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PubMed2002

Polyclonal autoantibodies against C1 inhibitor in a case of acquired angioedema.

BACKGROUND: Angioedema attributable to acquired C1 inhibitor (C1-INH) deficiency is a rare disease related to lymphoproliferative disorders or autoantibodies to Cl inhibitor. We describe a patient with angioedema and autoantibodies to C1 inhibitor. OBJECTIVE: To study the characteristics of autoantibodies to C1-INH in a patient with acquired angioedema. METHODS: Autoantibodies to Cl-INH were measured by enzyme-linked immunoadsorbent assay. Immunoglobulin (Ig)G autoantibody was purified by affinity chromatography on a protein G agarose column. We developed an enzyme-linked immunoadsorbent assay to determine whether the autoantibodies were directed against the C1-INH active center. RESULTS: IgM and mainly C1-INH IgG autoantibodies were detected; both had kappa and lambda chains. No monoclonal component was detected. The autoantibodies were directed against the Cl-INH active center. After various treatment strategies were attempted, an effective clinical response was attained with antifibrinolytic therapy. CONCLUSION: A case of acquired angioedema because of C1-INH deficiency was found to be attributable to the presence of polyclonal autoantibodies to C1-INH.

Aged↗

PubMed1999

[Hereditary or acquired angioedema caused by functional deficiency of C1 inhibitor--a still unfamiliar disease picture].

Hereditary angioneurotic oedema or hereditary angiooedema (HAE) and acquired angiooedema (AAE) are disorders of the C1-inhibitor (C1-INH) protein, caused by the lack, dysfunction or exhaustion of the C1-INH molecule. Inadequate function of C1-INH results in inappropriate control of various enzymes of the fibrinolytic, complement and kinin systems as well as of factor XII, being the initial enzyme of the kinin and contact coagulation systems. As C1-INH functional deficiency is rare and the clinical manifestation little known, even nowadays the most feared complication of the deficiency may evolve: death from acute airway obstruction. Patients deficient in C1-INH function whose clinical manifestations are misinterpreted as allergic angiooedema are most at risk for fatal laryngeal oedema. The therapy of allergic and C1-INH-related angiooedema is fundamentally different. The background for the hereditary form of inadequate C1-INH function is a gene defect. The predominant primary underlying disease of the acquired form of the deficiency (AAE) is a lymphoproliferative process.

Angioedema↗

PubMed1988

Molecular cloning of the cDNA coding for human C1 inhibitor.

A clone coding for the precursor form of C1 inhibitor has been isolated from a human liver cDNA library constructed in lambda gt11. This clone contains a cDNA insert of 1777 nucleotides, which includes 63 nucleotides coding for a signal sequence of 21 amino acids, 1434 nucleotides coding for the mature protein of 478 amino acids, a stop codon of TGA, and 265 nucleotides of the 3'-noncoding sequence followed by a poly(A) tail of 12 nucleotides. The predicted amino acid sequence of mature C1 inhibitor contains a unique region (positions 43 to 97) of 14 tandemly repeated copies of the tetrapeptide Gln-Pro-Thr-Thr and variants thereof. The carboxy-terminal sequence (positions 98 to 478) comprises the typical structural elements of a serine proteinase inhibitor (serpin). These findings indicate that C1 inhibitor is unique among the known members of the serpin superfamily due to the presence of an extra-domain of highly repetitive structure located at the amino-terminus of the inhibitor.

Amino Acid Sequence↗

PubMed1993

Influence of C1-inhibitor on inflammation, edema and shock.

C1-Inhibitor (Berinert, C1 INH), a 104 kDa protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation. C1 INH is used for the treatment of the hereditary angioneurotic edema. This paper will give a survey about the evidence in recent literature concerning the potential efficacy of the compound on other diseases associated with shock, capillary leakage and inflammation as well. In our own experiments we evaluated whether the compound could influence acute inflammatory reactions or the severe systemic inflammatory response syndrome (SIRS) as a consequence of an experimental septic shock. To prevent the sepsis-induced DIC we co-infused the thrombin inhibitors AT III or rec. hirudin in combination with C1 INH. Coinfusion of C1-inhibitor (50-200 U/kg x h) with either rec. hirudin or AT III significantly improved survival rate compared to thrombin inhibitor alone.

Angioedema↗

PubMed1993

Three-dimensional structure and molecular modelling of C1- inhibitor.

