Separate pathways of C activation by measles virus cytotoxic antibodies: subclass analysis and capacity of F(ab) molecules to activate C via the alternative pathway.
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Animals↗
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Results for “Complement Pathway, Alternative”
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Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases.
The complement system is pivotal in host defense but also contributes to tissue injury in several diseases. The assembly of C3 convertases (C4b2a and C3bBb) is a prerequisite for complement activation. The convertases catalyze C3b deposition on activator surfaces. Here we describe the identification of staphylococcal complement inhibitor, an excreted 9.8-kilodalton protein that blocks human complement by specific interaction with C4b2a and C3bBb. Staphylococcal complement inhibitor bound and stabilized C3 convertases, interfering with additional C3b deposition through the classical, lectin and alternative complement pathways. This led to a substantial decrease in phagocytosis and killing of Staphylococcus aureus by human neutrophils. As a highly active and small soluble protein that acts exclusively on surfaces, staphylococcal complement inhibitor may represent a promising anti-inflammatory molecule.
Bacterial Proteins↗
Clionasterol: a potent inhibitor of complement component C1.
Clionasterol (1a), clionasterol monoacetate (1b) and 5alpha,8alpha-epidioxy-24alpha-ethylcholest-6-en-3-ol (2), isolated from the marine sponge Xestospongia exigua, and beta-sitosterol (3) were tested for their influence on the classical (CP) and alternative (AP) pathways of activation of the human complement system in vitro. All the sterols inhibited the CP in a dose-dependent manner but no detectable effect was observed in the AP even at concentrations of 400 microM. Clionasterol was found to be a potent inhibitor of CP (IC50 = 4.1 microM) being ten-fold more active than beta-sitosterol. The presence of the epidioxy group on C-5 and C-8 of compound 2 caused a pronounced decrease of the inhibitory effect. Mechanistic studies on the anticomplementary effect of clionasterol revealed that it interferes with the complement component C1.
Animals↗
Activation of the alternative pathway of complement in childhood acute lymphoblastic leukemia.
Sequential studies in children with acute lymphoblastic leukemia have demonstrated that at diagnosis or relapse there is defective utilization of complement by the alternative pathway. Thus, the sera of 17/18 patients fail to completely consume C3 to C9 when incubated with zymosan or cobra venom factor (CoF). This underutilization is due to a specific inhibitor of C3 activation which has been partially isolated. By remission, the inhibotor disappears and the CoF and zymosan assays return to normal. In addition, serum levels of C3 and factor B are elevated at the time of diagnosis or relapse but fall to below 3 S.D. from the mean in nearly 60 per cent of the cases during induction therapy. Similarly, serum C4 levels which are normal at diagnosis fall to less that 3 S.D. from the mean in 7/12 cases during treatment. Low C3 levels correlate well with factor B values, suggesting that if C3 to C9 are utilized after the inhibitor has been eliminated, such utilization occurs primarily through the alternative pathway. Presumably, as illustrated by the low C4 levels, this activity is mediated by the ampliciation loop of the alternative pathway involving classical pathway generation of C3b.
Child↗
Complement activation by Coccidioides immitis: in vitro and clinical studies.
Mycelial- or spherule-phase derivatives of Coccidioides immitis caused a decrease in vitro of total hemolytic complement in serum from a nonsensitized person. Activation involved both classic and alternative pathways as shown by deprssion of hemolytic C4 and by generation of products of activation of components C3, C4, and factor B. In addition, functional complement activity or immunoreactive levels of complement components or both were measured in 23 patients with self-limited or disseminated coccidioidomycosis. Low total hemolytic complement was found in nine, usually during the early phase of primary illness, and was transient. Hemolytic C4 was low, and the effect of inulin to decrease complement levels was blunted, suggested both classic and alternative pathways may be deficient. However, associated depression of immunoreactive levels of components assayed (C3, C4, C5, factor B, and properdin) was not consistently found. This disparity raises the possibility of enhanced in vitro inactivation analogous to activation by immune complexes.
Coccidioides↗
Membrane sialic acid on target particles modulates their phagocytosis by a trypsin-sensitive mechanism on human monocytes.
