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Results for “Complement Pathway, Alternative”

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PubMed1995

Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs.

The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion.

Animals↗

PubMed1999

The influence of complement receptor type 1 (CD35) and decay-accelerating factor (CD55) on complement receptor type 2- (CD21) mediated alternative pathway activation by B cells.

The influence of complement receptor type 1 (CR1; CD35) and decay-accelerating factor (DAF; CD55), both down-regulators of complement activation, on the complement receptor type 2- (CR2) mediated alternative pathway (AP) activation of complement on normal B cells, was assessed. The data indicate that, while neither DAF nor CR1 hinder the function of the AP convertase formed on CR2, CR1 plays a significant role in the remodelling of C3b fragments, generated by the convertase and deposited at secondary acceptor sites on the B-cell surface, such that they become suitable ligands for CR2. The significance of this finding is briefly discussed.

B-Lymphocytes↗

PubMed1977

Evaluation of nonspecific (alternative pathway) opsonic activity by neutrophil chemiluminescence.

The role of alternative complement pathway activation in protection against infection is not well understood. We have investigated nonspecific opsonic activity in human adult, term neonatal and premature serum using the technique of neutrophil chemiluminescence (cl) to measure particle uptake. Following phagocytosis, neutrophils become metabolically active, produce excited molecular oxygen and emit a burst of light which can be detected and quantitated in a liquid scintillation counter. In the present study, zymosan particles were preopsonized in human serum and added to control neutrophils. Particles opsonized in adult serum produced a marked peak in CL. Serial dilutions of the serum prior to opsonization yielded proportionally lower peaks in CL. Opsonic activity as measured by the CL procedure was completely blocked by the addition of chelating agents which remove calcium and magnesium ions and block both classic and alternative complement pathway activation. Addition of an excess of magnesium ions (needed for alternative pathway activation) to the reaction mixture partially restored the opsonic activity. Opsonic activity as measured by the CL procedure was significantly depressed in approximately two-thirds of term and premature infant sera tested. Deficient nonspecific opsonic activity was closely correlated with serum levels of C3PA. These studies suggest that the CL procedure may be of value in the investigation of nonspecific opsonins in human serum.

Adult↗

PubMed1994

Complement activation in platelet concentrates is surface-dependent and modulated by the platelets.

Activation of platelets during storage may contribute to the loss of function and viability known as the platelet storage lesion. We investigated the role of complement activation as a possible mediator of the platelet storage lesion. We studied platelet bags stored up to 5 days under standard blood bank conditions and monitored the generation of several complement activation fragments from both the classical and alternative pathways. To assess the role of noncellular artificial surfaces in the activation of complement, parallel bags were prepared containing platelet-poor plasma. The levels of C4d and C3a increased steadily over time in storage, as did the level of the inactivated membrane attack complex SC5b-9. Generation of C4d, C5a, and SC5b-9 was greater in the absence of platelets than when platelets were present in the container. C5a levels in both groups were low and remained so during storage, suggesting that the C5a generated became surface associated. Using flow cytometry we detected C3 and C3a, but not C9, on the platelet surface. The percentage of C3-positive platelets peaked at the third day of storage; by day five platelet-associated C3 had declined. Decay accelerating factor expression on the platelet surface increased with time in storage and in parallel with CD63 expression. Based on the C4d levels, complement activation proceeded via the classical pathway; minimal generation of the alternative pathway activation fragment. Bb was seen in either the presence or absence of platelets. As an indirect measure of the activation of C1, the functional level of C1 esterase inhibitor (C1INH) was determined. C1INH levels declined over time in storage in bags containing only plasma; however, in the presence of platelets, the levels remained constant presumably because of release of C1INH from the alpha-granules of activated platelets.

Blood Platelets↗

PubMed1981

The intrinsic coagulation-kinin pathway, complement cascades, plasma renin-angiotensin system, and their interrelationships.

