Developmental aspects of complement components in the newborn. The presence of complement components and C3 proactivator (properdin factor B) in human colostrum.
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Age Factors↗
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[Studies of the properdin-system components in patients with bronchial asthma treated with bacterial vaccines].
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Adolescent↗
[Properdin system and cancer].
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Blood Proteins↗
The interaction of C3b bound to pneumococci with factor H (beta 1H globulin), factor I (C3b/C4b inactivator), and properdin factor B of the human complement system.
Pneumococcal cell walls are potent activators of the alternative complement (C) pathway; pneumococcal capsules are not. C3b that is deposited onto the cell walls of encapsulated organisms, however, functions inefficiently in host defense compared to C3b deposited onto capsular polysaccharides. Results of previous studies with guinea pig erythrocytes suggested that C3b deposited onto surfaces that do not activate the alternative pathway is rapidly inactivated. In the present study, we examined the interactions of C3b bound to pneumococcal capsules, to pneumococcal cell walls, and to the surface of sheep erythrocytes (E) with the serum control proteins, Factor H (beta 1H globulin) (H) and Factor I (C3b/4b inactivator) (I), and with Factor B (B) of the alternative C pathway. Conversion of bound C3b to C3bi was assayed by binding of radiolabeled conglutinin in a quantitative binding assay. Neither pneumococcal cell wall C3b nor capsular C3b was converted efficiently to a conglutinin-binding form by serum incubation. Experiments with purified C components showed that, after incubation with H and I, fewer conglutinin-binding sites were created on pneumococci than on E bearing equal numbers of C3b. Molecular analysis demonstrated that this did not result from cleavage of pneumococcal-bound C3b to an unusual, nonconglutinin-binding form of the molecule. Binding studies in which radiolabeled H was used demonstrated that the majority of C3b that is bound to both pneumococcal capsules and cell walls bound H with a lower affinity than did E-bound C3b. Studies of the binding of radiolabeled B demonstrated that C3b that was bound to pneumococcal cell walls and to E demonstrated equal affinity for B. In contrast, the majority of C3b that was fixed to pneumococcal capsules bound B with only 1/30 as high affinity. We conclude that pneumococcal capsules are not alternative pathway activators because the low affinity of capsular C3b for B leads to inefficient formation of an alternative pathway convertase, C3bBb. With regard to H binding, both cell wall- and capsular-bound C3b act as if they were in a "protected site" and resist degradation by the control proteins.
Binding Sites↗
Five new rare variants of the properdin factor B (BF) locus.
Investigations of local Minnesota whites and blacks demonstrated five new variants at the BF locus. All specimens were tested according to the recommended procedure of Mauff for proper nomenclature assignment and family data obtained when possible. This report brings the number of documented BF variants to 18.
Complement Factor B↗
[Properdin factor B: polymorphism, synthesis site and first case of genetic deficiency].
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Complement Factor B↗
[High association between properdin factors BfF1 and HLA-B 18 in a Portuguese family (author's transl)].
The HLA and the Bf systems were studied as part of a family investigation carried out in Portugal. In four generations the rare phenotype BfF1 could be determined four times and the BfF1S phenotype six times, HLA-B18 being simultaneously positive in all cases. Since the frequencies of the individual factors F1 and B18 do not differ essentially from those obtained in Central Europe and no inbreeding situation was present, the high-grade linkage disequilibrium between F1 and B18 may also be presumed for the Portuguese population. Neither among the F1/B18 homozygous nor among the heterozygous subjects could one discern any morbid state (e.g., insulin-dependent diabetes mellitus) from which an association with the F1/B18 haplotype could be deduced. Finally, the rarity of Bf factors, such as F1 and S0.7, is discussed from the standpoint of selection vs. mutation.
Complement Factor B↗
Fragments Ba and Bb derived from guinea pig factor B of the properdin system: purification, characterization, and biologic activities.
Functionally active guinea pig factor B was purified by a combination of chromatographic steps including Sephadex G-25, QAE A25, QAE A50, CM C50, and Sepharose 4B coupled with purified cobra venom factor. Purified factor B had a m.w. of 106,000 daltons and a single subunit structure. It was heat labile. After cleavage of native B with cobra venom factor coupled to Sepharose 4B in the presence of D, the resulting two fragments, the larger one (Bb) and the smaller one (Ba), were further purified. The m.w. of Bb and Ba was determined as 64,000 and 53,000 daltons, respectively, by SDS-PAGE. Neither of the fragments evoked a contraction of guinea pig ileum or histamine release from rat mast cells. Only the smaller fragment Ba (at a concentration of 120 nM) stimulated guinea pig peritoneal polymorphonuclear leukocytes to respond with increased movement. This activity as well as the antigenicity of Ba were heat stable, but were sensitive to trypsin digestion, whereas the antigenicity of Bb was heat labile.