Monolayers of human peripheral blood monocytes in the absence of exogenous proteins ingest a variety of natural particulate activators of the human alternative complement pathway. Sheep erythrocytes, which do not ordinarily activate the human alternative complement pathway or initiate a direct monocyte phagocytic response, can be modified to exhibit both functions by the deletion or alteration of membrane sialic acid residues. Enzymatic removal of the sialic acid residues with sialidase or their conversion to heptulosonic acid derivatives by limited oxidation with NaIO4 and reduction with BH4- have equivalent dose-response effects on the capacity of the altered sheep erythrocytes to initiate the phagocytic response by human monocytes or to activate the alternative pathway in human serum. The deposition of C3b on native sheep erythrocytes had little effect on their ingestion by human monocytes, whereas the fixation of C3b on desialated sheep erythrocytes had a synergistic effect on the percentage of monocytes ingesting such a particle. The monocyte receptor essential for ingestion of desialated sheep erythrocytes or desialated sheep erythrocytes bearing C3b was inactivated by concentrations of trypsin that also prevented the monocytes from ingesting natural activators of the human alternative complement pathway, but did not alter the receptors for C3b or the Fc portion of IgG. The capacity of the nonimmune host to respond to desialated particles by initiating the monocyte ingestive process and by activating the alternative complement pathway to provide the synergy afforded by C3b deposition on that particle represents a primitive biochemical basis for differentiation of nonself from self.
Cell Membrane↗
A factor activating complement via the alternative pathway in the supernatants of B cell lines transformed by Epstein-Barr virus and in sera obtained from patients with systemic lupus erythematosus.
Serum factors activating the alternative pathway of the complement (APC) were detected in 5 of 14 patients with systemic lupus erythematosus (SLE). Epstein-Barr virus (EBV)-transformed B cell lines were subsequently established from these patients and 6 of these produced factors capable of activating the APC. Using a limiting dilution technique, we obtained a clone which was producing a factor activating the APC (AF); by affinity column fractionation and polyacrylamide gel electrophoresis, the AF was found to have heavy and light chains comparable to those of normal human IgG. Normal human serum exhibited C3 split products (demonstrated by immunoelectrophoresis) in the presence of AF and under conditions permitting activation of the APC. Sera devoid of factor B, but not of C2 and C4, failed to catabolize C3 in the presence of AF. The AF failed to stabilize erythrocyte-bound C3bBb or C4b2a convertases, indicating that it was not a nephritic-factor-like molecule. We conclude that IgG molecules present in the sera and produced by EBV-transformed B cell lines from patients with SLE are apparently responsible, at least partially, for complement consumption in these patients.
B-Lymphocytes↗
Homozygous C2 deficiency: association with defective alternative pathway function and immunoglobulin deficiency.
Deficiency in the second component of complement (C2) is the most common homozygous complement deficiency. While approximately half of the affected individuals are apparently healthy, C2 deficiency may be associated with autoimmune diseases and rarely increased susceptibility to infection. We report 5 patients who had homozygous type I C2 deficiency in two families. Three of them suffered from frequent infections. These symptomatic patients had additional risk factors; the index cases in the first and the second family had IgG2 deficiency and IgA deficiency, respectively, and alternative complement pathway hemolytic activity was also low in both of them and in the sibling of the first index case. These results emphasize the probable role of other immunologic defects in the clinical presentation of C2 deficiency.
Child↗
Alternative pathway activation of the complement system in preterm infants with early onset infection.
The increased incidence of infection in preterm neonates has been related in part to their relative deficiency of most complement components, because complement is known to participate in the defense against bacterial and viral infections. In a prospective study, complement activation products were determined in 52 preterm infants. Twenty preterm infants suffered from proven early onset infection, 11 infants were presumed to suffer from infection, which could not be confirmed. Twenty-one preterm infants without infection or perinatal asphyxia formed the control group. EDTA plasma was obtained within the first 6 h after birth, and follow-up examinations were done in 15 patients with proven infection during the next 24 h. The complement activation products C3a-desArg, C3bBbP, and sC5b-9 were measured with enzyme immunoassay systems. In preterm neonates with early onset infection, a significant elevation of C3a-desArg was found in the very early course of the disease. C3a-desArg generation resulted from alternative pathway activation as shown by a concurrent increase of C3bBbP concentration. In addition, significantly higher concentrations of sC5b-9 predicted infection in the first few hours after birth. Thus, despite very low levels of native complement proteins, preterm babies are able to generate remarkable amounts of activation products of the complement cascade. The elevation of these activation products preceded by hours significant changes of routine laboratory markers of infection, such as leukocyte count, differential blood count, and C-reactive protein. Thus they might help to identify preterm neonates with severe systemic infection earlier than other laboratory parameters.
Age of Onset↗
Systemic lupus erythematosus and sickle hemoglobinopathies: a report of two cases and review of the literature.
Two adolescent black females with sickle cell disease who developed systemic lupus erythematosus (SLE) are presented. The recognition of SLE was delayed because all new symptoms were initially attributed to their underlying sickle cell disease. Nine similar cases have been previously reported. The hypothesis that a deficiency of the alternative complement pathway in some patients with sickle hemoglobinopathies predisposes them toward immune complex disorders was not confirmed in our study. Our first patient had normal and our second increased activity of the alternative pathway of complement activation.
