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PubMed1981

Systematic discovery and evaluation of complement inhibitors.

Methods are presented for an orderly search of a chemical file for complement inhibitors. Compounds are initially examined for intrinsic activity against dilute human components in vitro, using hemolytic assays to detect inhibitors of fluid phase C1, of late components lysis of EAC142, and of CVF-induced passive lysis of AET-treated human erythrocytes. Active compounds are then examined for activity against undiluted serum in vitro. Compounds passing this test are examined for activity in vivo against serum complement and complement-dependent lesions, viz. Forssman vasculitis, the reverse passive Arthus phenomenon, and Forssman shock. Methods are given for quantitation of these lesions.

Animals↗
PubMed1976

C1 inactivator.

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Amino Acids↗
PubMed1986

Lipopolysaccharides as complement inhibitors by complex formation with the purified third complement component (C3).

Lipopolysaccharides (LPS) from different bacteria in smooth or rough form (Y. enterocolitica, Y. pseudotuberculosis, E. coli, S. typhimurium, S. marcescens) strongly inhibited hemolytic C3 in incubation mixtures with purified C3. LPS from a core deficient mutant was still reactive, whereas lipid A no longer affected C3 activity. The physical state of LPS was critical for its effect on C3. Strand-like LPS structures formed by Ca++-induced aggregation of solubilized LPS, as shown by electron microscopy, demonstrated the highest reactivity with C3. Inhibition of hemolytic C3 was found to be due to complex formation between LPS and C3 by a hydrophobic reaction. The binding capacity of 1 microgram LPS-R and LPS-S was as high as 125 ng C3 and 56 ng C3, respectively. The C3b fragment required different reaction conditions for maximal binding. The strong binding capacity of LPS for the complement component C3 raises the possibility that LPS act as inhibitors of complement by interruption of the reaction cascade at local infectious sites with gram-negative bacteria.

Centrifugation, Density Gradient↗
PubMed1976

Irreversible enzyme inhibitors. Inhibitors of guinea pig complement derived by quaternization of substituted pyridines with benzyl halides.

A series of 83 compounds derived from hydrocarbon-substituted pyridines by quaternization with PhCH2Br usually containing a 2-SO2F or 6-Cl-2-SO2F group was synthesized and evaluated as inhibitors of guinea pig complement and in most cases its C1 component. The most active compounds were 3-(4-phenylphenylbutyl)-N-(6-choro-2-fluorosulfonylbenzyl) pyridinium bromide (43) and 3-(4-phenylphenylbutyl)-N-(2-fluorosulfonylbenzyl) pyridinium bromide (44), each showing 50% inhibition at 7.8 muM. The most effective irreversible inhibitor of the C1 component was N-(6-chloro-2-fluorosulfonylbenzyl)-5,6-benzoquinolinium bromide (87), which showed 50% inhibition at 4 muM.

Animals↗
PubMed1977

Inhibition of the reconstitution of the haemolytic activity of the first component of human complement by a pepsin-derived fragment of subcomponent C1q.

1. A fragment of subcomponent C1q, which contained all the collagen-like features present in the intact molecule, was isolated by pepsin digestion as described by Reid [Biochem. J. (1976) 155, 5-17]. 2. The pepsin-derived fragment of subcomponent C1q did not bind to antibody-coated erythrocytes under conditions where complete binding of sub-component C1q took place. 3. The peptic fragment blocked the reconstitution of C1 haemolytic activity by competing with intact subcomponent C1q in the utilization of a mixture of the other two subcomponents, C1r and C1s. 4. Reduction and alkylation of the interchain disulphide bonds in the pepsin fragment did not markedly affect its inhibitory effect, whereas heating at 56 degrees C for 30min completely abolished the effect. 5. Lathyritic rat skin collagen and CNBr-derived peptides of pig type II collagen showed no ability to mimic the inhibitory effect of the pepsin fragment when tested over the same concentration range as used for the peptic fragment. 6. The peptic fragment was unable to block efficiently the reconstitution of C1 haemolytic activity unless it was added to the mixture of subcomponents C1r and C1s before the attempt to reconstitute C1 haemolytic activity, in solution, or on the surface of antibody-coated erythrocytes. 7. Evidence was obtained that suggested that subcomponent C1q bound the subcomponent C1r-C1s complex more efficiently when the subcomponent C1q was bound to antibody than when it was free in solution.

Binding Sites, Antibody↗
PubMed1989

Inactivation of various proteinase inhibitors and the complement system in human plasma by the 56-kilodalton proteinase from Serratia marcescens.

The interaction of the 56-kilodalton (kDa) proteinase from Serratia marcescens with human plasma activated C1 (C1) inhibitor, alpha 2-antiplasmin, and antithrombin III was investigated. The 56-kDa proteinase was not affected by these inhibitors; on the contrary, all the inhibitors were inactivated by the 56-kDa proteinase within 2 to 6 h. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that all three inhibitors showed decreases in molecular weight of approximately 8,000 to 10,000 as a result of proteolytic cleavage by the 56-kDa proteinase. The 56-kDa proteinase also inactivated serum complement within 2 to 6 h. The loss of inhibitory activity caused by the 56-kDa proteinase, together with the effects of endogenous serine proteinases, may facilitate tissue destruction and inflammation.

Complement C1 Inactivator Proteins↗
PubMed1976

Occurrence of C1 inactivator and other proteinase inhibitors in euglobulin fractions and their influence on fibrinolytic activity.

