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PubMed1990

Hereditary angioedema: diagnosis and management.

Hereditary angioedema is a rare autosomal dominant disorder due to the deficiency of functionally active C1-inhibitor. It is characterised by recurrent episodes of subcutaneous and mucosal edema. We report a case of hereditary angioedema presenting with the classic features of recurrent swelling of the extremities, abdominal pain and laryngeal edema. Serum complement C3 level was normal but C4 was low. She responded well to danazol and had no further attacks of angioedema.

Adult↗
PubMed1995

Control of contact activation on end-point immobilized heparin: the role of antithrombin and the specific antithrombin-binding sequence.

The uptake and activation of FXII from blood plasma was studied in small-diameter polyethylene tubing, surface-modified by end-point immobilization of heparin. Two preparations of heparin were used to modify the contact-activating properties of the plastic tubing: unfractionated, functionally active heparin and low-affinity heparin, lacking the specific antithrombin-binding sequence and virtually devoid of anticoagulant activity. The uptakes of FXII on the two heparin surfaces were similar. No activated FXII could be demonstrated on the unfractionated heparin surface, whereas on the low-affinity heparin surface nearly all FXII underwent spontaneous activation. The suppression of FXII activation on the unfractionated heparin surface was investigated by using plasma depleted of antithrombin, complement C1 esterase inhibitor, or both. The removal of antithrombin resulted in extensive activation of FXII, whereas the depletion of C1 esterase inhibitor had only a minor effect. Experiments with recalcified plasma showed rapid clot formation during exposure to the low-affinity heparin surface. After depletion of antithrombin, but not complement C1 esterase inhibitor, the recalcified plasma clotted in contact with the unfractionated heparin surface as well. We conclude that antithrombin and the antithrombin-binding sequence in the surface-immobilized heparin are essential for the prevention of surface activation of FXII and triggering of the intrinsic coagulation system.

Animals↗
PubMed1980

The Clq receptor site on immunoglobulin G.

We propose that, the binding site for the complement subcomponent Clq on immunoglobulin G involves the last two (C-terminal) beta-strands of the C gamma 2 domain. This region contains a large number of accessible and highly conserved charged residues and charge is postulated as an important component of the Clq-IgG interaction. The conclusions are reached on the basis of accessibility and sequence conservation analyses of C gamma 2 amino acid residues, the use of specific inhibitors and chemical modification studies.

Amino Acid Sequence↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

Successful management of a B-type cardiac allograft into an O-type man with 3(1/2)-year clinical follow-up.

BACKGROUND: In May 1997, a 19-year-old male patient of histo-blood group type O suffering from congenital end-stage heart failure accidentally received a cardiac allograft of type B and is still alive in fair condition. METHODS: In addition to conventional immunosuppressive therapy, plasma exchange (PEX), extracorporeal immunoabsorption (EIA), intravenous immunoglobulins (IVIG), and C1 inhibitor were used. RESULTS: Such treatment successfully reduced both IgM and IgG anti-B levels and complement hyperactivity and allowed to reach the state of accommodation without obvious signs of rejection. The patient has been surviving for 42 months; retransplantation with an O-type heart remained unnecessary. CONCLUSION: Humoral rejection has been avoided in this patient, with PEX, EIA, IVIG, and C1 inhibitor substantially contributing to this success. With future availability of such combined therapies, preferably before transplantation, vascular rejection events caused by preformed antibodies and complement (ABO mismatch or anti-HLA) could be prevented or treated.

ABO Blood-Group System↗
PubMed1997

Examination of baseline levels of carboxypeptidase N and complement components as potential predictors of angioedema associated with the use of an angiotensin-converting enzyme inhibitor.

