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PubMed1987

Effect of muralytic enzyme degradation of streptococcal cell wall on complement activation in vivo and in vitro.

Rats given a single intraperitoneal injection of an aqueous suspension of peptidoglycan-polysaccharide polymers derived from group A streptococcal cell wall (PG-APS) develop a severe, chronic, erosive arthritis which resembles human rheumatoid arthritis. The treatment of PG-APS-injected rats with a single intravenous injection of 0.4 mg of mutanolysin prevents the development of chronic arthritis, even when administration of the enzyme is delayed until severe acute arthritis has developed. PG-APS activates complement both in vitro and in vivo. Digestion of PG-APS with mutanolysin in vitro destroys the ability to activate both the alternate and classical pathways of human serum complement, and the loss of complement activation parallels the extent of PG-APS degradation. There is also a reduction in the in vivo complexing of C3 with PG-APS in the limbs of PG-APS-injected rats treated with mutanolysin, compared to control rats injected with PG-APS and treated with phosphate-buffered saline. This association between loss of arthropathic activity and loss of activation of complement is consistent with the hypothesis that activated complement products form a part of the inflammatory mediators involved in the acute and chronic phases of bacterial cell wall-induced arthritis. This may also partially explain how mutanolysin treatment alleviates cell wall-induced arthritis in the rat.

Animals↗
PubMed2004

[ABO typing error caused by anti-IgM activated complements].

In order to determine the appraisal of ABO blood group accurately and ensure the safety of blood transfusion, an investigation was made on the influence of complement activated by antibody in appraising ABO blood group by using hemoagglutination test and direct antiglobulin test. Two samples of ABO blood group were collected from two donors. The results showed that the obverse and reverse patterns did not accord each other in two samples of ABO blood group, and their blood samples were both positive for anti-C(3) and were both negative for anti-IgG. It is concluded that the inconsistency of the obverse and reverse patterns in two samples of ABO blood group were proved to be caused by the complements activated by the antibody against IgM. Blood group O was finally determined for the two samples, and the influences of IgM antibody and complement on ABO blood group were excluded when the test proceeded. This method will be useful to determine ABO blood group accurately.

ABO Blood-Group System↗
PubMed2003

The influence of platelet additive solutions on cytokine levels and complement activation in platelet concentrates during storage.

BACKGROUND AND OBJECTIVES: The accumulation of platelet-derived cytokines in platelet concentrates (PC) during storage may contribute towards non-haemolytic transfusion reactions (NHTR). We investigated the effect of platelet storage medium on platelet activation, complement activation and cytokine levels in leucocyte-reduced PC. MATERIALS AND METHODS: Hyperconcentrated platelets (3000-6000 x 109/l) were collected by apheresis and diluted in 100% plasma, 70% PASIII, or 70% or 80% PASIII supplemented with magnesium and potassium (PAS IIIM). RESULTS: Levels of transforming growth factor-beta (TGF-beta) and regulated on activation, normal, T-cell expressed, and secreted (RANTES) increased during storage, as did the expression of P-selectin (CD62P), and were highest in PC stored in PASIII. In PC stored in PASIIIM, however, levels of TGF-beta and RANTES were not significantly different from PC stored in plasma. Levels of CD62P expression, however, remained higher in PASIIIM PC than in those stored in plasma by day 5, but were lower than PC stored in PASIII. C3a des arg levels increased during storage in all media with the exception of PASIII and, on day 7, were higher in PC stored in plasma compared to PC stored in the other media. CONCLUSIONS: Our results indicate that replacing plasma in PC with unmodified PASIII for storage results in higher levels of platelet-derived cytokines in PC. Furthermore, it appears that the nature of the medium used for storage of PC has a significant impact on platelet activation and cytokine levels of the PC. These implications should be taken into account when considering replacement of plasma with PAS.

Blood Platelets↗
PubMed1996

Modulation of natural IgM binding and complement activation by natural IgG antibodies: a role for IgG anti-Gal alpha1-3Gal antibodies.

