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PubMed2000

Activation of the alternative pathway of human complement by autologous cells expressing transmembrane recombinant properdin.

Properdin (P) is a serum glycoprotein that stabilizes the labile C3 convertase (C3bBb) of the alternative pathway of the complement system (AP). Thanks to its oligomeric nature, P specifically upregulates AP on surfaces without activating AP in the fluid-phase. We investigated whether human cells, displaying P at their membrane, could activate autologous AP. The cDNAs encoding human P and the transmembrane domain of human platelet derived growth factor receptor were fused together and expressed in human embryo kidney cells (HEK-293). Selected cells displayed P at their surface as shown by FACS. In contact with human serum at 37 degrees C, they triggered AP-mediated C3 deposition. SDS-PAGE analysis showed C3 covalently bound to various membrane proteins, but not to P itself. However, displayed P affinity could bind to serum or purified C3i at 4 degrees C. C3 binding was restricted to the cells displaying P, was inhibited by an anti-P mAb, and did not require serum P. Bound C3 allowed further C5, C7 and C9 deposition as well as cell lysis after blocking CD59 function. In contrast, wild-type cells, cells displaying factor D or truncated P (deleted from its 6th thrombospondin-like repeat) did not activate AP. We hypothesize that displayed P activates AP by stabilizing bystander C3b and/or by capturing serum C3iBb convertase. Finally, we suggest that P could be used for retargeting autologous complement to AP-resistant pathogens and tumor cells.

Amino Acid Sequence↗
PubMed1995

Recurrent meningococcal septicaemia and properdin deficiency.

A 32-year-old male presented with two episodes of meningococcal septicaemia, each of which was caused by a different serogroup of Neisseria meningitidis. Examination of the alternative pathway of complement revealed the rare X-linked disorder properdin deficiency (PD). Meningococcal Infection in complement deficiency states is discussed and the unusual features of this case are highlighted.

Adult↗
PubMed1976

[Polymorphism of factor B of the properdin system (C3PA, GBG, and Bf) and histocompatibility-complement linkage].

Several recent studies have shown that the genetic polymorphism of factor B of the Properdin system (GBG or Bf) is closely linked to the major histocompatibility complex (MHC). The genetic polymorphism of Bf, a component of the alternate pathway of complement activation, is revealed by "immunofixation" technique after prolonged high voltage agarose electrophoresis. In this report, we describe technique for the Bf grouping and give the results in two families showing the linkage between HL-A and Bf loci. The study of a family with a recombinant between the second HL-A locus (SD-2) and the major MLC locus (LD-1) provides evidence that the Bf locus is not located outside the MLC's because the Bf allele remains linked to the SD-2 allele. In this family, a crossover occurs between Bf and LD-1, and since crossovers between Bf and SD-2 have already been discovered, it is now possible to locate the Bf locus between SD-2 and LD-1. The Bf phenotypes were determined in the serum of 247 normal unrelated caucasian individuals from the area of Strasbourg. The calculated allele frequencies in this population are: BfS=0.757, BfF=0.219, BfS1=0.014, BfF1=0.010. These allele frequencies are intermediary between those found by ALPER and RITTNER. The linkage between MHC and the complement system is now even more evident after the discovery that genes involved in the synthesis of the second and fourth complement components also belong to the MHC on the chromosome 6. These linkages were demonstrated by the study of several families with hereditary C2 deficiency in the U.S.A., and one family with C4 deficiency discovered in Strasbourg. C2 deficiency was found to be associated with three kinds of HL-A haplotypes (HL-A 10, W18; HL-A 2, W18 and HL-A2, 4A2) and the LD-7a specificity. In the family with C4 deficiency, the C4 deficient gene is associated with the HL-A haplotype 2, T3, W10 and a new hitherto unknown MLC type "Re". The linkage between C4 and MHC has been demonstrated recently also in the mouse (the Ss protein in the complement C4 fraction in the mouse) and in the guinea pig. The significance of the genetic linkage between some important components of the complement system and MHC is still unknown. It appears necessary to study all the genetic markers located within or in the vicinity of the MHC region on the chromosome 6 in investigations of the relationship between "pathologic states and HL-A antigens".

Alleles↗
PubMed1988

A highly conserved amino-acid sequence in thrombospondin, properdin and in proteins from sporozoites and blood stages of a human malaria parasite.

