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PubMed1976

Production of antiserum to human properdin and demonstration of antigenic differences between the native and activated protein.

Antisera were raised in rabbits to human properdin in the precursor form (P) and in the activated state (P). On Ouchterlony analysis using the anti-P, reactions of complete identity were obtained between P, P, and properdin in twofold concentrated serum (NHS). However, when anti-P was used, a reaction of identity was obtained only between P and NHS, and a reaction of partial identity was formed between P and P and between properdin in NHS and P, suggestive of the fact that certain antigenic determinants in P may be lacking in P. The results indicate that activation of precursor properdin may involve proteolytic cleavage and/or conformational alterations of the molecule.

Animals↗
PubMed1975

Changes in the immunochemical properties of highly purified properdin in human serum.

The fate of highly purified properdin (P) upon introduction into normal human serum or properdin-depleted serum (RP) was investigated. It was observed that, concomitant with the activation of the alternate pathway components, properdin underwent immunochemical alterations characterized by a shift in mobility from gamma2 to beta2 position and by an increase in the sedimentation rate from 5.1S to between 6.8 and 9.3S. The immunoelectrophoretic behavior of C3 was also altered with the appearance of a beta2 arc in addition to the beta1C arc. The immunochemical properties of altered P resemble those of "native" properdin in fresh serum. The principle in serum (designated factor F) mediating these changes is a euglobulin with an approximate sedimentation rate and molecular weight of 9.0S and 250,000 daltons, respectively. The alteration in the immunochemical properties of P may be due to aggregation of P molecules or a complex formation between P and a serum euglobulin (probably C3) mediated by factor F and it is associated with loss of ability of P in initiate the alternate pathway of complement activation upon interaction with serum.

Animals↗
PubMed1991

Lysis of Neisseria gonorrhoeae initiated by binding of normal human IgM to a hexosamine-containing lipooligosaccharide epitope(s) is augmented by strain-specific, properdin-binding-dependent alternative complement pathway activation.

We studied the specificity of naturally acquired IgM bactericidal for strains of Neisseria gonorrhoeae that varied in sensitivity to the lytic action of normal human serum (NHS) and the relative ability of these strains to deplete the classical (CP) and alternative (ACP) C pathways. Lysis of both highly sensitive and relatively insensitive strains was inhibited by the same gonococcal lipooligosaccharides (LOS), as well as by Salmonella minnesota Re LOS and three hexosamine-containing glycose polymers. A polymer of N-acetylgalactosamine phosphate was the most inhibitory; a polymer of N-acetylglucosamine phosphate only partially inhibited. Neither 3-deoxy-D-manno-octulosonic acid (dOc1A) nor a polymer that contained dOc1A but not hexosamine inhibited NHS lysis. A co-polymer of N-acetylgalactosamine-dOc1A inhibited both bactericidal activity and the binding of IgM to the LOS of a highly serum-sensitive (sers) gonococcal strain. Carboxyl reduction of the dOc1A in this polymer did not affect its inhibitory capacity for gonococcal antibody, but abolished its binding to homologous antibody induced by vaccination. CP activity was not affected by vaccination. CP activity was not affected by absorption of NHS with gonococcal strains, whereas ablation of CP activity markedly but variously diminished lytic activity for highly sers strains. ACP activity was variously depleted by gonococcal strains, and the proportion of bacteria that could be lysed through the ACP varied among strains and among different populations of a given strain. The titer at which a strain was sensitive to NHS lysis was a function of its ACP consumption (p = 0.006), which accounted for 70% of the differences in titer among strains. Analyses of the absorbed sera revealed that the gonococci had variously depleted properdin from NHS as assessed by using an Ag-capture solid-phase RIA. Addition of purified properdin to absorbed sera restored ACP activity to normal levels. Western immunoblots of gonococcal lysates showed that purified properdin bound directly to a 39-kDa outer membrane protein. We conclude that both CP activation by IgM binding to LOS epitopes, one of which contains hexosamine, and ACP activation, which is a function of strain-specific direct binding of properdin, can initiate lysis of sers strains and that ACP activation, also enhances lysis and accounts for variations in sensitivity of sers strains.

Antigens, Bacterial↗
PubMed1993

Properdin, a positive regulator of complement activation, is expressed in human T cell lines and peripheral blood T cells.

Properdin plays an important regulatory role in the activation of the complement system. Here we report the biosynthesis of properdin in four different human T cell lines and in T cells purified from peripheral blood. Cell sorting experiments, in conjunction with Northern blotting, showed that both CD4- and CD8-bearing populations of T cells have the potential to synthesize properdin. The functional activity of properdin secreted from these T cell lines was determined in a hemolytic assay. In view of the numerous ways in which complement activation may influence cellular immune response, the present results indicate, for the first time, a possible interaction between the complement and the T cell system.