The most abundant natural IgG Abs in human serum are thought to be Abs specific for Gal alpha1-3Gal, a carbohydrate expressed in lower mammals. IgG Abs specific for Gal alpha1-3Gal have been postulated to contribute to host defense and to participate in the rejection of interspecies organ grafts. Our previous studies indicated, however, that IgM and not IgG anti-Gal alpha1-3Gal Abs activate complement on foreign surfaces, and thus the physiologic role of IgG anti-Gal alpha1-3Gal remains uncertain. We tested whether the IgG anti-Gal alpha1-3Gal in a human serum might in fact compete with IgM for binding and thus modulate complement fixation by IgM. Several lines of evidence suggested such competition might occur. First, the functional avidity of IgG and IgM for Gal alpha1-3Gal on cell surfaces were nearly within the same order of magnitude, and in some sera the molar concentrations of IgG and IgM anti-Gal alpha1-3Gal were comparable. Second, binding of human IgM to Gal alpha1-3Gal on cell surfaces was inversely correlated with the concentration of IgG anti-Gal alpha1-3Gal in serum. Third, combination of IgG and IgM Abs specific for Gal alpha1-3Gal demonstrated direct competition for binding. The presence of IgG anti-Gal alpha1-3Gal, which was predominantly IgG2, attenuated by up to 80% the fixation of C1q mediated by IgM, presumably by competing for antigenic sites recognized by IgM Abs that fix complement. Thus, IgG Abs specific for Gal alpha1-3Gal modulate complement activation by IgM specific for that structure and might in this way modulate the consequences that ensue when human blood is brought into contact with foreign organisms or xenogenic cells.

Animals↗
PubMed1991

Functionally active complement proteins C6 and C7 detected in C6- and C7-deficient individuals.

Two sensitive sandwich ELISAs based on monoclonal antibodies directed to native C6 and C7 allowed the detection and quantitation of these complement proteins in 20 out of 37 serum samples from individuals who had previously been classified as deficient in these proteins as assessed by immunochemical and/or functional assays. Furthermore, serum from four C6-deficient and one combined C6-/C7-deficient individual showed an increase in the terminal complement complex (TCC) and a decrease in native C6 and C7 after complement activation as assayed by specific ELISAs. Despite their (incomplete) deficiencies, these individuals therefore possess functionally active terminal complement proteins with respect to their ability to generate the TCC. As these individuals have no history of a susceptibility to neisserial infections, even low concentrations of functionally active C6 and C7 may provide sufficient protection against those micro-organisms whose destruction requires TCC formation.

Antibodies, Monoclonal↗
PubMed1990

Epithelial deposition of immunoglobulin G1 and activated complement (C3b and terminal complement complex) in ulcerative colitis.

The epithelial destruction seen in ulcerative colitis remains unexplained. Complement activation has been proposed to be involved, but no definite evidence has been available to this end. In the present study, we examined immunohistochemically ulcerative colitis lesions with monoclonal antibodies to activation neoepitopes in the complement component C3b and in the cytolytically active terminal complement complex. Colonic tissue specimens from 23 patients with ulcerative colitis were examined by indirect two-color immunofluorescence staining with monoclonal antibodies to the four human immunoglobulin G subclasses and to activated complement C3b or terminal complement complex. All except two patients had activated C3b deposited apically on the surface epithelium of involved mucosa. Immunoglobulin G1 was found on the epithelium in extensively prewashed specimens from 7 of 11 patients, and a striking colocalization of immunoglobulin G1, C3b, and terminal complement complex was observed in 4. Immune deposits were not observed in 31 noninflamed specimens from the same ulcerative colitis patients. Only 1 of 44 histologically normal mucosae from 17 controls and 1 of 10 colonic adenomas contained some epithelial complement deposits. It is concluded that activated complement is often deposited along the brush border of the surface epithelium in active ulcerative colitis lesions and may be associated with immunoglobulin G1 autoantibody.

Adolescent↗
PubMed1977

Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes.