Activation of the classical complement pathway is initiated by immune complexes consisting of IgM antibody or IgG subclasses 1, 2, and 3. Binding to Clq leads to activation of C1s and digestion of C4 and C2 to yield a C3 convertase. The alternative complement pathway is initiated by complex polysaccharides as well as immune complexes of the IgA class which interact with Factors B, D, C3, and properdin to yield a stabilized C3 convertase consisting of PC3Bb. Cleavage of C3 and C5 by either pathway yields the C3a and C5a anaphylatoxins which cause histamine release from mast cells and formation of the C5b6789 attack complex causes cell lysis. Both immunologic and nonimmunologic tissue damage can initiate the surface dependent pathways of coagulation, fibrinolysis, and kinin formation. Surface bound Hageman Factor interacts with complexes of prekallikrein and HMW-kininogen as well as Factor XI and HMW-kininogen to form activated Hageman factor, kallikrein, and Factor XIa. Factor XIa continues the coagulation pathway, kallikrein and Factor XIa convert plasminogen to plasmin and kallikrein digests HMW-kininogen to yield bradykinin. The Cl inhibitor, which inactivates Cls is the major plasma inhibitor of activated Hageman factor and kallikrein. In its absence, a potentially fatal form of angioedema is seen. The inactivator of the C3a and C5a anaphylatoxins is identical to carboxypeptidase N, the major plasma inactivator of bradykinin thus demonstrating the common control mechanisms which regulate the complement and kinin-forming pathways.

Blood Coagulation↗

PubMed2003

Demonstration of alternative and classical complement pathway activity in colostrum from buffalo (Bubalus bubalis).

Buffalo colostrum caused lysis of unsensitized red blood cells (RBC) from sheep, goats, rabbits and chickens. RBC from cattle and buffalo were resistant to lysis. That lysis was due to the presence of natural antibodies to these RBC was ruled out since there was no reduction in haemolytic titres even after adsorption with the respective RBC. The addition of EGTA to the diluent had no effect on the haemolytic activity. These findings indicate the presence of alternative complement pathway (ACP) activity in buffalo colostrum. The haemolytic activity of buffalo complement for unsensitized rabbit RBC was reduced to very low levels by heating at 50 degrees C for 45 min. Treatment with zymosan also inhibited the haemolytic activity, while inulin had no effect. The maximum activity of ACP occurred in the presence of 4 mmol/L Mg(2+) in the diluent. The range of ACP activities in colostrum from buffaloes varied from 4.06 to 8.48 CH50 units/ml. Using a standard system for titrating the classical complement pathway and rabbit red blood cells sensitized with goat haemolysin, the range of complement activity in buffalo colostrum was 4.81-6.77 CH50/ml.

Animals↗

PubMed1976

Mouse factor B of the alternative pathway of complement activation. I. Purification, characterization, and functional behavior.

Mouse factor B was purified and a monospecific antiserum was raised. The physicochemical data of this protein (108,000 m.w., 5.9 S, 5.9 to 6.05 isoelectric point) were determined. The functional behavior resembles that of human and guinea pig factor B and it operates efficiently in the C3 feedback cycle of the alternative pathway of complement activation. A provisional scheme is given for the operation of the C3bB enzyme on the cellular (macrophage) level.

Animals↗

PubMed1979

Effect of a streptococcal preparation on the complement system.

Streptococcal preparation OK-432 (Picibanil), clinically being used as an immunopotentiator, has been shown to activate the complement system either through the classical or the alternative pathway in vitro [15]. In this experiment, OK-432 was found to increase serum complement level in guinea pigs, and in human without malignancy, when investigated by hemolytic assay using sensitized sheep erythrocytes (EA) for the classical pathway activity and unsensitized rabbit erythrocytes (RaE) for the alternative pathway activity. Assay of complement components revealed a significant increase in C3, but decrease in Clq, while no specific tendency was observed in C4, C5, C9, properdin, C3 activator and Cl-inhibitor. These evidences suggested that OK-432 might potentiate immune response of the host by elevating serum complement level, in addition to activate the complement system.

Aged↗

PubMed2000

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis.