OBJECTIVE: To determine if mean levels of complement components and carboxypeptidase N differed when comparing patients who exhibited angioedema following angiotensin-converting enzyme inhibitor therapy to those who received angiotensin-converting enzyme inhibitor therapy but did not have angioedema. DESIGN: Case-control study nested within an 8-week, open-label study of the use of quinapril hydrochloride for hypertension in 12275 patients. SETTING: Multicenter, with sites throughout the United States. PATIENTS: Of the 36 patients with angioedema described, 22 participated in the study. They were matched to 48 controls by age, sex, race, length of follow-up, and geographical region. INTERVENTION: All patients received quinapril therapy prior to participation in this case-control study. MAIN OUTCOME MEASURES: Levels of carboxypeptidase N, total hemolytic complement, C1 esterase inhibitor, and C4, along with questionnaire data, including a history of angioedema-like episodes and family history of angioedema. RESULTS: The 22 patients had significantly lower mean levels of carboxypeptidase N (kininase I) (P = .03) and C1 esterase inhibitor (P = .04) compared with the 48 matched controls, but all mean values were within normal laboratory ranges. A history of prior angioedema-like episodes was associated with an approximate 6-fold increase in the subsequent risk of angioedema following angiotensin-converting enzyme inhibitor therapy. CONCLUSIONS: Small differences in levels of carboxypeptidase N or C1 esterase inhibitor may contribute to an increased risk of angioedema with angiotensin-converting enzyme inhibitor therapy. Given the large overlap in the distributions of carboxypeptidase N and C1 esterase inhibitor levels, prior testing could not be used to evaluate angioedema risk for an individual patient considering angiotensin-converting enzyme inhibitor therapy. A history of prior angioedema-like episodes was associated with increased risk, but this result should be interpreted with caution because of possible recall bias.

Angioedema↗
PubMed2007

Treatment of hereditary angioneurotic oedema (HANE) with tibolone.

OBJECTIVE: Eight women, aged 25-58 years, with hereditary angioneurotic oedema (HANE) were treated with tibolone, a synthetic steroid exhibiting oestrogenic, androgenic and progestational activity. DESIGN: Pilot study. RESULTS: Tibolone at a dose of 2.5-7.5 mg/day significantly reduced the number and severity of attacks and the number of ampoules of C1-esterase inhibitor (C1-INH) needed for symptomatic therapy. The efficacy of tibolone was comparable to that of danazol, while the androgenic side-effects were considerably reduced. CONCLUSIONS: Tibolone may represent an alternative to danazol administration for the prophylaxis of HANE in women.

Adult↗
PubMed1988

[Changes in the kallikrein-kinin and complement system in angiography using non-ionic contrast media].

To examine alterations of the kallikrein-kinin system and of the complement due to the bolus injection of newer non-ionic contrast agents, venous blood samples were taken before and 3 min after angiography. There were no adverse contrast reactions clinically evident. Prekallikrein, kallikrein inhibition, beta-factor XIIa inhibition, C1-esterase inhibitor, C1q, C3, ATIII, HMW-kininogen, fibrinogen and factor XII were determined. Bolus injection of the contrast medium caused an activation of the kallikrein-kinin system (p less than 0.05) with reduction of prekallikrein, kallikrein-inhibition, beta-factor XIIa inhibition and C1-esterase inhibitor. The levels of C1q and C3 were also decreased (p less than 0.05) indicating an activation of the complement. Our results demonstrate, that angiography causes a significant activation of the kallikrein-kinin as well as of the complement system in spite of the use of newer non-ionic contrast agents.

Angiography↗
PubMed1987

Prekallikrein activation, C1 esterase inhibitor, and factor XII as predictors of adverse reaction to contrast media. A prospective study.

The susceptibility of 152 patients to idiosyncratic reactions resulting from the administration of radiographic contrast media was studied. The rate of activation of plasma prekallikrein was measured in samples taken from these patients before they received contrast agents. Kallikrein inhibitor and factor XII levels were also determined. The tests were of no value in selecting the ten patients who subsequently experienced mild reactions. However, the possibility remains that one or more of the tests may have predictive value for patients who experience moderate or severe reactions.

Complement Activating Enzymes↗
PubMed1991

Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements.

The complete (17159 bp) nucleotide sequence of the gene for the human C1 inhibitor has been determined. The transcription initiation site was examined by primer extension using human liver mRNA, and the messenger 5'-end sequence was determined on clones obtained by the anchored polymerase chain reaction. The gene of this serpin molecule is split by seven introns, with junctions of phases zero and one. An outstanding feature of the intron sequences is the occurrence of 17 AluI repeats of all four ancestral subgroups, indicating that the gene has been invaded during consecutive waves of Alu amplification, including a recent one. These Alu repeats form the sites of deletion and insertion in several known lesions in the C1-inhibitor gene. There is no obvious promoter site of the TATA-box type at the 5' end of the gene, but instead it contains a region of potential H-DNA structure similar to that found upstream of the human c-myc gene.

