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PubMed1985

Complement activation and clearance in acute illness and injury: evidence for C5a as a cell-directed mediator of the adult respiratory distress syndrome in man.

The appearance of the adult respiratory distress syndrome (ARDS) during the course of acute illness is believed to result, in part, from intrapulmonary neutrophil sequestration and degranulation induced by circulating inflammatory mediators. To evaluate the role of complement-neutrophil interactions in the pathogenesis of ARDS in man, 34 patients suffering from intra-abdominal sepsis (seven), multisystem trauma (15), or acute pancreatitis (12) were serially studied with regard to neutrophil migratory responses to C5a and F-Met-Leu-Phe, lysosomal content of beta-glucuronidase and lysozyme, and simultaneously obtained plasma levels of immunoreactive C3adesArg and C5adesArg. Nineteen patients developed ARDS. In these patients, plasma C3adesArg levels obtained within 72 hours of admission to the hospital were elevated to 305 +/- 35 ng/ml compared with 145 +/- 16 ng/ml for patients who did not develop ARDS (p less than 0.0005). C5adesArg levels were not elevated in either group. In vitro studies showed that neutrophils from normal persons were able to clear all of the C5a/C5adesArg generated in up to 5% zymosan-activated serum, while no clearance of C3adesArg was identified. Patient migratory responses could be divided into three groups based on their initial (less than 72 hour) samples: (1) hyperresponsive to both N = formyl-methionyl-leucyl-phenylalanine (FMLP) and C5a, (2) specifically deactivated to C5a, and (3) deactivated to both C5a and FMLP. Patients in the latter two groups developed ARDS. Enzyme content of neutrophils from patients who developed ARDS showed a substantial fall in beta-glucuronidase and lysozyme levels. The finding of elevated plasma C3a levels and deactivation of migratory response to C5a support the contention that complement activation had occurred in these patients and that their neutrophils had been exposed to C5a/C5adesArg in vivo. The finding of nonspecific migratory dysfunction associated with lysozymal enzyme loss, a circumstance not reproducible in vitro by C5a exposure, suggests that other stimuli produced degranulation of neutrophils made hyperresponsive by prior exposure to C5a.

Chemotaxis, Leukocyte↗
PubMed2000

[The complement system: an old story or target of new therapeutic approaches?].

The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitor (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.

Complement Inactivator Proteins↗
PubMed1986

Prostaglandin and complement interaction in clinical acute respiratory failure.

This study investigated the interaction of plasma levels of circulating prostaglandins and activated complement in clinical acute respiratory failure (ARDS). Fifty patients at risk for ARDS were followed up for up to ten days. Arterial blood gases and plasma levels of complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and granulocyte aggregation (GA) were measured daily. Seventeen patients (34%) developed ARDS, with mortality of 41% vs 23% for patients without ARDS. Compared with patients without ARDS, the ARDS group had significantly increased plasma C3a (1,130 +/- 750 vs 636 +/- 368 ng/mL) and granulocyte aggregation (48 +/- 10 vs 17 +/- 4 percentage of the maximum light transmission [% max T]). Plasma C5a, TxB, or PGI did not change significantly with or without ARDS. No measured variable was significantly associated with mortality. Regression analysis revealed significant correlations between GA, TxB, PGI, and arterial oxygenation. Plasma C3a and GA are increased in ARDS, suggesting systemic complement activation. A complex series of interactions between the prostaglandins, complement, and GA appears to be involved in ARDS.

Acute Disease↗
PubMed2000

B-1 B cell IgM antibody initiates T cell elicitation of contact sensitivity.