Acute leukopenia occurs in all patients during the first hour of hemodialysis with cellophanemembrane equipment. This transient cytopenia specifically involves granulocytes and monocytes, cells which share plasma membrane reactivity towards activated complement components. The present studies document that complement is activated during exposure of plasma to dialyzer cellophane, and that upon reinfusion of this plasma into the venous circulation, granulocyte and monocyte entrapment in the pulmonary vasculature is induced. During early dialysis, conversion of both C3 and factor B can be demonstrated in plasma as it leaves the dialyzer. Moreover, simple incubation of human plasma with dialyzer cellophane causes conversion of C3 and factor B, accompanied by depletion of total hemolytic complement and C3 but sparing of hemolytic C1. Reinfusion of autologous, cellophane-incubated plasma into rabbits produces selective granulocytopenia and monocytopenia identical to that seen in dialyzed patients. Lungs from such animals reveal striking pulmonary vessel engorgement with granulocytes. The activated complement component(s) responsible for leukostasis has an approximate molecular weight of 7,000-20,000 daltons. Since it is generated in C2-deficient plasma and is associated with factor B conversion, it is suggested that activation of complement by dialysis is predominantly through the altermative pathway.

Adult↗
PubMed1998

High-dose intravenous immunoglobulin treatment activates complement in vivo.

Several complement modulating effects of high-dose intravenous immunoglobulins (IVIG) have been proposed from in vitro studies and experimental animal models. However, the in vivo effects of IVIG on plasma complement in humans are yet not known. We have investigated the in vivo effects of IVIG on complement in seven women with unexplained recurrent spontaneous abortion who were without evidence of autoimmune disease. Samples were obtained before and after the very first infusion of IVIG. There was a marked increase in immunoglobulin G (IgG) from (median and range) 12.4 (9.4-15.9) to 26.8 (22.4-30.0) g/l but no change in immunoglobulin A (IgA) or immunoglobulin M (IgM). A significantly increased complement activation was demonstrated using neoepitope-specific enzyme immunoassays to the activation products C3bc (median increased from 9.8 to 31.2 AU/ml), Bb (0.66-1.66 g/ml), C5a (10.5-12.7 ng/ml), and TCC (0.81-2.19 AU/ml) (P = 0.015 for all). There were no changes in antigenic concentrations of individual complement components or regulators (C1q, C4, C3, C1-inhibitor, C4b-binding protein) and no decrease in complement haemolytic activity (classical and alternative CH50), which were all within the normal range. The classical pathway activation products C1rs/C1-inhibitor complexes, C4bc and C4d were elevated in all patients before IVIG treatment and did not change significantly during treatment. In conclusion, IVIG induced a significant activation of complement in vivo.

Abortion, Habitual↗
PubMed1997

Streptococcal protein H forms soluble complement-activating complexes with IgG, but inhibits complement activation by IgG-coated targets.

Protein H, a surface protein of Streptococcus pyogenes interacting with the constant Fc region of IgG, is known to be released from the streptococcal surface by a cysteine proteinase produced by the bacteria. Poststreptococcal glomerulonephritis and rheumatic fever are conditions in which immune complexes and autoimmune mechanisms have been suggested to play pathogenetic roles. The present study demonstrates that addition of protein H to human serum produces complement activation with dose-dependent cleavage of C3. The activation was IgG-dependent and the result of complexes formed between IgG and protein H. These complexes were size heterogeneous with molecular masses of 400 kDa to 1.4 MDa. Using complement-depleted serum reconstituted with complement proteins, the activation by protein H was found to be dependent of the classical, but independent of the alternative pathway of complement. In contrast to results of experiments based on soluble protein H.IgG complexes, complement activation was inhibited by protein H when IgG was immobilized on a surface. The interaction between C1q and immunoglobulins represents the first step in the activation of the classical pathway, and protein H efficiently inhibited the binding of C1q to IgG immobilized on polyacrylamide beads. Protein H reduced C3 deposition on the IgG-coated beads and inhibited immune hemolysis of IgG-sensitized erythrocytes. Finally, significantly less C3 was deposited on the surface of protein H-expressing wild-type streptococci than on the surface of isogenic mutant bacteria devoid of protein H. The results demonstrate that protein H.IgG complexes released from the streptococcal surface can produce complement breakdown at the sites of infection, whereas complement activation on bacterial surfaces is inhibited. This should have important implications for host-parasite relationships. In addition, soluble protein H.IgG complexes might contribute to immunological complications of streptococcal infections.

