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PubMed1989

Interleukin 3-dependent mediator release in basophils triggered by C5a.

The anaphylatoxin C5a is a potent trigger for basophil degranulations, but in contrast to IgE-dependent basophil activation, it does not result in the synthesis of sulfidoleukotrienes (leukotriene C4/D4/E4). Thus, degranulation and the generation of lipid mediators are separately regulated cellular responses. Exposure of human blood basophils to the cytokine IL-3 alone does not induce the release of histamine in cells from most donors and never leads to the generation of LTC4, indicating that IL-3 is not a direct agonist for basophil mediator release. However, preincubation of basophils with IL-3 enhances the degranulation response to C5a. Most importantly, IL-3 "primes" basophils to release large amounts of leukotriene C4 after challenge with C5a (mean of 50 gp LTC4 per nanograms cellular histamine), while neither peptide alone is capable of inducing the formation of bioactive lipids. This effect is dose dependent, occurring at IL-3 concentrations considerably lower than are required to stimulate the growth of bone marrow progenitor cells. IL-3 affects the extent but not the time course of basophil degranulation, and leukotriene release of cells sequentially exposed to IL-3 and C5a occurs very rapidly concomitant with degranulation. A preincubation of the basophils with IL-3 is strictly required for C5a-induced LTC4 synthesis, but not for an enhancement of degranulation. Priming for C5a-induced lipid mediator generation occurs rapidly after exposure of the cells to IL-3, starting at 1 min and reaching maximal effects at 5 min, but this altered state of responsiveness is relatively long lasting. Cell fractionation studies indicate that the basophil is the source of lipid mediators and that IL-3 affects the basophil response directly. This study demonstrates that IL-3 is a potent modifier of effector functions of mature basophils; this is possibly of greater in vivo significance than its growth factor properties. The large amounts of LTC4 formed after triggering of IL-3-primed basophils may not only enhance but also qualitatively change the pathophysiological consequences of complement activation, and this might be important in the pathogenesis of immediate type hypersensitivity reactions, shock syndromes, and inflammation.

Basophils↗
PubMed1998

Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide.

Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the beta-amyloid peptide (Abeta), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Abeta deposits in NP. We report that Abeta peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Abeta with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.

Alzheimer Disease↗
PubMed1983

Transient neutrophil aggregation in a patient with infectious mononucleosis.

Transient neutrophil aggregation is reported in a case of infectious mononucleosis. The phenomenon was observed on a blood film patient just before splenic infarction and decreased after splenectomy. The aggregation was so important that differential blood count could not be done. A high serum level of circulating immune complexes was found, and fluorescent spots inside of granulocytes, presumably engulfed immune complexes, could be observed. It is suggested that C activation associated with high immune complexes in infectious mononucleosis is a possible pathogenetic mechanism inducing PMNs aggregation and immune tissue damage.

Adult↗
PubMed1987

Complement and anaphylatoxin responses to cross-clamping of the aorta. Studies during general anaesthesia with or without extradural blockade.

Complement activation and anaphylatoxin formation were studied in 28 patients undergoing aortic reconstructive surgery under general anaesthesia. In 12 of the patients an extradural catheter was placed in the L1-2 space and 2% mepivacaine was injected until blockade reached the T4 level. The remaining 16 patients were operated upon under general anaesthesia alone. Complement activation was not obvious until aortic cross-clamping. The release of anaphylatoxin was less pronounced during cross-clamping in the extradural group.

Aged↗
PubMedDate not supplied

The chemotactic effect of Bacteroides fragilis lipopolysaccharide.

The atypical Bacteroides fragilis lipopolysaccharide is chemotactic for polymorphonuclear leukocytes. The chemotactic activity is mediated by complement activated through the alternative pathway. This mediator has been isolated. It is a polypeptide with a molecular weight of 16,000 and is most likely the complement component C5a.

Animals↗
PubMedDate not supplied

The complement system in host defense and inflammation.

