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At least 19 recordsLinked to original sources
PubMed1975

Mechanisms of activation of the properdin system. Studies on properdin electrophoretic mobility in agarose activation of the alternative pathway.

The electrophoretic mobility of properdin in agarose with and without EDTA examined in sera from normal subjects and from patients with mesangiocapillary glomerulonephritis, systemic lupus erythematosus, rapidly progressive glomerulonephritis, mesangial IgG-IgA disease, minimal change glomerulonephritis and partial lipodystrophy. In 'EDTA agarose", the properdin arc of normal serum was always cathodal (gamma), whereas in non-EDTA agarose it was always (beta), indicating that agarose activated properdin with its consequent conversion from a cathodal to an anodal form. Using this change in the mobility of properdin to investigate activation of the properdin system, it was found that the lower the C3 concentration of diseased sera, the less able were they to support properdin conversion by non-EDTA agarose. This relationship we interpret as a manifestation of the requirement of an intact C3b feedback pathway for properdin activation. This view was supported experimentally by (i) decreasing ability of non-EDTA agarose to shift properdin mobility in normal serum as it was progressively depleted of components of the alternative pathway by cobra venom factor, C3 nehritic factor or Mg2+, and (ii) the inability of non-EDTA agarose to shift properdin in sera depleted of C3 or factor B, and in serum deficient in C3. The report of other workers that activated properdin causes generation of C3b, coupled with our finding that properdin activation depends on the C3b feedback, indicates that a system exists in which activation of the C3b feedback cycle allows activation of properdin, allowing in turn further amplification of the C3b feedback. That the anodal form of properdin may be a property of activated properdin was shown by our observations that properdin eluted from zymosan was anodal and activated, and that the properdin in the supernatant normal serum incubated with inulin was anodal.

Complement C3↗
PubMed1976

Clinical significance of serum properdin levels and properdin deposition in the dermal-epidermal junction in systemic lupus erythematosus.

61 biopsies of normal skin from the deltoid area and lesional skin from various sites from 48 patients with systemic lupus erythematosus (SLE) were studied for the presence of properdin, C3, C4, and immunoglobulins (IgG, IgM, and IgA) in the dermal-epidermal junction (DEJ) using direct and indirect immunofluorescence. Properdin was present in 50% of normal and 40% of lesional skins. Properdin was present without C4 in only 2 of 38 nonlesional skin biopsies and in only 2 of 20 lesions. There was no significant difference in incidence of deposition of any of the six proteins studied between nonlesional and lesional skin. The frequency of deposition of each of the proteins correlated with clinical disease activity. The presence of proteins in the DEJ did not correlate with the presence of active renal disease at the time of biopsy nor with previously documented active nephritis. In addition, no other single clinical manifestation correlated with the presence of DEJ deposition of any protein studied. IgA was not demonstrated in the DEJ of nonlesional skin of 16 patients in remission and was present in 7 of 23 patients with active disease (P less than 0.05). Deposition of properdin in lesional skin correlated with the presence of extracutaneous disease activity (P less than 0.05). Analysis of serologic studies on serum obtained at the time of biopsy revealed a statistically significant correlation between C4 and C3 (r = 0.67). This correlation was stronger than that between properdin and C4 (r = 0.37). Titer of antinuclear antibody and percent of DNA binding correlated better with C4 levels than with properdin levels. Serum properdin levels were significantly lower in patients with active disease than in those in remission (P less than 0.05). Serum properdin levels were significantly lower in patients with properdin deposits in lesional skin than in those without properdin deposits. The data suggest that both alternative and classical pathways are activated in patients with clinically active SLE.

Adolescent↗
PubMed1976

Multiple sedimenting species of properdin in human serum and interaction of purified properdin with the third component of complement.