Antigens, Bacterial↗
PubMed1975

Arthritis associated with chronic active hepatitis: complement activation and characterization of circulating immune complexes.

Circulating immune complexes were identified in cryoproteins isolated from serial serum samples from 6 to 10 patients with chronic active hepatitis (CAH) with frank arthritis and arthralgias. These immune complexes were not detectable in patients with uncomplicated CAH. Only cryoprecipitates from CAH patients with frank arthritis contained IgG, IgM, IgA, and complement components C3, C4, and C5. Hepatitis B surface antigen was concentrated several-fold in the cryoprotein immune complexes as compared with the serum concentration. The C3 activator fragment of the properdin complex was found in fresh serum in all patients with arthritis but was undetectable in patients with arthralagias and uncomplicated CAH. Thus, the presence of circulating complement-fixing immune complexes in patients with alternate complement pathways, and suggests that they play an important role in the pathogenesis of the arthritis.

Adult↗
PubMed2003

Association between complement factor H and proteoglycans in early human coronary atherosclerotic lesions: implications for local regulation of complement activation.

OBJECTIVE: Complement activation has been suggested to play a role in atherogenesis. To study the regulation of complement activation in human coronary atherosclerotic lesions, we examined the spatial relationships between the major complement inhibitor, factor H, and the complement activation products C3d and C5b-9. METHODS AND RESULTS: In early lesions (American Heart Association types II and III), factor H was immunohistochemically found in the superficial proteoglycan-rich layer in association with numerous macrophages and C3d, whereas C5b-9 was found deeper in the intima, where factor H was virtually absent. In vitro experiments involving surface plasmon resonance and affinity chromatography analyses demonstrated that isolated human arterial proteoglycans bind factor H, and functional complement assays showed that glycosaminoglycans inhibit the complement activation induced by modified low density lipoprotein or by a foreign surface. CONCLUSIONS: The present observations raise the possibility that proteoglycans, because of their ability to bind the major complement inhibitor factor H, may inhibit complement activation in the superficial layer of the arterial intima. In contrast, deeper in the intima, where factor H and proteoglycans are absent, complement may be activated and proceed to C5b-9. Thus, the superficial and the deep layers of the human coronary artery appear to differ in their ability to regulate complement activation.

Adult↗
PubMed2000

Complement activation in heart diseases. Role of oxidants.

Increasing evidence demonstrated that atherosclerosis is an immunologically mediated disease. Myocardial ischemia/reperfusion injury is accompanied by an inflammatory response contributing to reversible and irreversible changes in tissue viability and organ function. Three major components are recognized as the major contributing factors in reperfusion injury. These are: (1) molecular oxygen; (2) cellular blood elements (especially the neutrophils); and (3) components of the activated complement system. The latter two often act in concert. Endothelial and leukocyte responses are involved in tissue injury, orchestrated primarily by the complement cascade. Anaphylatoxins and assembly of the membrane attack complex contribute directly and indirectly to further tissue damage. Tissue damage mediated by neutrophils can be initiated by complement fragments, notably C5a, which are potent stimulators of neutrophil superoxide production and adherence to coronary artery endothelium. The complement cascade, particularly the alternative pathway, is activated during myocardial ischemia/reperfusion. Complement fragments such as the anaphylatoxins C3a and C5a, are produced both locally and systematically, and the membrane attack complex is deposited on cell membranes and subsequent release of mediators such as histamine and platelet activating factor (PAF), thereby causing an increase in vascular permeability with concomitant manifestation of cellular edema. Complement increases the expression of CD18 on the neutrophils and increases P-selectin expression on the surface of the endothelium. Mitochondria may be a source of molecules that activate complements during ischemia/reperfusion injury to myocardium, providing therewith a stimulus for infiltration of polymorphonuclear leukocytes. Tissue salvage can be achieved by depletion of complement components, thus making evident a contributory role for the complement cascade in ischemia/reperfusion injury. The complexities of the complement cascade provide numerous sites as potential targets for therapeutic interventions designed to modulate the complement response to injury. The latter is exemplified by the ability of soluble form of complement receptor 1 (sCR1) to decrease infarct size in in vitro models of ischemia/reperfusion injury. The mechanism(s) that initiates complement activation is not clearly known, although loss of CD59 (protectin) from cells compromised by ischemia/reperfusion may contribute to direct damage of the coronary vascular bed by the terminal complement complex. Therapeutic approaches to ischemia/reperfusion injury in general, and especially those involving complements, are at the very beginning and their potential benefits have still to be adequately evaluated. It may be noted that complement activation has both positive and negative effects and, therefore, might be modulated rather than abruptly blunted.

