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PubMed1998

Gamma interferon administration to patients with atopic dermatitis inhibits fibrinolysis and elevates C1 inhibitor.

Recombinant human gamma interferon was used to treat 10 atopic dermatitis patients. Recombinant gamma interferon was administered weekly for three consecutive days at 50 microg/M2 SQ for four weeks. All patients' dermatitis improved with recombinant gamma interferon therapy and plasma tumor necrosis factor-alpha levels rose with treatment. Recombinant gamma interferon treatment positively correlated with reduced total plasma fibrinolysis as measured by the fibrin lysis plate, plasmin-alpha2antiplasmin complexes, and tissue type plasminogen activator levels. Accordingly, plasminogen activator inhibitor levels increased. Treatment also was associated with a transient increase in thrombin-antithrombin III complexes. Recombinant gamma interferon resulted in a significant increase in C1 inhibitor antigen but not activity. Plasma prekallikrein, high molecular weight kininogen, and factor XII levels were not decreased. However, 5 of the 10 atopic dermatitis patients before therapy had circulating cleaved plasma high molecular weight kininogen detected on immunoblot, indicating prior kallikrein formation. The cleaved, circulating plasma high molecular weight kininogen disappeared in four out of the five original patients who were reexamined at one year after treatment. These combined data indicated that recombinant gamma interferon treatment reduced total plasma fibrinolysis. In untreated atopic dermatitis, circulating cleaved high molecular weight kininogen also may be a presenting manifestation.

Adolescent↗
PubMed2003

Management of hereditary angioedema: a Canadian approach.

C1 esterase inhibitor (C1-INH) deficiency is a rare disorder that lacks consensus for diagnosis therapy and management. Recognizing that Canada is behind the European approach to this disorder, we have formed the Canadian Hereditary Angioedema Society (CHAES)/Société d'angioédème héréditaire du Canada (SAHC) to foster knowledge of this disorder in Canada and to advance care of patients with this disorder in Canada. We here present a review of treatment of this disorder in Canada including prevention of angioedema events and use of replacement therapy and present an algorithm for diagnosis therapy and management of C1-INH deficiency in Canada for discussion at our International Conference on Hereditary Angioedema to be held in Toronto, Canada, October 24th to 26th, 2003.

Algorithms↗
PubMed1991

Acute consumption of C1 inhibitor in a patient with acquired C1-inhibitor deficiency syndrome.

Acquired C1-inhibitor (C1 INH) deficiency is usually found in association with an underlying disease that is believed to be responsible for increased C1 INH catabolism, ultimately leading to the development of C1 INH deficiency. We report a remarkable patient with acquired C1 INH deficiency in whom a unique progression of complement- and contact-system abnormalities has been observed. S. G. suffers from recurrent episodes of angioedema and hypotension. Results of repeated complement studies were initially normal, and the patient was diagnosed as having idiopathic anaphylaxis. Two years later, the patient was found to develop acute consumption of C1 INH with activation of the complement and contact systems during episodes of angioedema. The patient continued to have normal C1 INH levels and to have no evidence for complement- or contact-system activation between attacks of angioedema. One year later, her course evolved into a more typical course for acquired C1 INH deficiency consisting of continuously low functional C1 INH levels with evidence of activation of the complement and contact systems. S. G. provides a unique insight into the development of acquired C1 INH deficiency.

Acute Disease↗
PubMed2006

Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury.