As a consequence of gene cloning and DNA sequencing several gene families are emerging in the field of cell-cell recognition. These include immunoglobulins, integrins, certain extracellular glycoproteins and a family of functionally unrelated proteins which include factor B. We report here the cloning and sequencing of a gene from Plasmodium falciparum, coding for a protein we call thrombospondin related anonymous protein (TRAP), which shares certain sequence motifs common to other well-characterized proteins. The most significant homology is based around the sequence Trp-Ser-Pro-Cys-Ser-Val-Thr-Cys-Gly (WSPCSVTCG), present in three copies in region I of thrombospondin (TSP), six copies in properdin (P) and one copy in all the circumsporozoite (CS) proteins sequenced so far. TRAP also shares with certain extracellular glycoproteins, including TSP, the cell-recognition signal Arg-Gly-Asp (RGD), which has been shown to be crucial in the interaction of several extracellular glycoproteins with members of the integrin superfamily. Unlike the CS protein, TRAP is expressed during the erythrocytic stage of the parasite life cycle.

Amino Acid Sequence↗
PubMed1988

Analysis of the interaction between properdin and factor B, components of the alternative-pathway C3 convertase of complement.

The interactions between Factor B (B), its activation products Ba and Bb, properdin (P) and C3i or C3b, components that together form the alternative-pathway C3 convertase enzyme of human complement, have been analysed. Fluid-phase complexes of the purified components C3i, B and P were probed with the homobifunctional cross-linking reagent disuccinimidyl tartarate, and efficient cross-linking of B to P was observed. The 140 kDa B-P conjugate formed was cleaved by Factor D to yield a single product of 85 kDa. This is consistent with a Ba-P heterodimer, and suggests that the initial interaction of B and P includes an interaction of P with the Ba domain of intact B. (The Ba fragment is not retained in the active P-stabilized complex, C3bBbP). By contrast, no cross-linking of P to the Bb domain of B could be demonstrated. Binding studies on cellular intermediates also provided evidence for a site of interaction between B and P, with high concentrations of B inhibiting P binding to EAC3b (sheep erythrocytes coated with antibody and C3b). Neither isolated Ba nor Bb had any effect on the P-EAC3b interaction. High concentrations of B also accelerated the decay of the functional EAC3bBbP complex. These data indicate that the positive co-operativity of binding to C3i or to C3b between B and P is mediated, at least in part, through a direct interaction between B and P.

Complement Activating Enzymes↗
PubMed1971

An alternate complement pathway: C-3 cleaving activity, not due to C4,2a, on endotoxic lipopolysaccharide after treatment with guinea pig serum; relation to properdin.

The reaction between endotoxic lipopolysaccharide (LPS) and the guinea pig complement system was shown to proceed by way of an intermediate complex, LPS-X, which contains at least six guinea pig serum proteins. LPS-X, like [unk] (sheep erythrocytes carrying antibody molecules and [unk] complexes), destroys the C3 molecule by cleavage. On incubation at 37 degrees C, LPS-X loses its capacity to destroy C3 at about the same rate as the decay of [unk], so that it has been assumed that LPS-X carries [unk] sites that are responsible for the destruction of C3. We have now shown that monospecific rabbit antiguinea pig C2, which effectively inhibits C3 cleavage by [unk], does not interfere with the destruction of C3 by LPS-X. Furthermore, not more than a trace of C2a(d) is released from LPS-X on incubation at 37 degrees C. These results indicate that LPS-X does not carry a significant quantity of [unk] and, hence, that its capacity to destroy C3 is due to another factor which is presumably a component of the properdin system.

Animals↗
PubMed1975

Properdin: initiation of alternative complement pathway.

