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PubMed1993

[Complement analysis tests].

Although routine analysis of the complement system is rarely demanded, it is important from a diagnostical and therapeutical point of view to include the relevant tests when clinically required. Complement analysis should be performed when hereditary angioedema (C1 inhibitor deficiency) is suspected, and as part of investigation of patients with immunodeficiency (recurrent infections in childhood). Furthermore, complement analysis may be required in cases of recurrent systemic neisserial infections at any age, and to follow up certain autoimmune diseases. Only a few tests are available for routine purposes. These are reviewed briefly, with emphasis on collection and storage of samples prior to analysis. It is important that these guidelines be followed, to avoid misinterpretation of the results.

Angioedema↗
PubMed1992

[Hereditary angioedema. Control and treatment in 7 cases].

Hereditary angioedema (HAE) is due to a deficit of the C1 inhibitor (C1 INH) of a dominant autosomic inheritance. Seven patients are presented from a family with HAE, four of whom with poor prognosis due to the frequency and site of the angioedema. Prophylaxis was obtained with long-term danazol since antifibrinolytic drugs are not efficient in the prevention of outbreaks of angioedema. In three cases a concentrate of C1 INH was administered and in another as short term prophylaxis prior to surgery. C1 INH was more efficient under these indications than fresh plasma or antifibrinolytic drugs.

Adult↗
PubMed1995

A mutation unique in serine protease inhibitors (serpins) identified in a family with type II hereditary angioneurotic edema.

BACKGROUND: Hereditary angioneurotic edema (HANE) is an autosomal dominant disease due to genetic alterations at the C1 inhibitor gene. Mutations within the C1 inhibitor gene are responsible for the molecular defect in type II HANE. Most of the dysfunctional proteins result from mutations involving the Arg-444 (the P-1 site of the reactive center) or amino acids NH2-terminal to the reactive center. MATERIALS AND METHODS: We have studied a Spanish family with type II HANE by using polymerase chain reaction (PCR) to amplify the exon eight of the C1 inhibitor gene. The purified 338-bp PCR product was subcloned and transformed into competent cells. After overnight cultures, we extracted the cloning vector from the positive colonies and sequenced both strands of the PCR product from each patient and healthy members of the family. RESULTS: We show that affected individuals in this family have a missense mutation, changing an adenine to cytosine in the codon 445. This substitution changes threonine at the P-1' site of the reactive center to a proline. This mutation generates a new restriction site, recognized by Bsi YI. CONCLUSIONS: To our knowledge, this is the first molecular defect characterized in a Spanish family with type II HANE, and to date, this is the first reported mutation at the P-1' site of the reactive center in individuals with type II HANE. This new mutation located at the reactive center emphasizes once more time the enormous heterogeneity of this gene.

Adolescent↗
PubMed1979

Hereditary angioedema: lack of close linkage with markers on chromosome 6, with data on other markers.

Members of two Australian families with type A Hereditary Angioedema (HAE), having affected individuals in three generations, were typed for a large number of genetic marker systems in a search for close linkage with the locus controlling C1 inhibitor (C1 inh). The evidence from both families indicated lack of close linkage with HLA or with the loci for Bf and GLO on chromosome 6. Very close linkage was also excluded between the locus for C1 inh and the loci for 6PGD, PGM1 and MNSs. The other markers were not informative, but data on all systems showing variation are reported. The publication of similar data for other kindreds will help to determine lod scores for the probability of linkage between the C1 inh locus and loci controlling common protein polymorphisms. Linkage studies of this kind could establish whether the loci controlling type A and B HAE are identical or separate.

Adult↗
PubMed1999

C1-esterase inhibitor reduces infarct volume after cortical vein occlusion.

In order to clarify the role of complement as a mediator of cerebral infarct growth, we inhibited the classical complement activation pathway in a photochemical cortical vein occlusion model. Immediately after occlusion, rats were infused with either 0.9% saline (vehicle), or C1-esterase inhibitor (C1-INH) over 30 min. Regional cerebral blood flow (rCBF) decreased after occlusion, and was about 50% of baseline after 2 h. No difference was noted between experimental groups. Mean arterial blood pressure (MABP) and arterial blood gases were likewise unaffected by the treatment. However, administration of C1-INH had significantly reduced infarct volume by 72%, as evaluated after 5 days survival. Thus, the neuroprotective effect cannot be explained by an improvement of cerebral perfusion but rather by protection of the parenchyma in the penumbra.

