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PubMed2006

Hereditary angioedema managed with low-dose danazol and C1 esterase inhibitor concentrate: a case report.

BACKGROUND: Hereditary angioedema (HAE) is a rare life-threatening disease that can occur in pregnancy. CASE: A nulliparous woman was diagnosed as having HAE at 22 weeks of gestation after a series of symptomatic episodes. Following an initial course of C1 esterase inhibitor (C1EI) therapy for an acute episode of HAE, she was treated with danazol for prophylaxis. Danazol did not prevent recurrence of symptoms, its use was discontinued after six weeks. Thereafter, the patient was treated exclusively with C1EI at weekly intervals for exacerbations of her HAE. At 37 weeks' gestation, she delivered healthy 3050 g female neonate. At the time of discharge the female neonate had no signs of virilization or congenital anomalies. CONCLUSION: Low dose danazol was ineffective in treating this woman's HAE in pregnancy. The use of C1EI in pregnancy is associated with good outcomes.

Adult↗
PubMed1974

Elastase of Pseudomonas aeruginosa: inactivation of complement components and complement-derived chemotactic and phagocytic factors.

A purified elastase from Pseudomonas aeruginosa was highly destructive for fluid-phase and cell-bound C1 and C3 and fluid-phase C5, C8, and C9. Inactivation of C4, C2, C6, and C7 by the enzyme varied from 0 to 67%. Low concentrations of elastase generated, then inactivated, a chemotactic factor from human C5 but not from C3. Higher enzyme concentrations inactivated the C5 chemotactic activity at a faster rate. Elastase treatment of sensitized pseudomonads containing cell-bound C3 reduced the phagocytic indexes of polymorphonuclear leukocytes. The data support the proposed chemopathogenic role of the elastase in generation of the characteristic non-inflammatory Pseudomonas vasculitis.

Animals↗
PubMed1990

Specific, sensitive, precise, and rapid functional chromogenic assay of activated first complement component (C1) in plasma.

We present a new functional assay for the first complement component (C1) in plasma, based on its activation by inhibition of the C1-esterase inhibitor (C1-inh) when monospecific antiserum to C1-inh is added to the plasma. After maximal activation, we can determine the concentration of activated C1 by using an amidolytic rate assay with a chromogenic substrate. We have optimized the assay conditions with respect to incubation time, concentration of antiserum to C1-inh, ionic strength, and pH. Our method determines specifically the concentration in plasma of free activated C1, not complexes of activated C1 with C1-inh, and is not influenced by the concentration of C1-inh in the test sample. Concentrations of C1 correlated significantly with activities determined by a hemolytic assay (r = 0.55, t = 4.09, P less than 0.001). The estimated interassay CV was 5% and the intra-assay CV was 1%. The sensitivity, imprecision, and practical test performance of our assay are superior to those of conventionally used hemolytic assays.

Adult↗
PubMed1995

Factor VIIa in patients with C1-inhibitor deficiency.

In hereditary angioedema (HAE), normal C1-inhibitor (C1-INH) is low and the contact system activated. Recently, the findings of a tissue factor mutant selectively deficient in promoting the conversion of FVII to FVIIa, but with retained cofactor for FVIIa, made it possible to examine reliably the pre-existing content of FVIIa in HAE patients. This was of interest as FXIIa (mainly inhibited by C1-INH) is able to activate FVII directly. FVIIa in 21 remission HAE patients were within normal limits but nearly doubled as compared to their 23 normal siblings (p = 0.0017). Cold promoted activation of FVII (CPA) (common clot assay) was displayed in plasma of all 5 untreated patients (C1-INH function < 35%), but not in plasma of 2 patients treated prophylactically with danazol (C1-INH function about 40%). These results suggest that there is a minute, yet significant activation of FVII in patients with C1-INH deficiency.

Angioedema↗
PubMed2000

[Angioedema is caused by a defect in C1-inhibitor synthesis].

Deficit of the first component of complement inhibitor (C1-inhibitor, C1-inh) may clinically be manifested as angioedema. The disease is characterized by episodic swellings of mucosa and subcutaneous tissue at different locations of the body. Laryngeal swelling can be life-threatening. The major mediators of edema are discussed to be bradykinin and C2b derived peptides. These mediators increase capillary permeability. Antifibrinolytic agents (aminocaproic acid, tranexamic acid) and attenuated androgens (danazol or stanazolol) are used for prophylaxis. Prolonged use both of them might result in more or less severe side effects. In experiments in vitro it has been shown that IFN-gamma, IL-1, IL-6 have a stimulatory effect on C1-inh synthesis. We want to verify the practical use of probiotics as natural inductors of IFN-gamma synthesis for elevating C1-inh level.

