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PubMed1983

[Effective method of simultaneous isolation from human serum of highly purified factors B and D of the alternative pathway of complement activation].

A simple method for isolation from human serum of the complement alternative pathway factor B, in a yield over 40% and purity over 80% with respect to protein, has been developed. Such a high yield was reached due to rejection of ammonium sulphate fractionation and employment of only two chromatographic stages: on CM-Sephadex C-50 and on DEAE-Sepharose CL-6B. An additional chromatography on QAE-Sephadex A-50 provides factor B of 100% purity but with a loss of some amount of protein (yield approximately 20%). One of the fractions, obtained at the first stage of factor B purification, contained also factor D. After rechromatography on CM-Sephadex C-50 and gel filtration on Sephadex G-75 it afforded factor D in yield more than 60% and purity above 100%.

Chromatography, DEAE-Cellulose↗
PubMed1980

Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes.

Short-term cultures of human peripheral blood monocytes were shown to synthesize the alternative pathway complement components C3, factors B (B) and D (D), and properdin, the regulatory proteins C3b inactivator (C3bINA) and beta 1H, in addition to C2, C4, and C5. B, D, properdin, C3bINA, and C2 were detected by functional assays, whereas beta 1H, C4, C3, and C5 could only be detected using immunochemical procedures. Immunoperoxidase localization studies showed that all the cells in each culture contained each component, so it is possible that all monocytes synthesize each component. It is concluded that cells of the monocyte-macrophage series form a mobile source of complement components and regulatory proteins which can be concentrated at sites of inflammation.

Cells, Cultured↗
PubMed1991

Human complement component factor B rescues HIV-1-infected leukemic T cells from cytopathic death.

The addition of 5-10% of fresh normal human serum (NHS) from normal individuals into a culture of primarily HIV-1-infected CD4+ leukemic T-cell lines CEM and MT4 was found to rescue the infected cells from cytopathic death, enabling the cells to achieve growth within 10 days. The HIV-1-infected cells cultured in ordinary medium with fetal calf serum (FCS) all died within 10 days. The effect of NHS was ascribed to human complement component factor B and one or more factor B-dependent heat-labile co-factors. The cells which survived in the presence of NHS rapidly lost surface expression of CD4 and became completely resistant to rechallenge by HIV-1. Viral genomes were dramatically reduced in surviving cells within 30 days, and one cell-line CEM completely expelled them during this period. The results suggest that factor B has protective and potential therapeutic significance in HIV-1 infection.

CD4 Antigens↗
PubMed1985

Carbohydrate composition of the second, third and fifth components and factors B and D of human complement.

The carbohydrate composition of the second, third and fifth components of human complement (C2, C3 and C5) and of factors B and D was determined employing gas-chromatographic and mass-spectrometric methods. C2 was found to contain 15.9% carbohydrate composed of fucose, galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (approximate molar ratio 1:4:9:9:4). N-acetylglucosamine and mannose (approximate molar ratio 1:4), amounting to 1.7% of the mass of the molecule, were the only monosaccharides detected in C3. C5 contained 3.8% carbohydrate composed of galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (approximate molar ratio 2:4:4-5:2). The carbohydrate moiety of B consisted of fucose, galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (molar ratio 1:2:3:4:2). The total carbohydrate content of B was estimated at 8.6%. In addition to these monosaccharides, glucose (0.4-0.9%) was also detected in all preparations analysed. Glucose was the only sugar detected in D.

Carbohydrates↗
PubMed1989

Interleukin 6 stimulates synthesis of complement proteins factor B and C3 in human skin fibroblasts.

Human interleukin (IL) 6 is a multifunctional cytokine which is synthesized by fibroblasts in response to many stimuli, including bacterial lipopolysaccharide (LPS). During acute-phase response, liver cells secrete a specific group of proteins among which components of the complement system and IL 6 appear to be an important mediator of this response. Human skin fibroblasts also synthesize at least seven proteins of the complement system. Each of these seems to be characteristically regulated by soluble mediators of the inflammatory process. Here we report that in fibroblasts, IL 6 induces increases in the rate of synthesis of factor B and C3, activator proteins of the alternative pathway of complement activation. The increases in factor B and C3 were concentration dependent reaching about 40- and 15-fold, respectively. The protein increases were observed within 4 h after IL 6 addition to the cells and were accompanied by increase in factor B and C3 mRNA. The data suggest that the induction of factor B and C3 by LPS may be mediated, at least in part, by IL 6 induced by LPS. This new function of IL 6 could provide a local protection against invading agents through activation of the antibody-independent alternative pathway of complement activation.