Although B-1 B cells have received considerable attention, their actual role in the normal functioning of the immune system is unclear. The hypothesized role of B-1 cell IgM in natural protective immunity is just being established. We have uncovered a separate and novel role for B-1 cell IgM in initiating the elicitation of acquired T cell-dependent contact sensitivity (CS), the prototype of in vivo T cell immunity, early after immunization (within 4 days). The recent recognition of a similarly unanticipated role of B cells in a variety of T cell responses, may indicate that B-1 cell IgM has a broader role in immunity than thought previously. We showed that 24 hr CS responses, and rises in local IFN-gamma levels at 24 hrs later after antigen (Ag) challenge the ears, were absent in pan B cell and antibody deficient mice. The mechanism of B cell involvement in CS-initiation is via local C5a generation early (1-2 hrs) after antigen (Ag) challenge of the ears, in 4 day contact sensitized mice. C5a activates local mast cells to release serotonin (5-HT) and TNF alpha to induce endothelial ICAM-1 and VCAM-1, leading to T cell recruitment. We hypothesized that C5a was generated via complement activation due to antibodies forming local AgAb complexes, and that B-1 cell IgM was involved because isotype switching of B-2 cells to produce C-activating IgG isotypes, could not occur as early as day 4. Indeed, B-1 cell deficient CBA/N-xid mice lacked C5a in 2 hr ear extracts, and had impaired CS ear swelling and elaboration of IFN-gamma at 24 hrs. Importantly, adoptive transfer of purified normal peritoneal B-1 cells, or just i.v. injection of Ag-specific IgM monoclonal antibodies in sensitized xid, restored deficient early C5a and late 24 hr ear swelling. These results suggest that early after Ag challenge, specific B-1 cell IgM, produced at distant sites by prior sensitization, forms AgAb complexes that trigger elaboration of C5a, to activate mast cell release of vasoactive TNF alpha and 5-HT to initiate CS, leading to T cell recruitment. We postulate that antibody of various isotypes possibly may lead to local vascular activation to aid in T cell recruitment in a variety of T cell responses, but that very early after immunization, Ag-specific IgM produced by B-1 cells, preferentially serves this important function.

Adoptive Transfer↗
PubMed1987

Activation of human serum complement with allergens. I. Generation of C3a, C4a, and C5a and induction of human neutrophil aggregation.

To understand the relevance of allergens in generation of C3a, C4a, and C5a in normal human serum, we studied extracts of several allergens (house dust, house dust mite, Aspergillus fumigatus, and perennial ryegrass). Known complement activators zymosan and endotoxin were used as controls. Generation of C3a, C4a, and C5a (determined by radioimmunoassays) occurred with extracts of house dust and Aspergillus more than with house dust mite and ryegrass. Anaphylatoxins were produced both in dose and time-dependent fashions. Serum activated with house dust and Aspergillus extracts induced neutrophil aggregation when this serum was added to neutrophil suspensions. Less aggregation occurred when house dust mite and perennial ryegrass extract-activated sera were added to human neutrophils. We propose that some allergens may induce biologic responses by activation of sera and generation of anaphylatoxins as well as by IgE-mediated responses.

Adult↗
PubMed2002

Complement in allergy and asthma.

The complement system is a vital link between innate and adaptive immunity. Recently, several investigators have implicated the complement anaphylatoxins C3a and C5a as potential effectors in Type 1 hypersensitivity reactions, including urticaria, rhinitis and asthma. Thus, complement activation may synergize with classical IgE mediated responses, and inhibition of complement may prove therapeutic.

Anaphylatoxins↗
PubMed1990

A factor in serum lowers resistance and opens tight junctions of MDCK cells.

During an inflammatory reaction, factors in blood affect the permeability of endothelium and possibly organ epithelium. In this study we partially characterized a factor in human and canine blood that lowered the transepithelial electrical resistance (TER) of canine kidney epithelial cells (MDCK) and examined whether vascular permeability factors [complement component C3a and C5a and platelet-activating factor (PAF)] were responsible for this reaction. C3a and C5a caused a small (10-13%) dose-related decrease in the TER (alpha = 0.05), whereas PAF had no effect. In contrast, the factor found in both serum and plasma caused a large (60-83%) dose-dependent decrease (saturated at 30%) in the TER that was reversible within 60 min. The blood factor, which does not appear to be albumin, was heat stable and has an apparent molecular mass of 67 kDa. It preferentially decreased the TER of the epithelium when it came in contact with its basolateral surface and significantly lowered the resistance within 60 min by opening the zonula occludentes. These findings suggest that C3a, C5a, and a factor in blood can directly modulate the permeability of renal epithelium.