OBJECTIVE: The complement system is important in the development of autoimmune inflammation, including rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Complement receptor 1 (CR1) is involved in regulation of complement activity. Studies on models of autoimmunity have demonstrated that soluble CR1 (sCR1) is a potent therapeutic agent. The present study was thus undertaken to investigate the feasibility of antiinflammatory gene therapy to prevent CIA by delivery of genes encoding truncated sCR1 (tsCR1) and dimeric tsCR1-Ig. METHODS: Syngeneic fibroblasts or arthritogenic splenocytes, engineered to express tsCR1 using retrovirus-mediated gene transfer, were injected into DBA/1 recipients that had been immunized with bovine type II collagen (CII). In separate experiments, naked DNA containing tsCR1 and tsCR1-Ig genes was injected intramuscularly into the immunized animals. The clinical development of arthritis was monitored, anti-CII levels measured, and antigenic T cell response studied. Affinity-purified tsCR1-Ig was assayed for its inhibitory effect on the alternative complement pathway in mouse serum. RESULTS: Treatment of CII-immunized mice with the tsCR1-expressing cells inhibited development of CIA, reduced anti-CII antibody levels, and inhibited T cell response to CII in vitro. Intramuscular injections of DNA encoding the CR1 genes prevented the progression of disease. Furthermore, compared with full-length sCR1, purified tsCR1-Ig was more active in inhibiting the murine alternative complement pathway. CONCLUSION: Our findings demonstrated that tsCR1 and tsCR1-Ig, when delivered via gene therapy, had a beneficial effect on autoimmune inflammation. These results indicate that targeting the complement system in RA patients may be of clinical importance.

Animals↗

PubMed1979

The role of antibody and complement in phagocytosis by rabbit alveolar macrophages.

The relative importance of antibody and complement in the phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa, two common bacterial pathogens, by alveolar macrophages from rabbits was studied. Normal rabbit serum was a satisfactory opsonin for the phagocytosis of S. aureus but not for P. aeruginosa. Normal rabbit serum opsonized S. aureus by both the classic and the alternative complement pathways; loss of both pathways destroyed opsonic activity. The presence of complement was not required for maximal phagocytosis when 10% staphylococcal immune serum was used. However, an intact alternative complement pathway enhanced phagocytosis when the concentration of staphlyococcal immune serum was lowered to 0.3%. Similarly, 10% pseudomonas immune serum opsonized P. aeruginosa without complement. When the concentration of pseudomonas immune serum was lowered to 1%, either the classic or the alternative complement pathway could significantly enhance phagocytosis of P. aeruginosa. Similar results were obtained with alveolar macrophages activated with bacille Calmette-Guérin. These studies demonstrate the importance of complement in enhancing phagocytosis by alveolar macrophages of bacterial pathogens when antibody concentration is the limiting factor.

Animals↗

PubMed1981

Alternative complement pathway-dependent ingestion of fluolite particles by human granulocytes.

Fluorescent particles (Fluolite) with an average size of 0.1 micrometers were ingested by human granulocytes after incubation in fresh normal human serum (NHS). Ingestion was assessed by visual counting in a fluorescent microscope of cells containing particles. Ingestion required fresh normal serum and did not occur when serum was heated for 30 min at 50 degrees C or in the presence of ethylenediaminetetraacetic acid (EDTA). It did not occur in serum genetically deficient in C3b inactivator or in C3. Phagocytic activity was restored to C3-deficient serum by purified human C3 and to heat inactivated serum by purified factor B. Opsonic activity was present in NHS containing 5 mM Mg++ and 10 mM ethyleneglycoltetraacetic acid (EGTA) and in human serum genetically deficient in human C components C2 and C5. Agammaglobulinemic sera had normal opsonic activity. Opsonization of particles in this system is mediated through the alternative pathway of C activation, and its measurement serves as a simple quantitative functional assay for this system.

Complement Activation↗

PubMed1999

Complement activation by mycoloyl glycolipids from Mycobacterium tuberculosis and Rhodococcus ruber.