The complement system represents an important mediator of neuroinflammation in traumatic brain injury. We have previously shown that transgenic mice with central nervous system-targeted overexpression of Crry, a potent murine complement inhibitor at the level of C3 convertases, are protected from complement-mediated neuropathological sequelae in brain-injured mice. This knowledge was expanded in the present study to a pharmacological approach by the use of a recombinant Crry molecule (termed Crry-Ig) which was recently made available in a chimeric form fused to the non-complement fixing mouse IgG1 Fc region. In a standardized model of closed head injury in mice, the systemic injection of 1 mg Crry-Ig at 1 h and 24 h after trauma resulted in a significant neurological improvement for up to 7 days, as compared to vehicle-injected control mice (P < 0.05, repeated measures ANOVA). Furthermore, the extensive neuronal destruction seen in the hippocampal CA3/CA4 sublayers in head-injured mice with vehicle injection only was shown to be preserved - to a similar extent as in "sham"-operated mice - by the posttraumatic injection of Crry-Ig. Real-time RT-PCR analysis revealed that the post-treatment with Crry-Ig resulted in a significant up-regulation of candidate neuroprotective genes in the injured hemisphere (Bcl-2, C1-Inh, CD55, CD59), as compared to the vehicle control group (P < 0.01, unpaired Student's t test). Increased intracerebral Bcl-2 expression by Crry-Ig treatment was furthermore confirmed at the protein level by Western blot analysis. These data suggest that pharmacological complement inhibition represents a promising approach for attenuation of neuroinflammation and secondary neurodegeneration after head injury.

Animals↗
PubMed1997

Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds.

OBJECTIVES: Hereditary angio-oedema (C1-inhibitor deficiency) is a disease with protean manifestations which is often misdiagnosed initially. The purpose of this study was to delineate the clinical spectrum and course of this potentially life-threatening disease. SETTING: Ten members of two unrelated affected kindreds were repeatedly hospitalized in our service with attacks of angio-oedema. Among the 271 members of the two kindreds 69 were identified who reported typical attacks. DESIGN AND SUBJECTS: Detailed information on the clinical course and laboratory data (C1-inhibitor concentration and activity, C4 concentration) were obtained from 59 of the 69 affected subjects. RESULTS: C1-inhibitor concentration and activity were low in all affected patients. The disease had become manifest by age 30 years in 98%. Most patients suffered from attacks of subcutaneous swellings and abdominal pain, and half of the patients have had attacks affecting the airways. The frequency of attacks ranged from less than one to over 26 per year. Forty-two per cent had to be hospitalized at least once. Four have died of acute airway obstruction. Thirty-eight attacks in 10 patients hospitalized in our service were all treated successfully with fresh frozen plasma or with C1-inhibitor concentrate. Trauma, stress, insect stings and foodstuff were triggering factors, but the majority of attacks occurred without an identifiable trigger. Oral contraceptives and pregnancy led to worsening of symptoms. Nonetheless, all 36 pregnancies reported were carried to term. Twenty-five patients were on continuous treatment with attenuated androgens or tranexamic acid, but only seven were free of attacks in the year preceding the survey. CONCLUSION: Hereditary angio-oedema is an autosomal dominant disease with great variability of clinical expression and severity, even within a single kindred. It often goes unrecognized over years, and it may lead to death if, in case of impending airway obstruction, specific therapy is not instituted.

Acute Disease↗
PubMed1991

Western blot analyses of prekallikrein and its activation products in human plasma.

Prekallikrein (PK), a zymogen of the contact system, and its activation products, kallikrein (KAL), KAL-inhibitor complexes and fragments containing KAL epitope(s) have been detected in human plasma by immunoblotting with a monoclonal anti-human plasma PK antibody, MAb 13G11. Detection of antigen-MAb 13G11 complexes with peroxidase-conjugated anti-IgG showed that the two variants of PK (85- and 88-kDa) are the only major antigen species in normal, non-activated plasma. Upon plasma activation with kaolin, the intensity of the PK bands decreased with formation of complexes of KAL with C1 inhibitor (C1 INH) and alpha 2-macroglobulin (alpha 2 M) identical to those formed by the purified proteins. Immunoblots of normal plasma showed good correlation between the PK detected and the amount of plasma assayed. Increasing amounts of KAL incubated with a constant volume of PK-deficient plasma showed increasing amounts of KAL and of KAL-C1 INH and KAL-alpha 2 M complexes. Complexes of KAL-antithrombin III (ATIII) and the ratio of KAL-alpha 2 M/KAL-C1 INH were higher in activated C1 INH-deficient plasmas than in activated normal plasmas. Protein resolution by 3-12% gradient SDS-PAGE and epitope detection with [125I]MAb 13G11 showed four KAL-alpha 2 M species and a 45-kDa fragment(s) in both surface-activated normal plasma and complexes formed by purified KAL and alpha 2 M. Immunoblots of activated plasma also showed bands at the position of KAL-C1 INH and KAL-ATIII complexes. When alpha 1-antitrypsin Pittsburgh (alpha 1-AT. Pitts) was added to plasma before activation, KAL-alpha 1-AT. Pitts was the main complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1991