Animals↗
PubMed1986

Modulation of the immune response by anaphylatoxins.

Bioactive C3a and C5a fragments derived from the human complement compounds C3 and C5, respectively, possess immunoregulatory activities. C3a and C5a differentially influence in vitro immune function. C3a was found to be a potent suppressor of antigen-specific and polyclonal antibody responses. In contrast, C3a was unable to suppress antigen-or mitogen-induced B and T cell proliferation. Analyses of synthetic peptides based on the sequences of C3a revealed that the carboxy-terminal region of the molecule is responsible for immunosuppression. C3a-mediated suppression occurs through the activation of a nonspecific suppressor T cell pathway. In contrast to the results obtained with C3a, C5a was found to augment both in vitro humoral and cell-mediated immune responses. Regulation of immune function by complement components may form part of an in vitro nonspecific immunoregulatory network.

Adjuvants, Immunologic↗
PubMed1988

In vitro inhibition of the classical and alternate pathways of activation of human complement by N acetyl aspartyl glutamic acid (NAAGA).

A synthetic dipeptide, magnesium salt of N-acetyl-L-aspartyl-glutamic acid (NAAGA) identical to a natural dipeptide found as traces in cerebral tissues of mammalian brains, was shown to inhibit, in vitro, the hemolytic activity of both classical and alternate pathways complement; the required concentration of NAAGA was 2 to 10 mM. Cross immuno electrophoretic analysis demonstrated an inhibition of C3 cleavage by both classical and alternate pathway C3 convertases with 24 mM NAAGA. As expected, if C3 convertases were really the target of inhibition, the release of highly inflammatory C3a, C5a fragments scored by R.I.A. was impaired when complement was incubated with activators of classical and alternate pathways. Such a low molecular weight dipeptide, quite atoxic and inhibiting the complement dependent cytotoxicity and release of phlogistic by-products could be interesting for pharmacological manipulation of complement activation in inflammatory processes.

Complement Activation↗
PubMed1990

Proposed mechanism of the inflammatory attacks in familial Mediterranean fever.

Peritoneal and synovial fluids of patients with familial Mediterranean fever lack a protein that inhibits neutrophil chemotaxis by antagonizing the complement-derived inflammatory mediator C5a. The C5a inhibitor activity was studied with the use of a C5a binding assay where peritoneal fluids were tested for their ability to inhibit recombinant C5a binding to dibutyryl cyclic adenosine monophosphate-induced U937 cells. In contrast to normal peritoneal fluids, those from patients with familial Mediterranean fever contained less than 1% C5a inhibitor activity. Gel filtration and ion exchange chromatography of peritoneal fluids from those patients did not yield any fraction that inhibited C5a binding. We suggest that the serosal tissue of patients with familial Mediterranean fever is devoid of C5a inhibitor activity and that this deficiency may explain in part the local inflammatory episodes characteristic of this disease.

Ascitic Fluid↗
PubMed1995

Cellular expression of the C5a anaphylatoxin receptor (C5aR): demonstration of C5aR on nonmyeloid cells of the liver and lung.