In this discussion I have reviewed the major role of complement in host defense and inflammation. In addition, I have discussed dificiency states. Although these are rare, their clinical signs and symptoms can be predicted, at least in part, on the basis of our current understanding of the biological activities of complement and the various pathways of complement activation. This is not to say that complement plays no role in a wide variety of other illnesses. However, when complement plays a role in an illness, often this is not because it is functioning in an aberrant fashion. The usual situation is that complement is being activated and is serving its normal function in causing inflammation and damage to tissues under abnormal circumstances. Thus, for example, circulating antigen complexes may be deposited in the kidney, activate complement, and mediate tissue inflammation. In this case, complement is functioning normally but is being activated under abnormal circumstances. The same type of analysis can be made for many diseases of many different organ systems. At present, we have no drugs that are effective in humans in controlling the activation of complement and complement-mediated inflammation. We have not yet even established whether local variations in the activity of complement may affect the course of a clinical infection, but there is certainly strongly suggestive evidence to support this idea. It should be clear that under certain circumstances complement may well be a major factor in controlling the course of an infection. The near future should bring a vast expansion in our understanding of how complement contributes to specific clinical illnesses and to the defense of the host against specific microorganisms.

Angioedema↗
PubMedDate not supplied

The role of complement in the host's defense against Streptococcus pneumoniae.

In recent years there has been a growing realization that the complement systems plays an important role in the host's defense against infection and that it plays an especially critical role in both natural and acquired immunity to Streptococcus pneumoniae. The terminal components of the complement system, C3-C9, are responsible for most protective functions of the complement system. However, in order to subserve their protective functions, C3-C9 must first be activated. In vitro studies have shown that pneumococci are able to activate the terminal components of complement, C3-C9, by at least two different mechanisms, the classical and alternative pathways. Regardless of the pathway of their activation, C3-C9 produce anaphylatoxic, chemotactic, and opsonic activities in serum, each of which has the potential to play an important protective role in pneumococcal infections. Studies with experimental animals and the experience gained from study of complement deficiencies in humans have each fulfilled the promise of the in vitro studies by demonstrating that the complement system plays a biologically significant role in vivo in the host's defense against S. pneumoniae.

Animals↗
PubMed1980

Host factors in the formation of abscesses.

The role of host factors in the formation of subcutaneous abscesses due to Bacteroides fragilis or Staphylococcus aureus was investigated in athymic nude mice, mice deficient in the fifth component of complement (C5D), and mice pretreated with cobra venom factor (CVF). CVF-treated mice, inoculated with B. fragilis, had abscesses 62% larger than those of control mice at day 4 (P < 0.01), but no significant difference was observed when S. aureus was used. Athymic nude mice had significantly smaller abscesses than control animals at both days 4 and 7 after inoculation with either organism. There were no differences in abscess size or in the accumulation of neutrophils at day 4 when C5D mice were compared with control animals for either organism. The results suggested that the activity of the alternative complement pathway may influence abscess size and that chemotactic factors other than the fifth component of complement can supervene in C5D mice to produce encapsulated abscesses. The absence of thymic factors did not prevent containment of abscesses.

Abscess↗
PubMed1987

In vivo Streptococcus pyogenes C5a peptidase activity: analysis using transposon- and nitrosoguanidine-induced mutants.

The streptococcal C5a peptidase removes a six-amino-acid fragment from human C5a and thereby inactivates this chemotaxin. We used transposon and chemical mutagenesis to generate mutants of Streptococcus pyogenes that did not produce C5a peptidase. These mutants showed no alteration in expression of capsule, M protein, streptolysins O and S, or pyrogenic exotoxin C. Serial passage of a peptidase-producing strain in vivo resulted in a 100-fold increase in production of C5a peptidase. The presence of C5a peptidase delayed the accumulation of polymorphonuclear leukocytes (PMNLs) in the peritoneal cavities of mice after intraperitoneal challenge. However, there was no difference in virulence (as evaluated by LD50) between strains that produced and those that lacked C5a peptidase. Although C5a peptidase is expressed on the cell surface, antibody to this enzyme did not opsonize streptococci for phagocytosis in vitro. These studies show that C5a peptidase alters the normal host inflammatory response by delaying the accumulation of PMNLs at the foci of streptococcal infection.

Adhesins, Bacterial↗
PubMed2000

Evidence for activation of the alternate complement pathway in patients with juvenile rheumatoid arthritis.

OBJECTIVE: Complement activation has been shown to occur in patients with juvenile rheumatoid arthritis (JRA). Since the two pathways of complement are activated by different stimuli (the alternate pathway by microbial products and IgA, and the classical pathway by immune complexes), we decided to study the relative contribution of the two pathways of complement activation in patients with JRA. METHODS: In 56 patients with JRA, plasma levels of C3 and C4 were measured by turbidimetric assays, and those of C4d, factor Bb and sC5-9 complex by solid-phase enzyme immunoassays. Levels beyond the mean +/- 2 S.D. of normal were considered abnormal. RESULTS: Plasma C3 and C4 levels were decreased in one patient each. The C4d values were increased in 17 patients, whereas levels of factor Bb were elevated in 42 patients and levels of sC5-9 complex were elevated in 51 patients. The values of factor Bb and sC5-9 had a linear correlation (r = 0.75), but there was no significant correlation between C4d and sC5-9 levels (r = 0.36). CONCLUSION: Complement activation in JRA is initiated predominantly by the alternate pathway and culminates in the formation of terminal membrane attack complex.