Animals↗
PubMed1994

Temporal patterns of hemodynamics, oxygen transport, cytokine activity, and complement activity in the development of adult respiratory distress syndrome after severe injury.

The aim of this study was to search for early inflammatory mediators in severely traumatized patients that could predict the occurrence of adult respiratory distress syndrome (ARDS). We measured sequential plasma levels of tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), complement fragment C3a, and endotoxin. In addition, we measured sequentially the values of hemodynamics, oxygen transport, and pulmonary function. The temporal patterns seen in the patients who developed ARDS were compared with those who did not. In the patients who developed ARDS, the first observed findings were low cardiac index (CI) and oxygen delivery (DO2) followed by progressive increases in IL-6, IL-8 and C3a levels, worsening of pulmonary function, and increases in hemodynamic values. The maximum values of IL-6, IL-8, and C3a occurred after the onset of ARDS. In the patients who did not develop ARDS, initial oxygen transport values were not low, the levels of IL-6, IL-8, and C3a decreased rapidly from their initial peaks, and there were no further increases in hemodynamic values. In both ARDS and nonARDS patients, no measurable quantities of TNF, IL-1, or endotoxin were found. We concluded that none of the mediators we measured reached their peaks before the onset of ARDS and none were found to be predictive of posttraumatic ARDS. However, these and other mediators may augment or intensify the development of ARDS.

Adult↗
PubMed1993

Complement activation during saturation diving.

In this study, the levels of activated complement fragments C3a and C5a were measured on 11 U.S. Navy divers as they performed a 28-day saturation dive to a pressure equivalent of 1,000 feet of seawater (fsw, 31.3 atm abs). Two subjects developed symptoms consistent with the high pressure nervous syndrome (HPNS) and three were treated for type I DCS (joint pain only). These events allowed us to test two hypotheses: a) alterations in C3a or C5a levels during compression are related to the occurrence of HPNS and b) increases in complement fragments are an indicator of decompression stress associated with type I DCS. There was no correlation between changes in C3a and C5a levels during compression and the diagnosis of HPNS. Our results suggest that an increase in C3a and C5a levels during saturation diving correlates with decompression stress and the clinical diagnosis of type I DCS.

Analysis of Variance↗
PubMed2003

Flow cytometry based detection of HLA alloantibody mediated classical complement activation.

Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) testing is used to assess recipient presensitization and post-transplant alloantibody formation in transplant recipients. However, CDC test results can be affected by false-positive reactions brought about by autoantibodies or antilymphocyte reagents. As an alternative to the CDC-PRA assay, detection of HLA alloantibodies using HLA antigen-coated microbeads (FlowPRA test) was recently established. FlowPRA testing, however, does not distinguish between (presumably more harmful) complement-fixing and noncomplement-fixing alloantibodies. In this study, we established a novel assay allowing flow cytometric detection of HLA alloantibody dependent classical complement activation using the FlowPRA test. For the detection of complement activation, FlowPRA beads were incubated with sera from highly sensitized dialysis patients (CDC-PRA reactivity >60%) and then stained for C4 (C4d, C4c) and C3 (C3d, C3c) fragments, as well as C1q deposition using indirect immunofluorescence. We demonstrate alloantibody induced induction of C4 fragment, and in parallel C1q deposition to HLA class I or class II beads. As shown by immunoblotting, C4 staining was not due to the presence of preformed C4 fragment-IgG/M complexes. Indeed, C4 fragment deposition in our in vitro system was demonstrated to result from de novo complement activation. First, inactivation of C4 by treatment of sera with methylamine, which inhibits cleavage of the internal thioester, completely abolished C4 fragment deposition. Second, C4 fragment deposition was not observed in the evaluation of C4-free immunoadsorption eluates obtained from highly sensitized dialysis patients. After supplementation with complement, however, eluates induced C4 deposition. Deposition of C4 split products and C1q was temperature-dependent with maximum binding after incubation at 4 degrees C for 60 min. In contrast, maximum C3 fragment deposition was found at 37 degrees C. At this temperature, C3 deposition occurred in an alloantibody and C4-independent fashion, presumably as a result of alternative complement activation. In summary, we describe a novel cell-independent and easy-to-perform PRA test that permits flow cytometry based detection of alloantibody induced classical complement activation. Future studies will have to evaluate its possible relevance as an alternative to CDC-PRA testing in clinical transplantation.

