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PubMed1993

New procedure for the detection of complement deficiency by ELISA. Analysis of activation pathways and circumvention of rheumatoid factor influence.

A procedure using enzyme-linked immunosorbent assays for the assessment of complement function has been evaluated. The sera investigated were incubated in microtiter plates with solid-phase complement activators. Human polyclonal IgG or monoclonal IgM were used for classical activation pathway assays and Salmonella typhosa lipopolysaccharide (LPS) for alternative activation pathway assays. The analysis focussed on deposition of C9 and properdin as detected with enzyme-conjugated antibodies. In an attempt to avoid spurious results due to rheumatoid factors in patient sera, monoclonal mouse and chicken antibodies were unsuccessfully tested as indicator reagents in the assay with solid-phase IgG. However, the use of solid-phase IgM as an activator completely circumvented the influence of rheumatoid factors. With solid-phase IgG or IgM, properdin deposition occurred in the absence of factor D. A combination of assays is suggested for diagnostic purposes: IgM-coated plates with detection of bound C9 and properdin for the classical pathway and LPS-coated plates with detection of bound properdin for the alternative pathway. The procedure distinguished between defects of the classical activation pathway (C1, C4, C2), the alternative activation pathway (C3, factor B, factor D, properdin) and the terminal components (C5-C9). This analytical approach may be useful for detection of inherited complement deficiency and the assessment of complement function in acquired complement deficiency states.

Complement Fixation Tests↗
PubMed2006

Mannan-binding lectin (MBL)-mediated opsonization is enhanced by the alternative pathway amplification loop.

The complement system is a humoral effector in the innate immune system. Three activation pathways exist in the complement system, known as the classical pathway, the lectin pathway and the alternative pathway. Dysfunction of lectin pathway activation is caused by MBL deficiency. MBL deficiency in a cohort of healthy Caucasian blood bank donors was investigated with MBL genotyping and MBL plasma concentration. Recognition of the yeast-derived zymosan by MBL was investigated with Western blot. The involvement of the alternative pathway amplification loop in enhancing MBL-mediated opsonization of zymosan was investigated in a novel opsonophagocytosis assay for flow cytometry. Sera deficient for MBL, factor D or properdin were tested, and purified MBL, factor D or properdin were used to recover opsonization. The optimal receiver-operator characteristic (ROC) cut-off value for dividing the Caucasian cohort in MBL-sufficient and MBL-deficient was calculated at 0.7 microg/ml. Thirty-eight percent of the group had concentrations below 0.7 microg/ml. Zymosan eluates opsonized with MBL-sufficient sera contain high oligomers of MBL, while eluates from MBL-deficient donors contained hardly any MBL. The MBL-, factor D- and properdin-deficient sera showed reduced opsonophagocytosis by human control neutrophils, as compared to normal MBL-sufficient sera. This reduction in opsonization was restored to normal levels by addition of purified MBL, factor D and properdin. The absence of opsonization in the factor D- and properdin-deficient sera, but presence in normal serum after blocking with anti-C1q-F(ab)2 and anti-MBL-F(ab)2, demonstrates the involvement of the amplification loop in MBL-initiated zymosan opsonization, even at very low serum concentrations (up to 3%, v/v). In conclusion, our data demonstrate that the MBL-mediated route of complement activation depends on the alternative pathway amplification loop for optimal opsonization of zymosan.

Cohort Studies↗
PubMed1993

Serum bactericidal activity and induction of chemiluminescence of polymorphonuclear leukocytes: complement activation pathway requirements in defense against Neisseria meningitidis.

Serum bactericidal activity and chemiluminescence (CL) responses of polymorphonuclear leukocytes (PMNL) to pathogenic Neisseria meningitidis serogroups B and W-135 and to nonpathogenic serogroup 29E were examined with pooled normal human serum depleted of the complement proteins C1q, factor D, properdin and C5. Purified C1q, factor D, properdin and C5 were added alone or in combination. For investigation of serogroup W-135 meningococci, a C1q, factor D and properdin-depleted postvaccination serum with high concentrations of anticapsular antibodies was also used. Serogroup B and W-135 cultured to log phase were resistant to the bactericidal activity of pooled normal human serum but were efficiently killed through the classical pathway alone when the bacteria were cultured to stationary phase. Nonpathogenic serogroup 29E meningococci in log or stationary growth phases were efficiently killed in serum, predominantly through the classical pathway. Serogroup W-135 meningococci grown to log phase were resistant to classical pathway-mediated bactericidal activity in postvaccination serum but were killed on addition of alternative pathway proteins. Stationary phase serogroup W-135 meningococci were killed through both pathways in the postvaccination serum. In the pooled normal human serum CL responses of PMNL were consistently more pronounced with fully reconstituted C1q, factor D, properdin, C5-depleted serum than with serum reconstituted with C1q, factor D and properdin suggesting contribution of actions related to terminal components. In the absence of C1q, serogroup W-135 meningococci in postvaccination serum induced a significant but delayed alternative pathway-mediated CL response. CL responses induced by serum-opsonized meningococci, in contrast to serum bactericidal activity, were not influenced by culture conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Bactericidal Activity↗
PubMed1991