Blotting, Northern↗
PubMed1980

Partial sequence of human complement component factor B: novel type of serine protease.

Factor B (a component of the alternative pathway of complement) is believed to contain the proteolytic site of the complex enzymes C3 convertase (C3bB) and C5 convertase (C3bnB). Conflicting results have been obtained in regard to the inactivation of these enzymes by diisopropyl phosphorofluoridate but it has been suggested that activated Factor B (Factor B) is a serine protease with the active site in Bb, a COOH-terminal fragment of approximately 60,000 molecular weight. Partial amino acid sequence studies of Bb derived from human Factor B have shown that the NH2-terminal 40 residues have no homology with NH2-terminal sequences of other serine proteases. However, positioning of a further 170 residues out of approximately 290 residues in two continuous CNBr fragments from the COOH terminus has shown that there is a strong homology of sequence in this section. The active site residues histidine, aspartic acid, and serine all are present in positions corresponding with those of typical serine proteases. It is suggested that Factor B is a novel type of serine protease with a catalytic chain of molecular weight twice that of proteases previously studied and probably with a different activation mechanism.

Amino Acid Sequence↗
PubMed1990

Antiinflammatory effects of polypeptide growth factors. Platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor inhibit the cytokine-induced expression of the alternative complement pathway activator factor B in human fibroblasts.

The synthesis of complement components in human fibroblasts is modulated by mediators of inflammation such as cytokines. In particular, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce time- and dose-dependent increases in the synthesis of complement proteins factor B (FB), C3, and factor H (FH). Polypeptide growth factors are also soluble mediators released during inflammation and able to modulate many fibroblast functions. We have studied the effects of polypeptide growth factors platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) on the synthesis of complement proteins in cultured human fibroblasts. PDGF, EGF, and FGF alone did not affect the level of synthesis of any of the complement proteins analyzed, but simultaneous incubation of PDGF, EGF, or FGF with IL-1 and TNF resulted in a dose-dependent inhibition of the cytokine-enhanced expression of FB. Inhibition of FB synthesis was observed between 4 and 8 h of exposure to PDGF and persisted for 4 h after the removal of the growth factor. Analysis of steady-state levels of specific FB mRNA suggested that PDGF-induced inhibition of FB synthesis is mediated at a pretranslational level and that it requires new protein synthesis. The effect of the growth factors was limited to FB, with marginal or no inhibition on the cytokine-enhanced synthesis of C3 and FH, excluding the possibility that the inhibitory effects of PDGF, EGF, and FGF on FB synthesis were due to a negative modulation of the growth factors on cytokine cell membrane receptors. Specific inhibition of cytokine-induced increases in FB synthesis by the growth factors may represent down regulation of the acute inflammatory process, further permitting progression to processes of tissue repair and remodeling. Study of the interactions between cytokines and growth factors in the regulation of synthesis of complement proteins may also provide a system for investigating mechanisms of signal transduction of both polypeptide growth factors and cytokines.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Vaccinia virus complement-control protein prevents antibody-dependent complement-enhanced neutralization of infectivity and contributes to virulence.

