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PubMed1995

Human complement proteins C3b, C4b, factor H and properdin react with specific sites in gp120 and gp41, the envelope proteins of HIV-1.

Recently we reported the basic phenomenon of an interaction between the envelope glycoproteins of HIV-1 gp120 and gp41 and components of the human complement system, i.e. activated C4 (C4b) and activated C3 (C3b) and the complement regulator proteins factor H and properdin. In this study we analyze these interactions in detail. Using 46 overlapping peptides of gp120 attached to microtiter plates, binding of activated human C3 to 6 regions in gp120 was found (aa 100-129, 161-190, 231-250, 301-328, 410-449, 470-499). In competition assays with soluble peptides, representatives of four of these regions were capable to partially inhibit C3b binding to immobilized gp120. Activated human C4 interacted only with peptides covering aa 410-449, but both in direct binding assays and fluid phase inhibition studies. The multi-reactivity of gp120 with C3b was also supported by the fact that gp120 agglutinated erythrocytes coated with C3b. Guided by partial aa sequence homology of gp120 and human C4b binding protein (C4bp) as well as human properdin we detected binding of anti-properdin to aa 100-129 in gp120 and of anti-C4bp to aa 410-449 in gp120. This cross-reactivity was also confirmed by a monoclonal antibody directed against aa 416-443 of gp120, which could be shown to bind C4bp. Interestingly, aa 310-328, part of the V3-loop, were found to show an aa sequence similarity to human complement receptor type 3 (alpha-chain). Consequently, of the 4 (or possibly 6) interaction sites of gp120 with activated human C3, 3 may bind due to imitation of either properdin, CR3 or C4bp. In addition to C4b and C3b, we detected interaction of factor H with gp120; it selectively bound to aa 102-129. Using 14 overlapping peptides of gp41 attached to plates, we identified 4 areas in gp-41 (aa 561-585, 587-605, 615-635, 651-675) which bound human factor H. All of them except the first region partially inhibited factor H binding to gp41 in competition assays with soluble peptides. Properdin bound only to 2 regions (aa 584-614, 651-675). The first 3 sites in gp41 were already shown by us to share homology to sites in human C3. The region around aa 651-675 now also turned out to be similar to human C3. These data demonstrate that the interaction of both, gp120 and gp41, with the complement system is polyvalent and complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1989

Secondary structure in properdin of the complement cascade and related proteins: a study by Fourier transform infrared spectroscopy.

Six structural repeat motifs of 58 amino acids are found in the sequence of both mouse and human properdins. Twelve more examples of the motif are available from the sequences of thrombospondin, the terminal complement components, and the thrombospondin-related anonymous protein. The averaged Robson and Chou-Fasman secondary structure predictions show that there are 57-66% turn and 19-38% beta-sheet structures in the typical repeat motif. The high amount of turn structure is consistent with Gly, Pro, Cys, and Ser being the four most abundant amino acid residues in properdin. Comparisons with sequences found in the circumsporozoite protein from several species of malaria parasites show that their sequences and secondary structures strongly coincide only in a 18-residue segment. Further secondary structure analysis utilized Fourier transform infrared spectroscopy of human properdin in 2H2O buffers. These show a broad amide I band that, after second-derivative and deconvolution calculations, is shown to be composed of several components. Two at 1633 and 1683 cm-1 are strong evidence for beta-sheet structure, although overlap from beta-turns can also contribute. The presence of beta-turn structure is indicated by absorptions at 1662-1675 and 1645 cm-1. The properdin structure contains substantial quantities of beta-sheet and beta-turn structures, which is consistent with the secondary structure predictions and amino acid compositions. The length of the repeat motif is estimated as 3.3-4.3 nm, and an estimated 14-22% of nonexchanged amide protons reside in properdin. This is suggestive of a high degree of solvent accessibility in the structure.

Amino Acid Sequence↗
PubMed2000

Interaction of C3b(2)--IgG complexes with complement proteins properdin, factor B and factor H: implications for amplification.

