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PubMed2001

C1 inhibitor: analysis of the role of amino acid residues within the reactive center loop in target protease recognition.

Previous analysis of a naturally occurring C1 inhibitor P2 mutant (Ala(443)-->Val) indicated a role for P2 in specificity determination. To define this role and that of other reactive center loop residues, a number of different amino acids were introduced at P2, as well as at P6 (Ala(439)) and P8'/9' (Gln(452)Gln(453)). Ala(439)-->Val is a naturally occurring mutant observed in a patient with hereditary angioedema. Previous data suggested that Gln(452)Gln(453) might be a contact site for C1s. Reactivity of the inhibitors toward target (C1s, C1r, kallikrein, beta factor XIIa, and plasmin) and nontarget proteases (alpha-thrombin and trypsin) were studied. Substitution of P2 with bulky or charged residues resulted in decreased reactivity with all target proteases. Substitution with residues with hydrophobic or polar side chains resulted in decreased reactivity with some proteases, but in unaltered or increased reactivity with others. Second order rate constants for the reaction with C1s were determined for the mutants with activities most similar to the wild-type protein. The three P2 mutants showed reductions in rate from 3.35 x 10(5) M(-1)s(-1) for the wild type to 1.61, 1.29, and 0.63 x 10(5) for the Ser, Thr, and Val mutants, respectively. In contrast, the Ala(439)-->Val and the Gln(452)Gln(453)-->Ala mutants showed little difference in association rates with C1s, in comparison with the wild-type inhibitor. The data confirm the importance of P2 in specificity determination. However, the P6 position appears to be of little, if any, importance. Furthermore, it appears unlikely that Gln(452)Gln(453) comprise a portion of a protease contact site within the inhibitor.

Amino Acid Substitution↗
PubMed1985

Cleavage of the second component of complement by plasma proteases: implications in hereditary C1-inhibitor deficiency.

EDTA plasma from patients with hereditary angioedema (HAE), the genetic deficiency of C1-inhibitor, when incubated at 37 degrees produces a kinin-like activity which can induce contraction of oestrus rat uterus. The second component of complement (C2) has previously been suggested to be the source of this kinin-like activity, with the implication that C2-kinin is a normal product of complement activation. Our results show that purified human C2 is cleaved rapidly to C2a and C2b when added to HAE plasma, but not normal plasma or plasma from a danazol-treated HAE patient. However, the addition to HAE plasma of C2 at 20 X normal plasma concentration had no effect on the kinin activity generated on incubation at 37 degrees. In the presence of soya bean trypsin inhibitor, the rate of C2 cleavage and products were unaltered but no kinin activity was generated. C2 was cleaved by purified C1s to C2a and C2b. Incubation of C2 with trypsin resulted in cleavage to C2a and C2b followed by more extensive cleavage of both C2a and C2b. Kallikrein cleaved C2 to C2a and C2b but plasmin had no effect on C2. In no case was kinin activity generated. When C2 was cleaved by C1s to C2a and C2b then incubated with trypsin, kallikrein, or plasmin, no kinin activity was generated: only trypsin cleaved the C2 fragments further. The results suggest that C2 is not the source of the kinin-like activity generated in hereditary angioedema plasma.

Angioedema↗
PubMed1997

Regulation of C1-inhibitor function by binding to type IV collagen and heparin.

Serpins inhibit proteinases by a branched pathway, in which an intermediate serpin-proteinase complex can either form a stable covalent serpin-proteinase complex or produce reactive center cleaved serpin in a substrate reaction. It was tested whether these competing reactions could be regulated for the serpin C1-inhibitor by ligand binding. C1-inhibitor bound to type IV collagen, laminin, and entactin. Type IV collagen (10 microg/ml) caused an increase in the stoichiometry of inhibition for C1s inhibition by C1-inhibitor to 1.48 from 1.09 in the absence of ligand. A dose-dependent increase in the stoichiometry up to 1.27 in the presence of 100 microg/ml heparin was also observed. At low ionic strength the stoichiometry increased to 2.55. These data provide the first report that C1-inhibitor can bind to type IV collagen and also show that C 1-inhibitor can be regulated by ligand binding.