Normal human serum subjected to sucrose density gradient analysis exhibited multiple sedimenting species of properdin antigen. Properdin antigen distribution was dependent on serum concentration, ionic strength, temperature, and the presence of C3, and was not dependent on the presence of divalent metal cations or blood coagulation. In mixtures of purified components, properdin sedimented heavier in the presence of C3, C3b, or C3c. Addition of factor B to mixtures containing C3 and properdin was without effect. These data provide insights into earlier discrepancies concerning the sedimentation behavior of partially purified properdin, indicate a propensity of some constituents of the alternative pathway to form protein-protein complexes, and suggest caution in interpretation of immunopathological studies in which properdin deposits are found in the presence of C3.

ABO Blood-Group System↗
PubMedDate not supplied

Depressed synovial fluid levels of properdin and properdin factor B in patients with rheumatoid arthritis.

Two proteins in the properdin system, properdin and factor B, and complement components C4 and C3 were measured by radial immunodiffusion in serums and synovial fluids from 21 patients with rheumatoid arthritis (RA) and positive tests for rheumatoid factor, 9 patients with seronegative RA, and 10 with degenerative joint disease. In addition to depressions of synovial fluid C4 which correlated with lowered C3 in seropositive RA, consistent with activation of the classic pathway, low synovial fluid levels of factor B and properdin in seropositive RA indicate intraarticular activation of the properdin pathway as well.

Arthritis, Rheumatoid↗
PubMed1978

Binding of activated properdin to untreated erythrocytes: a new function of activated properdin.

Activated human properdin was found to be capable of binding to rabbit and sheep erythrocytes to form new intermediate cells of the alternative pathway of the complement system. The intermediate cells, termed EP, can react with B, D and C3 to form other intermediate cells, tentatively termed EPB(D)C3, which can be lysed by the subsequent action of six late-acting complement components, C3 to C9. The possibility of participation of C3, B, D or immunoglobulin in the formation of EP cells was neglected by the experiments in which the inhibition of the reactivities of P or EP by antisera to P, C3, B, D or immunoglobulins were investigated. The reduction in reactivities of P to E, or of EP to B, D and C3 was observed only when pretreated with antiserum to P. Furthermore, EP cells were agglutinated only by anti-P, not by antisera to C3 or IgG. The other possibility of participation of the classical complement components such as antibody, C1, C4 and C2 in the formation of EPB(D)C3 was excluded by the non-reactivities of EP with C4 and C2 and of EAC1 with B, D and C3. Thus, activated properdin is likely to function not only as modulator of preformed enzyme such as C3bBb but also as one of early-acting components of the alternative pathway.

Agglutination↗
PubMed1975

Properdin- and nephritic factor-dependent C3 convertases: requirement of native C3 for enzyme formation and the function of bound C3b as properdin receptor.

Two complex enzymes were assembled that both converted C3 to C3b, one consisting of activated properdin (P), native C3, proactivator (PA) and proactivator convertase (PAase), and the other of nephritic factor (NF) and the same three cofactors. By maintaining a critical concentration of PAase, the P-C3 convertase and the NF-C3 convertase were shown to function efficiently without formation of the C3b-feedback enzyme. The former two enzymes are distinct from the C3b-dependent C3 convertase in that they utilize native C3 instead of C3b and PA in an apparently uncleaved form. The P- and NF-C3 convertase express maximal activity within approximately 10 min at 37 degrees C and decay with a half-life of 35 min at 37 degrees C, which is in contradistinction to the reported lability of the C3b-feedback enzyme. P- and NF-C3 convertases are inhibited by their product C3b, which may constitute a heretofore unknown control of the alternative pathway. A direct physical interaction of P with native C3 and C3b was demonstrated by agglutination of C3b-bearing erythrocytes and by agglutination inhibition. Bound C3b thus constitutes the only known receptor of P and may fulfill an important localizing function for P and the P-C3 convertase in vivo. Although P and NF form functionally similar enzymes, they act independently of each other and are apparently immunochemically unrelated proteins.