Nascent C3b can form ester bonds with various target molecules on the cell surface and in the fluid phase. Previously, we showed that C3b(2)--IgG complexes represent the major covalent product of C3 activation in serum [Lutz, Stammler, Jelezarova, Nater and Späth (1996) Blood 88, 184--193]. In the present report, binding of alternative pathway proteins to purified C3b(2)--IgG complexes was studied in the fluid phase by using biotinylated IgG for C3b(2)--IgG generation and avidin-coated plates to capture complexes. Up to seven moles of properdin 'monomer' bound per mole of C3b(2)--IgG at physiological conditions in the absence of any other complement protein. At low properdin/C3b(2)--IgG ratios bivalent binding was preferred. Neither factor H nor factor B affected properdin binding. On the other hand, properdin strongly stimulated factor B binding. Interactions of all three proteins with C3b(2)--IgG exhibited pH optima. An ionic strength optimum was most pronounced for properdin, while factor B binding was largely independent of the salt concentration. C3b(2)--IgG complexes were powerful precursors of the alternative pathway C3 convertase. In the presence of properdin, C3 convertase generated from C3b(2)--IgG cleaved about sevenfold more C3 than the enzyme generated on C3b. C3b(2)--IgG complexes could therefore maintain the amplification loop of complement longer than free C3b.

Complement C3-C5 Convertases↗
PubMed1988

Analysis of the interactions between properdin, the third component of complement (C3), and its physiological activation products.

The interactions of properdin with both surface-bound and fluid-phase C3 (the third component of complement) and its activation products have been investigated by using a purified preparation of the 'native' form. At physiological ionic strength, a weak interaction with cell-bound C3b (the larger activation fragment of C3) could be demonstrated. In the presence of Factor B this interaction was enhanced, and further enhancement was seen when C3bBb sites were formed on the erythrocytes. The avidities of properdin for cell-bound iC3b (the initial product of Factors I and H action on C3b) and C3b were compared at low ionic strength, with that measured for iC3b being less than that for C3b. In contrast, the affinities of properdin for fluid-phase C3b, iC3b and C3c (the larger product of Factors I and H or CR1 (the C3b receptor) action on iC3b) were all very similar, and apparently much weaker than that for cell-bound C3b. No interaction with either native C3 or, more surprisingly, C3i (haemolytically inactive C3) could be detected. Properdin also inhibited Factor I binding to, and action upon, cell-bound C3b, but did not inhibit Factor I action on fluid-phase C3b. These data permit a more detailed description of the roles of properdin in the alternative pathway of complement activation, emphasizing its importance in concentrating activation at the activating surface.

Complement Activation↗
PubMed1990

Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcal infections.

High incidence of hereditary complement (C) deficiencies was found among 101 patients who had a meningococcal disease. This study revealed 11 non-related patients with complete C deficiency: five deficient in C7, three in C8, two in properdin and one in C2. Additional C-deficient individuals, most of them with no history of severe bacterial infections, were detected in family studies. The C8-deficient patients were found to have a selective deficiency of the C8-beta subunit and a reduced expression of the alpha/gamma subunit. Only a few families with properdin deficiency have been described so far. However, it is likely that frequent analysis of the activity of the alternative C pathway in survivors of severe bacterial infections will disclose numerous properdin-deficient patients. All our C7-, C8- and properdin-deficient patients are Sephardic Jews whose families originated from Morocco, Yemen (C7 and C8 deficient) or Tunisia (properdin deficient). This and other findings indicate that the type of complement abnormality found in association with meningococcal infections varies with the ethnic origin of the patient.

Adolescent↗
PubMed1994

Expression of properdin in human monocytes.

Properdin is the only known positive regulator of the alternative pathway of complement activation. Northern blot analysis of cell lines derived from fibroblasts, B-cells, hepatoma cells, and cells of the monocyte-macrophage lineage revealed properdin expression only in the myelomonocytic cell line HL-60, in the monoblastic cell line U-937 and in the monocytic line Mono Mac 6. Culture of Mono Mac 6 cells for 24 h with phorbol 12-myristate 13-acetate, bacterial lipopolysaccharide and the cytokines interleukin-1 beta and tumour necrosis factor-alpha enhanced mRNA abundance, with the strongest effect (tenfold) being observed with the lipopolysaccharide. In contrast, recombinant interferon-gamma consistently halved properdin mRNA abundance. The same pattern was found for the secretion of properdin as detected by ELISA of Mono Mac 6 supernatants. The suppressive effect of interferon-gamma on properdin mRNA abundance was also demonstrated for primary blood monocytes. The data suggest that the expression and secretion of this complement regulatory protein by monocytes is differentially regulated by cytokines and link the immune response with alternative pathway activation.