Plasma C1 inhibitor in malignant diseases: functional activity versus concentration.

Plasma C1 inhibitor (C1-INH) was determined in 64 patients with different malignant diseases and in 58 healthy persons. C1-INH antigen concentration was measured by radial immunodiffusion (RID), whereas its functional activity was assayed with chromogenic substrate. Within-run and day-to-day precision of both methods were good, with CVs ranging from 3.6 to 5.4%. Plasma C1-INH antigen concentrations were significantly higher in the patients than in healthy controls (P = 4.0 x 10(-3)), as were their C1-INH functional activities (P = 3.5 x 10(-3)). C1-INH activities obtained in the patient plasma samples were in correlation with their antigen concentrations (r = 0.914), showing that C1-INH synthesized in malignant disease was functional. However, the specific activity of the C1-INH (functional activity/antigen concentration ratio) was significantly lower in the patient group as compared with the controls (P = 2.1 x 10(-6)), indicating partial inactivation of plasma C1-INH in malignant diseases. The C1-INH specific activity in patients was inversely proportional to its antigen concentration.

Chromogenic Compounds↗
PubMed1997

[Angioedema caused by splenectomy with malignant lymphoma followed by multiple myeloma 7 years later].

Acquired C1-inhibitor (C1-INH) deficiency has been reported in patients with immunoglobulin abnormalities and lymphoproliferative disorders, and angioedema has appeared simultaneously with the lymphoproliferative disease. We present a 50-year-old woman with acquired C1-INH deficiency and angioedema which preceded by 7 years the diagnosis of malignant mantle cell lymphoma. During the interval she was treated with Danazole and there were no attacks of angioedema. When routine follow-up bone marrow aspiration revealed infiltration of nonspecified lymphoma cells, exploratory laparotomy and splenectomy were performed. A month later Danazol was stopped, C1-INH levels returned to normal and there were no attacks of angioedema. Mantle cell lymphoma consisting of lymphocytes with cytoplasmic IgM-lambda was diagnosed in the excised spleen but chemotherapy was not initiated. 6 months later, a second lymphoproliferative disorder, multiple myeloma IgA kappa, was diagnosed.

Angioedema↗
PubMed1985

Changes in protein conformation and stability accompany complex formation between human C1 inhibitor and C1-s.

The fluorescence spectrum of C1 inhibitor (C1-Inh) in aqueous buffer has a maximum at 324 nm which shifts to 358 nm in 6.0 M guanidinium chloride (GdmC1), indicating that fluorescent tryptophans are buried in the native protein. When titrated with GdmC1, the fluorescence intensity, polarization, and emission maximum of C1-Inh and C1-s exhibited clear transitions which were more prominent than those of the enzyme-inhibitor complex. Two of the variables (intensity and emission maximum) suggest biphasic unfolding of C1-Inh. Differential absorption measurements and sodium iodide quenching of intrinsic fluorescence were consistent with a net increase in the exposure of tryptophans and tyrosines upon complex formation. This reaction, i.e., complex formation, was also accompanied by an increase in the ability to enhance the fluorescence of the hydrophobic probe 8-anilino-1-naphthalenesulfonate. Fluorescence assays of heat denaturation showed transitions at 40 and 52 degrees C for C1-s and at 60 degrees C for C1-Inh whereas there was no detectable melting transition for the complex. Similarly, differential scanning calorimetric measurements revealed transitions at 42, 52, and 62 degrees C for C1-s and one transition at 60 degrees C for C1-Inh, with no major transitions detectable for the complex. The ratio of the calorimetric enthalpy to the apparent van't Hoff enthalpy for thermal unfolding of C1-Inh was 1.6. Taken together, these results suggest that C1-Inh and C1-s are each composed of at least two independently unfolding domains and that complex formation, which involves conformational change, yields a protein substantially more stable than either component alone.