The role of a viral gene product in evasion of the host immune response was investigated. The antibody-dependent complement-enhanced neutralization of vaccinia virus infectivity was prevented by the culture medium from vaccinia virus-infected cells. The vaccinia virus complement-control protein (VCP) was identified as the secreted product of vaccinia virus gene C21L and has homology to a group of eukaryotic genes encoding regulators of complement activation. Thus, the culture medium from cells infected with a C21L deletion mutant was VCP deficient and had little or no effect on antibody-dependent complement-enhanced neutralization. In addition, the anticomplement effect was associated with the C21L-encoded protein partially purified from the medium of cells infected with wild-type virus. Antibody-dependent, complement-enhanced neutralization of vaccinia virus occurred with a complement source that was deficient in the classical pathway complement component C4 and required the alternative pathway complement factor B. Furthermore, the presence of VCP abrogated the complement-enhanced neutralization in C4-deficient serum. Together with previous hemolysis data, the present result suggests that VCP can inhibit both the classical and alternative pathways of complement activation. Skin lesions caused by the C21L deletion mutant were smaller than those caused by wild-type virus, demonstrating an important role for VCP in virulence. The C21L deletion mutant also was attenuated in C4-deficient guinea pigs, consistent with in vitro studies. Vaccinia virus appears to have acquired the ability to regulate the complement cascade for the purpose of evading the host immune response.

Animals↗
PubMed1986

Regulation of the synthesis of the third component of complement and factor B in cord blood monocytes by lipopolysaccharide.

We compared the regulation of C3 and factor B synthesis in cord blood and adult monocytes by using techniques for identification and quantification of newly synthesized proteins, lipopolysaccharide (LPS) from several Gram-negative organisms, and precursors of LPS. Synthesis of C3 and factor B in cord blood monocytes was unaffected by lipid A (the active moiety of LPS extracted by the Westphal procedure). In contrast, adult monocytes increased C3 synthesis by 11.5-fold and factor B synthesis by 3.1-fold in response to LPS. This difference in cord blood monocyte response to LPS was specific in that other LPS-induced monocyte functions (superoxide production and phagocytosis) were stimulated comparably in both cord blood and adult monocytes by LPS. To characterize further this regulatory difference, the roles of LPS precursors, arachidonic acid metabolites, and of factor(s) released by adult monocytes were examined. Precursors of the lipid portion of LPS (lipid X and lipid Y), LPS isolated by trichloroacetic acid extraction, and endotoxin-associated protein (EAP) increased C3 and factor B synthesis in cord blood monocytes. Inhibitors of the lipoxygenase pathway (dexamethasone, ETYA) but not of the cyclooxygenase pathway (indomethacin) abrogated the response of adult monocytes to lipid A and EAP and of cord blood monocytes to EAP. Finally, co-incubation of adult monocytes and cord blood monocytes in LPS-containing medium resulted in enhancement of C3 and factor B synthesis in cord blood monocytes. These data suggest that the difference in LPS response between cord blood and adult monocytes may result from differences in lipid processing or protein recognition of LPS, differences in the production of lipoxygenase pathway products, and/or one or more regulatory factors. The availability of human mononuclear phagocytes which exhibit distinct differences in biosynthetic responsiveness to LPS should permit investigation of the molecular mechanism(s) by which LPS affects C3 and factor B gene expression.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1991

Changes in plasma complement C4 and factor B allotypes after liver transplantation.

Plasma complement allotypes for C4 and factor B were determined in 21 patients before and after liver transplantation together with donor typing. In 17 transplantations allelic differences between the patient and the donor could be shown. In all cases the patient's C4 and factor-B types converted to that of the donor, showing that the liver is the major source of plasma complement C4 and factor B.

Adult↗
PubMed1985

Leukocyte complement: interleukin-like properties of factor Bb.