Adolescent↗
PubMed1979

Immunopathological mechanisms in rheumatoid arthritis at the dual interface of the synovial membrane: the joint cavity and the pannus.

The significance of immune responses is examined in relation to clinicopathological changes in the rheumatoid joint and the concept of a dual site of action is developed. In the joint cavity interaction between immune complexes and complement is central to the phenomena observed, which depend on the generation of chemotactic factors and the ingress of polymorphs. Other chemical mediators--e.g. prostaglandins and lymphokines--are envisaged as playing a secondary or augmentory role. At the pannus-cartilage (and bone) junction the possibility is considered that changes are due to activation of a variety of cell types which results in enzymatic degradation of collagen in cartilage, osteolastic activity in bone and prostaglandin-induced depletion of bone. The production of migration inhibition factors by rheumatoid membranes is examined and some evidence in support of their lymphokine nature is found by gel filtration; their role as cell activators is considered.

Antigen-Antibody Complex↗
PubMed1987

C5a as a mediator of cutaneous inflammation.

C5a is an 11,000-dalton fragment of the fifth component of complement with potent anaphylatoxic and leukocyte chemotactic activities. Because C5a may play an important role in selected skin disorders as well as in systemic diseases with cutaneous manifestations, we have studied the clinical and histologic alterations produced by the intradermal injection of this potent soluble mediator of inflammation in human skin in vivo. These studies have outlined the biologic properties of human C5a within the context of cells resident in the skin, the cutaneous microvasculature, and interacting cellular elements of peripheral blood.

Anaphylatoxins↗
PubMedDate not supplied

Clinical applications of complement measurements in rheumatic diseases.

There is now convincing evidence that the complement system is involved in the pathogenesis of at least some of the manifestations of human rheumatic diseases. Complement measurements in serum and/or pathologic fluids from patients with these disorders not only reflect this involvement but also may provide important clues regarding the activity and extent of the disease processes. Future studies should provide additional information concerning the usefulness of such measurements for predicting the outcome of specific therapeutic regimens, and perhaps also be the basis for the evolution of new and more rational forms of therapy.

Antigen-Antibody Reactions↗
PubMed1987

C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin.

The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.

Adult↗
PubMed2002

Neutrophil adhesion molecule expression and serum concentration of soluble adhesion molecules during and after pediatric cardiovascular surgery with or without cardiopulmonary bypass.

BACKGROUND: Increased neutrophil activation by cardiopulmonary bypass (CPB) during cardiovascular surgery is thought to be responsible for postoperative complications. In children, the contribution of cardiovascular surgery alone to this response is not well-characterized. METHODS: Children undergoing surgery with CPB (CPB group, n = 35) and without CPB (control, n = 22) were studied (age, 3-17 yr). Blood was drawn 24 h preoperatively before medication, after anesthesia, after connection to CPB, at reperfusion, 4 h to 2 days after surgery, at discharge, and months after surgery. Neutrophil antigen expression and serum concentration of adhesion molecules, interleukin 8, and C5a (fragment of C5 complement) were analyzed by flow cytometry and enzyme-linked immunosorbent assay, respectively. RESULTS: With and without CPB, anesthesia and surgery induced decreased LFA-1 (CD11a-CD18), Mac-1 (CD11b-CD18), CD45, and CD54 (intercellular adhesion molecule 1) surface expression and sICAM-1 serum concentrations (all P < 0.001). sL-selectin serum concentration decreased with CPB (P < 0.001) but was not significantly altered in the control. In contrast, CD62L expression increased during CPB (P < 0.001). The time course of all analyzed markers was not significantly different between CPB and control, with the exception of sL-selectin (P = 0.017). One-day preoperative baseline values were reached days to months after surgery. Interleukin 8 and C5a serum concentrations increased after surgery in both the CPB group and the control group. CONCLUSIONS: Pediatric cardiovascular surgery leads to reduced adhesiveness and activity of circulating neutrophils. This reduction is more pronounced and sustained with CPB. These data may be useful in the assessment of novel therapeutic strategies.

Adolescent↗