Adolescent↗
Immunological aspects of adverse reactions to althesin.
Sequential plasma samples from 30 patients showing clinical signs of hypersensitivity to Althesin were investigated to determine if a specific immune response to the drug was present (as measured by classical complement pathway activation) or if a non-antibody-dependent alternative complement pathway activation was taking place. The patients were classified as those reacting on first exposure to Althesin and those who reacted adversely only on a second exposure. The alternative complement pathway, but not the classical pathway, was activated in five of the 13 first-time reactors, while in the remaining eight no complement activation was detected. In contrast, classical complement pathway activation was demonstrated in the blood samples of all 17 patients reacting on repeat exposure. Severe reactions occurred in nine of the 17 previously exposed patients compared with only one of the 13 reacting on first exposure to Althesin.
Adolescent↗
Serum haemolytic complement activities in 11 different MHC (B) typed chicken lines.
To study the relation between serum complement levels and the chicken MHC (B) complex, complement haemolytic activity was measured in sera from hens from seven pure-bred B-typed White and one Brown Leghorn lines, and three ISA-Warren lines that had been divergently selected for antibody responses to sheep red blood cells (SRBC). Significant differences occurred in the serum haemolytic complement activities, both belonging to the classic (CPW) and the alternative (APW) pathways, among the 11 different haplotyped chicken lines. Hens with high CPW and high APW titres predominantly displayed the B2 or B21 haplotypes. Chickens with low CPW and APW were found in B14 and B15 haplotypes. Haplotype B14 appears to be different in complement levels when present into the pure-bred lines or into the ISA-Warren line selected for low antibody responses to SRBC. Otherwise, the presence of B21 in ISA-Warren line selected for high antibody responses to SRBC does not differ with the B21 in the inbred lines (except in the NL-line for CPW values). In general the haplotypes B2 and B21 are found in chicken lines with enhanced disease resistance, and the B15 haplotype has been connected with enhanced disease susceptibility. Our results suggest that levels of haemolytic complement activity, either from the classical or from the alternative pathways, may underlie part of the immunocompetence ascribed to the MHC (B) complex in chickens.
Animals↗
Inhibition of human and guinea pig complement by heparin fractions differing in affinity for antithrombin III or in average molecular weight.
Heparin comprises a mixture of structurally related molecules. Affinity for antithrombin III (AT III) is a prerequisite for its anticoagulant activity, which also is dependent on its molecular weight. In this study heparin fractions prepared by affinity chromatography on immobilized AT III and by gel filtration chromatography were compared for their ability to inhibit complement mediated haemolysis and both classical and alternative pathway C3 activation as measured by crossed immunoelectrophoresis. In normal human serum, inhibition of haemolysis and of heat-aggregated IgG (HAGG) as well as zymosan induced C3 activation by heparin was found to be independent of its AT III affinity and of its molecular weight (range 4800-17,000), on a weight basis. In guinea pig serum similar results were obtained for inhibition of HAGG induced C3 activation, but inhibition of haemolysis showed a marked molecular weight dependency and was also reduced for the fraction with low affinity for AT III. This may reflect a species difference in the haemolytic action of human and guinea pig complement. It is concluded that inhibition of human complement by heparin is independent of its anticoagulant activity and of its size and it is suggested that a fraction of heparin with reduced risk for bleeding and platelet aggregation is a potential anti-inflammatory agent.
Animals↗
Reduced activity of DAF on complement enzymes bound to alternative pathway activators. Similarity with Factor H.
Attachment of C3b to activators of the alternative pathway of complement results in a decrease in regulatory activity expressed by Factor H. Decay-accelerating factor (DAF) and Factor H were found to exhibit quantitatively similar decreases in regulatory activity toward the C3 convertase (C3b,Bb) bound to activators, such as zymosan (Zym) and rabbit erythrocytes (ER), compared to non-activators, such as sheep (ES) and bovine (EB) erythrocytes. Purified DAF and Factor H, in 0.1% NP-40, were assayed by measuring the amount required to release 50% of the radiolabelled Bb in 10 min from C3b,Bb on Zym or cross-linked erythrocytes. The relative effectiveness (i.e. the restriction index, RI) of DAF for accelerating the decay of C3b,Bb on the various particles was: ES (1.0), ER (0.04) and Zym (0.03). The RI for Factor H was: ES (1.0), ER (0.04) and Zym (0.07). The rate of decay of C3b,Bb induced by DAF and Factor H showed similar restriction. The results suggest that the regulatory properties of DAF are reduced if the cells on which it resides become activators of the alternative pathway as a result of transformation, virus infection or surface alteration. These findings may explain reports of dysfunctional DAF on alternative pathway-activating cells.