New data on the structure of C1- inhibitor have become available as the result of the completion of its amino acid and nucleic acid sequences and its carbohydrate content, together with data from neutron scattering, crystal structure determinations, 1H NMR spectroscopy and Fourier transform infrared spectroscopy. C1- inhibitor is a two-domain protein. It is constructed as a heavily glycosylated N-terminal domain with 113 amino acids and 3 N-linked and 7 O-linked oligosaccharides, and a C-terminal domain with 365 amino acids and 3 N-linked oligosaccharides. Its molecular weights is calculated as 71,100, rather than the apparent value of 105,000 commonly reported from SDS-PAGE. Neutron scattering shows that C1- inhibitor possesses a distinct two domain structure in which an extended N-terminal domain with extended carbohydrate structures is attached to the C-terminal SERPIN domain. The length of C1- inhibitor is 18 nm, rather than that of 33 nm originally proposed from electron microscopy. Microcalorimetry supports the concept of two independently-folded domains in the C1- inhibitor structure. Combination of the C1- inhibitor sequence with crystal structure determinations of proteins belonging to the SERPIN superfamily of serine protease inhibitors shows that the protein structure of the C-terminal domain is well-described in terms of this structure. Comparison of the exon structure of C1- inhibitor with its presumed protein crystal structure shows that the 7 exons are distributed throughout the SERPIN fold with no obvious segregation into structural elements. Native C1- inhibitor is cleaved at its reactive centre loop to release a more stable cleaved form that is no longer active. 1H NMR spectroscopy shows that structures involved in hydrophobic interactions within the core of the SERPIN fold are preserved to within 0.05 nm before and after the transition. Fourier transform infrared spectroscopy shows the presence of alpha-helix and beta-sheet in both forms. Large changes are detectable in both the alpha-helix and beta-sheet contents of the SERPIN fold, and these changes are matched by a greater rate of 1H-2H exchange in 2H2O solvents in the native form than in the cleaved form. These data show that changes in the whole secondary structure and not just in the reactive site loop are involved in SERPIN inactivation.

Amino Acid Sequence↗

PubMedDate not supplied

[Preparation and clinical assays of Cl esterase inhibitors].

Seven preparation of Cl-estrase inhibitor (Clinh) were prepared from the serum form which factor IX had been absorbed previously. Despite always the same technique and conditions of isolation the degree of Clinh recovery differed, being sometimes fairly low, and ranging from 24% to 56% in relation to the initial plasma. The preparations contained cartain amounts of other proteins from the groups of alpha- and beta-globulins, particularly coeruloplasmin and components of complement C3, C4 and C9. The concentration of these components was low in relation to the concentration of the inhibitor. Some preparations contained also low amount of albumins. The preparation (about 20 thousand Clinh units) was transfused to a patient with congenital deficiency of Cl-esterase inhibitor at the time free of symptoms. The investigation of the blood obtained 30 minutes after transfusion showed complete inhibition of C-L-esterase. Administration of the preparation to the patient at the time of acute oedema caused in 5 episodes rapid regression of oedema or inhibition of its increase, in two cases no evident positive effect was obtained.

Acute Disease↗

PubMed1992

Hereditary angioedema.

Hereditary angioedema is a rare disease resulting from a lack of functional C1 esterase inhibitor (C1 INH). Several genetic defects can cause decreased production of the protein or the synthesis of a biologically inactive form. A similar, acquired condition is occasionally seen, associated with malignancies or as an autoimmune process. Disease severity varies greatly among affected individuals. Most patients have cutaneous, laryngeal, or gastrointestinal edema, often in combinations. The symptoms may appear spontaneously or result from a stimulus, usually trauma. When clinical suspicion exists, measurement of the C4 level screens for the disease. An assay showing low serum C1 INH function confirms the diagnosis. When disease severity warrants, symptoms can be controlled with anabolic steroids or antifibrinolytics. Doses should be increased before symptom-provoking events. Emergencies are treated with plasma infusions, fluids, and pain control. Where available, C1 INH concentrate is the treatment of choice. Therapy can usually be monitored by control of symptoms. With appropriate therapy, most cases remain well controlled.

Adult↗

PubMed2005

[Angioedema in hereditary deficiency of complement factor 1 esterase inhibitor and alpha 1-antitrypsin].