Adult↗
PubMed1978

The role of C1s, C1r and properdin in the initiation of the C3b-dependent feedback mechanism of the complement system.

The influence of activated C1s, C1r and properdin in the fluid phase initiation of the C3b-dependent feedback mechanism of the human complement was studied. It was found that C1s caused conversion of C3 and factor B in a normal serum, but not in a serum genetically deficient in C4 or in a serum to which Na2EDTA had been added. When a normal serum was incubated with C1r before incubation with C1s, only C3 was converted, whereas factor B remained in the unaltered native state. Properdin did not influence the C1s mediated conversion of C3 and factor B. When activated properdin was added to a properdin-depleted serum, both C3 and factor B were converted. Activated properdin was also incubated with purified C3 and purified C3b. It was shown that C3 was converted to C3b, but C3b was not degraded despite prolonged incubation.

Chromatography, Affinity↗
PubMed1993

Carrier detection in families with properdin deficiency by microsatellite haplotyping.

Human properdin deficiency is an X-linked disorder strongly predisposing to meningococcal disease which has been recorded in over 50 cases of various ethnic origins. Immunochemically, total deficiency (type I), partial deficiency (type II), and deficiency due to a dysfunctional molecule (type III) can be differentiated. It is therefore most likely that the causative molecular defects will show considerable genetic heterogeneity. Analysis of the properdin locus at Xp11.3-Xp11.23 has led to the characterization of two polymorphic (dC-dA)n.(dG-dT)n repeats located approximately 15 kb downstream from the structural gene. Three families (two Scottish Caucasoid, one Tunisian Sephardic) with seven deficient individuals were investigated immunochemically and using a nonradioisotopic polymerase chain reaction-based method for microsatellite detection. Probable and definite carriers frequently showed properdin levels which were in the normal range. No recombinants between the microsatellite loci and properdin deficiency were detected, thus allowing identification of the defective allele through the generations in all three pedigrees. Haplotyping for these highly polymorphic microsatellites in close physical linkage to the properdin gene can provide rapid and nonradioactive detection of carrier status and prenatal diagnosis without extensive sequencing analysis.

Base Sequence↗
PubMed1989

Analysis of the natural polymeric forms of human properdin and their functions in complement activation.

Many of the anomalies observed in studies or properdin may be explained on the basis of its ability to form a series of multi-subunit polymers and by differences in the functions of these forms of properdin. Dimers (P2), trimers (P3), tetramers (P4), and higher Mr polymers (Pn) of the 46,000-Da subunit were separated by gel filtration or by cation exchange chromatography of purified properdin. The specific activity of each form was measured in two assays. The native properdin activity of P4 was 10 times that of P2 (on a molar basis) with the order: P4 greater than P3 greater than P2 greater than Pn. During C activation P4 was found to be consumed first, P3 second, and P2 last, consistent with their measured specific activities. Assays for activated properdin showed that only Pn caused fluid phase C consumption when incubated in serum at normal concentrations. Pn accumulated during long term storage of purified P and freezing rapidly converted the smaller oligomers to Pn. The isolated oligomers were extremely stable, but did redistribute after denaturation-renaturation cycles by using low pH or guanidine. Renaturation after exposure of any species to denaturing conditions yielded mixtures of 20:54:26 (P4:P3:P2). This distribution was almost identical to that found in fresh normal human serum or plasma, suggesting that a distinct distribution of oligomers exists in blood that provides the C system with an apparently advantageous range of specific activities.

Chromatography, Gel↗
PubMed1977

[Anticomplement activity of a polyanion: pentosan sulfuric polyester. III. Mechanism of functional inactivation of the different properdin and complement system fractions].

In vitro, the drug pentosan-poly-sulfoester (PPS) changes the electrophoretic migration of different proteins from the complement and properdin systems, such as native C3 (beta 1C globulin), C3c (beta-1A globulin), C3d (alpha-2D globulin), C1s inactivator (ClsINA), Clq and properdin factor B (B). Their more anodal migration is the consequence of a molecular alteration and persists after prolonged dialysis. These structural changes, yet undefined, explain the loss of functional activity of these proteins, and the anticomplementary activity of this drug. Moreover, PPS is able to block the alternate pathway activation by its action on properdin factor B (C3 proactivator). In fact, in presence of PPS, the activators of the properdin systems such as C3 nephritic factor are inactive. These altered mobilities are also responsible for the overestimation in the antigenic concentration of B (+ 45%), C4 (+27%) and C3/C3c (+ 14%), found in human serum containing 50 mg/ml of PPS. PPS has an original action upon the complement and properdin systems, which allows its clinical use as a potent inhibitor of the humoral mediators of inflammation.