Adult↗
PubMed1977

Alternative pathway of complement: nonenzymatic, reversible transition of precursor to active properdin.

A method for the purification of properdin in precursor state (pre-P) has been elaborated. Precursor properdin, in contrast to activated properdin (P), does not initiate the formation of a C3 convertase when added to properdin-depleted serum, rather it requires the presence of an activating substance such as zymosan for expression of its activity. Comparing the activities of pre-P and P it was found that some P preparations contained significant amounts of pre-P because they were fully active only in the presence of zymosan. This observation indicated that P can partly revert to pre-P. Comparison by immunoelectrophoresis and sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed no charge or size differences between pre-P and P. Radiolabeled pre-P, when analyzed after its participation in the reactions of the pathway, displayed an unchanged subunit m.w. of 50,000. Taken together, these results strongly suggest that the transition of pre-P to P is due to a partly reversible change in the conformation of the protein rather than the result of proteolytic cleavage.

Complement System Proteins↗
PubMed1971

Glomerular deposition of properdin in acute and chronic glomerulonephritis with hypocomplementemia.

Kidney tissue from 97 patients was studied by immunofluorescent techniques using antiserum to purified properdin. All patients with acute poststreptococcal glomerulonephritis showed deposition of properdin and the third component of complement (C3), either as "humps" on the basement membrane, or in the mesangium. In all cases of chronic membranoproliferative glomerulonephritis, properdin and C3 were localized in the glomeruli, most commonly in a lobular pattern on the basement membrane. Activation of C3 by the properdin system may explain the depressed serum levels of C3 and terminal complement components even though levels of earlier components are normal, and the deposition of C3, often without immunoglobulins, in the kidneys of patients with acute glomerulonephritis or chronic membranoproliferative glomerulonephritis.

Acute Disease↗
PubMed1987

Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia.

A nine-year-old white boy with recurrent pneumococcal bacteremia is described. His serum had no hemolytic activity in either the classic or alternative complement pathways. Absence of classic pathway activity was secondary to a homozygous deficiency of C2. The parents had half-normal levels of C2, compatible with an autosomal recessive mode of inheritance. Measurement of serum properdin levels by radial immunodiffusion and enzyme-linked immunoabsorbent assay revealed a profound deficiency in the patient, normal levels in the father, and half-normal levels in the mother, suggesting X-linked inheritance of the deficiency. Addition of purified properdin to the patient's serum fully reconstituted the alternative pathway function. This patient's unique combination of inherited deficiencies of properdin and C2 is a likely explanation for his susceptibility to bacterial infection.

Child↗
PubMed1987

Congenital properdin deficiency and meningococcal infection.

We report a family in which three males in two generations had meningococcal infections; one of them died. Hemolytic activity of the alternative complement pathway in the two survivors and in one healthy boy belonging to the family was reduced, as measured in a kinetic system. These three individuals had 10-11% of normal properdin concentration in plasma, as measured by a catching ELISA method, while the other complement components were normal. Hemolytic complement activity was normalized when purified properdin was added. The data are compatible with an X-linked mode of inheritance of properdin deficiency.

Complement Activation↗
PubMed1988

Linkage analysis of the properdin deficiency gene: suggestion of a locus in the proximal part of the short arm of the X chromosome.

Properdin is a component of the alternative pathway of complement activation. Inherited deficiency of the protein predisposes an individual to develop meningococcal disease. A family segregating for properdin deficiency (McKNo 31206), in a manner consistent with X-linked recessive inheritance, was studied by RFLP analysis using 24 X-chromosome-specific DNA probes of known regional assignments. Linkage was observed to the OTC locus and the DXS7 locus. These results suggest that the properdin gene is located on the short arm of the X chromosome in the region Xp21.1-Xcen.

Chromosome Mapping↗
PubMed1988

Properdin, the terminal complement components, thrombospondin and the circumsporozoite protein of malaria parasites contain similar sequence motifs.

Properdin is a plasma glycoprotein which stabilizes the C3bnBb enzyme complex of the alternative pathway of the complement system. Unlike the classical pathway, which is initiated by interaction of C1q with the Fc regions of IgG or IgM antibodies in immune complexes, the alternative pathway can be directly activated via binding of C3b to surfaces of foreign organisms. The stabilized C3bnBbP complex activates components C3 and C5 resulting in opsonization of foreign material (via C3b) and assembly of the membrane attack complex (via C5b) on target cells. Therefore properdin greatly enhances complement-mediated clearance and inactivation mechanisms in both natural and acquired resistance to infection. This paper shows that the primary amino acid sequence of properdin is composed mainly of six repeating motifs, each of approximately 60 amino acids, and that similar sequences are found in thrombospondin, the circumsporozoite protein of malaria parasites and regions of the membrane-attack components of complement. These similarities may provide insight into the mechanisms by which parasites avoid host defences mediated by complement.

