Complement-mediated factors in cellular lysis.
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Cells↗
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Phylogeny of regulatory proteins of the complement system. Isolation and characterization of a C4b/C3b inhibitor and a cofactor from sand bass plasma.
We have previously demonstrated that the alpha'-chain of human activated form of the fourth (C4b) and third (C3b) component of C are cleaved by plasma or serum from vertebrate species spanning through 300,000,000 yr of evolution yielding fragments identical with those obtained with human plasma. In this study, we investigated the molecular basis of this reaction. We chose barred sand bass plasma because this is the most primitive species analyzed possessing these activities. Barred sand bass plasma proteins were separated on a Sephadex G-200 column and the eluted samples analyzed for C4b and C3b cleavage. Individual fractions were inactive, but degradation was obtained when proteins of 380 and 155 kDa were combined. In contrast to the human regulatory proteins, the sand bass proteins require Ca2+ ions. K76COOH, an inhibitor of human factor I, inhibited the function of the 155-kDa but not of the 380 kDa-fraction. Thus it appears that the 155-kDa fraction functions as the C4b/C3b cleaving enzyme (I) and the 380-kDa material as its cofactor. Further purification of the 380-kDa fraction yielded a protein that by SDS-PAGE consisted of two noncovalently linked subunits of 110 and 42 kDa at a molecular ratio of 2:1. These two chains were antigenically distinct, and constitute domains of the same protein. The 110-kDa peptide binds C4b and not C3b but it fully expresses the cofactor function for the 155-kDa fraction on the cleavage of both C4b and C3b. Limited tryptic digestion of the 110-kDa domain demonstrated C4b binding activity in fragments of 34, 25, and 23 kDa. The activity of the 34-kDa fragment was the same as that of the undigested protein. Comparison of the amino acid composition of the barred sand bass cofactor and of human C4bp shows similar high content of cysteine and proline but not of tryptophan. It differs from human factor H in cysteine, serine, proline, and tryptophan. These studies indicate that regulatory proteins for the C4b and C3b C fragments may have appeared very early phylogenetically.
Amino Acids↗
An abnormal plasma distribution of protein S occurs in functional protein S deficiency.
Protein S is a natural anticoagulant present in the plasma that serves as a cofactor for activated protein C. Patients deficient in protein S are subject to recurrent venous thrombotic disease. Protein S deficiency differs from other plasma protein deficiencies in that deficient patients often have normal or only mildly reduced levels of protein S in their plasma as detected by conventional immunologic methods but have markedly reduced functional protein S levels. This apparent discrepancy is due to the presence of two forms of protein S in plasma. The protein S is present free and in a complex with C4b-binding protein. The free form is functionally active, whereas the bound form is not. Examination by crossed immunoelectrophoresis of 31 functionally protein S-deficient individuals from seven families reveals that 29 of the 31 have all or most of their protein S complexed to C4b-binding protein with little or no free protein and have correspondingly low levels of protein S functional activity (type I deficiency). Two related protein S-deficient individuals show a different type of distribution with little or no protein S, either bound or free (type II deficiency). The detection and classification of protein S-deficient individuals requires the application of both a functional assay and an assessment of protein S distribution between bound and free forms.
Carrier Proteins↗
Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates.
Protein S, a vitamin K-dependent cofactor for activated protein C, exists in normal adult plasma in a free anticoagulantly active form and in an inactive form complexed to C4b-binding protein. Immunologic and functional levels of protein S and C4b-binding protein in plasma were determined for 20 newborn infants and compared with adult normal pooled plasma. Total protein S antigen levels averaged 23%, similar to other vitamin K-dependent plasma proteins. However, the protein S anticoagulant activity was 74% of that of adult normal plasma. This apparent discrepancy of activity to antigen was shown to be due to low or undetectable levels of C4b-binding protein, which results in the presence of most if not all of protein S in its free and active form. The relatively high level of anticoagulantly active protein S in infants may enhance the potential of the protein C pathway, thereby minimizing risks of venous thrombosis in this group.
Antigens↗
Protein S deficiency in sickle cell anemia.
To investigate the status of the protein C-protein S anticoagulant pathway in sickle cell disease, we measured protein C, total and free protein S, and C4b-binding protein levels in 20 subjects with sickle cell disease (Hb SS or SC). Mean total and free protein S levels were both significantly lower in subjects with sickle cell disease than in normal individuals, but greater reductions were observed for free S. The free protein S level was below the mean -2 SD for normal subjects in 12 subjects with sickle cell disease; the total protein S level was below this level in three subjects. Mean C4b-binding protein levels were normal in subjects with sickle cell disease, both during painful crisis and in the steady state, and no correlation was observed between the levels of C4b-binding protein and free protein S, suggesting that the low free protein S level was not caused by increased levels of C4b-binding protein. Crossed immunoelectrophoresis of plasma samples from eight subjects with sickle cell disease showed marked reductions in free protein S, with normal levels of protein S bound to C4b-binding protein. In contrast to the protein S level, mean protein C activity was normal in subjects with sickle cell disease, both during painful crisis and in the steady state. However, the protein C level was below the mean -2 SD for normal subjects on at least one occasion in four subjects with sickle cell disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Anemia, Sickle Cell↗
Production of nephritic factor of the alternative complement pathway by Epstein Barr virus-transformed B cell lines derived from a patient with membranoproliferative glomerulonephritis.