Considerable amounts of C1 inactivator and inter-alpha-trypsin inhibitor pecipitate during euglobulin fractionation of human plasma. The amount precipitated depends on the ionic strength and the pH during the fractionation procedure. In contrast, alpha1-anti-trypsin, alpha2-macroglobulinand antithrombin II are present in euglobulin fractions in trace amounts only. The fibrinolytic activity of the euglobulin fractions is inhibited by the endogenous C1 inactivator, particularly as shown by comparison of normal and hereditary angioneurotic edema (HANE) plasma.

Angioedema↗
PubMed1976

Acquired angioedema with lymphoproliferative disorder: association of C1 inhibitor deficiency with cellular abnormality.

A patient with a lymphoproliferative disorder, angioedema, and an acquired deficiency of the inhibitor of the activated first component of complement was studied. The patient's complement profile revealed depletion of the first component of complement, which has not been seen in angioedema of the hereditary type. There was no evidence for C1-depleting activity in the patient's plasma. The majority of the patient's peripheral blood mononuclear cells resembled B cells in their memebrane receptor properties and in that they carried easily detectable immunoglobulin, predominantly IgM. However, these cells were unusual in that they phagocytosed both latex particles and C3-coated erythrocytes. Morphological study of the cells infiltrating the patient's lung revealed immature, atypical, and plasmacytoid lymphocytes and immunoblasts. Both the patient's peripheral blood mononuclear cells and a suspension of cells from the pulmonary infiltrate were capable of depleting the first component of complement and its inhibitor from homologous plasma. Normal ABO-compatible cells did not possess this property. The data suggested that the patient's abnormal lymphoid cells may have interacted with the complement system to produce a biochemical defect and a clinical syndrome closely resembling angioedema of the hereditary type.

Aged↗
PubMed1977

[Study by means of enzymatic and immunochemical determination of Cl esterase inhibitor in 59 patients with hereditary angioneurotic edema].

Serum C1 esterase inhibitor was determined in 138 members of 18 italian families with hereditary angioedema by immunochemical and enzymatic assays. On the basis of quantitative and functional findings, the type A of hereditary angioedema was diagnosed in 44 subjects, and the type B in 15. Some technical devices concerning serum sample handling were identified. The influence of heparin, EDTA, and citrate on C1 esterase inhibitor activity of normal plasma was also investigated.

Adult↗
PubMed1982

Complement: activation, consequences, and control.

The activation of complement provides the humoral (fluid-phase) effector mechanism most responsible for immune-mediated injury. The classical pathway is activated by an antigen-antibody reaction. The binding of C1q initiates the sequential activation of the eleven proteins. The classical pathway has a calcium-dependent step (C1q, C1r, C1s) and a magnesium-dependent reaction (the enzymatic action of C1s on C4 and C2). The alternative pathway appears to be spontaneously activated, but the perpetuation of that activation is dependent upon the availability of an activating (or protective) surface which interferes with the inactivation of C3b by control proteins. The alternative pathway has a magnesium-dependent step, the binding of B to C3b to form the C3 convertase. Once initiated, the alternative pathway activation results in the sequential activation of nine proteins, six of which are common to both pathways. The activation of complement results in a variety of biologic consequences which can result in injury to the host. The potential destructiveness of the effects of complement activation is modulated by a series of control proteins.

Carrier Proteins↗
PubMed1986

Serum profiles of the regulatory complement proteins during the progression of renal damage in human glomerulonephritis.

Persistent activation of the complement system after escape from control by the regulatory proteins results in an excessive release of split products with inflammatory properties. Serum levels of the regulatory proteins of the complement system (Cl-INH, H, I and AT III) were assayed by the radial immunodiffusion technique in 521 serum samples from 124 patients with idiopathic chronic glomerulonephritis divided into two groups: 81 cases with normal renal function (NRF), and 43 cases with deteriorated renal function (DRF). Significant high mean levels of Cl-INH, H, I and AT III were found in patients with NRF, when they were compared with DRF patient groups. Positive correlations between the regulatory proteins and the corresponding complement components were found in patients with NRF, whereas they were reduced considerably in patients with DRF. Serial measurement of the control proteins showed a decay of the levels of Cl-INH, H and I in patients with progressive impairment of renal function. The presence of high levels of regulatory proteins suggest that a control mechanism may occur in patients with NRF; measurement of these proteins could, therefore, be of prognostic value, as the presence of high levels are indicative of a block of the complement system.

Antithrombin III↗
PubMed1985

Hyaluronic acid-complement interactions--I. Reversible heat-induced anticomplementary activity.

The in vitro interaction of hyaluronic acid (HA) with complement (C) classical-pathway activity has been investigated. It was found that native HA, even at a high concn (greater than 3 mg/ml), has a relatively weak anticomplementary activity. However, we report here that native HA can be reversibly altered by heat treatment such that C-inhibitory properties are manifested. We have determined in this study that a potent C-inhibitory activity can be obtained if HA solutions are thermally treated (100 degrees C), and stabilized by prompt freezing with prompt thawing just prior to the interaction with human serum complement. Several investigators have proposed that the intermolecular-associated strands of HA undergo a reversible decoupling upon thermal treatment and this decoupled state of HA can be semi-stabilized by quickly cooling the sample. This heat-treated HA strongly inhibits C1 as well as classical-pathway-mediated C3 conversion. However, if heat-treated HA samples are not stabilized but, rather, slowly cooled after heating or if heated HA samples are snapfrozen and then slowly thawed, the anticomplementary activity is gradually lost. Interestingly, the activity for this same sample can be regenerated by retreatment of the same sample with heat followed by low-temp stabilization, indicating the reversibility of the physical state of HA responsible for the anticomplementary effect. Since no detectable molecular degradation of thermally-treated HA was found, it was assumed that a heat-induced physical transition of HA (decoupled state) was responsible for the C-inhibitory effect.

Chromatography, Gel↗