[The titers and complement-activating abilities of anticentromere antibody in systemic sclerosis, other connective tissue diseases, and other related conditions].

The anticentromere antibody is considered to be a useful serologic marker for the CREST syndrome. But this antibody also appears in other related conditions less frequently. We classified 29 patients with anticentromere antibodies into 3 groups: (1) 16 patients with systemic sclerosis or Raynaud's phenomenon alone; (2) 7 patients with other connective tissue diseases; (3) 6 patients with other conditions. Ig class reactivities and complement-fixing abilities of anticentromere antibody were measured by the indirect immunofluorescence test. The whole Ig titers were high (1025 or more) in all patients belonging to group 1. However, the properdin-fixing anticentromere antibody titers of these patients were relatively low (256 or less). In contrast, the patients in group 2 and 3 were shown to have higher C3- and properdin-activating abilities which were determined by the ratios of the titers of C3- and properdin-fixing anticentromere antibody to the IgG titers although the whole Ig titers of these patients were widely distributed. These data suggest that the patients who have low whole Ig titers and/or high properdin-fixing titers do not belong to the scleroderma spectrum and that the patients without clinical features of scleroderma have high C3- and properdin-activating abilities.

Adult↗
PubMed1978

Complement C3 convertase: cell surface restriction of beta1H control and generation of restriction on neuraminidase-treated cells.

The alternative or properdin pathway of complement is primarily controlled by the endopeptidase C3b inactivator (C3bINA) and the nonproteolytic glycoprotein beta1H. The molecular mechanisms of control were investigated by performing binding studies of radiolabeled complement proteins to C3b bearing sheep erythrocytes (E(S)C3b). C3b was found to have distinct binding sites for beta1H, C3bINA, Factor B, and properdin. beta1H binding increased C3bINA binding 30-fold, while Factor B binding prevented C3bINA action on C3b and was competitive with beta1H binding. Properdin binding, which facilitates Factor B interaction with C3b, had no effect on the beta1H and C3bINA sites. Activators such as rabbit erythrocytes (E(R)) have previously been shown to interfere with the effectiveness of the control by C3bINA and beta1H, thereby allowing unrestricted formation of C3 convertase. Such restriction of control does not occur on the surface of E(S), a nonactivator of the alternative pathway. On the basis of comparative binding studies, restriction of control is explained entirely by reduced binding of beta1H to E(R)C3b relative to E(S)C3b. Access of properdin, Factor B, C3bINA, and the Fab fragment of anti-C3 to the two cell types was unrestricted. Restriction of beta1H control could be generated on the surface of E(S) by removal of cell-surface sialic acid with neuraminidase (acylneuraminyl hydrolase; EC 3.2.1.18). This enzymatic treatment converted E(S) from a nonactivator to an activator of the alternative pathway.

Binding Sites↗
PubMed1979

The activation mechanism of human complement system by immune precipitate formed with rabbit IgG antibody.

Immune precipitate (Ippt) formed between egg albumin and rabbit IgG antibody activated both pathways of the human complement system. On incubation with diluted serum, Ippt combined with several factors in the serum to form a complex which acquired C3- and C5-cleaving activities. In serum chelated with ethyleneglycol tetraacetic acid (EGTA), C3- and C5-cleaving activities of properdin system enzymes were formed on Ippt. Kinetic studies on the formation and the decay of C3- and C5-cleaving enzymes on Ippt revealed that C3- and C5-cleaving activites were almost dependent on the properdin system enzymes. The experiments in which C3-cleaving activity formed on Ippt was inhibited by anti-properdin or anti-B but not by anti-C4 supported the above results. The participation of the classical pathway was considered to accelerate the assembly of the properdin system enzymes.

Animals↗
PubMed1978

Serum complement components in Henoch-Schönlein purpura.