Nephritic factor of the alternative complement pathway (C3NeF) is an IgG autoantibody which binds to and stabilizes the C3 convertase (C3bBb) enzyme, and which has been detected mainly in sera from patients with membranoproliferative glomerulonephritis (MPGN) and partial lipodystrophy. To study the production of C3NeF, mononuclear cells isolated from the peripheral blood of patients with MPGN and C3NeF activity in their sera were infected with Epstein Barr virus (EBV) to establish active B lymphocyte cell lines. By using a modified C3NeF screening assay, we detected C3NeF activity in the supernatant of a B cell line derived from a patient with MPGN Type II, but in none of the supernatants of B cell lines derived from normal individuals. C3NeF-positive supernatants were investigated for their ability to conserve classical or alternative pathway C3 convertase activity by using EAC3bBb and EAC4b2a stabilization assays. C3NeF-positive supernatants stabilized the C3bBb convertase activity, but not the C4b2a convertase activity. Studies of the supernatants, using anti-human IgG affinity columns, showed that the C3NeF activity was in the IgG fraction; furthermore, C3NeF antibody agglutinated sheep erythrocytes coated with C3bBb, but not with C3b alone. On gel electrophoresis, both heavy and light chains of the C3NeF were comparable in size to that of normal human IgG molecules. We conclude that C3NeF, produced in vitro by EBV-transformed B cell lines derived from a patient with MPGN Type II, is functionally identical to the conventional C3NeF in serum. In vitro preparation of homogeneous NeF(s) should greatly facilitate the studies of the role of these autoantibodies in complement dysmetabolism.
B-Lymphocytes↗
[The influence of carrageenan, colchicine, 2,4-dinitrophenol, ethanol, galactose, indomethacin and liquoid on hemolytic complement activity (CH50E)].
The influence of Liquoid (0.00005, 0.00001%), Carrageenan (0.001% up to 0.000001%), Colchicine (0.01% up to 0.0025%), Indomethacin (1 X 10(-4) up to 2.5 X 10(-5) mol/1), Ethanol (10% up to 1.25%), Galactose (1 X 10(-1) up to 1 X 10(-2) mol/l) and 2.4-Dinitrophenol (5 X 10(-4) up to 1 X 10(-5) mol/l) on the total hemolytic activity of complement was tested. By Liquoid, Carrageenan, Colchicine and Ethanol in all studied concentrations an remarkable inhibition of the CH50E could be estimated. Indomethacin up to an concentration of 3.75 X 10(-5) mol/l reduced the activity partially. In contrast, Galactose and 2.4-Dinitrophenol have not influenced the complement titers.
2,4-Dinitrophenol↗
Natural killer cells are deficient in the surface expression of the complement regulatory protein, decay accelerating factor (DAF).
Decay-accelerating factor (DAF) is a 75,000 m.w. membrane protein that inhibits autologous complement C3 activation at the cell surface. One-color direct immunofluorescence with anti-DAF antibody and cytofluorographic analysis indicates that normal human monocytes and granulocytes are uniform in expression of DAF, whereas 23% of peripheral blood lymphocytes are DAF deficient. A two-color indirect immunofluorescence method, used to define the phenotype(s) of the DAF-deficient lymphocytes, was less efficient in DAF detection and led to overestimation of the fraction of deficient cells. Nonetheless, the difference between DAF expression by natural killer cells, identified by the CD16 and HNK-1 antigens, was marked. DAF deficiency was intermediate in cells expressing the CD2, CD3, CD4, or CD8 markers. On the basis of the phenotypic definition of natural killer cells and their contribution to the lymphocyte population, it is concluded that a uniform deficiency of DAF on natural killer cells accounts for about one-half of the DAF-deficient lymphocytes in peripheral blood of normal donors. The finding of a complete DAF deficiency in the lymphocytes from a patient with a lymphoproliferative disorder with the predominant proliferation of CD2+, CD3+, CD8+, HNK-1+ large granular lymphocytes gives additional support for the association of DAF-deficiency with natural killer cells.
Antigens, Differentiation, T-Lymphocyte↗
Determination of plasma protein S--the protein cofactor of activated protein C.
Protein S, an important cofactor of activated protein C, and C4b-binding protein were purified from human plasma. Specific antibodies against the purified proteins were raised in rabbits and used for the development of immunologic assays for these proteins in plasma: an immunoradiometric assay for protein S (which measures both free protein S and protein S complexed with C4b-binding protein) and an electroimmunoassay for C4b-binding protein. Ranges for the concentrations of these proteins were established in healthy volunteers and patients using oral anticoagulant therapy. A slight decrease in protein S antigen was observed in patients with liver disease (0.78 +/- 0.25 U/ml); no significant decrease in protein S was observed in patients with DIC (0.95 +/- 0.25 U/ml). Criteria were developed for the laboratory diagnosis of an isolated protein S deficiency.