The small-complement C5 activation fragment, C5a, is a potent phlogistic molecule that, on binding to the C5a Receptor (C5aR), mediates contraction of smooth muscle, enhances vascular permeability, and promotes leukocyte functions such as directed chemotaxis, degranulation, mediator release, and production of superoxide anions. Although C5aR expression has traditionally been thought to be limited primarily to myeloid blood cells, including neutrophils, monocytes, macrophages, and eosinophils, we report here that C5aR is expressed by liver and lung cells as well as by cells in several other tissues. By Northern blot analysis, it was determined that mouse liver, baboon liver, human liver, and the human hepatoma-derived cell line HepG2 express a normal size (2.3 kb) C5aR mRNA; in HepG2 cells, the quantity of C5aR mRNA was comparable to that contained in dbcAMP-differentiated U937 cells. HepG2 cells were demonstrated to express the C5aR on their cell surface by flow cytometric and immunofluorescence analyses as well as by 125I-C5a binding assays. The binding data indicated that HepG2 cells express a single class of C5aR with a Kd of 1.18 nM and approximately 28,000 receptors per cell. In vivo expression of C5aR in human liver cells was demonstrated by in situ hybridization and immunohistochemistry analyses. Northern blot analysis of murine and baboon organs shows that, in addition to the liver, other tissues express C5aR mRNA in significant quantities, including the spleen, lung, heart, kidney, and intestine. Moreover, mice treated with LPS show a large increase in C5aR mRNA in all these tissues except the intestine. Immunostaining of human lung tissue demonstrated that bronchial and alveolar epithelial cells, as well as vascular smooth muscle and endothelial cells, also express the C5aR. Collectively, these data indicate that the C5aR is expressed in several different types of cells in liver and lung, and in yet undetermined cell types in spleen, heart, intestine, and kidney. Furthermore, these data suggest that the C5a anaphylatoxin mediates previously unrecognized functions by binding to tissue cells that express the C5aR.

Amino Acid Sequence↗
PubMed1996

Increased release of tumor necrosis factor-alpha and interleukin-6 in women with the syndrome of hemolysis, elevated liver enzymes, and low platelet count.

BACKGROUND: Complement is activated in preeclampsia and complement products are known to activate macrophages. The aim of this study was to determine whether the macrophage derived cytokines, interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha, are released in patients with a form of severe preeclampsia characterized by the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). METHODS: Complement activation and plasma levels of cytokines were studied in 11 women with HELLP syndrome and in 11 controls with uncomplicated pregnancies. To further evaluate the connection between complement activation and cytokine release an in vitro study on heparinized whole blood incubated with recombinant C5a was performed. RESULTS: In the HELLP group, complement anaphylatoxin C5a was increased in plasma at delivery (p < 0.01) and one day after delivery (p < 0.05), terminal C5b-9 complement complex was elevated in plasma at delivery (p < 0.001) and one day after (p < 0.01), plasma levels of interleukin-6 were increased one day after delivery (p < 0.01), and plasma concentrations of tumor necrosis factor-alpha were elevated at delivery (p < 0.01), compared with corresponding levels in controls. All parameters normalized within one week. Interleukin-I beta did not differ between the groups. In vitro, recombinant C5a incubated in whole blood gave a dose-dependent release of interleukin-6. No increased release of interleukin-1 or tumor necrosis factor-alpha was seen after incubation. CONCLUSIONS: Since cytokine release occurs in severe preeclampsia, inflammatory mechanisms may participate in the pathophysiology of severe preeclampsia.

Adult↗
PubMed1989

The role of the complement system in the pathogenesis of multiple organ failure in shock.

The results of our experiments suggest that the development of MOF is the result of a concerted autodestructive inflammatory process affecting the endothelium which is probably triggered off by the complement system. The combination of two noxious events (application of a low dose of endotoxin during hemorrhagic shock) leads to an enormous intravasal activation of complement including formation of C5a and the deposition of active split products of C3 (C3a, C3b) in the tissue of lung, liver, small intestine and kidney. Histological examination revealed ARDS-like pulmonary changes with inflammatory microvascular lesions and granulocytic infiltration primarily in the liver and to a lesser degree in the intestines and the kidney. The severity of organic lesion closely correlated with the extent of complement deposited. This corroborates the clinical observation that pulmonary and hepatic lesions are always the first signs of MOF, no matter what kind of noxious influence (trauma or peritonitis) gave rise to its development (Mc Menamy, 1980). Which mechanisms are involved in the processes by which active split products of C3 cause damage to tissue? C3a possesses strong chemotactic forces which can bring about aggregation of granulocytes in the tissue. Deposition of C3b on the contrary may lead to the formation of the cytolytically active membrane-attack-complex with the result of direct cell damage. We did not find any severe organic lesion or deposition of complement in our controls (endotoxin only, hemorrhage only). Our results suggest that MOF is a sequel of a generalized, autodestructive, inflammatory process which results from a hyperintensive and uncontrolled humoral immunoresponse to noxious events.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylatoxins↗
PubMed1991

Complement activation in relation to development of preeclampsia.