Serum levels of C1q, C4, C3, C5, factor B, and properdin were measured in patients with Henoch-Schönlein purpura (HSP). In the cases of acute HSP, 9 of 23 (39%) had a low CH50, and 5 of 17 (30%) a low properdin; C1q, C4, and C3 levels were not depressed. In 10 cases with chronic nephritis following HSP, complement components were normal except for 2 with reduced C4 and one with low properdin. These findings confirm that complement activation occurs in HSP; the low serum levels of properdin in the acute group indicate that there is activation of the alternative pathway in these patients.

Acute Disease↗
PubMed1978

Requirements for the solubilization of immune aggregates by complement. The role of the classical pathway.

In this paper we examine the role of the classical pathway in the complement-mediated solubilization of immune precipitates (CRA). Serum reagents were depleted of the alternative pathway components properdin and factor D. Both depleted reagents lack CRA although they have almost intact hemolytic activity. Also, immune complexes were not solubilized when incubated with high concentrations of the classical pathway components (C1, C4, C2, and C3. We conclude that CRA is not mediated by the classical pathway alone. Activation of the classical pathway by the immune aggregates greatly enhances CRA. The effect of the classical pathway is to deposit C3b on the antigen-antibody lattice and promote the assembly of a lattice-associated, properdin-dependent C3-convertase. Although C3, C4, and properdin were detected on complexes solubilized by serum in the presence of Ca++ and Mg++, only C3 and properdin were found on the complexes when Ca++ had been chelated by ethylene glycol-bis-(beta-aminoethyl ether), N,N'-tetraacetic acid. In both situations the aggregates were capable of converting C5 in the fluid phase. However, no C5 was found on the solubilized complexes. These findings suggest that in contrast to nascent C3b and C4b, nascent C5-9 lacks binding affinity for immune aggregates.

Antigen-Antibody Complex↗
PubMed1988

Assembly of the membrane attack complex promotes decay of the alternative pathway C3 convertase on Neisseria gonorrhoeae.

C3, C4, factor B, properdin, and C2 binding to serum-sensitive and serum-resistant gonococci was quantitated in C8-deficient and normal human serum by using fluorescein-conjugated antibodies and 3H-labeled components. Organism and serum-specific differences were noted, the most striking of which involved factor B and properdin binding to the serum-sensitive strains in the different sera. C3 binding to these organisms was quantitatively and kinetically equivalent in C8-deficient and normal human serum. In contrast, factor B and properdin binding reached a plateau after 5 min in C8-deficient serum but peaked and fell to control values in normal human serum. Identical results were obtained with normal human serum immunochemically depleted of C8. Between 7 and 15% of the bound C3 participated in formation of the alternative pathway convertase C3bBb/P. Reconstitution of the C cascade by adding purified C8 to C8-deficient serum led to the loss of factor B previously bound to the organisms. Factor B loss occurred coincident with bacterial killing and membrane disruption as observed by electron microscopy. Prevention of membrane disruption by depleting normal human serum of lysozyme had no effect on killing and failed to prevent factor B loss. Stabilization of the C3bBb complex with Ni2+ prevented factor B loss as well as gross membrane disruption but not bacterial killing. C2 (the classical pathway analog of factor B) binding to gonococci was equivalent in C8-deficient and normal human serum peaking within 2.5 min and falling to control values in both sera thereafter. We conclude that the assembly of the membrane attack complex promotes decay of C3bBb/P with release of factor B and properdin but not C3 from the organism surface. Membrane disruption does not appear to be required for this effect. This activity may represent a mechanism to limit continued C consumption.

Blood Bactericidal Activity↗
PubMed1978

Hereditary C2 deficiency and systemic lupus erythematosus associated with severe glomerulonephritis.

Although an unusually high incidence of immunological diseases has been described in patients with hereditary C2 deficiency, the severity of these illnesses has been relatively mild, suggesting that blocking complement activation beyond C4 may protect against significant complement-mediated inflammation. This report describes studies in a C2-deficient patient with severe systemic lupus erythematosus (SLE) and diffuse proliferative glomerulonephritis. An immunopathological study of the kidney revealed the deposition of properdin, properdin factor B, C3 and C5 in a pattern similar to immunoglobulin G deposits. Serum properdin and properdin factor B levels were low at various times during the patient's course. In vitro complement fixation studies showed C3 fixation by glomerular deposits could occur via the alternative pathway. Studies of the immune deposits in the patients' skin revealed similar results. These studies suggest that inflammation may be effectively mediated via the alternative complement pathway in the C2 deficiency-lupus syndrome.

