect of G-1 beads on granulocyte functions. In vitro exposure of human peripheral blood to G-1 beads caused downregulation of L-selectin expression and upregulation of Mac-1 expression on granulocytes, leading to a marked reduction of adhesive capacity of granulocytes to endothelial cells. The exposure also led to decreased granulocyte chemotactic activity to IL-8. The number of granulocytes and monocytes clearly decreased during Adacolumn cytapheresis. Granulocytes showed marked phenotypic changes of L-selectin(Low) and Mac-1(Hi) after passing through Adacolumn in vivo. Expression of TNF-alpha and chemokine receptors was downregulated. In addition, TNF-alpha and IL-1beta producing capacity of peripheral blood leukocytes was decreased after Adacolumn cytapheresis and these changes lasted even one week after the cytapheresis. The level of complement fragments, C3a and C5a, increased, while bradykinin concentration did not change during Adacolumn cytapheresis. Exposure of human peripheral blood to G-1 beads, both in vitro and in vivo, caused a significant reduction of adhesive capacity and proinflammatory cytokine producing capacity of peripheral blood leukocytes. Such changes were not observed after sham apheresis. Despite complement activation, tolerability of Adacolum cytapheresis was not influenced. These findings may at least partly explain the beneficial effect of Adacolumn cytapheresis in the treatment of autoimmune diseases.

Adult↗

PubMed1998

Site-directed C3a receptor antibodies from phage display libraries.

Recent cloning of the human C3a receptor (C3aR) revealed that this receptor belongs to the large family of rhodopsin-type receptors. A unique feature of the C3aR is the large second extracellular loop comprising about 175 amino acid residues. We constructed combinatorial phage Ab libraries expressing single chain Fv Abs from BALB/c mice immunized with the affinity-purified second extracellular loop of the C3aR, fused to glutathione-S-transferase. A panel of anti-C3aR single chain Fv fragments (scFvs) was selected after four rounds of panning using the second extracellular loop of the C3aR, fused to the maltose binding protein as Ag. Sequencing of the clones obtained revealed three different groups of scFvs, the epitopes of which were mapped to two distinct regions within the loop, i.e., positions 185 to 193 and 218 to 226, representing the immunodominant domains of the loop. By flow cyotmetric analyses, the scFvs bound to RBL-2H3 cells transfected with the C3aR, but not to cells transfected with the C5aR or to nontransfected RBL-2H3 cells. In addition, the scFvs bound to the human mast cell line HMC-1. Immunofluorescence studies showed C3aR expression on polymorphonuclear granulocytes and monocytes, but not on lymphocytes. In addition, no C3aR expression was observed on human erythrocytes or platelets. Surprisingly, none of the scFvs alone or in combination inhibited C3a-induced Ca2+ mobilization from RBL-2H3 cells transfected with the C3aR. In addition, C3a did not displace binding of the scFvs to the receptor, strongly suggesting that the N-terminal part of the second extracellular loop is not involved in ligand binding.

Amino Acid Sequence↗

PubMed1989

Characterization of C3a receptor-proteins on guinea pig platelets and human polymorphonuclear leukocytes.

The expression of specific membrane receptors for C3a was determined on guinea pig C3a-sensitive (gp R+) platelets and human polymorphonuclear leukocytes (hu PMNL). Binding studies with 125I-labeled C3a from gp or hu sources and Scatchard analysis applied to the binding data revealed the existence of two receptor classes on gp R+ platelets; a high-affinity class with about 200 binding sites/cell and Kd = 1.7 x 10(-9) M, and a relatively low-affinity class with Kd = 10(-8) M and about 500 sites/cell. Hu PMNL express a homogeneous receptor class with Kd = 3 x 10(-8) M and 40,000 sites/cell. Molecular characterization of the C3a receptor on gp R+ platelets was achieved by (a) cross-linking photoaffinity-labeled receptors to bound 125I-labeled C3a; (b) photoaffinity labeling receptors with a 13-amino acid residue C3a analogue 125I-Nap-Ahx-13; and (c) use of chemical cross-linkers like disuccinimidylsuberate to cross-link receptors with 125I-C3a. All three techniques gave rise to very similar labeling patterns. With the photoaffinity labeling methods, a diffuse band pattern was observed with an apparent molecular mass of 95-123 kDa with 125I-C3a as label, and 85-105 kDa with 125I-Nap-Ahx-13 as label. Chemical cross-linking of 125I-C3a revealed three distinct bands with molecular masses of approximately 123, 108 and 95 kDa. Subtracting the contribution of the cross-linked ligands, the C3a receptor on gp R+ platelets appears to be a protein complex, consisting of one to three components with estimated molecular masses between 83-114 kDa.

Adenosine Triphosphate↗

PubMed2005

The C3a receptor antagonist SB 290157 has agonist activity.

The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.

Animals↗

PubMed1989

Phospholipase A in acute lung injury after trauma and sepsis: its relation to the inflammatory mediators PMN-elastase, C3a, and neopterin.