Binding Sites↗
PubMed1984

Molecular architecture of human properdin, a positive regulator of the alternative pathway of complement.

The structure of the human properdin molecule was investigated by hydrodynamic, spectroscopic, and transmission electron microscope studies. Sucrose density gradient ultracentrifugation of purified, functionally active properdin showed a single component sedimenting at 5.5 S. Electron microscopic examination by two different methods, however, revealed polydispersity of the protein which consisted of cyclic dimers, trimers, tetramers, pentamers, and higher cyclic oligomers. Approximately 80% of the oligomers were dimers, trimers, and tetramers. Monomers could not be detected. These polymers could be partially separated by gel filtration on Sephacryl S-300 and all fractions were active in terms of binding to C3b. The specific activity increased with oligomer size. When reexamined after incubation at 37 degrees C for 4 h or at 4 degrees C for 2 weeks, the chromatographic behavior of the oligomers and their electron microscopic appearance were unchanged, suggesting that in vitro no rapid equilibration occurred. The protomer is clearly visualized within polymers as a flexible, rod-like structure 26.0 nm in length and 2.5 nm in diameter, with pronounced thickening at each end. The monomer is bivalent with respect to binding to other properdin monomers and the binding sites are localized to the ends of the structure. A model could be devised which is consistent with the distinct geometry of the intersubunit contacts observed in micrographs. The circular dichroism spectrum of properdin suggests the presence of little alpha helix or beta structure and shows positive ellipticity at 231 nm. In contrast to previous investigators, we conclude that isolated human properdin is polydisperse and consists of a set of cyclic polymers constructed from a single highly asymmetric and flexible protomer.

Binding Sites↗
PubMed1989

Localization of the properdin structural locus to Xp11.23-Xp21.1.

Properdin is a serum protein belonging to the alternative pathway of complement activation whose absence is often associated with fatal bacterial infections. Properdin deficiency segregates with an X-linked recessive pattern and its position has been recently refined by genetic linkage analysis to the proximal part of the X-chromosome short arm near the OTC and DXS7 loci. We have hybridized an 0.8-kb genomic clone encoding part of the human properdin gene to a panel of somatic cell hybrids retaining different portions of the human X chromosome and thereby localized the probe to Xcen-Xp21.1. Furthermore, in situ hybridization of the same probe to replication banded metaphase chromosomes refined this localization to the region Xp11.23-Xp21.1 (with a peak grain distribution in the region equivalent to Xp11.4). As OTC and DXS7 map to Xp21.1 and Xp11.3, respectively, the data presented here strongly suggest that the X-linked deficiency syndrome is due to a defect in the locus encoding the structural properdin gene or in a physically close regulatory locus.

Autoradiography↗
PubMed2005

Streptococcal pyrogenic exotoxin B cleaves properdin and inhibits complement-mediated opsonophagocytosis.

Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcal (GAS) infection. The reduction of phagocytic activity by SPE B may help prevent bacteria from being ingested. In this study, we investigated the mechanism SPE B uses to enable bacteria to resist opsonophagocytosis. Using Western blotting and an affinity column immobilized with SPE B, we found that both SPE B and C192S, an SPE B mutant lacking protease activity, bound to serum properdin, and that SPE B, but not C192S, degraded serum properdin. Further study showed that SPE B-treated, but not C192S-treated, serum blocked the alternative complement pathway. Reconstitution of properdin into SPE B-treated serum unblocked the alternative pathway. GAS opsonized with SPE B-treated serum was more resistant to neutrophil killing than GAS opsonized with C192S-treated or normal serum. These results suggest that a novel SPE B mechanism, one which degrades serum properdin, enables GAS to resist opsonophagocytosis.

Animals↗
PubMed1975

Activation of the properdin pathway of complement in patients with gram-negative bacteremia.