Six hundred eighty-five primigravidas followed as a series had complement activation evaluated by the formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes in venous blood. Samples for complement determinations were obtained four times during pregnancy, in pregnancy weeks 12-16, 20-24, 28-32, and 34-36. Seven of the women developed preeclampsia and one of them the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). Eleven others with uncomplicated pregnancies were selected as a control group. Plasma samples were taken from these 18 women at delivery and 1 and 7 days after delivery. At delivery, plasma C5a levels were significantly greater in the preeclamptics than in controls, and four of the seven preeclamptics had elevated plasma C3a values compared with controls. One week after delivery, these plasma anaphylatoxins had returned to normal. Elevations of the anaphylatoxins could not be detected before the women developed clinical signs of preeclampsia. No alterations in terminal C5b-9 complement complexes could be observed in the women with preeclampsia. However, the women who developed HELLP syndrome had elevated plasma concentrations of C3a, C5a, and terminal C5b-9 complement complex at delivery. These values returned to the normal range 1 week after delivery. We conclude that complement activation in the systemic circulation does not occur early in pregnancy and that plasma concentrations of C3a, C5a, or terminal C5b-9 complement complex cannot be used as predictors of preeclampsia.

Adult↗
PubMed2000

Lack of effect of anti-C5a monoclonal antibody on endothelial injury by gas bubbles in the rabbit after decompression.

Previous studies have shown that gas bubbles activate the complement system in vitro, generating C5a. The effect of anti-C5a monoclonal antibody 4B1C11 in preventing endothelial damage caused by decompression in the pulmonary artery of the rabbit was examined. The endothelial response was measured using tension measurements in the blood vessel wall. The mean bubble count for all rabbits (n = 24) was 4.2+/-3.1 bubbles x cm(-2), and ranged from 0 to 15 bubbles x cm(-2). Animals with many bubbles showed significantly more vascular damage than those with fewer bubbles. Anti-C5a monoclonal antibody could not prevent endothelial damage than that occurred after exposure to this level of gas bubbles. The maximum number of gas bubbles present is important for the endothelial damage. We speculate that the endothelial damage observed was mainly mechanical. A possible beneficial effect of anti-C5a antibody can thus be masked at a high degree of bubble generation. This study, together with a previous paper, demonstrates that gas bubbles cause endothelial damage from decompression both in the pig and in the rabbit.

Acetylcholine↗
PubMed1981

Identification of classical anaphylatoxin as the des-Arg form of the C5a molecule: evidence of a modulator role for the oligosaccharide unit in human des-Arg74-C5a.

A functionally active and potentially lethal fragment of the fifth component of complement (C5) is generated during complement activation in serum from animals of various species. This factor, termed the "classical" anaphylatoxin, was isolated from porcine serum and was identified chemically as the des-Arg derivative of the well-characterized C5a molecule. Unlike the C3a and C4a anaphylatoxins, porcine C5a does not require the COOH-terminal arginyl residue for spasmogenic activity. Further degradation of porcine des-Arg(74)-C5a by carboxypeptidase Y removed glycine-73 and leucine-72 and decreased the intrinsic spasmogenic activity by >90%. Hence, we conclude that, although the arginyl residue is not essential, the COOH-terminal sequence Leu-Gly-Arg contributes structural information that accounts for >90% of C5a activity. Human des-Arg(74)-C5a, like its porcine counterpart, has instrinsic anaphylatoxin activity; however, higher concentrations were needed to contract the guinea pig ileal tissue (i.e., 1 muM for human des-Arg(74)-C5a versus 1 nM for porcine des-Arg(74)-C5a). Furthermore, the des-Arg form of human C5a was only 0.1% as active as porcine des-Arg(74)-C5a for enhancing vascular permeability in guinea pig skin. In addition to these biological differences, numerous chemical differences exist between the human and porcine des-Arg(74)-C5a molecules, the most prominent feature being an oligosaccharide entity associated uniquely with the human C5a. When the oligosaccharide unit of human des-Arg(74)-C5a was removed by glycosidases, leaving a single glucosamine residue attached to the side chain of asparagine-64, activity was enhanced. The human des-Arg(74)-C5a molecule devoid of the complex oligosaccharide unit exhibited 10-fold stronger spasmogenic activity and 20- to 50-fold greater permeability-enhancing activity than did human des-Arg(74)-C5a containing the oligosaccharide. Consequently, the oligosaccharide associated with human C5a modulates or suppresses potentially harmful activities of this anaphylatoxin. The relatively high levels of spasmogenic activity associated with porcine des-Arg(74)-C5a indicate that this factor is poorly controlled by endogenous serum carboxypeptidase, whereas human C5a is virtually inactivated by the enzyme. Hence, the influence of this oligosaccharide in suppressing human des-Arg(74)-C5a activity is of major physiologic importance in protecting man from potentially toxic effects of this complement factor.