Amino Acid Sequence↗
PubMed1984

Mapping of the properdin-binding site in the third component of complement.

The properdin-binding site in the human third complement component (C3) was mapped by using isolated C3b, C3c, alpha- and beta-chains of C3 and C3 polypeptide fragments and an enzyme-linked-immunosorbent-assay procedure. The C3 chains and the polypeptide fragments were purified to homogeneity by preparative sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The alpha-chain polypeptides included a 68 kDa and a 43 kDa polypeptide, which were generated by cleavage of C3b with factors I and H, and a 40 kDa, 33 kDa (C3d) and 27 kDa polypeptide, which were generated by cleavage of C3b with porcine elastase. It was shown that properdin binds to C3b, C3c, alpha-chain, and to the 43 kDa (factor-I + H-derived), as well as to 40 kDa (elastase-derived) alpha-chain fragment, but not to the beta-chain 68 kDa, 33 kDa (C3d) and 27 kDa alpha-chain fragments. Thus the binding site for properdin resides on the 40-43 kDa C-terminal alpha-chain fragment of C3.

Binding Sites↗
PubMed1992

Characterization of the human properdin gene.

A cosmid clone containing the complete coding sequence of the human properdin gene has been characterized. The gene is located at one end of the approximately 40 kb cosmid insert and approximately 8.2 kb of the sequence data have been obtained from this region. Two discrepancies with the published cDNA sequence [Nolan, Schwaeble, Kaluz, Dierich & Reid (1991) Eur. J. Immunol. 21, 771-776] have been resolved. Properdin has previously been described as a modular protein, with the majority of its sequence composed of six tandem repeats of a sequence motif of approximately 60 amino acids which is related to the type-I repeat sequence (TSR), initially described in thrombospondin [Lawler & Hynes (1986) J. Cell Biol. 103, 1635-1648; Goundis & Reid (1988), Nature (London) 335, 82-85]. Analysis of the genomic sequence data indicates that the human properdin gene is organized into ten exons which span approximately 6 kb of the genome. TSRs 2-5 are coded for by discrete, symmetrical exons (phase 1-1), which supports the hypothesis that modular proteins evolved by a process involving exon shuffling. TSR1 is also coded for by a discrete exon, but the boundaries are asymmetrical (phase 2-1). The sequence coding for the sixth TSR is split across the final two exons of the gene with the first 38 amino acids of the repeat coded for by an asymmetric exon (phase 1-2). This split at the genomic level has been shown, by alignment analysis, to be reflected at the protein level with the division of repeat 6 into TSR-like and TSR-unlike sequences.

Amino Acid Sequence↗
PubMed2003

Ontogeny of complement regulatory proteins - concentrations of factor h, factor I, c4b-binding protein, properdin and vitronectin in healthy children of different ages and in adults.

Previous studies of human in vivo complement protein levels have only compared data for neonates with that from adult sera. Here, we establish the normal concentration ranges of the following complement regulatory proteins in healthy Brazilian children of different age groups (neonates: 1 month-1 year, 1-6 years and 6-13 years) and in adults: factor H (fH), factor I (fI), C4b-binding protein (C4 BP), properdin and vitronectin. We found that the concentrations of fH, fI, properdin and vitronectin in neonates are significantly lower than in adults. Remarkably, the concentration of C4 BP is below the method resolution (<50 micro g/ml) in 76% of the sera from neonates, while adults presented 199-532 microg/ml of C4 BP in their sera. The concentration of properdin in the sera from neonates and up to 1-year-old children was less than that observed in older children. Adults presented vitronectin levels significantly higher than all the other age groups in the study. No significant sex differences in the concentrations of all the studied regulatory proteins were detected. This study reveals the ontogeny of complement system in greater detail than previously available and may point to the reasons why neonates have higher susceptibility to develop life-threatening pyogenic infections. These reference values will be of use in clinical and laboratory investigations of disorders associated with low levels of these regulatory proteins.

Adolescent↗
PubMed2000

Properdin, the positive regulator of complement, is highly C-mannosylated.