To determine the pathway used for activation of complement component C3, serum levels of components C1, C4, C2, C3, C5, C6, and C9 and two properdin factors, properdin and factor B, were measured in 42 patients with gram-negative bacteremia, in 19 of whom shock subsequently developed. Mean levels of the classical components C1, C4, and C2 in bacteremic patients in whom shock subsequently developed did not differ significantly (p greater than 0.05) from those of patients with uncomplicated bacteremia. Levels of properdin, factor B and C3, C5, C6, and C9 were significantly (p less than 0.05) decreased in patients with shock in comparison with those with uncomplicated bacteremia. Taken together, these findings are consistent with activation of C3 and the terminal complement sequence, C5-C9, occurring primarily by the properdin pathway, in patients with gram-negative bacteremia eventuating in shock. Biologically active products released during activation of C3-C9 may contribute to the development of shock.

Bacteria↗
PubMed1956

Quantitative studies on the properdin-complement system.

Quantitative methods have been developed for the estimation of C'3 and properdin. With these methods, the kinetics of the over-all reaction between properdin, zymosan, and C'3 were investigated. The reaction followed first order kinetics, provided zymosan was in excess, and the serum not diluted beyond 1/4. The reaction rate was proportional to the temperature, and an activation energy of 20,500 calories/mole was found. The distinction between total properdin and available serum properdin is discussed.

Complement System Proteins↗
PubMed1991

Granulocyte functions and Neisseria meningitidis: influence of properdin-deficient serum.

Granulocyte-mediated reactions such as opsonization, chemotaxis, and release of granulocyte myeloperoxidase and lactoferrin were studied in properdin-deficient and normal human serum incubated with serogroup A and W-135 meningococci. There were no differences between the sera when serogroup A meningococci were studied. Opsonic and chemotactic activity were impaired against serogroup W-135 meningococci in properdin-deficient serum. Restitution with properdin restored both activities. We found similar release of myeloperoxidase and lactoferrin from granulocytes challenged with serogroup A or W-135 meningococci in either sera. These findings are in accordance with the clinical observations of meningococcal infections caused by serogroup W-135 in properdin-deficient patients as well as the absence of infections caused by serogroup A meningococci.

Chemotaxis, Leukocyte↗
PubMed1976

C3b inactivator in the rheumatic diseases. Measurement by radial immunodiffusion and by inhibition of formation of properdin pathway C3 convertase.

C3b inactivator (C3bINA) has been measured in biologic fluids by radial immunodiffusion using a monospecific antiserum prepared in rabbits, and by a hemolytic assay which measures the reduction in the capacity of EAC43 cells bearing limited C3b sites to form C3B, the alternative pathway C3 convertase. The radial immunodiffusion and hemolytic assays show a good correlation (r = 0.86 P less than 0.001). Measurement of C3bINA concentrations in the sera of patients with systemic lupus erythematosus showed that during exacerbations of disease activity C3bINA concentrations tended to be lower, usually in association with reductions in C4, C3, factor B, and properdin, and sometimes with reductions of the alternative pathway proteins, factor B, and properdin alone. Supranormal values for C3bINA were found in the sera of 14 of 20 patients with seropositive rheumatoid arthritis and 3 of 9 seronegative patients, but none of 7 patients with degenerative joint disease. Synovial fluid concentrations of C3bINA, after correction for total synovial fluid protein and serum concentration of the enzyme, were significantly reduced in patients with rheumatoid arthritis compared to patients with degenerative joint disease (P less than 0.05). In both serum and synovial fluid from patients with rheumatoid arthritis, there was a good correlation between the concentrations of C3bINA and those of C3, factor B, and properdin, but not that of C4, suggesting that levels of C3bINA may serve to modulate recruitment of the properdin amplification loop in this disease.

Animals↗
PubMed1989

Another Swedish family with complete properdin deficiency: association with fulminant meningococcal disease in one male family member.

Inherited deficiency of the complement component properdin is described in a Swedish family without any previous history of meningococcal infections. The properdin-deficient index patient died from a fulminant infection caused by Neisseria meningitidis serogroup Y. Family investigation revealed properdin deficiency in the patient's half-brother and in the maternal grandfather. The half-brother had a history of pneumococcal pneumonia and meningitis probably caused by Borrelia burgdorferi. Opsonic and bactericidal functions of serum were examined in the half-brother after immunization with tetravalent meningococcal vaccine. Vaccination promoted opsonization of N. meningitidis serogroups C and Y but not of serogroups A and W-135. The serum bactericidal activity increased against serogroup C and to some extent against serogroup W-135. This report emphasizes the importance of investigating the complement system even in families with single cases of fulminant meningococcal disease. Individuals with properdin deficiency might be protected from infection by immunization.

Adolescent↗