Animals↗
PubMed1985

Depressed classical complement pathway activities in chronic lymphocytic leukaemia.

Haemolytic activities of the classical and alternative complement pathways, and levels of C1, C4, C3, factor B and C1 inhibitor (C1-INH) were measured in 85 serum samples from 46 patients with chronic lymphocytic leukaemia (CLL). Significantly decreased mean C1 and C4 levels were found, and the haemolytic activities of these components were low or low normal in more than 50% of the sera tested. In 15 sera from 5 patients a complement profile characteristic of acquired C1-IHN deficiency was observed. These results indicate that the depression of the activity of the classical complement pathway is a frequently occurring feature in CLL.

Antigen-Antibody Complex↗
PubMed1979

Acquired C1 esterase inhibitor deficiency and angioedema: a review.

A case of acquired C1INH deficiency with angioedema is described. Fifteen cases are thus far recorded. The clinical syndrome of angioedema in these patients closely resembles hereditary angioedema (HAE). Most cases are associated with a paraprotein, cryoglobulin, or autoantibody, which presumably initiates C1 activation and C1 Inhibitor consumption. C1INH, C4 and C2 levels are low in acquired C1INH deficiency, as in HAE. A distinguishing feature is that C1 titers are very low in the acquired disease and only minimally depressed, if at all, in HAE. Most cases have appeared in patients with an underlying lymphoproliferative or autoimmune disease. Therapy is directed at the underlying disorder, but androgen therapy may be helpful in preventing attacks. Future potential therapeutic approaches are discussed.

Angioedema↗
PubMed1988

Hereditary angioedema in Czechoslovakia. Clinical, immunological, genetic and therapeutic studies of 16 families.

The analysis of the findings in 16 families with hereditary angioedema detected in Czechoslovakia over the years 1975-1986 is being presented. In 14 families C1-inhibitor deficiency and in two families afunction of C1-inhibitor was established. Of the total number of 175 examined family members C1-inhibitor defect was registered in 66 subjects (60 with deficiency and 6 with afunction), and of these 48 suffered from clinical symptoms of edematous attacks affecting the skin, larynx, intestine and urinary tract, whereas 18 subjects were asymptomatic. Genealogical studies confirmed that the defect is inherited as an autosomal dominant trait. In 16 patients long-term prophylactic treatment with Danol was introduced. The effective minimum dosage was tested individually for each patient.

Angioedema↗
PubMed1982

Familial angioedema associated with C1 esterase-inhibitor deficiency. A new genetic variant in hereditary angioedema?

In the absence of a positive family history for hereditary angioedema (HAE), both siblings in a family were found to have clinical and laboratory findings similar to those in HAE. Both siblings became symptom free after receiving danazol treatment, accompanied by a subnormal rise in C1 esterase inhibitor and C4 levels. As both siblings and their father share HLA haplotype A2, B7, the influence of other HLA loci on the clinical expression of this disorder should be considered. Although the disorder found in these siblings may be inherited as a recessive disorder, which to our knowledge has never been described before, or may have developed as the result of spontaneous genetic mutation, it is more appropriate to classify these two cases as familial angioedema until proved otherwise.

Adolescent↗
PubMed1988

The distortive mechanism for the activation of complement component C1 supported by studies with a monoclonal antibody against the "arms" of C1q.

A mouse monoclonal antibody (IgG1 isotype) against human C1q (MAb 130) is presented that activates C1 in serum through its antigen-binding sites at an optimal molar ratio of 3 MAbs:1 C1q. The antibody does not inhibit binding of C1q to IgG. Experiments with pepsin- and collagenase-digested C1q showed that MAb 130 binds to the fibril-like strands (arms) of C1q, close to the globular heads. Bivalency of MAb 130 was a requirement for C1-activation, but not for binding to C1q. Increasing the segmental flexibility of the intact antibody by reduction and alkylation destroyed its capacity to activate C1. A MAb against the globular heads of C1q completely inhibited C1-activation by aggregated IgG (AHG), but did not prevent activation by MAb 130. C1, reconstituted by adding C1q-stalks that lack the globular heads to C1q-depleted serum was not activated by AHG, whereas activation by MAb 130 was not affected. Activation of serum-C1 by AHG and MAb 130 was inhibited by addition of excess purified C1-inhibitor in a comparable and dose-dependent manner. Sucrose-gradient analysis indicated a predominance of stable complexes of a single C1q-molecule with three MAbs at the optimal activating ratio. When isolated and added to C1q-depleted serum, these complexes activated C1 efficiently. A mechanism for activation by MAb 130 is proposed that supports the "distortive" model of C1-activation.