Absorption↗
PubMed1976

[Contributions to the study of properdin. 4. Report: in vitro model study on the effect of cattle properdin on Escherichia coli].

Light and electron microscopy were used in model experiments to study a high-titre "properdine-system" culture and its action in terms of altering E. coli bacteria. The reaction was altogether strongly predominated by the three following phases of lysis. 1. Onset of massive agglutination after few minutes; 2. Decomposition of bacterial structure by lysis after ten to twelve hours; 3. Terminal phase of lysis after two to three days (amorphous detritus).

Agglutination↗
PubMed1975

[The properdin titer in women with labor pathology or gynecological disease and the role of this titer in the prognosis].

Properdin-titers of 1350 women were determined to appreciate the properdin-system in obstetrics and gynaecology. At first the means of properdin of healthy pregnant women (separated to three months-terms) and blood donors were determined. Then the quantities of properdin-system of pregnant women, parturients and lying-in women with pathologic processes and extragenital diseases and of patients with gynaecologic diseases were explored. The properdin-titer of healthy women at the end of gestation was increased. With a level of 99,6 units the central properdin-titer of these women was lower than the central titer of female blood donors with a level of 109,6 units. During delivery the properdintiter of healthy women decreased, in the period after childbirth it increased again. The determination of properdin of pregnant women, parturients and lying-in women with rheumatic heart defects and gestosises is of great importance. The properdin-titer was low in cases with severe heart diseases and a long issue. The prognostic significance of the test demonstrates the good event of pregnancies, deliveries, post partum periods and late gestosises of women with high properdin-titer regardless of the severity of the pathological state. In comparison with the titer of healthy lying-in women attention is to be directed to the slow rising of the properdin-titer of lying-in women after complicated pregnancy. In cases of gynaecological diseases the determination of the properdin-titer has three purposes: The control of the severity of the disease, the control of the effectiveness of the therapy and the evidence of the prognosis. This is especially conclusive for inflammatory diseases of the genital organs. The worse the turn of the inflammatory disease, the more was the decrease of the properdin-titer and the slower was the activation of the properdin-system in the organism. In cases of septic diseases the importance of the properdin level for prognostic assertion must also be pointed out. The remaining low properdin-titer and its further decrease is characteristical for most of these patients, who show in spite of modern therapeutical methods a long turn of the disease, new septic metastases and a considerable reduction of the general state of health.

Abortion, Illegal↗
PubMed1975

Metabolism of properdin in normal subjects and patients with renal disease.

Properdin deposition has been recognized in glomeruli of patients with acute and chronic nephritis and lupus nephritis, and low serum properdin levels have been found in these disorders. These findings suggest that properdin may be involved in the production of glomerular damage and that low properdin levels may be due to hypercatabolism. The study was designed to examine the metabolism of properdin in normal subjects and to look for an abnormality in five patients with systemic lupus erythematosus with renal involvement and in six patients with membranoproliferative glomerulonephritis or dense deposit disease (MPGN). Highly purified human properdin was prepared by elution from zymosan, followed by DEAE-cellulose and carboxymethyl-Sephadex chromatography, and labeled with 125I by the iodine monochloride method. Parameters of metabolism were determined by monitoring plasma and urinary radioactivity at frequent intervals after the intravenous injection of 1-2 muCi of labeled material. The fractional catabolic rate (FCR) of properdin in normal subjects was found to have a very narrow range of 0.78-1.0,% of the plasma pool per hour (mean 0.95%). In systemic lupus erythematosus, the FCR was regularly elevated with a range of 1.21-2.30% (mean 1.70%). In MPGN, FCR was elevated in three patients (1.22, 1.94, and 2.08%) and within or below the normal range in three (0.78, 1.00, and 1.00%). Properdin levels were reduced in two patients who had the highest FCR's noted in the study. Properdin synthetic rates in normals varied from 4.1 to 14.3 mug/kg per h (mean 9.1) and was not found to be reduced in any patient. Properdin catabolism was found to be normal in a patient deficient in the C3b inactivator. These studies show that properdin is hypercatabolized in patients with renal disease and that decreased properdin levels when they occur in these patients can be entirely explained on the basis of this hypercatabolism.