Calorimetry↗
PubMed2003

Acquisition of stcE, a C1 esterase inhibitor-specific metalloprotease, during the evolution of Escherichia coli O157:H7.

Escherichia coli O157:H7 is a source of foodborne illness, causing diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome. E. coli O157:H7 secretes, via the etp type II secretion system, a metalloprotease, StcE, that specifically cleaves the serpin C1 esterase inhibitor. We determined by hybridization techniques the prevalence of stcE and etpD, a type II secretion gene, among diarrheagenic E. coli strains. stcE and etpD are ubiquitous among the O157:H7 serotype and are found in some enteropathogenic E. coli O55:H7 strains but are absent from other diarrheagenic E. coli. stcE was acquired on a large plasmid early in the evolution of E. coli O157:H7, before the inheritance of the Shiga toxin prophage. Other plasmidborne virulence factors, such as ehxA, katP, and espP, were acquired later by the enterohemorrhagic E. coli 1 complex in a stepwise manner. These data refine the sequential model of E. coli O157:H7 evolution proposed elsewhere.

Complement C1 Inactivator Proteins↗
PubMed1984

Relative roles of burn injury, wound colonization, and wound infection in induction of alterations of complement function in a guinea pig model of burn injury.

Stimuli involved in induction of alterations of the complement system and production of circulating inhibitor(s) of phagocytic function of polymorphonuclear neutrophils following burn injury were investigated using a guinea pig model of scald burn injury. The activity of C1-C9, assessed by measurement of total hemolytic complement, was found to increase primarily in response to burn injury per se, whereas reduction in the activity of the alternative complement pathway was shown to develop in association with natural colonization and local burn wound infection with bacterial pathogens. Invasive burn wound infection induced experimentally with Staphylococcus aureus, Pseudomonas aeruginosa, or Candida albicans exacerbated this latter abnormality, caused consumption of C1-C9 activity, and was associated with appearance of serum factors that depressed phagocytosis of Escherichia coli 075 by peritoneal polymorphonuclear neutrophils. Thus injury and coexistent infection both play important roles in induction of humoral alterations of host defense associated with burn injury.

Animals↗
PubMed1989

Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency.

A case of hereditary angioedema (HAE) type I (inherited C1-inhibitor [C1 INH] deficiency) and a case of late-onset acquired C1 INH with angioedema is described. In both patients, long-term prophylaxis with C1 INH had become necessary because treatment with danazol and epsilon-aminocaproic acid was not effective or not tolerated. Consequently, both patients received a pasteurized concentrate of C1 INH continuously for a period of 1 year in a dosage that kept them free of symptoms. The patient with HAE was administered 500 units of C1 INH intravenously every 4 or 5 days, whereas the patient with acquired angioedema required 1000 units of C1 INH every 5 days. As a result of this long-term prophylaxis, both patients became free or nearly free from their episodes of cutaneous and internal edema. The low plasma levels of C1 INH, C4, and C2, rose. In the patient with acquired C1 INH deficiency, the swellings increasingly reappeared after 10 months, although the patient's antibody titer did not rise during treatment. No side effects were recorded during therapy. In particular, both patients remained HIV and hepatitis B antibody negative.

Angioedema↗
PubMed1990

Cloning and DNA sequencing of the fbc operon encoding the cytochrome bc1 complex from Rhodobacter sphaeroides. Characterization of fbc deletion mutants and complementation by a site-specific mutational variant.