HISTORY AND CLINICAL FINDINGS: A 15-year-old girl had suffered from episodic, sometimes threatening angioedema of the face, nasopharyngeal space and distal extremities beginning at age 13. EXAMINATIONS: A C1-esterase inhibitor (C1-INH) deficiency was revealed protein-chemically and functionally. There was also an alpha (1)-antitrypsin (AAT) deficiency with heterocygotic phenotype PiMZ. The combination of C1-INH and AAT deficiency was also found in the patient's mother and brother. THERAPY AND COURSE: Under 8-month therapy with 200 mg/d danazol per os (reduction of the dosis in the last month to 100 mg/d), there was no further edema, the C1-INH concentration normalized and there was also an increase in C1-INH function. During the observation period, use of the emergency set with C1-INH concentrate was not required. CONCLUSIONS: This is the first reported case of angioedema in combination of two hereditary enzyme defects C1-INH deficiency (autosomal-dominant genetics) and AAT deficiency (autosomal-recessive). In addition to a survey of current literature, the current state of diagnostics and therapy of the hereditary angioedema is presented.

Administration, Oral↗

PubMed1987

Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema.

Hereditary angioneurotic edema (HANE) results from deficiency of complement 1 inhibitor (C1 INH). In type I HANE, C1 INH is present in serum at levels 5-30% of normals. Using cultured monocytes and biosynthetic labeling of proteins, C1 INH was detected in supernatants of cells from HANE patients at levels 20% of those detected in normals. The intracellular reduction of C1 INH in patients' monocytes approached 50%. The study of C1 INH messenger RNA (mRNA) by Northern blot analysis indicated that in HANE patients' monocytes a message of normal size is present at about half the concentration of that from normal cells. One of the patients analyzed showed the presence of a genetically inherited abnormal mRNA (1.9 kb) in addition to the normal mRNA (2.1 kb). Southern blot analysis of DNA from peripheral blood leukocytes did not show any difference in quantity or in sizes of endonuclease restriction fragments between patients and normals. The defect(s), therefore, in type I HANE is pretranslational, but is not due to a deletion or to a major chromosomal rearrangement.

Angioedema↗

PubMed1988

Genomic and cDNA cloning of the human C1 inhibitor. Intron-exon junctions and comparison with other serpins.

Amino acid sequencing of trypsin fragments of C1 inhibitor gave regions of low codon degeneracy that were used for oligonucleotide probes. Human liver cDNA libraries gave clones containing most of the protein sequence, showing that the inhibitory domain belongs to the 'serpin' class of protein inhibitors. Fragments of these cDNA clones were used to probe human genomic cosmid libraries. The genomic sequence was found to be about 17 X 10(3) base pairs, with a coding sequence of approximately 1800 base pairs containing introns at amino acid positions--6, 162, 207, 275, 321, 395, and one in the 5' non-coding region. There is very little similarity of intron position amongst the serpin genes. All but one of the intron positions in the C1 inhibitor structural gene correspond to surface residues if C1 inhibitor is considered to have a structure similar to the cleaved form of alpha 1-antiproteinase. The serine and threonine residues in the N-terminal 100 amino acids of the sequence thought to carry complex carbohydrates are found in a single exon.

Amino Acid Sequence↗

PubMed1990

Immunoblotting of plasma in a pregnant patient with hereditary angioedema.

Hereditary angioedema (HAE), an autosomal disorder caused by a deficiency of C1 inhibitor, is characterized by attacks of localized swelling, laryngeal edema, or abdominal pain. Plasma samples from one pregnant patient were studied serially by functional and quantitative immunochemical assays as well as immunoblot assays for high molecular weight kininogen (HMWK) and/or prekallikrein/kallikrein (PK/K). An immunoblot of this patient's HMWK from plasma obtained before she became pregnant and when she was well revealed that it was mostly an intact protein of 120 kd, similar to immunoblot results of normal plasma HMWK. In plasma samples taken throughout her pregnancy, before, during, and after clinical attacks of angioedema, all of her plasma HMWK was shown to be cleaved into the 45 kd light chain form. After delivery of the infant the 120 kd form of intact plasma HMWK returned to her plasma. In comparison, immunoblot studies on 21 normal and abnormal pregnancies revealed that plasma HMWK was an intact protein at 120 kd. That this patient's plasma during her pregnancy was contact activated was determined by additional immunoblot studies for PK/K. Immunoblot assay for plasma PK/K revealed kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form seen only in activated plasma samples. The findings of kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form disappeared after delivery. These combined studies on this patient show that the structures of HMWK and prekallikrein as indicated by immunoblot assays were altered during pregnancy. Immunoblot assays for detection of changes in the structure of HMWK and prekallikrein may be objective laboratory studies for documenting clinical attacks of hereditary angioedema, their onset, and their resolution.