It has been previously shown that the activated form of Factor B (Factor Bb) of the alternative pathway of complement activation stimulates monocyte spreading and killing of xenogenic erythrocytes and staphylococci. Factor Bb also stimulates lymphocyte blastogenesis in vitro, and native (uncleaved) Factor B is a major constitutive product of murine macrophages. To evaluate the possible "monokine" or "lymphokine"-like properties of Factor Bb, a radioimmunoassay was developed to measure the quantities of Factor B in phytohemagglutinin (PHA)-mitogen-stimulated cultures of human peripheral blood mononuclear cells. Nonstimulated mononuclear cell cultures from human peripheral blood (containing 10-14% monocytes and greater than 85% lymphocytes) at a density of 3 X 10(6) cells/ml (in serum-free medium) released less than 7 X 10(-10) M/liter (60 ng/ml) of Factor B antigen in 24 hr at 37 degrees C, and when mononuclear cells were stimulated with PHA mitogen in serum-free medium, the levels of Factor B antigen in media at 24 hr were significantly higher 1-3 X 10(-8) M/liter (0.9-2.8 micrograms/ml). The molecular size of Factor B in these media was 50-65 kDa by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a size appropriate for Factor Bb (60 kDa). Since pathological effects of macrophages in autoimmune disease may result from the release of lysosomal hydrolases, the effects of purified Factor Bb on mononuclear phagocytes were investigated in an in vitro system of murine peritoneal exudate macrophages. Factor Bb induced secretion of marker lysosomal hydrolases N-acetyl-beta-D-glucosaminidase (hexosaminidase) and beta-glucuronidase from thioglycollate-elicited murine peritoneal exudate macrophages in a dose-response and kinetic manner. Hydrolase release was induced in serum-free medium without a known particulate activator at a concentration of 80-200 nM (5-13 micrograms/ml) Factor Bb. Maximal release occurred in 3-5 hr at 37 degrees C and extracellular enzyme activity of hexosaminidase and glucuronidase increased as intracellular enzyme levels decreased, suggesting that Factor Bb triggers release of these enzymes from intracellular lysosomal pools. These results provide an example of a complement protein which is synthesized, released, and activated during mononuclear cell culture and which induces release of lysosomal enzymes from macrophages. In conventional terminology, Factor B or Factor Bb might be termed a "lymphokine," "monokine," or "interleukin".

Complement C3↗
PubMedDate not supplied

[Complement and immunoglobulin levels in pregnant women with EPH gestosis].

The authors determined C3 and C4 complements, factor B properdin and immunoglobulins G, M and A in 20 healthy pregnant patients and in 20 patients with EPH gestosis. The analysis was performed in mothers sera, umbilical sera and amniotic fluid, and properdin factor B and IgG in urine. They used the nonfellometric technique with immunochemistry analyzer. The C3 complement was very increased in the serum of mothers with EPH gestosis, and complement C4 was slightly increased in the serum of EPH gestosis, and complement C4 was slightly in the serum of EPH gestosis, and complement C4 was slightly increased in the serum of mothers and umbilical sera. Factor B properdin was very increased in mothers sera and decreased in urine. Higher concentrations of immunoglobulin G were found in umbilical sera than in mothers sera. Increased concentrations of sera in mothers, the umbilicus and urine were observed in patients with EPH gestosis. In these patients IgM was decreased in the serum of mothers and the umbilicus. IgM was decreased in the serum of mothers and significantly increased in umbilical sera. Significant changes in patients with EPH gestosis were noted.

Complement Factor B↗
PubMed1981

Quantitative differences between complement factor-B phenotypes.

In a study of 365 unrelated blood donors the structural polymorphism was determined by high-voltage electrophoresis followed by immunofixation with monospecific anti-Bf serum as described by Alper, Boenish & Watson (1972), and serum levels were measured by rocket-immunoelectrophoresis as described by Sjöholm (1975). We found that the mean level of Factor B in relation to structural phenotypes varies significantly in the order BfF greater than BfFS greater than BfS, though great variation was observed within types. A similar difference was also found with a functional assay of Factor B in agarose plates, although this method is less accurate. Concerning the biological functions, such as opsonization and bacteriolysis, it might be that individuals with the BfF allele are more able to withstand infectious agents than BfS subjects. The Bf polymorphism may therefore be transient, the BfF allele being in a process of replacing BfS by natural selection.

Alleles↗
PubMed1995

Activation of the endothelium by IL-1 alpha and glucocorticoids results in major increase of complement C3 and factor B production and generation of C3a.