Animals↗
Quantitation of the membrane attack complex of complement in an air-driven ultracentrifuge.
A sensitive assay of complement (C) activation via either the classical or alternative pathway was developed by evaluating assembly of the terminal complexes (C5b-9)2 or SC5b-9. Activation of serum containing [125I]C7 resulted in the formation of a stable, radiolabeled complex which was separable from its precursors by sedimentation in an air-driven ultracentrifuge. The radioactivity in the sediment was directly proportional to the amount of complex formed and assembly of the complex could be detected after C activation by aggregated IgG in concentrations as low as 10 micrograms/ml. Mild detergents such as Triton X-100 could be included in the reaction mixture, because they affected neither the assembly nor the integrity of the complexes. The assay, which detects both assembly of the membrane attack complex (MAC or (C5b-9)2) on target membranes and formation of SC5b-9 in fluid phase, measures the potential of certain substances to trigger the cytolytic phase of C regardless of whether the classical or alternative pathway was activated. However, by using serum depleted of either factor B or C1q, activation of either pathway can be assessed individually.
Cell Membrane↗
Activation of complement by pathogenic and nonpathogenic Entamoeba histolytica.
Previous studies had demonstrated that strains of Entamoeba histolytica isolated from patients with colitis or amebic liver abscess were resistant to complement-mediated killing, whereas strains from asymptomatic patients were readily lysed by non-immune serum. Both serum-sensitive and serum-resistant strains of E. histolytica depleted complement rapidly as assessed by CH50, C3, and C7, and C5-9 hemolytic activities. Activation of the alternative pathway was important in lysis of nonpathogenic strains, as demonstrated by lysis by NHS (60.9 +/- 15.6%) and NHS + 5 mM EGTA (59.3 +/- 4.5%) as well as by C4-deficient guinea pig serum (72.8 +/- 7.1%) and C2-deficient human serum (64.4 +/- 11.1%), but not by NHS + 5 mM EDTA. Classical pathway activation also occurs as both pathogenic and nonpathogenic strains deplete greater than 98% of C4 activity, although it is not necessary for lysis. Pathogenic strains are not lysed by either the classical or the alternative pathway. These results suggest that pathogenic strains of E. histolytica activate complement but are able to evade an important host defense, complement-mediated lysis.
Animals↗
Restriction of the alternative pathway of human complement by intact Trypanosoma brucei subsp. gambiense.
We studied the interaction of African trypanosomes with human complement. Bloodstream forms of Trypanosoma brucei subsp. gambiense isolated from mice activated the alternative pathway of complement during a 30-min incubation in vitro. In human serum, all cells remained intact and motile during this period. C3 was detected on the surface by a direct binding assay with a monoclonal antibody which recognizes C3b and iC3b. C3 deposition could also be detected by this radioimmunoassay when parasites were incubated with purified C3. Such C3 binding was enhanced by factor B, factor D, and magnesium. Surface deposition of factor B was demonstrated both by flow immunofluorescence analysis and binding of radiolabeled factor B. C3 binding and factor B binding were inhibitable by EDTA but not by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N' -tetraacetic acid (EGTA). The inhibited binding could be restored by addition of magnesium. No human immunoglobulin G or mouse immunoglobulin was detected on the trypanosome surface. By flow cytometry, neither human C5 nor polymerized C9 was detected on trypanosomes incubated in serum, although this assay was able to detect C5 and C9 on the surface of complement-treated human erythrocytes. Using a radioimmunoassay which measures C5b-9 in serum, we found that there was no generation of SC5b-9 in serum which had been incubated with trypanosomes. We concluded that, although trypanosomes activate the alternative pathway of complement, they are not lysed, because the cascade does not continue beyond the establishment of C3 convertase.
Animals↗
A knowledge-based system for automatic interpretation of an analytical profile of complement factors.
A comprehensive assay to evaluate the complement system includes functional tests of both classical and alternative pathways and immunochemical measurements of C3, C4, B, C1-INA, and C3d. The purpose of this analytical profile is to screen for rare hereditary deficiencies and acquired abnormalities of complement and to define the activation pathway in cases of complement consumptive processes. Based on several years' experience, a routine was established in our laboratory to report the data to the clinician, together with a computer-generated interpretive statement. This routine was formulated into a knowledge base by specifying a series of decision rules for each of the complement disorders. After the rules were tested and updated against some 400 complement profile analyses, reasonable analytical comments were produced by the system. This knowledge-based system for reporting and interpreting complement results offers several advantages: the interpretative work is facilitated and made more reliable; a consistent interpretative comment is generated that is recognized and therefore more meaningful for the clinician; the communication of analytical procedures and policy is enhanced.
Artificial Intelligence↗