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PubMed1991

Genomic organization and subchromosomal in situ localization of the murine granzyme F, a serine protease expressed in CD8+ T cells.

Granzyme F belongs to a closely related family of seven murine serine proteases stored in cytoplasmic granules of lymphoid cell populations. In contrast to the murine granzymes A to E and G, granzyme F is exclusively expressed in the CD4-CD8+ subset of peripheral T cells. To characterize the genomic sequences responsible for its highly restricted expression, we isolated a cosmid clone and sequenced a 7.5-kb genomic fragment that contains the promoter region and all five exons of the murine granzyme F gene. A TATA box sequence is located at position -25 relative to the transcription initiation site, which was determined by RNase protection. The genomic organization of granzyme F is similar to that of granzyme B and granzyme C, leukocyte elastase, cathepsin G, rat mast cell protease II, and complement factor D (adipsin). By the use of two fluorochromes for simultaneous high resolution in situ hybridization, the granzyme F gene was localized in close proximity distally from the TCR alpha-chain locus on mouse chromosome 14.

Amino Acid Sequence↗
PubMed1978

Plasma levels of complement components and complement haemolytic activity in protein-energy malnutrition.

The plasma levels of complement haemolytic activity (CH50) of some complement components and of C3d, a C3 breakdown product, were measured in fifty-nine African children with various types of protein-energy malnutrition (PEM) including kwashiorkor, before and during recovery. A significant decrease of CH50, C3, C9 and factor B was observed in PEM without a concomitant decrease of C4 and C5. Increased plasma levels of C3d were also found in PEM patients. Two mechanisms seem to be involved in the impairment of the complement system in PEM: (1) a decreased synthesis of at least C3 and C9 as suggested by a significant correlation between C3 or C9, levels and those of albumin and cholinesterase; (2) an increased catabolism of C3 possibly due to an activation of the alternative complement pathway, as suggested by the increased level of C3d and the decreased level of factor B which are significantly correlated with C3 levels but not with albumin levels. These data support the possible role of a relative complement deficiency upon the decreased resistance to infections observed in malnourished children.

Child, Preschool↗
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↗
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↗
PubMed1982

The activation of the alternative pathway C3 convertase by human plasma kallikrein.

Human plasma kallikrein can replace factor D for the activation of the alternative pathway C3 convertase of human complement. The factor B cleavage patterns by factor D and kallikrein are indistinguishable. The ability of kallikrein to cleave factor B is influenced by the magnesium ion concentration and the C3b concentration. Factor D is about ten-fold more effective on a molar basis, for the alternative pathway C3 convertase activation than is kallikrein. The physiological role of the action of kallikrein on the alternative pathway C3 convertase is discussed.

Centrifugation, Density Gradient↗
PubMed1986

Human complement protein D catabolism by the rat kidney.

Factor D (D) is an essential component of the alternative complement pathway. To determine whether D is catabolized by the kidney and, if so, at what site, we studied the renal handling of human D by in vivo nephron microperfusion and in vitro perfusion of rat kidneys. Human D was purified and labeled with 125I. Individual nephrons were perfused in vivo at varying rates with perfusate that contained 125I-D and [14C]inulin. When nephrons were perfused from proximal sites with perfusate 125I-D in a concentration of 3.0 micrograms/ml, urinary recovery of 125I-D increased (P less than 0.05) from 57.7 +/- 5.0 to 74.4 +/- 2.5% as tubule fluid flow rate was increased from 10 to 40 nl/min; recovery of 125I-D was less than (P less than 0.001) [14C]inulin recovery at all perfusion rates. At 20 nl/min, an increase in perfusate 125I-D concentration from 1.5 to 3.0 micrograms/ml was associated with an increase (P less than 0.001) in urinary 125I-D recovery (42.1 +/- 4.0 vs. 65.8 +/- 2.6%). Similarly, the addition of unlabeled D, 30 micrograms/ml, to 125I-D, 3.0 micrograms/ml, increased urinary 125I-D recovery (95.3 +/- 2.1%) at 20 nl/min. When nephrons were perfused from early distal segments at 10 nl/min, 125I-D recovery (91.2 +/- 4.3%) did not differ from [14C]inulin recovery (95.8 +/- 1.3%). In the isolated perfused filtering kidney, the concentration of intact 125I-D in the perfusate declined 60.3 +/- 14.6% over 1 h. 83.4 +/- 6.3% of the decrement in 125I-D was catabolized by the kidney; the remainder was excreted in the urine as intact D. When glomerular filtration was prevented by increasing perfusate albumin concentration to 16 g/dl, perfusate intact (125I-D) remained unchanged over 1 h. These data show that human D is catabolized by the kidney via glomerular filtration and reabsorption by the proximal nephron. Reabsorption of D appears to be a saturable process.

Animals↗
PubMed1977

Interaction of zymosan and of activated properdin with factor D-depleted guinea pig serum: implications for the mechanism of initial C3 cleavage via the alternative complement pathway.

Factor D of the alternative C pathway was specifically removed from guinea pig serum. The resulting serum reagent (RD) supported neither the formation of a C3-cleaving enzyme on zymosan (Z) nor the inactivation of C3 or of factor B in the presence of Z or activated properdin (P). Addition of purified D to RD restored these properties. Studies were limited amounts of purified D were added to RD with Z or P as activating substances, gave the following results: (1) Inactivation of B and of C3 occurs in the presence of minute amounts of D. (2) C3 inactivation is more efficient than B inactivation and proceeds even in the absence of detectable enzymatic B activation. (3) C3 cleavage at any D concentration tested is always accompanied by uptake of C3 fragments onto Z. With respect to initial C3 cleavage via the alternative C pathway these data suggest that the initiating reaction is D-dependent, very efficient in depositing C3 fragments on particulate activating substances such as Z and able to utilize factor B in an apparently uncleaved form.