Binding, Competitive↗
PubMed1988

C-reactive protein-mediated complement activation in polymyalgia rheumatica and other systemic inflammatory diseases.

An immunoglobulin-independent deposition of the complement (C) components C4 and C3 occurs on rat kidney medullary structures, when sera of patients with various inflammatory diseases are studied by indirect immunofluorescence. The diagnostic value of this new test (C4-C3-IFT) for polymyalgia rheumatica (PMR) is stressed, since all sera from patients with active disease yielded positive reactions. Though highly sensitive with respect to PMR, C4/C3-IFT is not specific for this syndrome. Examples of positive reactions in systemic inflammatory diseases other than PMR are documented. Besides the clinical studies, C4/C3-IFT reactivity was analyzed with regard to the mechanisms of the reaction. Experimental data are presented which suggest that C-reactive protein (CRP) binds to rat kidney structures, thereby activating the classical C cascade. As a result of CRP-C interaction, C4 and C3 components are fixed to distinct renal medullary structures. Because of its technical simplicity, C4/C3-IFT can routinely be used to screen patients' sera for CRP-mediated C activation. This ex vivo test system may contribute to a better understanding of pathophysiological functions of serum CRP in various inflammatory diseases.

Antigen-Antibody Complex↗
PubMed1993

[Behavior of esterase inhibitor C1 in patients with urticaria due to aspirin hypersensitivity].

The aim of the study was to evaluate concentration and activity of C1 esterase inhibitor (C1 INH) in patients with aspirin-sensitive urticaria. Deficiency of C1 INH is the basis for hereditary angioneurotic oedema. The study was performed in 32 subjects with aspirin-sensitive urticaria. The value of C1 INH in examined patients was the same as in control group. It seems there is no coexistence of aspirin-sensitive urticaria and C1 esterase inhibitor deficiency.

Adult↗
PubMed2001

Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.

Animals↗
PubMed2001

Detection of complement C1-inhibitor with a piezoelectric immunosensor.

A novel piezoelectric immunosensor has been developed for the detection of human complement C1-inhibitor. Anti-C1-inhibitor antibody was immobilized onto the gold electrodes of a 9 MHz AT-cut piezoelectric crystal. Coating the crystal with polyethyleneimine adhesion, followed by a glutaraldehyde cross-linking method to immobilize antibody showed better results than the physical adsorption method with respect to sensitivity and reproducibility. Under the optimized experimental conditions, the sensor showed good response to the C1-inhibitor in the range from 2.0 x 10(-8) to 1.2 x 10(-6) g. Other proteins in human serum did not remarkably interfere with the detection. The crystals could be regenerated 5 times, when bound materials on the crystal surface were eluted by strong acid and strong alkali solution and subsequently cleaned in an ultrasonic cleaner.

Biosensing Techniques↗
PubMed1987

Modulation of monocyte complement synthesis by interferons.

Recombinant Escherichia coli-derived gamma-interferon has been shown to stimulate synthesis of the second component of complement (C2), factor B and C1 inhibitor, but to inhibit synthesis of the third component (C3). alpha- and beta-interferons stimulate synthesis of factor B and C3 inhibitor, inhibit C5 synthesis but do not alter synthesis of C2. alpha- and beta-interferons act synergistically with gamma-interferon to enhance both factor B and C1-inhibitor synthesis.

Cells, Cultured↗
PubMedDate not supplied

The value of C1 esterase inhibitor in patients with aspirin-sensitive urticaria.

The aim of the study was to evaluate the concentration and activity of C1 esterase inhibitor (C1 INH) in patients with aspirin-sensitive urticaria. C1 INH deficiency is the basis of hereditary angioneurotic edema. The study was performed on 32 subjects with aspirin-sensitive urticaria. The value of C1 INH in examined patients was the same as in the control group. There seems to be no coexistence of aspirin-sensitive urticaria and C1 esterase inhibitor deficiency.

Adolescent↗
PubMed1994

Initial studies on the administration of C1-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy.