Anaphylatoxins↗
Polymorphism of properdin factor B (Bf) in some Italian populations.
In order to contribute to the definition of a map of the distribution of Bf polymorphism in Italy, we typed numerous population samples (for a total of 2033 individuals) from several regions of Italy: provinces of Bologna, Potenza and Matera, middle Sangro valley (Chieti) and northern, central and southern Sardinia. A new method was used which consisted of cellulose acetate electrophoresis followed by immunofixation and staining with Coomassie blue. The results obtained highlight marked differences in the distribution of Bf phenotypes and allele frequencies in Italy. To be noted in particular are the relatively high incidence of the Bf*S allele and the low incidence of Bf*F in Potenza and the significantly different pattern of the Sardinian samples compared to those from mainland Italy. This may be due to the low incidence in Sardinia of the Bf*S allele and above all to the exceptionally high frequency of the Bf*F1 variant.
Alleles↗
The role of Fcgamma receptor polymorphisms and C3 in the immune defence against Neisseria meningitidis in complement-deficient individuals.
Individuals with either a late (C5-9) complement component deficiency (LCCD) or properdin deficiency are at increased risk to develop meningococcal disease, often due to serogroups W135 and Y. Anti-meningococcal defence in both LCCD persons and properdin-deficient individuals without bactericidal antibodies depends mainly on phagocytosis. Three types of opsonin receptors are involved in phagocytosis by polymorphonuclear cells (PMN). These represent the polymorphic FcgammaRIIa (CD32) and FcgammaRIIIb (CD16b) receptors, and the C3 receptor CR3 (CD11b/CD18). When the distribution of FcgammaRIIa and FcgammaRIIIb allotypes was assessed in 15 LCCD and in 15 properdin-deficient patients with/without previous meningococcal disease, we found the combination of FcgammaRIIa-R/R131 with FcgammaRIIIb-NA2/NA2 allotypes to be associated with previous meningococcal disease (odds ratio 13.9, Fisher's test P = 0.036). No such relation was observed in the properdin-deficient patients. The importance of FcgammaRIIa allotypes was also demonstrated using in vitro phagocytosis assays. PMN from FcgammaRIIa-R/R131 homozygous donors internalized IgG2 opsonized meningococci W135 significantly (P < 0.05) less than PMN from FcgammaRIIa-H/H131 donors. When properdin-deficient serum was tested, it was observed that reconstitution with properdin resulted in enhanced PMN phagocytosis of the W135 meningococci (P = 0.001). This enhanced phagocytosis was parallelled by an increase in C3 deposition onto the opsonized meningococci W135 (r = 0.6568, P = 0. 01). We conclude that the occurrence of meningococcal disease in LCCD patients is associated with certain FcgammaR allotypes. Properdin-deficient individuals are susceptible to meningococcal disease because of an insufficient C3 deposition on the surface of meningococci, resulting in insufficient phagocytosis.
Adolescent↗
Complement fixation by solid phase immune complexes. Reduced capacity in SLE sera.
We describe an ELISA for assessment of complement function based on the capacity of serum to support fixation of complement components to solid phase immune complexes (IC). Microplates were coated with aggregated bovine serum albumin (BSA) followed by rabbit anti-BSA IgG. The solid phase IC were reacted with human serum. The uptake of C3b, C4b and properdin was measured using biotinylated F(ab)2 antibodies to each of the proteins, avidin alkaline phosphatase, and paranitrophenyl phosphate. Serial samples obtained from 15 patients with systemic lupus erythematosus were investigated. Out of 72 sera, 24 showed a reduced capacity to support incorporation of C4b into solid phase IC. Thirty-one of the sera showed low C3b binding and 59 of the sera a reduced uptake of properdin. The incorporation into solid phase IC of C3b and C4b as well as of C3b and properdin were closely correlated at high disease activity. In general, patients with severe disease manifestations showed low values in the uptake assays. Judging from the results obtained by analysis of serial samples, the uptake of C3b, C4b and properdin, complement mediated solubilization of fluid phase IC and the concentrations of C1q binding IC were useful indicators of disease activity in the patients. The concentrations of circulating C4, C3 and properdin varied less consistently according to disease activity. The concentrations of serum properdin were never found to be low, which was in contrast to the finding of reduced properdin uptake by solid phase IC in most of the samples.