Animals↗
PubMed1988

A simple isolation procedure for functionally pure components of the bovine alternative complement pathway (ACP) C3 convertase and bovine conglutinin (K).

A simple multicomponent isolation procedure for bovine C3, factor B, factor D and conglutinin (K) from a single serum sample is described. The components of the alternative pathway C3 convertase were isolated in milligram quantities from 800 ml bovine serum and were found to be functionally pure with respect to each other and to factors H and I.

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

New synthetic inhibitor to the alternative complement pathway.

The inhibitory effects of 6-amidino-2-naphthyl 4-guanidinobenzoate (FUT-175) on the activities of factor B, factor D and cobra venom factor (CVF) X Bb were examined. FUT-175 bound specifically to the Bb fragment of factor B or CVF X Bb. FUT-175 was a non-competitive inhibitor of the esterolysis of L-leucyl-L-alanyl-L-arginine naphthylester by factor B and CVF X Bb. FUT-175 also inhibited the haemolytic activity of factor B, the C3 convertase activity of CVF X Bb and the factor B-cleaving activity of factor D. The concentration of FUT-175 causing 50% inhibition of these activities was 10(-5) - 10(-4)M.

Animals↗
PubMed1984

Amino acid sequence of human D of the alternative complement pathway.

The primary structure of human D, the serine protease activating the C3 convertase of the alternative complement pathway, has been deduced by sequencing peptides derived from various chemical (CNBr and o-iodosobenzoic acid) and enzymatic (trypsin, lysine protease, Staphylococcus aureus V8 protease, and chymotrypsin) cleavages. Carboxypeptidase A was also used to confirm the COOH-terminal sequence. The peptides were purified by high-pressure liquid chromatography. The proposed sequence of human D contains 222 amino acids and has a calculated molecular weight of 23 748. It exhibits a high degree of homology with other serine proteases, especially around the NH2-terminus as well as the three residues corresponding to the active-site His-57, Asp-102, and Ser-195 (chymotrypsinogen numbering). This sequence homology is highest (40%) with plasmin, intermediate (35%) with pancreatic serine proteases, such as elastase, trypsin, chymotrypsin, and kallikrein, and least (30%) with the serum enzymes thrombin and factor X. D, however, exhibits only minimal amino acid homology with the other sequenced complement serine proteases, Clr (25%) and Bb (20%). The substitution of a basic lysine for a neutral amino acid three residues NH2-terminal to the active-site serine as well as a small serine residue for a bulky aromatic amino acid at position 215 (chymotrypsinogen numbering) in the binding pocket may be important in determining the exquisite substrate specificity of D. The presence of His-40 which interacts with Asp-194 (chymotrypsinogen numbering) to stabilize other serine protease zymogens [Freer, S. T., Kraut, J., Robertus, J. D., Wright, H. T., & Xuong, N. H. (1970) Biochemistry 9, 1997] argues in favor of such a D precursor molecule.

Amino Acid Sequence↗
PubMed1988

Synthetic peptide inhibitors of complement serine proteases--I. Identification of functionally equivalent protease inhibitor sequences in serpins and inhibition of C1s and D.

Sequence homology comparisons between serum serine protease inhibitors led to the prediction that the C-terminal sequences are functionally equivalent and represent an essential protease binding domain. Inhibition of complement serine protease D cleavage of factor B and of C1s cleavage of C4 by synthetic peptides containing sequences from the C-termini of three serum serine protease inhibitors supports this prediction. These functionally equivalent peptides represent a new class of inhibitors of D and C1s as well as other serum serine proteases.

Amino Acid Sequence↗
PubMed1979

[Alternative complement pathway (author's transl)].

The dual role of the alternative complement pathway in recognition of foreign substances by a non-immune host and in the intrinsic regulation of the complement sequence is now well recognized. Activation of this pathway occurs through escape from its regulatory mechanisms induced by the activating principle; its functional expression depends on the respective levels of the component proteins C3, factor B, factor D and properdin, and on the control proteins beta 1H and C3bINA. This article presents recently acquired knowlege on the molecular mechanisms of activation, regulation and behaviour under pathological conditions of the alternative complement pathway.

Complement Activation↗
PubMed1982

Complement-mediated inhibition of immune precipitation. II. Analysis by sucrose density gradient ultracentrifugation.

The factors influencing the ultracentrifugation characteristics of immune complexes generated in the presence of fresh normal human serum have been analysed. In the absence of alternative pathway factors B, D or Properdin, the size of complexes was increased. When classical pathway function was blocked, in C1q deficient serum or in the presence of Mg EGTA, although the proportion of complexes remaining in solution were reduced their size was similar to those formed in normal human serum. In C2 deficient serum, a heterogeneous population of complexes was generated. In all instances repletion with the appropriate missing complement component reversed the abnormality. We conclude that there is normally a rapid sequential process of classical followed by alternative pathway activation leading to stable soluble complexes. In the absence of C1 activation the alternative pathway process requires precipitation of the antigen-antibody aggregates whereas in normal serum these events occur in the fluid phase. We suggest that in C2 deficient serum the C1 and/or C4 reacted complexes fail to activate the alternative pathway efficiently.

Animals↗