Amino Acid Sequence↗
PubMed2003

Effect of complement fragment 1 esterase inhibition on survival of human decay-accelerating factor pig lungs perfused with human blood.

BACKGROUND: The role of complement in hyperacute lung xenograft rejection has not been fully elucidated. The present study evaluates the effect of complement (C) 1 esterase inhibition on hyperacute rejection of human decay-accelerating factor (hDAF)-positive pig lung by human blood. METHODS: Using a modification of an established ex vivo model, right and left lungs from individual animals were surgically isolated and separately perfused. Pigs homozygous for hDAF were perfused with fresh human blood that was either untreated or treated with complement 1 esterase inhibitor (C1-Inh) at doses of 1 U/ml (n = 5), 5 U/ml (n = 3) or 10 U/ml plasma (n = 5). RESULTS: Only C1-Inh at 10 U/ml prolonged survival time (230 +/- 48.3 minutes) as compared with controls (65.6 +/- 26.5 minutes, p < 0.05) and diminished complement activation (C3a and C5a, p < 0.05). Interestingly, a low concentration of C1-Inh increased the pulmonary vascular resistance (PVR; 1 U/ml: 0.54 +/- 0.3; 10 U/ml: 0.19 +/- 0.08). Sequestration of neutrophils (92 +/- 3%) and platelets (64 +/- 13%) was not prevented by any concentration of C1-Inh. Tissue deposition of C3b and C5b-9 were diminished by hDAF expression, and further blunted by treatment, with 10 U/ml C1-Inh. CONCLUSIONS: Complement plays a critical role in early events of lung hyperacute rejection (HAR). However, even potent inhibition of C1 esterase and C3/C5 convertase, using serum C1-Inh in pig lungs homozygous for hDAF expression, does not prevent rapid lung injury. Our findings implicate innate immune pathways resistant to efficient complement regulation, and suggest a role for neutrophils and platelets in the lung's particular vulnerability.

Animals↗
PubMed1987

C5a-specific modulation of phagocyte functions in patients with localized bacterial infections.

Chemotaxis, enzyme release and superoxide-anion (O2-) generation of purified peripheral blood neutrophils (PMN) and monocytes were studied in a total of 87 patients suffering from localized bacterial infections. Shortly after disease onset, single or several PMN functions became non-responsive to the complement split product C5a. Functional activities elicited by the synthetic peptide f-met-leu-phe or leukotriene B4 remained unaltered. C5a-specific impairment lasted one to several days and returned to normal with the subsidence of the disease. C5a elicited release of beta-glucuronidase as well as generation of superoxide-anions was seen more often to be impaired as compared to chemotactic migration. In contrast to PMN, monocytes from the same patients failed to show paralleling C5a-specific functional alterations. There was no correlation between impairment of PMN functions and plasma levels of the complement split-products C3a and C4a as determined by RIA. It is concluded that in acute infectious disease a graded C5a-specific modulation of PMN functions may be present. This phenomenon is transient and not paralleled by functional alterations of monocytes or changes in plasma complement levels.

Bacterial Infections↗