Adolescent↗
PubMed1999

Effect of C1-inhibitor in a rat model of necrotizing enterocolitis.

Our aim was to investigate the effect of C1-inhibitor (C1-INH) in a rat model of necrotizing enterocolitis (NEC). Twenty-four anesthetized and artificially ventilated rats received 0.1 mg/kg endotoxin. Fifteen minutes later, the animals in the study group (n = 12) were treated with 200 IU/kg C1-INH whereas the control animals (n = 12) received normal saline. In all animals, FiO(2) was reduced after 90 min from 0.21 to 0.05 and ventilation continued until 180 min or death. All animals developed shock symptoms. Drop in mean arterial blood pressure was more pronounced and survival time was shorter in the control group. Whereas the C1-INH activity increased in the study group, it decreased in the control group. The extent of macroscopic intestinal lesions did not differ between the groups. In conclusion, C1-INH did not prevent shock, but mitigated and delayed its course.

Animals↗
PubMed2003

C1-esterase inhibitor and a novel peptide inhibitor improve contractile function in reperfused skeletal muscle.

To determine the role of inhibition of complement activation in the contractile function of skeletal muscle ischemia-reperfusion (I/R) injury, the rat extensor digitorum longus (EDL) muscles underwent 3 h ischemia and received human C1-esterase inhibitor (C1-INH, 100 IU/kg), a synthetic C1q A chain peptide with a similar inhibitory effect on activated C1 (peptide, 5 mg/kg), or human serum albumin control. Results showed a significant overall increase in tetanic contractile forces of the reperfused EDL in both C1-INH and peptide groups compared to controls. Maximum improvement occurred with peptide treatment at 120-Hz stimulation, with an increase in force from 38 +/- 4% of normal in controls to 52 +/- 4% in peptide-treated rats. There were no significant differences between C1-INH and peptide groups. Plasma C3 and C4 activities were significantly increased in both treated groups, suggesting inhibition of complement activation. Our results suggest that complement activation is involved in I/R injury, and inhibition of complement activation may therefore represent a potential therapeutic approach to reducing or preventing I/R injury.

Animals↗
PubMed1979

[Clinical and immunological studies on acquired heat contact urticaria (author's transl)].

A case of localized urticaria in an otherwise healthy young woman, produced only by direct contact of the skin with heat, is described. The minimal temperature of urtication was 44 degrees C (immersion of the forearm in hot water for 5 min). Redness and painful oedema immediately developed without reflex flare. Total serum IgG, IgA, IgM, IgE, complement factors C3 and C4, and alpha1-antitrypsin were in the normal range, whereas the C1-inhibitor level was slightly decreased. There was no evidence of circulating immune complexes in the serum. A skin test and a RAST with house dust were positive, but there were no signs of respiratory atopy. An attempt for passive transfer of heat urticaria into the abdominal skin of a rhesus monkey failed, but was successful for house dust. A treatment trial with ketotifen, a new, perorally acting anti-allergic drug, was poorly effective, but dexchlorpheniramine maleate, a classical antihistaminic, in a dose of 12 mg daily completely suppressed the swelling evoked by heat, but not the erythema, suggesting that other tissue or plasma factors than histamine may be involved in the mechanism of heat urticaria in this patient.

Adult↗
PubMed1985

Atypical hypocomplementemic vasculitis syndrome in a child.

We report a patient who developed recurrent urticaria and angioedema at age 2 years, severe hypocomplementemic glomerulonephritis at 11 years, and end-stage renal disease at 14 years. His disease resembled the hypocomplementemic vasculitis syndrome but was atypical in its early age of presentation, severe hypocomplementemia, and progression to end-stage renal disease. Serum C1q levels were extremely low, and C4, C2, C3, and C5 levels were significantly reduced. Serum C1 inhibitor (C1INH) levels were slightly low, presumably from consumption. Circulating C1INH-C1r-C1s complexes were evidenced by reduced ratios of functional to antigenic C1INH and antigenic C1r to C1s. Family members had normal functional and antigenic levels of all complement components studied. The patient's serum, erythrocytes, platelets, and mononuclear cells did not activate complement when mixed with normal target serum. Absence of a circulating complement activator and the low serum C3 and C5 levels suggested the presence of a solid-phase complement activator, possibly related to renal or systemic vascular endothelium. As in patients with homozygous deficiencies of classical pathway components, a severe, prolonged, acquired C1q deficiency may have predisposed this patient to the development of glomerulonephritis.