Activation of the complement and contact systems occur in patients with septic shock and is associated with a poor outcome. Activation of both systems is regulated by a common inhibitor, C1-esterase inhibitor (C1-Inh). Functional levels of C1-Inh are normal or slightly decreased in septic patients although this inhibitor is an acute phase protein. Moreover, an increased turn-over of C1-Inh in sepsis likely occurs since levels of proteolytically inactivated ("modified") C1-Inh are increased in this syndrome. One may therefore postulate that in sepsis there is a relative deficiency of C1-Inh. Here we will summarize our preliminary studies in 11 patients with septic shock, who received high doses of C1-Inh for up to 5 days. Activation of complement and contact systems also occurs in "a human model for septic shock" i.e., the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2). The similarity between VLS and sepsis is not only reflected by similar patterns of complement and contact activation, but also by comparable hemodynamic and biochemical changes, and by the involvement of a number of other inflammatory mediators, such as the release of pro-inflammatory cytokines, and activation of coagulation and fibrinolysis and of neutrophils. Here we will also summarize our initial studies of the effect of C1-Inh administration to 6 patients with the VLS induced by IL-2. Our results indicate that high doses of C1-Inh can be safely administered to patients with septic shock or with the VLS, and may attenuate complement and contact activation in these conditions. Whether this therapy may reduce mortality and or morbidity of either syndrome has to be established by double-blind controlled studies.

Blood Coagulation↗
PubMed2003

Binding of activated Factor XII to endothelial cells affects its inactivation by the C1-esterase inhibitor.

It is well known that activated Factor XII (FXIIa) and kallikrein are rapidly inactivated in plasma as a result of reaction with endogenous inhibitors. The purpose of this may be to prevent uncontrolled deleterious spreading and activation of target zymogens. Both FXII and the complex plasma prekallikrein/high molecular mass kininogen become activated when they bind, in a Zn2+-dependent manner, to receptors on human umbilical vein endothelial cells (HUVEC). The C1-esterase inhibitor (C1-INH) is by far the most efficient inhibitor of FXIIa. In the present study it has been investigated whether binding of FXIIa to HUVEC might offer protection against inactivation by C1-INH. It appeared that the relative amidolytic activity of purified FXIIa bound to the surface of HUVEC decreased according to the concentration of C1-INH in medium; however, the decrease was smaller than that measured for inactivation of FXIIa in solution. The secondary rate constant for the inactivation was 3-10-fold lower for cell-bound than for soluble FXIIa. The inactivation was found to be caused by C1-INH binding to cell-bound FXIIa. Accordingly, the amidolytic activity of saturated amounts of cell-bound FXIIa was reduced in the presence of C1-INH and was theoretically nonexistent at physiological C1-INH concentrations. Amidolytic activity was, however, present on HUVEC incubated with plasma indicating that the endogenous C1-INH did not completely abolish the activity of FXIIa generated during the incubation period. This supports the hypothesis that binding to endothelial cells protects the activated FXII against inactivation by its major endogenous inhibitor. Hence, the function of FXII may be localized at cellular surfaces.

Cells, Cultured↗
PubMedDate not supplied

Glucocorticoid-induced elevations of C1-esterase inhibitor: a mechanism for protection against lethal dose range contrast challenge in rabbits.

Rabbits pretreated with methylprednisolone acquired significant protection against an intravenous challenge of meglumine iodipamide. In comparison to controls, the pretreated rabbits showed moderate elevations of Factor XII, and rather striking elevations of C1-esterase inhibitor. Treated rabbits also showed significantly less granulocytosis. It is believed that the protective effect can be ascribed to the modulation of acute phase reactants by increased concentrations of C1-esterase inhibitor.

Animals↗
PubMed2000

C1 inhibitor deficiency and angioedema of the small intestine masquerading as Crohn's disease.

A case of C1 inhibitor deficiency presenting as localized edema of the small intestine is described. A 16-year-old, previously healthy woman presented with recurrent attacks of abdominal pain and vomiting following minor abdominal trauma. Investigations including computed tomography scan and barium studies confirmed localized edema of the jejunum. At laparoscopy, Crohn's disease was suspected; however, a subsequent enteroscopy was normal. Complement levels revealed a low C4 level, and C1 inhibitor deficiency was later confirmed. Attacks of abdominal pain began after starting oral contraceptives and have not returned since stopping the birth control pill. This rare cause of abdominal pain is examined, and C1 inhibitor deficiency and angioedema are reviewed.

Abdominal Pain↗