Properdin is the positive regulator of the alternative pathway of complement activation. The 53-kDa protein is essentially composed of six thrombospondin type 1 repeats, all of which contain the WXXW motif, the recognition sequence for C-mannosylation. C-Mannosylation is a post-translational modification of tryptophan residues in which, in contrast to the well known N- and O-glycosylation, the carbohydrate is attached via a C-C bond to C-2 of the indole moiety of tryptophan. C-Mannosylation was first found in human RNase 2 and interleukin-12. The terminal complement proteins C6-C9 also carry this modification as part of their thrombospondin type 1 repeats. We studied the C-mannosylation pattern of human properdin by mass spectrometry and Edman degradation. Properdin contains 20 tryptophans of which 17 are part of a WXXW motif. Fourteen tryptophans were found to be modified 100%. This is the first example of a protein in which the majority of tryptophan residues occurs in the C-mannosylated form. These results show that C-mannosylated proteins occur at several steps along the complement activation cascade. Therefore, this system would be ideal to investigate the function of C-mannosylation.

Amino Acid Sequence↗
PubMed1994

Serum immunoglobulins in Heymann's experimental nephritis modulate binding of properdin and factor-H to sulpho-glycosphingolipids II3SO3(-)-Gg3Cer and III3SO3(-)-,II3SO3(-)-Gg3Cer.

The nephropathic effects of Heymann's experimental nephrites involve autoallergic serum antibodies directed against rat kidney membrane constituents. In assessing the action of glycolipids as possible autoallergens in these conditions, it was found that heterologous and autologous Heymann's nephritis sera antibodies recognize that rat kidney sulphatides, II3SO3(-)-Gg3Cer (Stri1), and III3SO3(-)-,II3SO3(-)-Gg3Cer (Stri2). Two antibody populations in Heymann's sera, each reacting with only one of the two sulphatides, could be observed. It was further shown that human factor-H and properdin, pivotal regulators of the alternative pathway of complement activation, both bound to Stri2 in vitro. This binding of factor-H and properdin was differentially affected by affinity-purified anti-Stri2 antibodies of Heymann's nephritis sera. Whereas the interaction between factor-H and Stri2 was inhibited by the antibody, that of properdin was enhanced.

Animals↗
PubMed1975

Dermal-epidermal deposition of complement components and properdin in systemic lupus erythematosus.

Skin lesions and clinically normal skin of thirteen patients with systemic lupus erythematosus (SLE) were examined, by the use of immunofluorescent techniques, to determine the presence of CIq, C3, C3 proactivator (C3PA), properdin, immunoglobulins (IgG, IgA, and IgM), and fibrin. IgM deposition was present in all thirteen skin lesions and in eleven normal areas tested, whereas IgG deposition occurred in eleven of the lesions but in only six normal areas. IgA was the least frequently encountered immunoglobulin. CIq deposition occurred in all thirteen skin lesions, and C3 deposition was present in twelve. Seven of nine and eight of eleven clinically normal areas demonstrated CIq and C3 deposition, respectively. Although less intense that CIq and C3 deposition, properdin deposition occurred in eight of the thirteen skin lesions tested but in only two of nine normal areas. C3PA deposition was of greater intensity than was properdin, but was seen in only five lesions and three clinically normal areas. Seven skin lesions and two normal areas also demonstrated fibrin deposition. Although alternate pathway activation is apparent, our findings suggest that the classical pathway (CI to C9) is the primary complement pathway involved in SLE skin.

Adult↗
PubMedDate not supplied

The properdin system: composition and function.

This article summarized the physicohemical data on the factors which compose the properdin system in guinea pig and man. The following other topics are discussed: (1) Activation of the properdin system; (2) Formation of the initiating and amplification C3 convertases; (3) Formation of the C5 convertase, and (4) Regulatory control mechanisms of the properdin system.

Animals↗
PubMed1975

Activation of the complement and properdin systems in rheumatoid arthritis.

The classic (C1, C4, and C2) and properdin factors (D, C3b, and B) of complement generate C3 convertases that are capable of cleaving C3 and subsequently activating C5-C9. Both C1 and factor D are serine esterases, and both convertases undergo decay and regeneration. In seropositive rheumatoid arthritis, where intraarticular activation of the classic early components (C1, C4, and C2) by immunoglobulin complexes appears to predominate, findings of relative depressions in synovial fluid levels of factor B indicate recruitment of the amplification loop (D, C3b, and B), and relative declines in properdin levels suggest activation of the properdin pathway as well. Quantitative analysis of the complement system in disease states requires several different approaches: measurement of function and antigenic concentration to assess the functional integrity of the protein; determination of component metabolism to appreciate the relative contributions of hypercatabolism and hyper- or hyposynthesis to the plasma level; and for compartmentalized disease, measurement of the component in the appropriate biologic fluid and determination of local tissue synthesis.

Antigen-Antibody Complex↗