Angioedema↗
PubMed1995

Inhibition of activation of human T lymphocytes by the complement C1 esterase inhibitor.

The major histocompatibility complex (MHC) class I molecules have been shown to be substrates to both of the complement C1 esterases. The effect of a C1 esterase-mediated cleavage of the MHC class I molecules on the activation process of lymphocytes was investigated by including the complement C1 esterase inhibitor (C1-Inh) in the medium during activation of human peripheral lymphocytes by staphylococcal enterotoxin A (SEA). The C1-Inh was shown to inhibit the activation of both CD4+ and CD8+ cells. No effect on activation of B lymphocytes was recorded, although the complement C1 complex was shown to bind to the B lymphocytes. Furthermore, the C1 complex bound to mononuclear cells was shown to be cleaved into molecular weights corresponding to the activated forms of the C1 esterases. The effect of the C1-Inh was much more pronounced at low cell density and the inhibition was not affected by the addition of interleukin-2 (IL-2). However, the inhibition was reduced when the cells were disturbed by addition of new portions of C1-Inh, 24 and 48 hr after the initiation of the activation. This indicates that the C1-Inh interference with the activation of T lymphocytes is mediated through a mechanism that requires some form of cell contact.

Complement C1↗
PubMed1989

Accentuated complement activation in patient plasma during the adult respiratory distress syndrome: a potential mechanism for pulmonary inflammation.

The adult respiratory distress syndrome (ARDS) represents an acute inflammatory lung disorder, characterized by both refractory hypoxemia and a mortality rate approaching 95%. Researchers have proposed that activation of the complement (C) system may play a role in the development of the pulmonary inflammation associated with ARDS. The purpose of this investigation was to determine whether complement activation occurs to a greater extent in patients with ARDS than in patients without ARDS, thereby providing a potential mechanism for the acute inflammation seen in ARDS. In this study, we assessed plasma complement activation by measuring complement activation by-products: C1rC1s-C1 inhibitor complex and C3b-P complex, generated subsequent to activation of the classical and alternative pathways, respectively, and also the terminal complement complex, formed after activation of either the classical or alternative complement pathway. Multivariate discriminant analysis revealed that these three complement activation complexes could distinguish patients with ARDS from those without ARDS (p less than 0.04). Furthermore, these three complexes provided a more sensitive discriminator of ARDS than did plasma levels of C3a desarginine (p greater than 0.30), C5a desarginine (p greater than 0.41) and total hemolytic complement activity (CH50) (p greater than 0.72). We conclude that a temporal association exists between the complement activation and the development of ARDS. Therefore, we suggest that complement activation by-products be included in the armamentarium for ARDS.

Adult↗
PubMed1999

C1q and C4b bind simultaneously to CR1 and additively support erythrocyte adhesion.

Previously, we showed that soluble C1q bound specifically to CR1 on transfected cells. If the CR1-C1q interaction were to participate in immune complex clearance, then this interaction should support E adhesion. Using a tip plate adhesion assay, we found that immobilized C1q mediated adhesion of human E. E binding to C1q was specifically inhibited by polyclonal anti-CR1 Fab fragments. Intact C1 was not efficient as an adherence ligand until it was treated with EDTA or the C1 inhibitor to remove the C1r2C1s2 complex from C1, leaving C1q. Titration of C1q alone, C4b alone, and C1q + C4b indicated that the two complement ligands were additive in their ability to support CR1-mediated adhesion of E. Analysis of binding to immobilized CR1 using a BIAcore instrument documented that C1q, C4b, and C3b binding were independent events. Additionally, C1q-dependent binding of immune complexes and heat-aggregated IgG to E was documented. These experiments confirm that the immune adherence receptor in humans, CR1, is the single receptor for all of the opsonic ligands of complement, provide evidence for a single C1q binding site on LHR-D of CR1, and suggest that C1q may participate in immune clearance.

Antigen-Antibody Complex↗
PubMed1989

Monocyte C1-inhibitor synthesis in patients with C1-inhibitor deficiency.

