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Results for “Complement Pathway, Alternative”

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PubMed1995

Human complement activation via the alternative pathway on porcine endothelium initiated by IgA antibodies.

The role of the classical pathway (CP) and the alternative pathway (AP) of complement activation in hyperacute xenograft rejection remains a matter of considerable debate. In addition, it is unknown whether IgG and IgA antibodies activate complement, although these antibodies have been found in hyperacutely rejected xenografts. This study was initiated to assess a possible role of the AP of complement activation in a pig-to-human transplantation model using fresh human sera and isolated antibodies with cultured porcine endothelial cells (PEC) as targets. IgM, IgG, monomeric IgA, and dimeric IgA (dIgA) antibodies with reactivity toward PEC as determined by ELISA were isolated from pooled normal human sera. Serum from patients with agammaglobulinemia was used as a source of human complement. C3 and C4 deposition on nonfixed PEC during CP (1% serum) or AP activation (10% serum with MgEGTA) was analyzed using an ELISA. Complement-mediated PEC lysis was tested in a 51Cr release assay. Using normal human sera as the source of antibodies and complement, C3 and C4 deposition was already found after 10 min of incubation in the CP, whereas an increasing amount of C3 was found in the AP. During AP activation, no C4 deposition was observed, indicating that CP activation did not contribute to the observed AP-mediated C3 deposition. Moreover, dIgA antibodies caused deposition of C3 and not C4. Purified IgM and dIgA antibodies (1 mg/ml) in the presence of 10% agammaglobulinemic serum showed a mean specific PEC lysis of 31% and 28%, respectively. Agammaglobulinemic serum alone or with IgG or monomeric IgA antibodies had no detectable lytic activity. In conclusion, dIgA antibodies might play an additional role in pig-to-human xenograft rejection by activating human complement via the AP.

Acute Disease↗

PubMed2001

Role of complement in Mycobacterium avium pathogenesis: in vivo and in vitro analyses of the host response to infection in the absence of complement component C3.

We investigated the importance of the host complement system in the pathogenesis of disease mediated by the intramacrophage pathogen Mycobacterium avium. Mycobacteria opsonized with complement are efficiently ingested by macrophages through various complement receptors. Furthermore, unlike other bacteria, mycobacteria can activate both the alternative and classical complement pathways in the absence of specific antibodies. Therefore, to examine the role of complement in the mycobacterial infection process in vivo, mice deficient in complement component C3 were infected with M. avium. Surprisingly, C3-deficient mice infected intravenously with M. avium displayed no difference in bacterial burden or granulomatous response compared to wild-type control mice. C3-sufficient mice and C3-deficient mice were equally susceptible to infection by M. avium regardless of the genotype at the bcg locus, a locus known to confer susceptibility to infection with intracellular pathogens. In vitro studies using mouse bone marrow-derived macrophages resulted in significant M. avium invasion of macrophages in the absence of C3; however, the kinetics of infection were delayed compared to complement-mediated invasion. The data indicate that complement does not play an essential role in mediating M. avium infections in the mouse and suggest either that other invasion mechanisms can compensate for the absence of complement-mediated entry or that complement is not a major mycobacterial opsonin in vivo.

Animals↗

PubMed1989

Complement activation by the alternative pathway is modified in renal failure: the role of factor D.

Factor D, an essential enzyme of the alternative pathway (AP) of complement, is eliminated by the kidney, and its plasma concentration increases 10-fold in end-stage renal disease (ESRD). The purpose of this study was to analyze the consequences of factor D accumulation. A number of in vitro assays were used to analyze AP activation in normal human serum (NHS), in normal serum supplemented with purified factor D to 10-fold its normal concentration (10 x D), and in sera of patients with ESRD. When compared with NHS, in 10 x D: 1) Spontaneous fluid-phase activation of complement at 37 degrees C was greatly increased as measured by C3 cleavage, 2) The lysis of rabbit erythrocytes, a function of the AP, was accelerated, 3) More C3 fragments bound to cuprophane membranes and to immune precipitates; both reactions were accompanied by the formation of more C5a, 4) Complement mediated solubilization of antigen-antibody precipitates was enhanced. Sera of patients with ESRD behaved similarly to 10 x D in all assays used, i.e., enhanced AP function, although complement activation measured in these assays varied widely from one individual to another. Thus, the elevated factor D concentration observed in renal failure might have important pathophysiological consequences, some of which could be detrimental (e.g., C5a produced during hemodialysis), while others might be beneficial, e.g., solubilization of immune precipitates.

Aged↗

PubMed1978

Immunologic defect of the alternate pathway-of-complement activation postsplenectomy: a possible relation between splenectomy and infection.