Inflammatory mediators involved in the pathogenesis of the adult respiratory distress syndrome (ARDS) are products of the humeral cascade systems like the complement cascade and substances released from neutrophil granulocytes and macrophages like proteases, O2-radicals and arachidonate products. Phospholipase A2 (PLA) was shown by Vadas et al. to be correlated with circulatory shock in the sepsis syndrome, the probably most important underlying disease of ARDS. In a clinical study in 48 patients at risk for ARDS after trauma and sepsis we found plasma PLA elevated (52 +/- 5 U/l) in sepsis, with a positive correlation to the complement split product C3a (r = 0.42, p less than 0.01) and neopterin (r = 0.49, p less than 0.05), which serves as a marker of macrophage stimulation. Elastase-alpha 1PI and C3a showed higher plasma levels in patients with ARDS compared with non-ARDS patients, whereas the neopterin and PLA concentrations were not different with regard to ARDS. The relation between PLA and neopterin shown in the study is consistent with the possibility of macrophages being a source of the plasma PLA, as reported in experimental studies.

Biopterins↗

PubMed2002

Nafamostat mesilate attenuates radical formation in the rat lung infused with endotoxin.

We previously reported direct evidence of respiratory bursting by neutrophils in the pulmonary circulation of endotoxin-infused rats. To evaluate the effect of the protease inhibitor nafamostat mesilate (NM) on leukocyte-mediated radical formation in the pulmonary circulation of rats infused with endotoxin, we observed and measured the number of sticking leukocytes and quantified radical production in the pulmonary circulation of endotoxin-infused rats by means of a fluorescent imaging technique. Plasma C3a (desArg) was also measured using an enzyme-linked immunosorbent assay. Three groups (n = 5) of rats were infused with 4.5 mg/kg/h endotoxin (Et group), 50 microg/kg/h NM + endotoxin (NM group), or physiological saline (Ct group) for 2 h. The number of the leukocytes adhering within pulmonary capillaries, oxygen radical production in the rat pulmonary circulation, and plasma C3a (desArg) were all lower in the NM group than in the Et group. The leukocytes producing oxygen radicals were confirmed to be neutrophils by electron microscopic analysis of cerium deposition. We conclude that NM attenuates plasma C3a formation, neutrophil adherence to pulmonary capillaries, and their production of oxygen radical in rats infused with endotoxin.

Animals↗

PubMed1994

Complement activation during storage of single-donor platelet concentrates.

Single-donor platelets are stored up to 5 days prior to transfusion. Since contact of plasma to plastic surfaces may lead to complement activation, we investigated whether there is any increase in the complement factors C3a, C4a and C5a in routinely stored single-donor platelet concentrates. C3a levels increased about 40-fold during a 7-day storage. C4a levels also increased with storage time but to a lesser extent. By contrast, C5a levels remained stable throughout this period. ADP- and collagen-induced aggregation was impaired after storage of platelets, indicating severe functional injury. In platelet-poor plasma stored under identical conditions a comparable increase in C3a and C4a concentrations was observed. The loss of platelet function during storage might at least in part be due to the excessive anaphylatoxin concentrations observed.

Blood Donors↗

PubMed1986

Unusual anaphylatoxin dynamics after head injury--case report.

The case reported exemplifies a clinical picture markedly at variance with the chronology of symptoms and laboratory findings generally held to be typical in patients with post-traumatic shock. During a protracted clinical course this young man with a skull fracture and epidural haematoma experienced profound hypotension and adult respiratory distress syndrome (ARDS) well in advance of marked fourfold rise of circulating peripheral C3a desArg anaphylatoxin levels. This raises a note of caution with regard to diagnostic and/or therapeutic decisions based on anaphylatoxin assessment of neurosurgical trauma patients at risk of ARDS.

Adult↗

PubMed1988

Effects of cardiopulmonary bypass on pulmonary leukostasis and complement activation.

We measured white blood cell counts and complement component (C3a, C4a, and C5a) and prostacyclin levels, and studied lung biopsy specimens, in 16 patients undergoing cardiopulmonary bypass and compared them with four patients undergoing other pulmonary procedures. Bypass caused no significant elevation in peripheral venous white blood cell counts. Higher counts were present in the right atrium compared with the left atrium. Patients who underwent bypass had elevated complement component and prostacyclin concentrations before operation and these levels increased further during operation. Trapping of polymorphonuclear leukocytes occurred in pulmonary alveolar capillaries and venules after bypass. We conclude that bypass activates complement components primarily of the alternative pathway and leads to increased blood prostacyclin levels. These changes are accompanied by polymorphonuclear leukocyte accumulation in the lungs and may be important in initiation of the adult respiratory distress syndrome in these patients.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Anaphylatoxin C3a enhances mucous glycoprotein release from human airways in vitro.