Anticoagulants↗
The reactivity of the complement system.
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Animals↗
Immunobiology and clinical importance of the complement system of man.
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Antibodies↗
Complement effects on the infectivity of Plasmodium gallinaceum to Aedes aegypti mosquitoes. I. Resistance of zygotes to the alternative pathway of complement.
Gametocytes are the intraerythrocytic stages of malaria parasites that infect mosquitoes. When gametocytes of the chicken malaria parasite Plasmodium gallinaceum are ingested by a mosquito they become extracellular in the mosquito midgut, form gametes, and fertilize within 10 to 15 min after the insect has taken a blood meal. Gametocytes of P. gallinaceum were infectious when fed to Aedes aegypti mosquitoes in blood meals containing native serum from chickens or from the non-host species, man or sheep. Gametocytes stimulated to undergo gametogenesis and to fertilize in vitro were also infectious when fed to mosquitoes in native chicken serum. However, native serum from most non-host species, including sheep and man, suppressed the infectivity of newly fertilized zygotes to mosquitoes and lysed the zygotes in vitro. These effects were shown to be due to the activity of the alternative pathway of complement (APC) in the serum of the non-host species. After mild trypsin treatment, the zygotes of P. gallinaceum no longer infected mosquitoes in the presence of native chicken serum, although in heat-inactivated chicken serum their infectivity was normal. We conclude that trypsin-sensitive components on the zygotes surface protect them from destruction by the APC of their native host. The ability of gametocytes of P. gallinaceum to infect mosquitoes in the presence of native human serum is probably due to proteases that inactivate the APC of human serum before the gametes and zygotes emerge as extracellular parasites in the blood meal.
Aedes↗
[Method for determining the anticomplement activity in immunoglobulin preparations].
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Complement Fixation Tests↗
Delayed removal of renal-bound antigen in decomplemented rabbits with acute serum sickness.
We have examined the effects of complement depletion, brought about by cobra venom factor (CVF), on the clearance of radiolabelled BSA from the kidney in acute serum sickness in rabbits. The decomplemented group showed a significant decrease in the rate of clearance of renal-bound antigen with a mean half-clearance time of 19.5 days (range 9.3--60) vs 11.3 (range 8.7--15) for the control group. C3 was rapidly cleared from the glomerulus (as assessed by immunofluorescence) when further deposition was prevented by treatment with CVF. Glomerular immune complexes apparently activated the alternative pathway in vitro. These findings suggest that in immune complex nephritis, the clearance of deposited complexes from the kidney is complement-dependent.
Animals↗
Reactions and side reactions to drugs.
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Complement Activation↗
Studies on phytohemagglutinin-induced peritonitis of mice: dynamics of inflammatory responses and influence of anticomplementary agents and anti-inflammatory drugs.
The intraperitoneal injection of phytohemagglutinin in the mouse resulted in the marked accumulation of leukocytes, especially macrophages, in the peritoneal cavity between 8 and 36 h after the injection. Parallel to the accumulation of macrophages, exudation of plasma proteins into the peritoneal cavity was observed. When the effect of anticomplementary agents (FUT-175 and K-76 COONa) and anti-inflammatory drugs (indomethacin and dexamethasone) on phytohemagglutinin-induced peritonitis was examined, FUT-175, K-76 COONa and indomethacin suppressed only the plasma protein exudation. On the other hand, dexamethasone suppressed both the accumulation of macrophages and the plasma protein exudation.
Animals↗
Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro.
Plasma samples from patients with nephritic factor (NeF) were examined for their C3 converting activity. C3, C3dg, C5 and the fluid phase terminal complement complex (TCC) were quantified. All patients had evidence of C3 activation with low plasma C3 and high C3dg. Some patients had normal C5 and normal TCC levels, and thus no evidence of terminal pathway activation in vivo; others, with slower C3 conversion in vitro, had low C5 levels with TCC either elevated or in the upper normal range, suggesting in vivo activation of the terminal pathway. These observations were confirmed by in vitro experiments using purified NeFs. It is concluded that considerable activation of C3 may occur in vivo without a simultaneous activation of the terminal pathway, and that NeF is heterogeneous with regard to its ability to activate complement.
Adult↗
C3 nephritic factor (C3NeF): dissociation of cell-bound and fluid phase stabilization of alternative pathway C3 convertase.
Fluid phase C3 conversion by C3 nephritic factor (C3NeF) is usually easily detectable and forms the basis of the C3NeF screening test. We have described a group of patients with membranoproliferative glomerulonephritis or partial lipodystrophy and hypocomplementaemia who have an unusual C3NeF which stabilizes cell-bound C3 convertase of the alternative pathway (C3bBb) but causes such weak fluid phase C3 conversion that a C3NeF screening test is negative. These patients have low concentrations of C5 in serum.
Adolescent↗