Total hemolytic complement (CH50) and activation of the alternate mechanism were measured in eight patients before and after splenectomy and compared to similar measurements made in a control group of patients following other abdominal surgery. In the splenectomy group, alternate-pathway-mediated activation of C3 was significantly different from the controls. The mean five-day postsplenectomy value of 16 percent for the immunoelectrophoretic conversion of C3 to C3i was depressed (p<0.001) from the presplenectomy value of 85 percent and five-month postsplenectomy level of 71 percent (p<0.01). The difference between presplenectomy and five-month postsplenectomy values was not significant. Further, activation of C3 in patients five days postsplenectomy was significantly less (p<0.01) than in the five-day postoperative controls. In both the splenectomized patients and control group, five-day postoperative determinations indicated an increase in CH50 values and a decrease in degree of activation of Factor B. The spleen appears to manufacture certain substances required for activation of C3 via the alternate mechanism. That the manufacture is eventually assumed by other immune-competent organs is shown by the eventual increase of activation toward preoperative levels five months postsplenectomy. This defect in C3 activation may account for the tendency of splenectomized patients to have an increased incidence of bacterial infections and sepsis in the postoperative period.

Adult↗

PubMed1984

Tissue culture demyelination by normal human serum.

Serum from all of 20 normal individuals induced some degree of demyelination when applied to well-myelinated mouse cerebellum cultures. An intact complement sequence through C5 is required. Demyelinating activity was heat labile at 56 degrees C for 30 minutes but was not destroyed at 50 degrees C for 30 minutes (which inhibits properdin factor B and alternate complement pathway activation, but not the classic complement pathway). Sera from patients with agammaglobulinemia, C4 deficiency, or C6 deficiency all induced demyelination. Our results suggest that tissue culture demyelination results from nonimmunoglobulin activation of the alternate complement pathway and is not limited to sera from patients with neurological disease.

Animals↗

PubMedDate not supplied

Plasma separation using a hollow fiber membrane device.

A disposable hollow fiber device was evaluated by collecting approximately 550 ml of normal donor plasma (n = 43) and by performing sham (n = 10) and therapeutic (n = 12) plasma exchanges. Blood was processed at 70 ml per min, and plasma flux averaged 23 (collection) and 25 (exchange) ml per min (mean separation efficiencies of 52 and 60%, respectively). The procedures were tolerated well by all donors and patients. The plasma hemoglobin concentration in separated plasma averaged 1 mg per dl, and cell contamination was negligible (mean of 1, 3, and 6 RBCs, platelets and WBCs/microliter, respectively). There was no evidence of in vivo classical or alternative pathway complement activation as assessed by total hemolytic complement generation (CH50), alternative pathway hemolytic activity (AP50), C3 conversion, or C5 activation, nor were unexpected changes seen in the results of laboratory tests performed after the procedure. Sieving coefficients during sham plasma exchange averaged as follows: albumin, 1.03; IgM, 1.0, IgG, 1.0; IgA, 0.98; factor V, 1.07; factor VII, 0.89; factor VIII, 1.05; and factor IX, 1.19. The device appears to be useful for separation of cell-free plasma from blood during therapeutic plasma exchange procedures.

Blood Component Removal↗

PubMed1987

[Effect of SOS repair in enterobacteria on their interaction with the complement system].

The interaction of E. coli (serovar 0124) and its rec A-mutants with serum complement resulting in the alternative pathway activation was studied. Bacteria VT1240 (original smooth strain), VT1241 (rough mutant) and VT 2240 (recA56 mutant) were shown to be complement-sensitive when treated with 1.5 X 10(8)--1.9 X 10(8) cells per ml of normal human serum, while the cells with SOS-activated system (recA441 mutant, strain VT3251) retained their viability. An alternative pathway of complement activation was minimal with E. coli VT1241, while VT3251 demonstrated intermediate activity. To decrease the level of complement components (AH50) and factor B (BH50) by 50%, 3.5 X 10(6)--4.5 X 10(6) cells of VT1240 and VT2240 strains were required. R-mutants and recA441 mutants caused a 50% reduction in AH50, when used in the amount of 6.4 X 10(7) and 2.6 X 10(7), respectively, the same degree of BH50 decrease was achieved with the amounts used equal to 1.1 X 10(8) and 4.3 X 10(6), respectively. C3 conversions caused by 4 X 10(8) cells in I ml of the normal human serum in the four strains tested accounted for 5-15%.

Complement Pathway, Alternative↗

PubMed1975

Streptococcal preparation as an activator of host-mediated immune response: cellular immunity and alternate pathway of complement.

Streptococcal preparation, OK-432, was examined for its ability to initiate a host-mediated immune response. Aged individuals with negative skin response to phytohemagglutinin (PHA), as well as reduced in vitro blastoid transformation of lymphocytes, were treated with OK-432, and the response to PHA appeared in two out of three cases. The preparation was also demonstrated to convert C3 proactivator of complement when incubated with fresh human serum, as tested by immunoelectrophoresis, indicating the possibility that OK-432 might activate the alternate pathway of complement.

Aged↗

PubMed1976

A quantitative study on the activation of the alternative pathway of complement by mouldy hay dust and thermophilic actinomycetes.