Activation of the classical complement (C) system involves conversion of C1 to its active state with subsequent cleavage of C4 and -d C2 so as to form the classical C3 convertase, C42 (a bar indicates the activated form of a protein), which sequentially cleaves C3 and C5 to initiate the cytolytic event associated with the complete reaction. An alternative, pr properdin-dependent, pathway to complement activation generates a C3 convertase, C3B, that is formed by cleavage of B with D in the presence of a C3b, the major cleavage fragment of C3. C3b is capable of binding activated properidin (P) with resultant stabilization of C3B, which otherwise rapidly decays by loss of B activity. Initial cleavage of C3, a prerequisite for formation of C3B, is demonstrated to occur through the interaction of native C3 and B in the presence of either D or P alone, or together. The effect of P on the interaction of D, B, and C3 is attributed to stabilization of C3B as has been shown for C3B. Larger amounts of P and B with C3 in the absence of D form a C3 convertase that is designated (P)C3B to indicate that demonstrable cleavage of B does not occur although the active site is available. The generation of this initial convertase, as assessed by C3 inactivation, is dose-related to P and B inputs. The presence of both P and D greatly augments initial cleavage of C3 with D fully uncovering the active site of B and P stabilizing that site.

Complement C3↗
PubMed1992

Biological activities of peptides and peptide analogues derived from common sequences present in thrombospondin, properdin, and malarial proteins.

Thrombospondin (TSP), a major platelet-secreted protein, has recently been shown to have activity in tumor cell metastasis, cell adhesion, and platelet aggregation. The type 1 repeats of TSP contain two copies of CSVTCG and one copy of CSTSCG, per each of the three polypeptide chains of TSP and show homology with peptide sequences found in a number of other proteins including properdin, malarial circumsporozoite, and a blood-stage antigen of Plasmodium falciparum. To investigate whether these common sequences functioned as a cell adhesive domain in TSP, we assessed the effect of peptides corresponding to these sequences and an antibody raised against one of these sequences, CSTSCG, in three biological assays which depend, in part, on the cell adhesive activity of TSP. These assays were TSP-dependent cell adhesion, platelet aggregation, and tumor cell metastasis. We found that a number of peptides homologous to CSVTCG promoted the adhesion of a variety of cells including mouse B16-F10 melanoma cells, inhibited platelet aggregation and tumor cell metastasis, whereas control peptides had no effect. Anti-CSTSCG, which specifically recognized TSP, inhibited TSP-dependent cell adhesion, platelet aggregation, and tumor cell metastasis, whereas control IgG had no effect. These results suggest that CSVTCG and CSTSCG present in the type I repeats function in the adhesive interactions of TSP that mediate cell adhesion, platelet aggregation, and tumor cell metastasis. Peptides, based on the structure of these repeats, may find wide application in the treatment of thrombosis and in the prevention of cancer spread.

Amino Acid Sequence↗
PubMed1973

The relationship of glycine-rich -glycoprotein to factor B in the properdin system and to the cobra factor-binding protein of huan serum.

Factor B activity of the properdin system was found to be identical with purified glycine-rich beta-glycoprotein (GBG) but was distinct from the normal human serum protein capable of forming a C3-inactivating complex with a protein from cobra venom (CoF). Factor B activity coincided with electrophoretically separated GBG genetic variants, whereas the CoF-binding protein did not. GBGase destroyed factor B as it cleaved GBG but did not destroy the C3-inactivating activity of the CoF-binding protein. During incubation of serum with CoF, GBG did not change in molecular size, nor was there any coincidence in the immunoelectrophoretic mobilities of CoF and GBG. It was not possible to precipitate labeled CoF incubated with serum by anti-GBG, nor labeled GBG from serum incubated with CoF by anti-CoF. The CoF-binding capacity of serum was 2 mg/100 ml or less or under 6.5% of the serum concentration of GBG. When labeled CoF was added to serum below the binding capacity, complete complexation of the CoF was demonstrated, whereas CoF was largely uncomplexed when CoF was added in amounts equimolar to GBG.

Animals↗
PubMed1975

Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase.

A function of P in the alternative complement pathway is to prolong the first order decay of the hemolytic sites on EAC43B in a dose-dependent manner. As the number of initial convertase sites is not changed, even when activated properdin (P) increases the t1/2 10-fold or more, P acts to stabilize rather than to uncover additional sites. P binds to EAC43 to generate EAC43P in a reaction that proceeds slightly more rapidly at 15 degrees C than at 0 degrees C, but reaches the same plateau and does not require divalent cations. The presence of P on EAC43P not only stabilizes the convertase subsequently formed on that cell, but, alternatively, permits transfer to convertase sites on other cells with the stability of the recipient intermediate being dependent on the P available for transfer. The capacity of P to bind to C3b and stabilize C3B contrasts with the inhibitory effect of the C3b inactivator on formation of this amplification convertase.