Amino Acid Sequence↗
PubMed1993

Recombinant C1 inhibitor P5/P3 variants display resistance to catalytic inactivation by stimulated neutrophils.

Proteolytic inactivation of serine protease inhibitors (serpins) by neutrophil elastase (HNE) is presumed to contribute to the deregulation of plasma cascade systems in septic shock. Here, we report a supplementary approach to construct serpins, in our case C1 inhibitor, that are resistant to catalytic inactivation by HNE. Instead of shifting the specificity of alpha 1-antitrypsin towards the proteases of the contact activation and complement systems, we attempted to obtain a C1 inhibitor species which resists proteolytic inactivation by HNE. 12 recombinant C1 inhibitor variants were produced with mainly conservative substitutions at the cleavage sites for HNE, 440-Ile and/or 442-Val. Three variants significantly resisted proteolytic inactivation, both by purified HNE, as well as by activated neutrophils. The increase in functional half-life in the presence of FMLP-stimulated cells was found to be 18-fold for the 440-Leu/442-Ala variant. Inhibitory function of these variants was relatively unimpaired, as examined by the formation of stable complexes with C1s, beta-Factor XIIa, kallikrein, and plasmin, and as determined by kinetic analysis. The calculated association rate constants (k(on)) were reduced twofold at most for C1s, and appeared unaffected for beta-Factor XIIa. The effect on the k(on) with kallikrein was more pronounced, ranging from a significant ninefold reduction to an unmodified rate. The results show that the reactive centre loop of C1 inhibitor can be modified towards decreased sensitivity for nontarget proteases without loss of specificity for target proteases. We conclude that this approach extends the possibilities of applying recombinant serpin variants for therapeutic use in inflammatory diseases.

Amino Acid Sequence↗
PubMed1982

[Acquired angioneurotic edema caused by acquired deficiency of C1 esterase inhibitor disclosing lymphoproliferative syndrome. Apropos of a case, review of the literature].

One case of acquired angio-neurotic oedema is described and discussed with the other cases recorded in literature since Caldwell's one in 1972. This entity is characterized by: --the late onset of angio-oedema but its presence only in about half cases, --a complement deficiency resulting from the lack of C1-esterase inhibitor, --the absence of familial identical cases, --the great frequency of associated illnesses overall lympho-proliferative diseases, --the therapeutic response to either etiologic treatment of the associated disease or to the symptomatic effect of drugs used in hereditary angio-neurotic oedema.

Aged↗
PubMed1988

Acquired angioedema: observations on the mechanism of action of autoantibodies directed against C1 esterase inhibitor.

We describe a mechanism of action of autoantibodies reactive with the C1 esterase inhibitor (C1EI) molecule found in three patients with acquired angioedema without associated diseases. All of these patients have a circulating C1EI of lower molecular weight than that of normal control subjects. When native C1EI was added to patient, but not control, plasmas, it was cleaved to a lower molecular weight fragment under conditions that allowed contact system activation. In a partially purified system, patient immunoglobulin preparations impaired stable complex formation between plasmin and C1EI and exaggerated the cleavage of the latter to a lower molecular weight fragment. We propose that the autoantibody does not interfere with the cleavage of the bait sequence of the inhibitor but reduces the availability of the reactive center of the molecule in a way that interferes with the irreversible inhibition of target enzymes. In this way unregulated activation of the kinin and complement pathways occurs, leading to disease manifestations via as yet uncharacterized mediators.

Angioedema↗
PubMedDate not supplied

Statin drugs do not affect serum complement activation in vitro.

