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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↗
PubMed1994

Human liver-derived HEP G2 cells produce functional properdin.

Properdin stabilizes the alternative complement pathway C3 convertase and is synthesized by monocytes and myelomonocytic cell lines. Hepatic production of properdin has never been documented, although most other complement components are synthesized by liver. Human liver-derived Hep G2 cells were examined for the ability to produce properdin by using the polymerase chain reaction (PCR). Amplified properdin message was detected by using Southern transfer and hybridization to a murine properdin cDNA probe. Sequencing of the PCR product revealed that the Hep G2 message was nearly identical to the cDNA sequence from U937 cells. Subsequently Hep G2 cultures were stimulated with interleukin (IL-6), 25 micrograms/ml, and culture supernatants were assayed for the presence of properdin by using dot blots. Properdin concentration increased over time, and we found no obvious difference between properdin production by IL-6-stimulated and unstimulated Hep G2 cells. Finally, alternative pathway decay assays confirmed the presence of functionally active properdin in the culture supernatant. Thus, functional properdin is a product of Hep G2 cells, suggesting that biosynthesis of properdin may occur in hepatocytes. Properdin synthesis was not augmented by IL-6, a finding that is consistent with previous observations that properdin is not an acute phase reactant.

Base Sequence↗
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↗
PubMed2003

The endothelium as physiological source of properdin: role of wall shear stress.

Properdin is a positive regulator of the alternative pathway of complement activation. It can be released by peripheral blood cells but is not synthesized in the liver and the physiological source of properdin in plasma is unknown. The endothelium is an extra-hepatic source for several complement components and shear stress can modulate their expression. The aim of this study was to analyze shear stress-exposed endothelial cells (EC) as physiological source for plasma properdin. Human umbilical vein EC (HUVEC) and human cardiac microvascular EC (HCMEC) were exposed to shear stress using a cone-and-plate apparatus and properdin expression was analyzed by RT-PCR, Northern, and Western blot. mRNA for properdin is barely detectable in untreated EC but strongly induced by laminar shear stress exposure (6 dyn/cm(2); 24 h). Properdin is induced also at the protein level and is released in the extracellular compartment. Properdin up-regulation requires a shear stress of 2-3 dyn/cm(2), is not transient, and is reversible by restoration of static conditions. Turbulent flow exposure results in two times higher induction of properdin than laminar flow exposure. The ability of endothelial cells exposed to shear stress to synthesize properdin proposes the endothelium as physiological source for plasma properdin and suggests a link between flow conditions and the modulation of the alternative pathway. Furthermore, the stronger properdin induction by turbulent flow may suggest an involvement in the pathology of atherosclerosis.

Cells, Cultured↗
PubMed1995

Characterization of mutant forms of recombinant human properdin lacking single thrombospondin type I repeats. Identification of modules important for function.

Properdin is a serum glycoprotein that up-regulates the alternative pathway of complement by stabilizing the C3b-Bb complex. It also binds sulfated glycoconjugates, such as sulfatide, in vitro. Properdin is composed of cyclic dimers, trimers, and tetramers of a 53-kDa monomeric subunit. The monomer contains an N-terminal region of no known homology and six thrombospondin type 1 repeats (TSRs) of approximately 60 amino acids. To identify the regions of properdin important for function, we have expressed human properdin, and mutant forms each lacking a single TSR, in Chinese hamster ovary cells. In addition, limited tryptic digestion yielded "nicked" properdin by the cleavage of one peptide bond in TSR5. The structural and functional properties of these altered forms of properdin were investigated. Properdin "nicked" in TSR5 is unable to bind C3b but retains its overall structure and its ability to bind sulfatide. The removal of TSR5 prevents C3b and sulfatide binding. Properdin lacking TSR4 is unable to stabilize the C3b-Bb complex but is able to bind C3b and sulfatide, and shows the presence of monomers and dimers in an electron microscope. Properdin without TSR3 is able to stabilize the C3b-Bb complex, to bind C3b and sulfatide, and forms dimers, trimers, and tetramers. Properdin lacking TSR6 is unable to form oligomers. The N-linked carbohydrate of properdin is not required for oligomerization or stabilization of the C3b-Bb complex. The results implicate TSR5 in both C3b and sulfatide binding, and suggest that TSR4 may also be involved in stabilization of the C3b-Bb complex.

Amino Acid Sequence↗
PubMed1996

Molecular characterization of properdin deficiency type III: dysfunction produced by a single point mutation in exon 9 of the structural gene causing a tyrosine to aspartic acid interchange.