The ubiquinol: cytochrome-c oxidoreductase (cytochrome bc1 complex) is a central component of the mitochondrial respiratory chain as well as the respiratory and/or photosynthetic systems of numerous prokaryotic organisms. In Rhodobacter sphaeroides, the bc1 complex has a dual function. When the cells are grown photosynthetically, the bc1 complex is present in the intracytoplasmic membrane and is a critical component of the cyclic electron transport system. When the cells are grown in the dark in the presence of oxygen, the same bc1 complex is a necessary component of the cytochrome-c2-dependent respiratory chain. The fact that the bc1 complex from R. sphaeroides has been extensively studied, plus the ability to manipulate this organism genetically, makes this an ideal system for using site-directed mutagenesis to address questions relating to the structure and function of the bc1 complex. In the current work, the cloning and complete sequence of the fbc operon from R. sphaeroides is reported. As in other bacteria, this operon contains three genes, encoding the Rieske 2Fe-2S subunit, the cytochrome b subunit, and the cytochrome c1 subunit. Recombination techniques were used to delete the entire fbc operon from the chromosome. The resulting strain cannot grow photosynthetically, but can grow aerobically utilizing a quinol oxidase. Photosynthetic growth is restored by providing fbc operon on a plasmid, and the reappearance of the protein subunits and the spectroscopic features due to the bc1 complex are also demonstrated. Finally, a mutation is introduced within the gene encoding the cytochrome b subunit which is predicted to confer resistance to the inhibitor myxothiazol. It is shown that the resulting strain contains a functional bc1 complex which, as expected, is resistant to the inhibitor. Hence, this system is suitable for the detailed characterization of the bc1 complex, combining site-directed mutagenesis with the biochemical and biophysical techniques which have been previously developed for the study of photosynthetic bacteria.

Amino Acid Sequence↗
PubMed2004

The effects of interferon-alpha2a on concentrations of immunoglobulins, complement and lymphocytes in patients with multiple sclerosis.

Multiple sclerosis (MS) patients treated with type I interferon experience reduced disease activity. Because immunoglobulins (Igs), complement and lymphocytes have been given a role in the pathogenesis of MS, we investigated the longitudinal effect of interferon-alpha2a (IFNA) on the variability of these parameters. Patients were treated for 6 months with 4.5 million international units (MIU) IFNA (24 patients), 9.0 MIU IFNA (21 patients) or placebo (23 patients). IFNA induced a significant increase in concentrations of total IgG and IgG subclasses 1, 3 and 4. At 6 months, the mean concentration of IgG had increased by 1.51 g/l (CI: 0.82, 2.21) in the 9.0 MIU IFNA group. There was no significant effect of IFNA treatment on concentrations of IgG2 and IgA, while the effect on IgM was borderline significant. After 6 months, IgM had increased by 0.29 g/l (CI: -0.01, 0.65) in the 9.0 MIU IFNA group. IFNA induced a significant increase in the concentration of C1 inhibitor (INH). At 3 months, the mean concentration of C1 INH had increased by 0.033 g/l (CI: 0.01, 0.05). At 3 months, C4 had increased by 0.05 g/l (CI: 0.01, 0.09) in the 9.0 MIU IFNA group. The effect of IFNA on C4 was inconclusive but indicates an effect during the initial phase of the treatment. C3 showed no significant treatment-mediated change. IFNA induced a significant decrease in lymphocyte concentrations by 0.56 x 106 lymphocytes/ml (CI: -0.81, -0.31) at 3 months. There were no significant associations between changes in immune parameters and changes in clinical and magnetic resonance imaging scores. The results verify that IFNA modulates and activates both the innate and the adaptive arms of the immune system. The observations should be of relevance when evaluating mechanisms of action of IFN treatment in MS.

Antineoplastic Agents↗
PubMed1999

C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model.