Antibodies, Monoclonal↗
PubMed1992

Evaluation of the chromatographic procedure for the preparation of a high-purity C1-esterase inhibitor concentrate from cryosupernatant plasma.

This report is an analysis of the parameters involved in the preparation of a C1-esterase inhibitor concentrate. We investigated ways to improve the purification by finding the optimal pH, ionic strength, and quantity of chromatographic media to use at each step. The optimisation of the process gave a greater than two-fold increase in both yield and purity over published methods. The product retained more than 50% activity upon dry heat-treatment at 80 degrees C for 72 h, and the yield of the heat-treated product was 180 I.U./kg of plasma.

Chromatography↗
PubMed2003

Acquired C1-esterase inhibitor deficiency: a rare cause of episodic acute abdominal pain and ascites.

C1-esterase inhibitor deficiency is a rare yet classic medical cause of acute abdominal pain mimicking a surgical emergency. A hereditary form and a very rare acquired form of the disease exist, and both give rise to a similar clinical syndrome despite a different pathogenic mechanism. We describe a typical case of acquired C1-esterase inhibitor deficiency in a 65-year-old woman presenting with recurrent acute abdomen and ascites who had undergone two negative surgical interventions before diagnosis was eventually established. Both the diagnostic and therapeutic approach to this rare condition should be known by emergency physicians for two reasons: (1) it may present as an acute abdominal emergency resulting in unnecessary surgical intervention; and (2) it may cause life-threatening upper airway obstruction as a result of laryngeal oedema.

Abdominal Pain↗
PubMed1990

Clinical and experimental approaches to the prevention of atherosclerosis by immunological regulations.

To evaluate the involvement of the complement system in atherogenesis, we investigated the effect of camostat mesilate (CM), C1r, and C1 esterase inhibitor on cholesterol-induced atherosclerosis in rabbits. We also examined the effect of sodium dextran sulfate (DS, molecular weight: 7000), which is reported to be effective in preventing arteriosclerotic diseases and in inhibiting cholesterol-induced atherosclerosis in experimental animals, on complement activation in vitro and in vivo. The administration of CM reduced the formation of atherosclerotic lesions in cholesterol-fed rabbits. DS inhibited complement pathway in vitro, and the administration of DS reduced the C3a level in subjects. These results suggest that complement activation may possibly be involved in the atherosclerotic process.

Aged↗
PubMed1976

In vitro activation of C1s in plasma of patients with hereditary angioneurotic oedema.

The serum of patients with hereditary angioneurotic oedema contains small amounts of inhibitor of Cl-esterase (Cl-s) which is usually present in appreciable amounts in the serum of healthy individuals. In the citrated plasma of these patients in remission Cl-s activity was not detectable, but prolonged incubation with various alcohols, detergents, acetone, phenols and metal chelating agents generated the enzyme. Normal plasma did not respond to these reagents. The generation of Cl-s by alcohol and EDTA was inhibited by addition of natural inhibitor of Cl-s but not by soyabean trypsin inhibitor, trasylol and hexadimethrine bromide. Hexadimethrine bromide did not block the generation when experiments were carried out in silicon coated glassware. Incubation with kaolin and kallikrein generated Cl-s in remission plasma. Density gradient centrifugation studies showed that alcohol caused at least partial dissociation of Cl in remission plasma but not in normal plasma. This effect was similar to that of EDTA described in earlier reports. The possible explanations for the findings are discussed.

Alcohols↗
PubMed1979

C1q: isolation from human serum in high yield by affinity chromatography and development of a highly sensitive hemolytic assay.