Constitutive secretion of complement C3 and factor B by the endothelial cell (EC) is lowered by therapeutic concentrations of glucocorticoids such as hydrocortisone or dexamethasone, whereas regulatory protein factor H production is increased by these hormones. In contrast, the proinflammatory cytokine IL-1 alpha has a stimulatory effect on C3 and factor B secretion by the endothelium and an inhibitory effect on factor H secretion. In this study, we examined the combined effect of IL-1 alpha and glucocorticoids on C3 and factor B expression by the endothelial cell. When dexamethasone or hydrocortisone were added to IL-1 alpha, significant potentialization of IL-1 alpha-induced stimulation of C3 and factor B production was observed, occurring at various concentrations of either stimuli. Dose-response experiments indicate that, in vitro, optimal concentrations are in the range of 10(-7) to 10(-5) M for dexamethasone and 50-200 U for IL-1 alpha. In contrast, dexamethasone counteracts, in an additive way, the inhibitory effect of IL-1 alpha on regulatory complement protein factor H production by EC. Such a potentialization between glucocorticoids and IL-1 alpha was not observed for another marker of endothelial activation, IL-1 alpha-induced stimulation of coagulation tissue factor expression. The association of glucocorticoids and IL-1 alpha therefore appears to be a specific and major stimulus for the secretion of complement C3 and factor B, two acute-phase proteins, by the endothelium. As a result of the in vitro endothelium stimulation by glucocorticoids and IL-1 alpha, C3a is generated in the vicinity of the endothelial cell. This study further suggests that complement activation, with its deleterious consequences, may result from the stimulation of endothelium in situations where high levels of IL-1 alpha and endogenous glucocorticoids coexist, such as in septic shock.

Cells, Cultured↗
PubMed1983

Molecular cloning and characterization of the gene coding for human complement protein factor B.

Four cosmid clones, each with an average insert size of 40 kilobase pairs and containing the factor B gene, were isolated from a human genomic DNA library. The clones were identified by hybridization with a 515-base-pair cDNA probe isolated by using a unique 17-base synthetic oligonucleotide probe from a human liver cDNA library. The cosmid clones were characterized by restriction endonuclease digestion and Southern blotting, and a partial restriction map of the DNA represented in the cosmids was constructed. The Bb portion of the factor B gene is about 4 kb in length. DNA sequence analysis has resulted in the determination of 3.3 kb of sequence at the 3' end of the gene. This region codes for amino acids 87-505 of Bb and includes the whole of the serine proteinase domain of the protein. The three active site residues of histidine, aspartic acid, and serine found at positions 267, 317, and 440 of the Bb sequence, respectively, lie on separate exons. Other functional regions within the serine proteinase domain are separated also by intervening sequences.

Amino Acid Sequence↗
PubMed1989

Two forms of guinea pig factor B of the alternative complement pathway with different molecular weights.

Two forms of guinea pig factor B (B) of the alternative complement pathway with different mol. wts (Mr) have been isolated from plasma and characterized. The Mr of the two B species, tentatively termed B1 and B2, were estimated to be about 100,000 and 96,000, respectively, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Incubation of B with guinea pig C3 and human factor D (D) in the presence of Mg2+ generated two cleavage fragments of B, namely Ba and Bb. Although the Bb fragments showed the same migration corresponding to an Mr of 62,000, Ba fragments showed different mobilities corresponding to an Mr of 38,000 from B1 and 34,000 from B2. Digestion of B1-Ba, the Ba fragment derived from B1, and B2-Ba, the Ba fragment derived from B2, with endoglycosidase F resulted in a band at Mr 30,000 on an SDS-PAGE in both cases, indicating a difference in structure of the asparagine-linked oligosaccharide moiety in B1-Ba and B2-Ba. No difference in antigenicity was noted between B1 and B2 on immunodiffusion with anti-B sera. Immunoblotting analysis showed that all individual Hartley guinea pigs examined in this study possessed both B1 and B2 at similar levels, as determined by the intensity of staining of their sera. Furthermore, treatment of their serum with zymosan led to the generation of two Ba species corresponding to the Ba fragments from B1 and B2. The capacity to form C3/C5 convertase, as determined by hemolytic assay, was found to be similar between B1 and B2. Furthermore, kinetics of the decay of C3 convertase showed the same half-life of 3.0 min at 30 degrees C. The NH2-terminal amino acid sequences of B1 and B2 and their Bb fragments were determined and found to be identical.

Amino Acid Sequence↗