In this study, we examined complement activation by mycoloyl glycolipids (MGL) such as trehalose-6,6'-dimycolate (TDM), often termed cord factor, and trehalose-6-monomycolate from Mycobacterium tuberculosis and Rhodococcus ruber, and also examined the effect of complement binding to MGL on phagocytosis by human monocytes. TDM and TMM, but not glucose mycolate, mannose mycolate or fructose mycolate which differ from TMM only in carbohydrate moiety, exhibited complement activation. TDM and TMM of M.tuberculosis exhibited stronger complement activation than those of R.ruber, the mycolic acids of which are much shorter than those of M.tuberculosis. Neither mycolic acids nor trehalose, which are products of TDM and TMM by hydrolytic cleavage, exhibited no complement activation. TDM activated complement through the alternative pathway, since supplementation with C4-deficient serum completely restored classical pathway-mediated hemolytic activity of complement which had been previously consumed by TDM. Next, we examined the effects of TDM and TMM on phagocytosis by human monocytes. Coating of heat-killed Staphylococcus aureus cells with TDM or TMM did not enhance their phagocytosis by monocytes, while, in the presence of complement, phagocytosis of these cells increased significantly. These findings suggest that TDM and TMM act as virulence factors that enhance the entry of mycobacteria into phagocytes via binding of C3 through activation of the alternative complement pathway.

Adjuvants, Immunologic↗

PubMed1982

Methylprednisolone inhibits the alternative and amplification pathways of complement.

Methylprednisolone sodium succinate limited the ability of zymosan or lipopolysaccharide to activate complement in normal serum by the alternative amplification pathways. Methylprednisolone limited B consumption in a reaction mixture which contained purified C3b, D, and B, indicating that soluble steroid directly inhibited the amplification pathway. The ability of soluble steroid to inhibit events in the alternative and amplification pathways of complement may provide a partial explanation for the effectiveness of steroids in treating gram negative septic shock.

Complement Activation↗

PubMed1976

Genetic loci of components of the classical and alternate pathway of complement activation: a new dimension of the immunogenetic linkage group (HLA) on chromosome 6 in man.

In this review, a working hypothesis is put forward that functional cooperation of various types of cells and proteins in immune recognition, mediation and response is maintained by a common chromosomal region which evolved over millions of years from a common ancestor by gene duplication. In brief, the known functions of the H-2 complex are discussed (susceptibility and resistance to viral infection, immune response genes, T-B cell interaction as non-self recognition and response). The addition of loci of the classical and alternate pathway of complement activation to the HLA region (i.e., C2, C4 and the Bf system) is reviewed with respect to functional relationship to immune recognition and mediation mechanisms. As expected according to this hypothesis, genes for late-acting components (C3, C5, C7 and C8 in man, C5 in mice) have so far not proved to be linked to HLA.

Animals↗

PubMed1993

Membrane cofactor protein (CD46) protects cells predominantly from alternative complement pathway-mediated C3-fragment deposition and cytolysis.

Membrane cofactor protein (MCP) cDNA was transfected into Chinese hamster ovarian tumor (CHO) cells and the functional properties of the expressed protein were studied. Cells adherent to flasks were essential for continuous expression of MCP on CHO cells. If the cells were maintained in noncoated flasks, MCP expression was markedly reduced but upon being transferred to coated flasks reexpressed the protein. MCP expressed on CHO cells had the expected m.w., approximately 50 kDa, and possessed factor I-cofactor activity. By a propidium iodide incorporation assay and by 51Cr release assay, antibody-sensitized CHO cells expressing MCP were protected from C-mediated cytotoxicity. The inhibition of lytic activity correlated with a decrease in C3 deposition. This host cell protective activity was exerted efficiently for the alternative pathway. The classical pathway was not blocked by MCP unless the cells were presensitized with low concentrations of antibody. These results imply that MCP primarily protects host cells from alternative pathway-mediated C3 targeting. In a pathologic state such as autoimmune diseases, the binding of an autoantibody to a target may overcome this protective effect of MCP via the classical pathway.