Xenotransplantation may be a future alternative due to increased shortage of organs. Classical complement activation is central in hyperacute rejection in pig-to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a regulator of the complement and contact systems, on hyperacute rejection. Pig kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or human serum albumin (n = 6) was added. The survival of the C1-INH perfused kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all) compared with the marked complement activation in the controls. No contact activation was found. Leukocytes and platelets were substantially activated (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P-selectin) in the control group, and this activation was markedly reduced by C1-INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement.

Animals↗
PubMed1984

Cold enhancement of blood coagulation: observations on the role of C1(-)-inhibitor.

The effect of incubation at 4 degrees C upon the one stage prothrombin times and the Thrombotest times of plasma from normal people, females taking oral contraceptive agents (O.C.A.'s) or in the third trimester of pregnancy, and patients with hereditary angioneurotic edema (H.A.N.E.) was measured to determine if enhancement of coagulant activity was regularly associated with reduced amounts of C1(-)- inhibitor (C1(-)-INH) in the plasma. Cold-enhanced coagulant activity was not always found in H.A.N.E. plasmas, markedly deficient in C1(-)- INH, and when found, the addition of purified C1(-)-INH to the plasma did not always prevent its development in vitro. Females taking O.C.A.'s regularly demonstrated cold-enhanced plasma coagulant activity in this series, as did pregnant females tested, as reported by others. The relation of C1(-)-INH levels in plasma to the cold-enhanced plasma coagulant activity was imperfect. In plasma obtained during pregnancy, but not exposed to 4 degrees C, C1(-)-INH levels were low despite minimal shortening of the Thrombotest time. Thus, these observations suggest that reduced levels of C1(-)-INH in plasma was not directly related to the tendency to generate enhanced coagulant activity at 4 degrees C. Other factors must be critical to the development of this activity, and the failure to block its development in C1(-)-INH deficient plasmas by adding purified C1(-)-INH at venesection suggests that events which initiate the development of this property may have occurred in vivo.

Angioedema↗
PubMed2005

C1-esterase inhibitor deficiency and elective caesarean section.

C1-esterase inhibitor deficiency is a rare disorder of the complement system characterised by episodes of cutaneous and mucosal oedema. Life-threatening airway oedema can follow airway instrumentation or minor trauma. We describe the successful management of a 37-year-old primiparous woman with inherited C1-esterase inhibitor deficiency who was admitted at 38 weeks' gestation for elective caesarean section. Whilst undergoing general anaesthesia 18 months previously she had experienced facial and pharyngeal oedema despite prophylaxis (one unit of fresh frozen plasma). On this occasion she underwent elective caesarean section following intrathecal anaesthesia with 0.5% hyperbaric bupivacaine 2 mL and diamorphine 300 microg. Cardiovascular stability was ensured using glycopyrolate and intravenous Hartmann's solution 2 L; a live female infant was delivered successfully. There were no peri- or postoperative complications. Regional anaesthesia is the safest method for providing surgical anaesthesia in the obstetric patient. We believe elective caesarean section under regional anaesthesia should be considered if there are predicted difficulties with vaginal delivery.

Adult↗
PubMed1978

[Treatment of hereditary angioneurotic edema with androgens].

Hereditary angioedema (HANE) is a rare, life-threatening disease due to the deficiency of C1 inhibitor (C1 Inh). Androgen therapy has been recently shown to be effective for prophylaxis of Hane attacks. Since life-long androgen therapy may be hazardous, this study was designed to define the minimal doses required for effectiveness. Ten patients from six different families were treated during cumulative 73 months by danazol and/for methandrostenolone. One tablet/day of either drug was the minimal requirement to prevent any attack in all patients. When 3 tablets/day were given, complement abnormalities were simultaneously rapidly reversed. When 1 tablet/day was given the biological effect was barely detectable, except for C2. Serum C2 levels may, therefore, represent the best criteria of androgen therapy effectiveness. Thus, an excellent clinical result can be obtained with much lower doses of androgens than previously stated. This result seemed important with respect to the serious dose-dependent risk of androgens.

Adult↗