Inherited properdin deficiency is an X-linked recessive disorder clinically manifested by susceptibility to meningococcal disease. Deficiency of properdin is characterized by complete absence (type I), very low level presence (type II), or the presence of a dysfunctional properdin protein in serum as found in one Dutch family (type III). To better understand the dysfunctional protein on the molecular level, samples from three members of the Dutch family were analyzed by direct genomic sequencing. The sequence of the complete gene, including 10 exons and 9 introns, covering about 6500 bases was determined. The dysfunctional properdin was found to be caused by a single T to G mutation in exon 9, which gives rise to a substitution of a tyrosine by an aspartic acid residue at position 387. This change to a hydrophilic amino acid affects the function of the properdin molecule, although the oligomerization of dysfunctional properdin molecules was similar to that of normal properdin. In binding studies with C3b and properdin in serum, no properdin deposition was detected with the type III deficient serum. Inhibition studies with different decapeptides revealed distinct inhibitory sequences, and indicated also that the part of properdin containing the type III mutation was not directly involved in the binding to C3b. The mutation most likely causes conformational changes that make the properdin molecule dysfunctional by affecting its binding to C3b.

Amino Acid Sequence↗
PubMed2005

The role of properdin in the assembly of the alternative pathway C3 convertases of complement.

Complement is a powerful host defense system that contributes to both innate and acquired immunity. There are three pathways of complement activation, the classical pathway, lectin pathway, and alternative pathway. Each generates a C3 convertase, a serine protease that cleaves the central complement protein, C3. Nearly all the biological consequences of complement are dependent on the resulting cleavage products. Properdin is a positive regulator of complement activation that stabilizes the alternative pathway convertases (C3bBb). Properdin is composed of multiple identical protein subunits, with each subunit carrying a separate ligand-binding site. Previous reports suggest that properdin function depends on multiple interactions between its subunits with its ligands. In this study I used surface plasmon resonance assays to examine properdin interactions with C3b and factor B. I demonstrated that properdin promotes the association of C3b with factor B and provides a focal point for the assembly of C3bBb on a surface. I also found that properdin binds to preformed alternative pathway C3 convertases. These findings support a model in which properdin, bound to a target surface via C3b, iC3b, or other ligands, can use its unoccupied C3b-binding sites as receptors for nascent C3b, bystander C3b, or pre-formed C3bB and C3bBb complexes. New C3bP and C3bBP intermediates can lead to in situ assembly of C3bBbP. The full stabilizing effect of properdin on C3bBb would be attained as properdin binds more than one ligand at a time, forming a lattice of properdin: ligand interactions bound to a surface scaffold.

Binding Sites↗
PubMed1996

Carrier detection by microsatellite haplotyping in 10 properdin type 1-deficient families.

Properdin deficiency carrier identification is relevant, because properdin-deficient persons have an increased risk of contracting meningococcal disease. Vaccination against meningococcal disease at a young age may provide protection. Accurate detection of this deficiency is needed. Microsatellite haplotyping with the PFCI and PFC2 markers closely linked to the properdin gene locus at Xp11.3-Xp11.23 may offer an easy and accurate identification of carriers of the properdin deficiency gene. The chance to study 91 relatives belonging to 10 families with complete (type 1) properdin deficiency offered a unique opportunity to assess whether properdin type 1 deficiency is associated with a distinct microsatellite haplotype. Haplotyping with the closely linked PFC1 and 2 markers yielded five different haplotypes, which did not support the concept of a founder effect. Among the 28 women carriers, two had normal properdin levels and in five the PFC1,2 polymorphism was not informative owing to homozygosity. Extending the microsatellite haplotyping with three additional markers (DXS1126, DXS426 and DXS7) yielded informative haplotypes in all meioses. We concluded that microsatellite haplo-typing using five markers in close proximity to the properdin gene locus is an accurate method of detecting carriers of the properdin deficiency gene and of properdin-deficient persons within a family at a young age.

Female↗
PubMed2000

Molecular characterisation of 10 Dutch properdin type I deficient families: mutation analysis and X-inactivation studies.

Properdin type I deficiency is characterised by complete absence of extracellular properdin, a positive regulator of the alternative pathway of complement activation. Properdin deficiency is associated with increased susceptibility to severe meningococcal disease. We have identified the genetic defect in 10 Dutch families. Six different mutations and one sequence polymorphism in the properdin gene were found. All amino acid substitutions were limited to conserved amino acids in exons 7 and 8 in contrast to the premature stops that were found in other exons. The missense mutations may alter the protein conformation in such a way that properdin will not be secreted and therefore catabolised intracellularly. The decreased properdin levels found in some healthy females carrying one mutated properdin gene were studied for X-inactivation. Most carriers with extreme low or high properdin levels showed preferential X-inactivation for the normal or mutated X chromosome, respectively. We observed some exceptions, suggesting additional regulation of properdin excretion apart from X-inactivation.

DNA↗
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↗