Adult↗
Increased resistance to infection and accompanying alteration in properidin levels following administration of bacterial lipopolysaccharides.
It has been shown that injection of lipopolysaccharides, derived from a variety of Gram-negative bacterial species, evokes in mice a rapidly developing rise in resistance to infection with Gram-negative pathogens. This is accompanied by an elevation in properdin titer, at times to levels 2 to 3 times the normal. The rate, magnitude, and duration of these responses are dependent on many factors, the most important of which are the quantity and timing of the lipopolysaccharide administered. The increased resistance to infection evoked in mice by lipopolysaccharides was effective against infections produced by endotoxin-bearing organisms-bacterial species highly susceptible in vitro to the bactericidal action of the properdin system. Properdin titers of mice prior to infection provide an incomplete picture of the subsequent reaction of the host to the infective agent. Following infection with Gram-negative organisms, properdin levels accurately reflect the bacteriologic course and outcome of the infection. Thus, in control animals, properdin titers progressively declined and the animals died, while in mice appropriately treated with lipopolysaccharide, properdin levels were either maintained in the normal range or increased, depending on the dose and time of administration of lipopolysaccharide; this was always accompanied by successful management of the infection. The complex nature of the alterations produced in the host by lipopolysaccharides is stressed. It is pointed out that the increase in the ability of the host to cope with Gram-negative infections may be the result of stimulation of other defense mechanisms, in addition to the properdin system.
Animals↗
Isolation and characterization of Guinea pig properidin.
Guinea pig properdin was purified to homogeneity by employing as an assay during isolation its capacity to augment the hemolytic activity of a heterologous human C3b-dependent C3 convertase, C3B. The purified protein elicited a monospecific antibody response in a rabbit. The antiserum, by immunodiffusion, gave a reaction of identity between a protein in whole guinea pig serum and the immunogen. A solid phase immunoadsorbent prepared with the antiserum removed properdin function from the purified protein. The purified guinea pig protein exhibited the classical properdin function of reconstituting a human RP for zymosan-induced C3 inactivation. The guinea pig properdin also agglutinated red cell intermediates bearing either guinea pig or human C3b and retarded the decay of homologous C3 convertase, C3B. These activities are the same as those observed for purified human properdin and validate the amplification function of properdin on terminal component activation in a second species.
Animals↗
Lysis of measles virus-infected cells by the purified cytolytic alternative complement pathway and antibody.
The dependence of antibody-and-complement-mediated lysis of virus-infected cells on the alternative pathway was examined utilizing the isolated cytolytic alternative pathway--a system consisting of the six purified proteins of the alternative pathway of activation (C3, factors B and D, beta 1H, C3b inactivator and properdin), and the five proteins of the membrane attack pathway (C5--9) of complement. HeLa cells acutely infected with measles virus were lysed by anti-viral IgG and the isolated cytolytic alternative pathway with an efficiency comparable to whole human serum. IgG and its F(ab')2 fragment were equally effective in inducing lysis by the isolated cytolytic alternative pathway, binding of approximately equal to 5 X 10(7) molecules per cell being required for 50% lysis; in contrast, no lysis occurred when equivalen or greater amounts of Fab' were bound to the virus-infected cell. Properdin was required for lysis. No lysis occurred if properdin was deleted from the isolated cytolytic alternative pathway, and lysis was diminished by 80% in properdin-depleted serum. Uptake of [125I]C3b from the isolated alternative pathway onto measles virus-infected cells occurred in the absence of properdin, but was accelerated in the presence of properdin. The 11 proteins of the isolated cytolytic alternative pathway are thus sufficient for lysis of measles virus-infected cells bearing anti-viral IgG or F(ab')2 without any other serum protein.
Antibodies, Viral↗
The interaction of glycoprotein C of herpes simplex virus types 1 and 2 with the alternative complement pathway.
Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) binds the human complement fragment C3b, but the two proteins differ in their ability to bind C3b on infected cell surfaces. In addition, gC-1, but not gC-2, accelerates the decay of the alternative pathway C3 convertase, thereby affecting later steps of the complement cascade. Previously, we constructed linker insertion and deletion mutants of gC-1 and gC-2 and used transient transfection to express mutant proteins in uninfected cells. In spite of the differences between gC-1 and gC-2, C3b binding was localized to residues within the central portion of both proteins, encompassing the first four cysteines. For gC-1, deletion mutants lacking amino acids 33 to 123 or 367 to 469 or lacking both regions still bound C3b. We recombined these deleted forms of gC-1 into gC-39, an HSV-1 strain lacking the gC gene. The altered forms of gC-1 were incorporated into virions, expressed on the surface of infected cells, and bound C3b. We used these proteins to investigate the structural basis for the inhibitory action of gC-1 on the complement cascade. We found that gC-1 does not inhibit formation of the alternative pathway C3 convertase. This convertase is stabilized by the serum protein properdin. Purified gC-1, but not gC-2, inhibits the binding of properdin to C3b, suggesting that this destabilizes the convertase. The mutant lacking amino acids 367 to 449 was able to inhibit properdin binding to a limited extent when present at high concentrations, although it bound to C3b more weakly than wild-type gC. In contrast, the protein lacking amino acids 33 to 123 was unable to inhibit properdin binding to C3b. Thus, gC-1 contains two structural domains, one for C3b binding, residues 124 to 366, and another, residues 33 to 133, which interferes with properdin binding to C3b.
Animals↗
Classical complement pathway activation in membranoproliferative glomerulonephritis.
Levels of components of the classical and alternative complement pathways and the activity of the C3 nephritic factor (C3NeF) were measured in serum specimens from patients with type I (subendothelial deposits) and type II (intramembranous dense deposits) membranoproliferative glomerulonephritis (MPGN) and the results compared with the levels in normal subjects. Although C3 and C5 concentrations were comparably depressed in type I and type II, the levels of Clq and C4 were lower in type I and the correlation coefficients between Clq vs. C4 and C4 vs. C3 were higher than in type II. The profile was highly suggestive of classical pathway activation. In contrast, in type II MPGN, factor B levels were lower and C3NeF activity was more frequently detectable and higher. A feature of interest was that type I, as compared to type II, was characterized by significantly lower serum concentrations of properdin, higher and more significant correlation coefficients between serum properdin concentrations and those of Clq, C4 and C3, and consistent glomerular deposition of properdin. The involvement of properdin in type I may reflect recruitment of a pathway resembling the C1 bypass mechanism, said to involve C1, properdin, factor B and C3-9.
Adult↗
Low prevalence of complement deficiencies among patients with meningococcal disease in Norway.
Sera from 98 individuals who had survived meningococcal disease were analysed for classical and alternative pathway haemolytic activity and the complement components C3, C4 and properdin. No complete deficiency was found. However, median properdin concentration was only 86% in the disease group compared with the controls (P < 0.001). Properdin was also significantly lower in serogroup C disease (median 76%) compared with serogroup B disease (median 90%, P = 0.005). Severe properdin deficiency is an established risk factor for meningococcal disease. The present data may indicate that even moderately reduced properdin level can increase the risk of developing meningococcal disease.
Adolescent↗
Mechanism of complement inactivation by glycoprotein C of herpes simplex virus.
Glycoprotein C (gC) of both herpes simplex virus type 1 (HSV-1) and HSV-2 interacts with complement C3b and protects the virus from complement-mediated neutralization. To study the mechanism by which gC modulates complement activation, we expressed both gC-1 and gC-2 in a baculovirus expression system. Baculovirus recombinants containing gC genes spanning the entire gC-1 sequence (gC-1-TMR) or only the extracellular domain(s) of gC-1, gC-2, or a deletion mutant of gC-1 lacking residues 33 through 123 were expressed in sf9 insect cells. Binding of the expressed proteins to human C3 and C3 fragments was assessed by direct and competition ELISA. All four expressed proteins bound to C3, C3b, and C3c but not to C3d, suggesting 1) that the binding sites for these proteins are located in the C3c region of C3; and 2) that gC, in contrast to other C3-binding proteins, interacts with native C3. We have also examined the interaction of native C3 with gC-1 expressed on the HSV-1-infected cells. Analogous to recombinant proteins, gC-1 expressed on the infected cells also bound to native C3. The ability of baculovirus-expressed gCs to inhibit the interaction of C3b with its ligands was also analyzed. We found that gC-1, but not gC-2, inhibited the binding of C5 and properdin to C3b and also inhibited the alternative pathway-mediated lysis of rabbit erythrocytes. Inhibition of alternative pathway-mediated lysis and properdin binding to C3b, but not of C5 binding to C3b, required the transmembrane segment of the gC-1. The specificity of gC interactions was examined by studying the interaction of gC with C3 from various species. In contrast to properdin, both gCs bound to cobra C3; this finding suggests that gC-1 and properdin bind to different sites on C3b. Further analyses suggested that gC-1 sterically hindered access of C5 and properdin to C3b.
Binding, Competitive↗