Because C3a may be generated during the course of pulmonary inflammatory reactions, we investigated the ability of C3a to affect mucous glycoprotein (MGP) secretion from cultured human airways. C3a, but not C3a des Arg, caused a dose-related increase in MGP release (maximal after 4-6 h), with as little as 15 micrograms of C3a per milliliter stimulating a 40% increase. The experimental evidence suggested that immunologically specific C3a was required for the secretagogue actions, as monospecific anti-C3a inhibited the reaction, as well as specifically absorbing the secretagogue from solution. Moreover, it appeared that C3a does not require mast cell activation, eicosanoid generation, or macrophage-derived mucus secretagogue synthesis for its effect, since (a) no evidence of histamine release accompanied C3a-induced MGP release, and dibutyryl cAMP failed to affect C3a-induced MGP release, while reducing the actions of reversed anaphylaxis; (b) MGP release caused by C3a was not influenced by eicosatetraynoic acid or specific cyclooxygenase inhibitors, and no leukotrienes were detectable on the supernatants of C3a-stimulated airways; and (c) cycloheximide failed to affect C3a secretion-stimulating actions. Thus, C3a is a potent mucus secretagogue, and, possibly, acts directly as a glandular stimulant. It seems likely that C3a generated in the course of pulmonary inflammation might contribute to the mucus secretion associated with pulmonary infections.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1995

[Evaluation of serum granulocyte colony stimulating factor and granulocyte counts in patients with extracorporeal circulation].

To clarify the physiologic roles of granulocyte colony stimulating factor (G-CSF) in increasing granulocyte after extracorporeal circulation (ECC). The serum levels of G-CSF, C3a, granulocyte elastase and granulocyte count were examined in 26 patients undergone open heart surgery. These patients were divided into two groups, the long perfusion group (11 patients) and the short perfusion group (15 patients). Granulocyte increased immediately after ECC and reached maximum 48 hours after ECC in both groups. C3a showed significant increase at the end of ECC and decreased rapidly after ECC in both group. G-CSF showed high levels 3 and 6 hours after ECC in the short perfusion group and moderate increase prolonged until 48 hours after ECC in the long perfusion group. Granulocyte elastase showed high levels 6 hours after ECC and decreased to the normal value 48 hours after ECC in the short perfusion group, and high levels prolonging until 48 hours after ECC in the long perfusion group. Increase of granulocyte count might be affected with increase of compliment (C3a) and G-CSF at the early and late phase after ECC, respectively. Granulocyte elastase increased differently by the duration of perfusion time.

Adult↗

PubMed2004

Effects of extended storage of whole blood before leucocyte depletion on coagulation factors in plasma.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the quality of leucocyte-depleted plasma produced from leucocyte-depleted whole blood, stored for different periods of times before filtration through polyurethane filters. MATERIALS AND METHODS: Whole blood was collected, from 48 voluntary donors, into quadruple blood bag sets with integrated whole-blood filters, and stored at room temperature for 1, 2, 6, or 18 h before filtration. Five samples were taken: one directly from the donor; one immediately after collection; one before and one after filtration; and one from plasma units before freezing. All samples were analysed for the following parameters: prothrombin time; activated partial thromboplastin time; prothrombin fragments F1+2; fibrinogen; factors VIII, XI and XII; von Willebrand factor antigen; ristocetin cofactor activity; collagen-binding capacity; multimers; and complement C3a-desArg. RESULTS: Different whole-blood storage times before filtration did not have a significant effect on the stability of coagulation factors. The activity of all investigated coagulation factors in plasma was generally above 90 U/dl, even after 18 h of storage of whole blood before filtration. von Willebrand factor multimeric distribution remained stable throughout the process. However, activation of complement did occur during storage. CONCLUSIONS: Leucodepleted plasma originating from leucodepleted whole blood maintains a satisfactory level of coagulation factors, even after the storage of whole blood for 18 h at room temperature before filtration.

Adult↗

PubMed2003

Mannan binding lectin in febrile adults: no correlation with microbial infection and complement activation.

AIMS: To study the role of the mannan binding lectin (MBL) pathway of complement activation in the host defence to microbial infection in vivo, and the role of MBL in infectious mortality in non-selected patients. METHODS: A prospective observational study on 177 hospitalised medical patients with new onset fever. The presence, origin, and microbial cause of infection, the circulating MBL and complement activation product 3a (C3a), and the 28 day hospital course were determined. RESULTS: The patients had median MBL values similar to healthy blood donors: 18% of the patients and 14% of the blood donors had MBL deficiency, with values below 0.1 microg/ml. Median C3a was higher in patients with microbiologically confirmed infection than in those without, whereas there was no difference in MBL values or frequency of deficiency among patient groups with or without positive local cultures or bacteraemia. The mortality rate was 8% and the outcome groups did not differ in MBL. In febrile adults hospitalised in internal medicine wards, microbial infection induces complement activation, independently of MBL. CONCLUSIONS: The results argue against a predominant role for the MBL pathway of complement activation and a deficiency of MBL predisposing to serious and invasive microbial infection in non-selected adults.

Adolescent↗