Animals↗
PubMed1976

Binding of components of the properdin system to cultured human lymphoblastoid cells and B lymphocytes.

Immunofluorescence studies showed that properdin (P) and factor B bind to C3-C3b receptor bearing human lymphoblastoid cells (Raji, Daudi) and B type human peripheral lymphocytes (HPL). P bound to Raji cells first incubated with normal human serum (NHS). EDTA, but not EGTA, halted the binding of P to cells incubated with NHS. However, fixation of P to Raji cells, after incubation with NHS first reacted with inulin, was independent of Ca++ and -g++ ions. Fixation of P to Raji cells depended on the presence of C3 or C3b and occurred in the absence of factor D and factor B. Binding of P to B type HPL was detectable only after incubation of these cells with NHS first reacted with inulin; under these conditions binding of P to Raji cells was also greatly enhanced. With both Raji cells and HPL, factor B was detectable on cell surfaces only after incubation of these cells with NHS first reacted with activators of the P system. Binding of factor B to cells required the presence of C3b and binding or stabilization of cell bound factor B necessitated the presence of activated P. P and factor B were detectable only on cultured cells having C3-C3b receptors. However, incubation of NHS with all lymphoblastoid cell lines studied resulted in activation of P and cleavage of factor B. Binding of P and factor B to cells may follow one of three sequences; (a) activated P in fluid phase combines with C3, factor D, and factor B, and the whole complex fixes to cellular C3-C3b receptors via its C3 moiety; (b) C3b generated in fluid phase combines with P, C3, factor D, and factor B and binds to C3-C3b receptors; or (c) C3 or C3b first binds onto the C3-C3b receptors and thereafter interacts with P, factor D, And factor B. Binding of components of the P system to cells or other particles may relate to such biological phenomena as lysis, phagocytosis, proliferation, attraction of other cell types, and alteration of responsiveness to external stimuli.

ABO Blood-Group System↗
PubMed1976

Nonspecific complement activation by streptococcal structures. II. Properdin-independent initiation of the alternate pathway.

Complement consumption by isolated membranes and walls from Group A streptococci and various other gram-positive microbes has been tested. These microbial structures were found to activate the alternate complement pathway. However, unlike endotoxin, inulin, or other plant polysaccharides, activation of complement by our material was found to bypass properdin. The activating factor(s) also differs from cobra venom in its/their requirement for factor D. Preliminary experiments suggest this factor isolated from membranes to be a protein and to have a mol wt greater than 40-60,000 daltons. Our studies have led us to speculate that the phylogenetic role of the alternate complement pathway may be the primordial nonspecific defense system which has retained certain fundamental aspects up to the present time.

Antigens, Bacterial↗
PubMed1976

Activation of the alternative (properdin) pathway of complement by Candida albicans and related species.

Accumulations of neutrophilic granulocytes within the epidermis and beneath the stratum corneum of the skin are a prominent histologic feature of experimental and clinical candidiasis. The mechanism of cell accumulation was studied by standard chemotactic methods. Suspensions of viable or heat-killed Candida sp caused marked chemotaxis of human neutrophils in fresh serum. Culture supernatants of Candida sp were not chemotactic. Chemotaxis was dependent upon fresh serum, and could be abolished by heating the serum to 56 degress C for 30 min, suggesting that interaction of these organisms with a heat-labile serum factor generated a chemoattractant. Incubation of Candida sp with fresh human serum resulted in the conversion of the third component of complement and properdin factor B, as measured by immunoelectrophoresis. Conversion did not occur in serum chelated with EDTA, or heated to 50 degress C for 30 min (to destroy factor B). Conversion was present in serum chelated with EGTA (to deplete calcium), or genetically deficient in the fourth component of complement. By contrast, the three components of the kinin-forming system (Hageman factor, prekallikrein, high-molecular-weight kininogen) were not activated by Candida sp. We suggest that Candida sp do not release a chemotactic substance but, in the presence of serum, activate the alternative pathway of complement, generating chemotactic factors.

Candida↗
PubMed1978

C-reactive protein, C3, C4 and properdin during the Jarisch-Herxheimer reaction in early syphilis.