Materials associated with the induction of farmer's lung were incubated with fresh normal human serum in the presence of magnesium ethylene glycol tetra-acetic acid (MgEGTA) or ethylene diamine tetra-acetic acid (EDTA) and results compared with material known to activate the alternative pathway of complement--zymosan. Results show that Micropolyspora faeni organisms are as active as zymosan in reducing complement (C) levels in the presence of MgEGTA, with a 50% reduction in CH50 at approximately 140 mug/ml. Thermoactinomyces vulgaris organisms produced a 50% CH50 reduction at approximately 1-25 mg/ml and two samples of respirable mouldy hay dust (MHD) at approximately 5-6 mg/ml whereas extracts of M. faeni and T. vulgaris reduced the CH50 titre by 17% and 39% respectively at 16 mg/ml in the presence of MgEGTA. Organisms and extracts did not reduce the CH50 titre in the presence of EDTA even at the maximum concentration quoted by more than 3%, thus it is considered that alternative pathway activation was responsible for C utilization in the presence of MgEGTA. Respirable MHD used less than 4% available C at 4 mg/ml in the presence of EDTA but at 8 mg/ml dust 11% and 28% available CH50 were used compared with 79% and 81% respectively in the presence of MgEGTA. The elution of immunoglobulin binding material from MHD may be responsible for apparent CH50 consumption in the presence of EDTA.

Allergens↗

PubMedDate not supplied

Statin drugs do not affect serum complement activation in vitro.

Statin drugs prevent coronary heart disease through anti-inflammatory mechanisms in addition to the well-known reduction of low-density lipoproteins. The complement system plays an essential role in the inflammatory response and has been postulated to be modified by statins. A direct role for statins in complement activation, however, has not been previously investigated. We therefore studied the effect of statins on in vitro complement activation. Pravastatin, atorvastatin and the active metabolite of the latter, ortho-hydroxy atorvastatin, were added to normal human serum and incubated for 1 h in the absence or presence of aggregated immunoglobulin (classical pathway activation) or cobra venom factor (alternative pathway activation). The degree of complement activation, as detected by specific complement-activation products for the classical pathway (C1rs-C1-inhibitor complexes), the combined classical and lectin pathway (C4bc), the alternative pathway (C3bBbP) and the final common pathway (C3bc and TCC), was not affected by pre-incubation of the serum with any of the statins. Statins do not affect complement activation directly, but indirect effects in vivo may well be operative.

Atorvastatin↗

PubMed1998

Contrasting roles of mannan-specific monoclonal immunoglobulin M antibodies in the activation of classical and alternative pathways by Candida albicans.

Polyclonal antimannan immunoglobulin G (IgG) activates the classical complement pathway and accelerates initiation of the alternative pathway by Canidida albicans. This dual role was assessed for two antimannan IgM monoclonal antibodies (MAbs). MAb B6.1 is specific for an epitope on the acid-labile portion of C. albicans phosphomannan; MAb B6 is specific for an epitope on the acid-stable region. Both MAbs were potent activators of the classical pathway but poor facilitators of alternative pathway initiation.

Antibodies, Monoclonal↗

PubMed1979

Neonatal cellular and humoral immunity to group B streptococci.

The mechanisms of host resistance to group B streptococci have not been defined precisely. In the studies reported here we have assessed the contributions of both humoral and cellular factors in protection against strains of this group. With assays of specific opsonic activity based upon the production of polymorphonuclear leukocyte chemiluminescence and radiolabeled bacterial uptake, we have demonstrated that specific heat-stable antibody and the classic complement pathway are major factors in opsonization of these organisms. In the absence of specific antibody, fresh serum resulted in markedly reduced bacterial uptake indicating, at best, a minor role for the alternative complement pathway. Additional studies have indicated that strain-specific antiphagocytic factors as well as type-specific ones may play a role in the virulence of these organisms. Neonates who developed group B streptococcal sepsis usually lacked opsonic activity in their infecting strain. In addition, polymorphonuclear leukocytes from normal term and stressed neonates showed impaired metabolic activation as measured in the chemiluminescence assay following exposure to opsonized group B streptococci. These results suggest that neonates who develop group B streptococcal disease may have defects in both the humoral and cellular aspects of their acute inflammatory response which may contribute to the high mortality observed in this most fulminant of bacterial infections.

Antibody Formation↗

PubMed1984

Absolute requirement for complement in monoclonal IgM antibody-mediated protection against experimental infection with type III group B streptococci.

The role of complement in the protective and opsonic activity of monoclonal IgM antibody to type III group B streptococci (GBS) was examined in a neonatal rat model of infection and in vitro with human sera as the complement source. C3 levels in uninfected neonatal rats were less than 50% of those in adult rats, similar to the low complement levels observed in human neonates. The monoclonal type III-specific IgM antibody provided protection to neonatal rats (with unaltered complement levels) that were infected intra-peritoneally or intranasally with type III GBS. In contrast, neonatal rats depleted of complement by administration of cobra venom factor were not protected by IgM antibody. In vitro, classical complement pathway activity was adequate in sera from well, term neonates and GBS-infected neonates in the presence of higher concentrations of the monoclonal IgM antibody. At lower IgM levels, however, the alternative complement pathway was less efficient in both neonatal sera and adult sera.

Adult↗

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↗