Animals↗

PubMed2000

The effect of the antithyroid drug propylthiouracil on the alternative pathway of complement in rats.

The effect of propylthiouracil (PTU) on the lytic activity of complement in rat serum was investigated in vivo. Rats (180+/-10 g) were treated daily by gavage with PTU doses of 1-50 mg/200 g body weight for time intervals ranging from 1 to 30 days. Serum classical pathway (CP) and alternative pathway (AP) activities were determined 24 h after the last dose. A single dose of 50 mg/200 g body weight was administered to additional groups and the animals were sacrificed after periods of 1-48 h. The results showed a relatively small reduction ( approximately 30%) in CP activity, evident only in animals treated with 50 mg of PTU for three weeks. However, a clear and opposite effect of PTU, an increase in lytic activity reaching values up to 180% of controls, was observed on AP activity. This effect was seen at all PTU doses used, and occurred within 4 days of treatment with the highest dose. Maximum activity was observed at intermediate intervals, depending on the PTU dose, with a return to control levels occurring after the longer periods of treatment. The lytic activity of serum from animals treated with a single PTU dose of 50 mg/200 g body weight and sacrificed 1-48 h after dosing did not differ from controls. Serum levels of thyroid hormone (triiodo L-thyronine, T3, and thyroxine, T4) were determined in representative groups of treated animals (injected with 5 mg of PTU/200 g body weight/day). These were either undetectable or considerably lower than those of controls. The serum PTU levels of these rats increased for up to 22 days, reaching values of 2-4 microg/ml.PTU is described in the literature as a modulator of both cellular immune responses and antibody production. Upon complement activation fragments of complement components bind to immune complexes and to specific receptors on cells of the immune system. Thus, alteration in AP activity caused by PTU treatment suggests a possible mechanism by which the drug exerts its modulatory effect. Increased complement AP activity might affect events as antigen presentation and hence the onset and course of the immune response.

Animals↗

PubMed1983

Steroids inhibit activation of the alternative-amplification pathway of complement.

Previous studies have demonstrated the ability of methylprednisolone sodium succinate to inhibit complement activation. Two other glucocorticosteroids and three different soluble steroids which lacked glucocorticoid activity were found in the present study to have the capacity to inhibit lysis of sheep erythrocytes by the alternative-amplification pathway. These compounds also inhibited fluid-phase consumption of B in a reaction mixture that contained purified C3b, B, and D, indicating that they exert a direct effect on the generation of alternative amplification pathway convertase. These findings suggest that the capacity to inhibit convertase generation by glucocorticosteroids in high concentration is independent of glucocorticoid activity.

Complement Activation↗

PubMed1977

Host cell modification of lymphocytic choriomeningitis virus and Newcastle disease virus altering viral inactivation by human complement.

Complement in human serum inactivated several enveloped viruses, but for some viruses the degree of inactivation depended on their passage history. In short, human serum detected cell-induced modifications of virions. Normal human serum, lacking detectable neutralizing antibodies to the virions, inactivated lymphocytic choriomeningitis virus (LCMV) and Newcastle disease virus (NDV) when the viruses were passed through some cell lines but not others. Host cell modification was further documented with LCMV since antibody to the cell (in conjunction with a complement source) inactivated virus produced by that cell. The mechanism by which human serum inactivated LCMV passed through L cells was determined. By using serum immunochemically depleted in the classical complement pathway component C4 and/or the alternative complement pathway component factor B, as well as other methods, it was shown that LCMV was inactivated via the classical complement pathway. Absorption and immune precipitation experiments indicated that the inactivation of LCMV by complement was mediated by natural antibody directed against the host (L-929) cell. NDV grown in chick embryo cells could be unactivated by either complement pathway in the absence of the other. A requirement for antibody could not be demonstrated in the NDV system. On the basis of these data it is proposed that alterations in virulence dependent upon passage of the virus in cells or animals may be partially explained by changes in virus sensitivity to human serum inactivation.

Animals↗