The occurrence of plasma CRP during the febrile response after the first injection of penicillin was followed in 10 patients with early syphilis. An increase in CRP was noted after 12 hours, with a maximum after 24 hours. The appearance of this acute phase protein could not be correlated to cutaneous reaction, increased body temperature or leukocytosis, nor were baseline values of CRP correlated to clinical or serological activity of the infection. Patients with high levels of CRP prior to treatment suffered the most intense systemic reactions. No activation of the complement system during the Jarisch-Herxheimer reaction was detected from sequential determinations of C3, C4 and properdin.

Adult↗
PubMed2005

Analysis of properdin (BF) genotypes associated with litter size in a commercial pig cross population.

Properdin (BF) was investigated as a candidate gene influencing litter size in a commercial pig cross population. The BF gene was chosen because of its integral role in influencing uterine epithelium growth and because several quantitative trait loci (QTL) with impact on reproductive traits have been detected near the centromere of porcine chromosome 7. A total of 123 F2 (Large White x Landrace) x Leicoma sows were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The sows were divided into two extreme performance groups, one with a high litter size (n = 61, > or = 14.3 piglets per litter) and the other with a low litter size (n = 62, < or = 11.3 piglets per litter). Although genotype and allele frequencies were uneven with 2.4% (AA), 16.3% (AB), 81.3% (BB) and 0.11 (A): 0.89 (B), the allele A was the unfavourable one, leading to less offspring. With regard to the level of significance at p < 0.05, the total number of born (TNB) and number of born alive (NBA) piglets were associated with BF genotypes. The genotype AA led to 10.55 TNB and 10.00 NBA, whereas the genotype BB led to 13.19 TNB and 12.11 NBA. The genotype AB was intermediate. In future, a systematic mating test is necessary in order to obtain more balanced genotype frequencies. Furthermore, it should be taken into consideration that the investigated polymorphism is located in an intronic region and the causative mutation is not clear yet.

Animals↗
PubMed1991

Normal human serum depleted of C1q, factor D and properdin: its use in studies of complement activation.

Normal human sera were depleted of C1q, factor D (D) and properdin (P) by a simple and reproducible procedure providing reagents for analysis of complement-dependent functions. Classical pathway activity was restored with purified C1q, and alternative pathway activity with purified D and P. Since both activation pathways were abolished, antibodies and other components could be removed without loss of complement activity during immunoabsorption procedures. Synergism between the two pathways during haemolysis of rabbit erythrocytes was clearly demonstrated, and was also found on analysis of C3 cleavage in serum incubated with other alternative pathway activators such as zymosan and inulin. Experiments with a Neisseria meningitidis serogroup W-135 strain isolated from a patient with inherited P deficiency showed that both pathways were capable of supporting antibody-dependent killing of the bacteria in serum. The alternative pathway was possibly more efficient than the classical pathway in the assay system. In C1q,D,P-depleted serum with high concentrations of anticapsular IgG antibodies, the addition of D alone resulted in efficient alternative pathway-mediated killing. The alternative pathway was equally efficient in a C1q,D,P-depleted serum with low concentrations of anticapsular antibody, but in this case the reaction required both D and P.

Animals↗
PubMed1983

Granulocyte phagocytosis of Streptococcus pneumoniae in properdin-deficient serum.

Properdin (P)-deficient human serum containing type-specific anticapsular antibodies and having an intact classical pathway of complement did not support efficient granulocyte phagocytosis of Streptococcus pneumoniae serotypes 6A, 14, 19F, 23F, or 35 in an opsonophagocytic assay. Compared with pooled control serum, the difference was most pronounced for serotypes 14 and 23F and at a final serum concentration of 16%. The reduced phagocytic killing of S. pneumoniae serotype 23F in P-deficient serum was due rather to defective opsonization than to impaired intracellular killing. The uptake of C3 by the serotype 23F strain was found to be low in P-deficient serum. The addition of native P promoted C3 fixation as well as opsonization. The activity of P was abolished by heat treatment (56 degrees C, 30 min). Experiments with Mg EGTA to block C1 activation suggested that serotype 23F pneumococci were more dependent on the classical pathway for opsonization than were serotype 35 pneumococci, which appear to be partly opsonized through the alternative pathway alone.

Adult↗