Adolescent↗
PubMed1977

Pathways of complement activation in chronic discoid lupus: serologic and immunofluorescence studies.

To assess the relative roles of the classic and alternative pathways of complement activation in chronic discoid lupus erythematosus (CDLE), serum levels of properdin, C3, and C4, and deposition of these proteins in the dermal-epidermal junction (DEJ) of 20 CDLE patients were compared to the findings in patients with clinically active and inactive SLE. Properdin was demonstrated in the DEJ of 10 of 14 (71%) histologically typical skin lesions from patients with CDLE, usually in association with deposits of immunoglobulin, C3, and C4. Properdin levels in CDLE patients were significantly increased (137 +/- 34%) (P less than 0.05) when compared to normal controls (101 +/- 18%) or to patients with clinically active SLE (89 +/- 32%). C3, C4, DNA-binding, and antinuclear antibody tests in CDLE were indistinguishable from those in normals, but significantly different from patients with active SLE (P less than 0.05). The complement profiles of patients with clinically inactive SLE resembled those of CDLE patients more closely than those of active SLE patients.

Adult↗
PubMed1994

Serum complement levels before and after the onset of acute post-streptococcal glomerulonephritis. A case report.

Low serum C3, properdin, and C5 levels found in the acute stage of acute post-streptococcal glomerulonephritis (APSGN) indicate the presence of aggressive complement activation. We followed serum complement component levels in a child hospitalized with erysipelas who developed APSGN on the 2nd hospital day. Her initial serum sample, obtained prior to the clinical onset of nephritis, had a low properdin level and normal C3 and C5 levels despite the presence of C3 splitting activity. Two days later she developed gross hematuria and subsequent sera contained low C3, properdin, and C5 levels, as is usual in APSGN. These observations suggest that complement activation, predominantly through the alternative pathway, precedes the clinical onset of APSGN.

Acute Disease↗
PubMed1978

Activity of the alternative pathway of complement in the newborn infant.

Levels of C3, properdin, factor B, and C3 to C9 activity were markedly reduced in cord sera taken from 94 normal newborn infants. Nevertheless, cord serum supported complete activation of its own alternative pathway by zymosan or CoF. Lysis of a target cell, however, was defective; nearly 75% of cord sera had reduced rabbit erythrocyte CH50 titers. These were partially increased by the addition of factor B and properdin, and totally restored by adding factor B, properdin, and C3 to C9. Therefore, although the alternative pathway of the neonate is intact, it appears to be limited in its ability to generate an adequate number of stable and active enzymatic sites on a target cell membrane.

Complement Activation↗
PubMedDate not supplied

Assembly and regulation of the complement amplification loop in blood: the role of C3b-C3b-IgG complexes.

Amplification of complement activation in blood and serum starts on multi-protein complexes that act as precursors of an alternative C3 convertase. Among these covalently linked C4b-, C3b-, and IgG-containing complexes C3b-C3b-IgG complexes represent the major species containing C3b and IgG. Recent work on their purification and characterization is discussed. Special emphasis is placed on the arrangement of ester bonds in these complexes and their dual type of partial protection from inactivation. Partial protection from inactivation is mediated by properdin which binds to these complexes in the complete absence of any other complement protein. High dose IgG, known to stimulate inactivation of these complexes, appears to lower properdin binding in a process that also involves factor H. Properdin stimulates factor B binding to these complexes and renders them far better precursors of a C3 convertase than C3b. The available information allows a suggestion for a new scheme on how the amplification loop is assembled and regulated in blood and serum.

Antibody Formation↗
PubMed1980

Antibody-independent activation of the alternative complement pathway by measles virus-infected cells.

When HeLa cells acutely infected with measles virus were incubated in a mixture containing only the six proteins of the alternative pathway of complement activation (C3, factors B and D, beta 1H, C3b inactivator, and native properdin) without antibody, there was activation of the alternative pathway as shown by progressive uptake of 125I-labeled C3b onto the cell surface. This C3b uptake was blocked by EDTA and was not shown by uninfected cells. The rate of 125I-labeled C3 uptake by infected cells was the same in the absence and presence of properdin; however, when antiviral IgG was bound to the cell surface, the rate of C3 uptake was increased in the presence of properdin. Significant 125I-labeled C3 uptake was first detectable when cells were studied at 12 hr after infection, when cells expressed viral polypeptides on their surface. There was also progressive uptake of 125I-labeled C3 onto measles virus-infected cells incubated in human serum depleted of both IgG and C4. Hence, the human alternative pathway of complement activation can be initiated on the surface of measles virus-infected cells independent of IgG antibody. However, lysis of the infected cells only occurs when antiviral antibody is present.