C1q, a subcomponent of the first component of complement, has been isolated from human serum in fully hemolytically active form by affinity column chromatography and gel filtration with Bio-Gel A-5M. The affinity column was prepared by covalent coupling of purified human IgG to CNBr-activated Sepharose 4B. Final yields of C1q ranged from 25 to 40% with 650- 890-fold purification based on recovery of hemolytic activity. The preparations were free of contaminating serum proteins as judged by SDS-polyacrylamide gel electrophoretic and immunochemical criteria. The final C1q preparations were also devoid of any demonstrable C1q-inhibitor activity. A C1q-depleted reagent (C1qD) was obtained from the nonabsorbed protein containing fractions of the human IgG-Sepharose 4B affinity column and utilized in conjunction with sensitized sheep erythrocytes (EA) for the detection and quantitation of C1q hemolytic activity. Employing optimal quantities of C1qD in the hemolytic assay mixture, the highly purified C1q preparations contained 0.5 to 1 x 10(13) effective molecules/mg and 0.5 to 1 x 10(12) effective C1q molecules/ml of human serum. This assay would therefore reproducibly detect less than 1 ng of C1q hemolytic activity.

Chromatography, Affinity↗
PubMed1977

Rapid loss of factor XII and XI activity in ellagic acid-activated normal plasma: role of plasma inhibitors and implications for automated activated partial thromboplastin time recording.

Rapid prolongation of the aPTT of normal plasma upon incubation with ellagic acid containing aPTT reagents was observed. The aPTT prolongation was not due to time-dependent changes in pH in the incubation mixture or loss of activity of the labile coagulation factors VIII and V but occurred as a result of rapid progressive inactivation of ellagic acid-activated factors XII and XI. Prolongation of the aPTT and loss of contact factor activities was not observed in plasma incubated with particulate activator reagents. This finding seemed to indicate that adsorption of factors XII and XI to larger particles during the activation process might protect these factors from inactivation by naturally occurring plasma inhibitors. Evidence is presented which supports previous findings that C1-INH, alpha1-AT, and antithrombin (in the presence of heparin) contribute to factor XIIa and XI a inactivation in ellagic acid-activated plasma and that plasma albumin may compete with factor XII for ellagic acid binding. The data indicate that ellagic acid-containing aPTT reagents have unfavorable properties which seriously limit their usefulness in the clinical laboratory, particularly in respect to recording of the aPTT with certain fully automated clot timers.

Antithrombins↗
PubMed1975

Effects on serum complement of normal and pre-eclamptic pregnancy and of oral contraceptives.

The complement system was studied in normal gestation and puerperium, in pre-eclampsia and in women taking oral contraceptives. In 12 normal pregnancies, CH50 titres, C4, C3, C6 and C7 were increased throughout pregnancy; the serum concentration of C1 inhibitor was decreased in the last 2 quarters but greatly raised after delivery. Oral oestrogen-progestogen contraceptives also raised C3 but in contrast to pregnancy lowered CH50, C6 and C7. The different effects of pregnancy and of oral contraceptives may be due to materno-foetal immune reactions. In 9 patients with pre-eclamplsia, complement levels showed a wider scatter and a significantly higher C3 level than in normal pregnancy. Conversion of C3 to C3i was found in 2 of these patients.

Complement C3↗
PubMed1977

[Abdominal manifestations in hereditary acute angioneurotic oedema. Value of study of the complement system (author's transl)].

Four individuals of the same family suffered from a functional deficiency in C1 esterase inhibitor. In three of them, the manifestations of hereditary angioneurotic oedema were abdominal, paroxystic and pseudo-surgical. They were related to the development of visceral or mucosal oedema. The measurement of total complement (and of its fractions) during the acute episode, as well as dynamic complement studies between attacks, represent a simple method for indicating the probable diagnosis. Only estimation of the functional activity of C1 esterase inhibitor provides definite evidence. Familiarity with the clinical and biological characteristics of these acute abdominal episodes makes it possible to avoid repeated, unnecessary operations in these patients. They should be treated medically, under surgical surveillance, since a patient with angioneurotic oedema may have nevertheless a specific lesion, in addition. In addition, the episode may spread at any time, resulting in oedema of the glottis requiring tracheotomy or immediate intubation.

Abdomen, Acute↗