Monocytes of seven out of eight patients with type 1 C1-inhibitor (C1-inh) deficiency (HAE) produced 40% as much C1-inh as monocytes from normal donors (controls). In contrast, monocytes from three patients with type 2 and three patients with acquired C1-inh deficiency produced similar amounts of C1-inh as controls. Recombinant gamma-interferon (gamma-interferon 10 ng/ml) stimulated C1-inh production of C1-inh (eight-10-fold) by control and patients' monocytes. Monocytes from patients with type 1 HAE contained 40% the level of C1-inh messenger ribonucleic acid (mRNA) found in control monocytes. Gamma-interferon increased the abundance of C1-inh mRNA by the same extent in both control and patients' monocytes. C1-inh protein and mRNA were undetectable in the monocytes of one patient, unless stimulated by gamma-interferon. Under these conditions, his monocytes produced comparable amounts of C1-inh (protein and mRNA) as gamma-interferon-stimulated monocytes of the other type 1 HAE patients. The data suggest that in most type 2 HAE patients there is a lesion in the C1-inh gene such that mRNA is transcribed by a single allele.

Angioedema↗
PubMed1987

Activation of human C1: analysis with Western blotting reveals slow self-activation.

The first component of human complement was separated from C1-INH by sucrose linear gradient ultracentrifugation. Activation of C1 was studied in the absence and presence of immune complexes; activation was monitored by SDS-PAGE and Western blot. When the partially purified native C1 preparation was incubated at 37 degrees C without immune complexes, activated C1s appeared after 30 min in the case of eightfold dilution with respect to the original serum, and after 45 min with 32-fold dilution. Kinetics of appearance of activated C1r was the same as that of activated C1s. From the following results, we concluded that spontaneous activation may be partially due to proteolytic enzymes contaminating the preparation: 1) a nonspecific protease inhibitor, PMSF, completely inhibited spontaneous activation but did not inhibit the activation of C1 by immune complexes; 2) alpha 2-macroglobulin partially inhibited spontaneous activation, and 3) although spontaneous activation in the absence of PMSF was relatively slow, activated C1 accelerated spontaneous activation that was completely blocked by C1-INH. In contrast to spontaneous activation, the partially purified native C1 was rapidly activated by immune complexes: within 5 min almost all C1 was activated by rabbit IgG anti-human IgM-human IgM complexes. These results support conclusions derived from activation studies when using native C1 and hemolytic assays, and do not support those derived from the activation studies with reconstituted C1 and SDS-PAGE analysis. We suggest that the contradictions can be resolved if one assumes that C1 activation can be both an intra- and intermolecular process; which process dominates is determined by the state of C1 and by experimental conditions.

Antigen-Antibody Complex↗
PubMed1985

[Primary structure of the glycan chains of normal C 1 esterase inhibitor (C 1-INH) after NMR analysis at 400 MHz].

The primary structural analysis of O- and N-linked carbohydrate chains of the C-1-esterase inhibitor purified from normal serum was carried out by 400-MHz 1H-NMR spectroscopy. C-1-esterase inhibitor protein of a molecular weight of 116,000 daltons contains 24 O-glycans: NeuAc (alpha 2-3) Gal (beta 1-3) GalNAc, 4 N-glycans: NeuAc (alpha 2-6) Gal (beta 1-4) (GlcNAc (beta 1-2) Man (alpha 1-3) [NeuAc (alpha 2-6) Gal (beta 1-4) GlcNAc (beta 1-2) Man (alpha 1-6)] Man (beta 1-4) GlcNAc (beta 1-4) GlcNAc and 2 N-glycans: NeuAc (alpha 2-3) Gal (beta 1-4) GlcNAc (beta 1-2) Man (alpha 1-3) [NeuAc (alpha 2-3) Gal (beta 1-4) GlcNAc (beta 1-2) Man (alpha 1-6)] Man (beta 1-4) GlcNAc (beta 1-4) GlcNAc. 30% of the N-glycans are fucosylated.

Carbohydrate Conformation↗
PubMed1994

Tonsillectomy in a patient with hereditary angioedema after prophylaxis with C1 inhibitor concentrate.