Case-Control Studies↗
PubMed1983

Influence of epididymal maturation on the capacity of hamster and rabbit spermatozoa for complement activation.

Hamster and rabbit spermatozoa released from the epididymis were tested for the ability to activate complement via the alternative pathway. While hamster spermatozoa were more active, the spermatozoa of both species reduced complement activity in homologous and also human serum previously adsorbed to remove sperm antibodies, and they bound C3 in the presence of EGTA + Mg2+. Hamster spermatozoa from the caput epididymidis were more anticomplementary and bound more C3 than did cauda spermatozoa and, though less marked, a similar difference was evident between caput and cauda spermatozoa from the rabbit epididymis.

Animals↗
PubMed1996

Burkholderia pseudomallei activates complement and is ingested but not killed by polymorphonuclear leukocytes.

The mechanism by which Burkholderia pseudomallei is resistant to lysis by human serum is unknown but may include interference with complement activation, effective opsonization, or complement-mediated lysis. We investigated the interaction of B. pseudomallei with complement in the presence and absence of specific antibody to determine potential mechanisms of serum resistance. We demonstrated rapid activation and consumption of complement by B. pseudomallei which, in the absence of specific antibody, occurred predominantly via the alternative pathway. Complement activation was associated with deposition of the opsonically active C3b and iC3b fragments on the bacterial surface. C5b-9, detected on the bacterial surface after opsonic periods of 1 to 60 min, was susceptible to elution by 1 M NaCl, indicating that resistance to complement-mediated lysis may result from deposition of the membrane attack complex in a nonmicrobicidal location. To define the role of opsonins, we investigated the ability of polymorphonuclear leukocytes (PMNL) to phagocytose B. pseudomallei. Phagocytosis of bacteria by PMNL, and the observed oxidative response, was significantly increased by opsonization of organisms with complement and/or specific antibody. Despite opsonophagocytosis by PMNL and the production of an oxidative response, no significant bacterial killing was observed.

Burkholderia pseudomallei↗
PubMed1994

Differences in complement activation between complement-resistant and complement-sensitive Moraxella (Branhamella) catarrhalis strains occur at the level of membrane attack complex formation.

The mechanism of resistance to human complement-mediated killing in Moraxella catarrhalis was studied by comparing different complement-sensitive and complement-resistant M. catarrhalis strains in a functional bystander hemolysis assay and an enzyme-linked immunosorbent assay (ELISA) for soluble terminal complement complexes. Complement-resistant stains appeared to activate complement to the same extent as, or even slightly better than, complement-sensitive strains. This indicates that complement-resistant strains do not inhibit classical or alternative pathway activation but interfere with complement at the level of membrane attack complex formation. A clear difference in dose-response curves for resistant and sensitive strains was observed both in the bystander hemolysis assay and in the ELISA. Complement-resistant strains showed optimum curves, whereas complement-sensitive strains gave almost linear curves. We conclude that resistant strains bind and/or inactivate one of the terminal complement components or intermediates involved in membrane attack complex formation. Trypsin, known to abolish complement resistance, changed the optimum dose-response curve of a resistant strain to a linear one, which strongly suggests that complement resistance is mediated by an M. catarrhalis-associated protein. This protein acts directly or through the binding of a terminal complement inhibitor present in serum.

Bacterial Proteins↗