Antibodies, Viral↗
PubMed1976

Consumptive opsoninopathy: possible pathogenesis in lethal and opportunistic infections.

Serum levels of properdin, Factor B and C3 and the ability of these sera to opsonize E. coli 075 were measured in 17 patients with surgical infections ranging in severity from mild to fatal. There was good direct correlation between severity of infection, serum levels of properdin and C3, and the ability of the serum to support opsonization. The levels of Factor B were not significantly reduced when measured by radial immunodiffusion, but immunoelectrophoresis showed conversion. Restoration of full opsonic activity was accomplished only by the addition of a combination of C3, Factor B, and properdin in excess. The findings provide evidence that severe bacterial infection causes a consumption of opsonic proteins which may result in a reduced ability of the patient's serum to opsonize bacteria and thereby further increase susceptibility to infection.

Adolescent↗
PubMed1982

In vitro complement activation by intercellular antibodies.

By in vitro complement immunofluorescence, 6 sera from pemphigus with intercellular antibodies were tested for their capability to fix C1q, C4, C3, and properdin. All 6 serum samples yielded positive reaction for C3 staining. Three serum samples gave positive staining for C1q, 5 serum samples for C4, and 3 serum samples for properdin, respectively. Substitution of C2 deficient serum as a complement source inhibited C3 and properdin staining but not positive C1q and C4 staining. These results are best explained by the concept that complement activation in vitro by intercellular antibodies occurs via the classical pathway followed by assembly of the C3 amplification mechanism.

Antibodies↗
PubMed1975

Function of the classical and alternate pathways of human complement in serum treated with ethylene glycol tetraacetic acid and MgCl2-ethylene glycol tetraacetic acid.

An immunochemical and functional analysis of the classical and alternate complement pathways in human serum was performed in the presence of 10 mM ethylene glycol tetraacetic acid (EGTA) and MgCl(2)-EGTA (MgEGTA), chelating agents which have been recently utilized as a means of distinguishing between these two complement pathways. Total hemolytic activity, integrity of the C1 complex, hemolytic activity of C2, conversion of factor B (C3 proactivator), and complement-dependent bactericidal activity were studied. The effect of these chelators on activation of complement pathways by Escherichia coli, by sensitized erythrocytes as a prototype of activators of the classical pathway, and by zymosan as a prototype of alternate (properdin) pathway activators was studied. Human serum containing 10 mM EGTA, which provides almost no ionized calcium and considerably less ionized magnesium than unchelated serum, allowed consumption of complement via the alternate (properdin) pathway, but blocked the classical pathway as judged by disintegration of the C1 complex and lack of utilization of C2. However, activity of the alternate complement pathway in EGTA serum, as judged by conversion of factor B and bactericidal activity against gram-negative bacteria, was distinctly suboptimal. Addition of magnesium ion in a concentration equimolar to EGTA (MgEGTA serum), while still providing conditions in which the C1 complex dissociated, significantly enhanced alternate complement pathway-mediated bactericidal activity. However, in MgEGTA serum considerable fluid-phase activation of the alternate pathway, as indicated by decrease in 50% hemolytic complement (CH(5 0)) titers and conversion of factor B to its active form in the absence of any activating challenge, was observed. Moreover, some fluid-phase consumption of C2 was observed in MgEGTA serum, even though, as mentioned, the C1 complex was shown to be dissociated under these conditions. MgEGTA-related activation of C2 and of the alternate (properdin) pathway of complement was significantly enhanced by the presence of zymosan and E. coli. These results indicate that use of the chelating agents EGTA and MgEGTA to differentiate between classical and alternate pathway activation of human complement is more complex than has hitherto been suggested. In EGTA serum, spontaneous activation of either pathway does not occur but bactericidal activity, as a measure of biologic function of complement, is suboptimal. In MgEGTA serum, bactericidal activity is fully expressed, but there is considerable instability, in terms of fluid-phase activation, in Mg(2+)-dependent components of both pathways. Thus, caution is indicated in the use and interpretation of the effects of these chelating agents on biologic functions mediated by either pathway of human complement.

Blood Bactericidal Activity↗