BACKGROUND: A 15-year-old young man with a history of recurrent streptococcal pharyngitis and hereditary angioedema presented for tonsillectomy. Preoperative physical examination was normal with the exception of enlarged pharyngeal tonsils with crypts and pustules; there was no evidence of angioedema. Laboratory studies were remarkable for a C4 level of 8 mg/dL (normal 20-50 mg/dL) and C1 inhibitor (C1 INH) level of 4 mg/dL (normal 11-26 mg/dL). OBJECTIVE: To report the use of C1 INH concentrate as prophylactic treatment for a patient with hereditary angioedema who required tonsillectomy. METHODS: The patient was treated with stanozolol 4 mg po quid and clindamycin 150 mg po tid during the week before the procedure. Two hours prior to surgery, he received 2300 plasma units of intravenous C1-inhibitor (Human) Vapor Heated, IMMUNO (IMMUNO Clinical Research Corporation, New York, NY). RESULTS: Approximately eight hours after an uncomplicated tonsillectomy, the patient began to experience crampy abdominal pain, typical of his hereditary angioedema. Beginning 22 hours after surgery, he had facial swelling and complained of difficulty swallowing and the sensation of throat swelling. The symptoms resolved over the next eight hours. Serial laboratory examinations revealed: [table: see text] CONCLUSIONS: We believe that the occurrence of abdominal pain, facial swelling, and difficulty swallowing suggests that this patient may have experienced a mild, generalized flare of hereditary angioedema during the postoperative period in spite of prophylactic therapy with both anabolic steroids and C1 INH concentrate. This serves as a reminder that patients with hereditary angioedema require close observation following invasive procedures even after premedication with stanozolol and C1 INH concentrate.

Adolescent↗
PubMed1993

C1 esterase inhibitor gene expression in rat Kupffer cells, peritoneal macrophages and blood monocytes: modulation by interferon gamma.

Kupffer cells (KC) represent the main part of the tissue macrophages. Beside phagocytosis of particulate material, involvement of KC in immunological and inflammatory reactions has been supposed. As C1 esterase inhibitor (C1-INH) is a serine protease inhibitor involved in such processes, the aim of this work was to study C1-INH synthesis in KC and, by comparison, in peritoneal macrophages (PM) and blood monocytes (MC) of the rat. C1-INH synthesis was studied on the protein level by biosynthetic labeling, immunoprecipitation, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, and on the RNA level by Northern blotting of total RNA or by in situ hybridization. KC were found to express C1-INH gene spontaneously. C1-INH synthesis represents 1.3 +/- 0.2% of total protein synthesis at day 1 of culture and the absolute amount each cell synthesis remains constant during the whole time in culture. Transcripts of C1-INH were detected both in freshly isolated and in cultured KC. In contrast, spontaneous C1-INH gene expression was not detectable in freshly isolated PM, but only in cultured PM. In MC, C1-INH was not detectable at any time, whatever. Treatment of the cells with interferon gamma increased C1-INH synthesis in KC and in PM and caused an induction of C1-INH synthesis in MC. The results suggest that constitutive C1-INH synthesis is a functional marker for mature tissue macrophages.

Animals↗
PubMed2002

StcE, a metalloprotease secreted by Escherichia coli O157:H7, specifically cleaves C1 esterase inhibitor.

Escherichia coli O157:H7 causes diarrhoea, haemorrhagic colitis, and the haemolytic uraemic syndrome. We have identified a protein of previously unknown function encoded on the pO157 virulence plasmid of E. coli O157:H7, which is the first described protease that specifically cleaves C1 esterase inhibitor (C1-INH), a member of the serine protease inhibitor family. The protein, named StcE for secreted protease of C1 esterase inhibitor from EHEC (formerly Tagn), cleaves C1-INH to produce (unique) approximately 60-65 kDa fragments. StcE does not digest other serine protease inhibitors, extracellular matrix proteins or universal protease targets. We also observed that StcE causes the aggregation of cultured human T cells but not macrophage-like cells or B cells. Substitution of aspartic acid for glutamic acid at StcE position 435 within the consensus metalloprotease active site ablates its abilities to digest C1-INH and to aggregate T cells. StcE is secreted by the etp type II secretion pathway encoded on pO157, and extracellular StcE levels are positively regulated by the LEE-encoded regulator, Ler. StcE antigen and activity were detected in the faeces of a child with an E. coli O157:H7 infection, demonstrating the expression of StcE during human disease. Cleavage of C1-INH by StcE could plausibly cause localized pro-inflammatory and coagulation responses resulting in tissue damage, intestinal oedema and thrombotic abnormalities.

Blood Proteins↗