Statin drugs prevent coronary heart disease through anti-inflammatory mechanisms in addition to the well-known reduction of low-density lipoproteins. The complement system plays an essential role in the inflammatory response and has been postulated to be modified by statins. A direct role for statins in complement activation, however, has not been previously investigated. We therefore studied the effect of statins on in vitro complement activation. Pravastatin, atorvastatin and the active metabolite of the latter, ortho-hydroxy atorvastatin, were added to normal human serum and incubated for 1 h in the absence or presence of aggregated immunoglobulin (classical pathway activation) or cobra venom factor (alternative pathway activation). The degree of complement activation, as detected by specific complement-activation products for the classical pathway (C1rs-C1-inhibitor complexes), the combined classical and lectin pathway (C4bc), the alternative pathway (C3bBbP) and the final common pathway (C3bc and TCC), was not affected by pre-incubation of the serum with any of the statins. Statins do not affect complement activation directly, but indirect effects in vivo may well be operative.

Atorvastatin↗
PubMed1994

A cluster of mutations within a short triplet repeat in the C1 inhibitor gene.

Mutations in the C1 inhibitor gene that result in low functional levels of C1 inhibitor protein cause hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and death. Among 60 unreported kindred with the disease, four patients were discovered to have mutations clustered within a 12-bp segment of exon 5 from nucleotide 8449 to nucleotide 8460. This short segment of DNA contains three direct repeats of the triplet CAA and is immediately preceded by a similar adenosine-rich sequence (CAAGAACAC). These triplet repeats make this region susceptible to mutation by a slipped mispairing mechanism. There are two other short triplet repeat elements in the coding region for this gene, but they have not become mutated in any kindred examined. This suggests that the apparent enhanced mutation rate in this region of exon 5 may be influenced by DNA structural characteristics.

Amino Acid Sequence↗
PubMed1986

Alpha 2-plasmin inhibitor-plasmin complexes in synovial fluid.

The role of the fibrinolytic enzyme system in inflammatory joint disease has been addressed by several experimental approaches. In our study we examined synovial fluid (SF) in several different diseases for alpha 2-plasmin inhibitor-plasmin complexes by an enzyme linked immunosorbent assay (ELISA). These complexes are present in both rheumatoid and nonrheumatoid SF, with highest levels seen in septic arthritis. Thus the plasminogen system is intact in inflammatory SF, and plasmin may play a role in the local inflammatory process.

Antifibrinolytic Agents↗
PubMed1986

Sheep serum complement sensitisation of sheep erythrocyte-rabbit antibody complexes for haemolysis by guinea-pig complement plus EDTA or Mg2+-EGTA.

Sheep erythrocyte (E)-rabbit antibody (A) complexes incubated with sheep serum diluted up to 1:5120 or 1:20480 and washed can be haemolysed by guinea-pig (g-p) serum (complement, C) containing EDTA or Mg2+-EGTA respectively as haemolytic finishing reagents. Sheep E carrying a high dose of rabbit A were necessary for this reaction, particularly with g-p C-EDTA. G-p serum (stored by freezing) was active as a haemolytic finishing reagent with both EDTA and Mg2+-EGTA. Reconstituted freeze-dried g-p serum (also stored by freezing) was haemolytically active with Mg2+-EGTA only. G-p serum preserved by Richardson's method did not function as a finishing reagent with EDTA or Mg2+-EGTA. A non-haemolytic prozone occurred with sheep E-rabbit A treated with dilutions of sheep serum or body fluid up to 1:160, particularly when g-p C (frozen)-EDTA was used as the finishing reagent. Sheep E-rabbit A were sensitized by serum, foetal lamb serum, pericardiac-, synovial- or ovarian follicle-fluids colostrum or milk for haemolysis by g-p C (frozen)-EDTA or -Mg2+-EGTA. With the C3 inhibitors cobra venom factor or salicylaldoxime, serum sensitisation of sheep E-rabbit A for haemolysis by g-p C (frozen)-EDTA or -Mg2+-EGTA was not blocked. Sensitisation by serum heated at 50 degrees C for 30 min (partial inactivation of C2) was incomplete. Inhibitors of C1 (antrypol, chelators of Ca2+ or heating serum at 56 degrees C for 30 min) partially or fully blocked sensitisation for haemolysis by both g-p C (frozen)-EDTA or -Mg2+-EGTA. These results show that at a minimum, components C1, C4 and C2 are present and functionally active in serum and some body fluids of sheep.

Animals↗