Adolescent↗
PubMed1976

A molecular concept of the properdin pathway.

The sequential events of the properdin system were analyzed. Properdin-depleted serum allows the formation of a Factor B- and D-dependent C3 convertase. This enzyme, called the properdin-receptor-forming enzyme, was shown to utilize a novel serum component, the initiating factor. The protein is a beta-globulin in precursor form and is distinct from immunoglobulins. The function of the enzyme is to deposit C3b on the surface of activator particles. Apparently doublets of C3b are required for the formation of the properdin-activating principle. It consists of a complex containing surface-bound C3b and activated Factor B. properdin precursor is activated by binding to this complex without detectable change in molecular weight. The transition of properdin precursor to activated properdin is probably caused by a conformational change. The complex, consisting of bound C3b, properdin, and activated Factor B, represents the enzyme that acts on C5, thereby initiating self-assembly of the membrane attack system. Native C3 is not needed for the function of the enzyme. It is disassembled by soluble C3 or C3b and its formation is under the control of the properdin-receptor-destroying enzyme, which may be identical with the C3b inactivator.

Beta-Globulins↗
PubMed1976

Alternative pathway of complement: recruitment of precursor properdin by the labile C3/C5 convertase and the potentiation of the pathway.

In this study the physiological role of properdin and the differential subunit composition of the solid phase enzymes of the pathway have been explored. Cell-bound C3 and C5 convertase differ in their C3b requirement. Apparently one molecule of C3b is sufficient to allow formation of C3 convertase (C3b,B), whereas two or more are required for generation of C5 convertase (C3bn,B). This conclusion was drawn from results indicating the critical role of the spacial distribution of C3b molecules on the cell surface in enzyme formation. While the C3/C5 convertase is fully capable of acting on C5 and thereby initiating the assembly of the cytolytic membrane attack complex, it is exceedingly labile and vulnerable to destruction by the C3b inactivator. It is the apparent role of properdin to confer a degree of stability upon the labile enzyme and to protect its C3 convertase function against enzymatic destruction. To achieve these effects, precursor properdin (pre-P) is recruited in a binding-activation reaction by the labile C3/C5 convertase. Multiple C3b molecules appear to be needed for the formation of properdin-activating principle. Three modes of regulation have been described, which involve spontaneous dissociation enzymatic degradation by C3b inactivator and disassembly by beta1H. The functional differences of pre-P and activated properdin (P) were delineated, pre-P displaying a weak affinity for C3b and P the capacity of strong interaction, P generating a soluble C3 convertase in serum and pre-P being unable to do so. Because of the profound differences between native pre-P and the laboratory product P, the question was raised as to whether soluble P represents an unphysiological form of the protein. On the basis of this and other studies, the conclusion was reached that in vitro properdin recruitment constitutes the terminal event of the properdin pathway, and that properdin augments the function of C3/C5 convertase without changing its substrate specificity.

Animals↗
PubMed1975

Cleavage of the third complement component (C3) and generation of the spasmogenic peptide, C3a, in human serum via the properdin pathway: demonstration of inhibitory as well as enhancing effects of epsilon-amino-caproic acid.

Human and guinea pig serum loses hemolytic activity of the third complement component (C3) during incubation at 37 degrees C. The loss is due to specific C3 cleavage involving the properdin system. This is concluded from the finding that C3 inactivation is prevented by EDTA, by elimination of properdin factor B, and unimpaired in C4 deficient guinea pig serum. In the presence of 1 M epsilon-amino-caproic acid (EACA) spontaneous C3 cleavage is considerably enhanced and accompanied by the appearance of biologically active C3a. Lower concentrations of EACA inhibit rather than enhance C3 cleavage in serum. The inhibitory effect of EACA is due to interference with the interaction of the properdin factors and their action on C3 as demonstrated in various systems: the assembly of an active C3-cleaving complex on zymosan, its regeneration after decay by factor D and factor B (GBG), cleavage of GBG by C3b and factor D in systems of purified components, and cleavage of C3 by preformed properdin complexes. Reactions involving the cobra venom factor were likewise depressed. In all these systems EACA was inhibitory even at 1M concentration. No single step in the development or action of an active properdin system was found to be enhanced by 1 M EACA. The enhancing effect of high concentrations of EACA on C3 cleavage in serum may be explained by its observed inhibition of C3b inactivator (C3bINA). This factor controls the properdin system by destroying C3b. In serum the inhibitory effect of 1 M EACA on C3bINA appears to allow escape of the properdin system from its control and thus to increase its net activity toward C3 despite inhibition of the enzymic reactions proper. At lower concentrations the effect of EACA on C3bINA is apparently less significant; therefore, at low concentrations of EACA, its inhibitory effects on C3 cleavage by the properdin system in serum prediominate.

Aminocaproates↗
PubMed1977

Risk of bladder tumors among benzidine workers and their serum properdin levels.

Serum properdin levels were determined for 21 benzidine operators at 6-month intervals for 2 years after termination of exposure to this carcinogen. Of this group, 7 developed bladder cancers within a 4-month period prior to the initial assay, and all 7 showed properdin levels below the median for the group as a whole. Two of the 3 workers who had had a brief exposure previously to beta-naphthylamine developed benign bladder tumors but had no malignant neoplasms up to 13 years later. The properdin assays of these 3 men remained consistently at or above the median values. No man developed a bladder tumor who was exposed less than 6 years to benzidine, even though 2 of these men showed low properdin levels. Of the 4 whose properdin levels were initially above the median but dropped below in subsequent assays, 3 developed bladder cancers 0.5, 4, and 9 years later. Only 1 man whose properdin level remained high in 1958-59 developed a bladder cancer 7 years later, and his immunologic picture may have been complicated by recovery from a larynx tumor in 1954. Recurrence of bladder tumors among the original 9 cases has occurred only among the 5 whose properdin levels remained below the median. The 1 whose ranking fell most dramatically (from 13 to 19) has had 13 recurrences in 13 years.

2-Naphthylamine↗
PubMed1975

The effect of anticomplementary substances on properdin in normal and C2-deficient sera.

The effect of anticomplementary substances, including zymosan, cobra venom, endotoxin, inulin and immune complexes, on serum properdin concentration and immunoelectrophoretic mobility was studied. In normal serum, zymosan, inulin and immune complexes 'fixed' properdin, while in C2-deficient serum, only zymyosan 'fixed' properdin. Slowly migrating properdin (P) was detected in normal serum following activation by endotoxin and cobra venom but in C2-deficient serum only with cobra venom. Endotoxin did not activate the alternative pathway proteins studied in C2-deficient serum. Fast migrating properdin (P) represented activated properdin and occured as a result of activation of properdin in the Noble agar medium used for electrophoresis provided sufficient cofactors, including Mg2+, were present.

Antigen-Antibody Complex↗
PubMed1977

Quantitative measurement of properdin in normal human serum by electroimmunoassay and single radial immunodiffusion.

Properdin in normal serum was measured by electroimmunoassay (EIA) and single radial immunodiffusion (SRID). Fresh sera gave much lower properdin values in SRID in gels containing Mg2+ ions. Storage of sera at 4 degrees C resulted in a gradual increase of the properdin values measured by SRID but not of those of the EIA. With 10 mM of EDTA in the gels no difference between the properdin values obtained by the different methods was found. Evidence is presented that immunodiffusion values of properdin might be affected by precipitation of a C3-properdin complex in gels containing Mg2+ ions after the activation of the properdin system by agarose.

Complement C3↗