Adult↗

PubMed1998

Identification of a C-->T mutation in the reactive-site coding region of the C1-inhibitor gene and its detection by an improved mutation-specific polymerase chain reaction method.

Mutations in the C1-inhibitor (C1-INH) gene, leading to low functional levels of C1-inhibitor protein, cause hereditary angioedema (HAE). The disease is characterized by episodic edema in a number of organs. Typically, swellings occur in extremities and face, often accompanied by crampy abdominal pain. Laryngeal edema may lead to suffocation. Type II HAE patients have low functional C1-INH values stemming from only one normal allele. Antigenic C1-INH values, however, are normal or increased owing to the presence of a dysfunctional protein from the mutated allele. The mutations are usually found in exon 8 coding for the amino acids near the reactive centre (P1). Previously, no mutations in the C1-INH gene had been published from the Scandinavian countries. In this work, exon 8 of the C1-inhibitor gene was sequenced in members of two different kindreds, from western and northern Norway, who were suffering from HAE type II. A common point mutation was found within the bait region encoding the reactive centre. The codon CGC was converted to TGC at position 17970, corresponding to an Arg-->Cys replacement which reportedly is the second most frequent type II HAE mutation. This information was utilized to develop a mutation-specific polymerase chain reaction (PCR) for the identification of affected family members. The antisense 17-mer primer (5'-AAGACCAGCAGGGTGCA-3') was successfully applied and AmpliTaq Gold was used in the PCR.

Angioedema↗

PubMed1999

Angioedema due to acquired C1-esterase inhibitor deficiency in a patient with Helicobacter pylori infection.

The first component of the classical pathway of the complement system, C1 is regulated by a serum protein, the C1-esterase inhibitor (C1-INH). Deficiency of this protein leads to the release of vasoactive mediators (C2 kinin and bradykinin) that increase vascular permeability and can induce edema formation in subcutaneous and submucosal tissues. The genetic variant of C1-INH deficiency is inherited as an autosomal dominant trait and causes hereditary angioneurotic edema. The acquired form of C1-INH deficiency is characterized by similar manifestations and can occur in association with lymphoproliferative diseases, malignancy, immune disorders, and infections. The authors present a case of acquired C1-INH deficiency in a patient with Helicobacter pylori infection. Complete eradication of this pathogen was followed by the resolution of symptoms and normalization of serum complement levels. It seems therefore probable that in this patient, acquired C1-INH deficiency was related to Helicobacter pylori infection. To our best knowledge, no similar observations have been published so far. Specific immune reactions are important contributing factors in H. pylori. Excessive consumption of complement by antibodies directed against H. pylori is a potential cause of C1-INH deficiency observed in our case.

Adult↗

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↗

PubMed1999

Human homozygous type I plasminogen deficiency and ligneous conjunctivitis.

On the basis of a questionnaire sent to the ophthalmology departments of hospitals throughout Germany, 10 patients with ligneous conjunctivitis or pseudomembranous disease, ranging in age from 1 to 71 years were identified. All 10 patients had severely reduced plasminogen levels. Genetic analysis revealed homozygous type I plasminogen deficiency (which had not previously been described in humans) in 7 patients and compound heterozygous plasminogen deficiency in 1 patient. Clear differentiation was not possible in 2 patients. Most of the parents had heterozygous plasminogen deficiency. None of the patients had experienced any episodes of thrombosis. Additionally, the following observations were made: 1) Levels of polymorphonuclear (PMN)-elastase protein were markedly elevated in 6 of 6 patients and 10 of 11 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XII deficiency was found in 3 of 6 patients tested. 3) C1-inhibitor was elevated in 2 of 4 patients, prekallikrein was elevated in 1 of 4 patients, and plasminogen activator inhibitor type 1 was elevated in 1 of 4 patients. Infusions of lys-plasminogen concentrate induced pronounced fibrinolytic activity as indicated by high levels of D-dimer, increases in plasmin-antiplasmin complex and decreases in polymorphonuclear elastase. C1-inhibitor, prekallikrein and PAI-1 normalized after repeated infusions of lys-plasminogen. In contrast to dysplasminogenemia, severe type I plasminogen deficiency might be seen as a problem of extravascular space, in particular of the mucous membranes, possibly triggered by mechanically induced or inflammatory lesions of the vessels supplying the tissue.

Adolescent↗

PubMed2001

C1-inhibitor: an anti-inflammatory reagent with therapeutic potential.

Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis.

Animals↗

PubMed1989

Pathways of kinin formation and role in allergic diseases.

We have developed new assays for the assessment of the plasma kinin forming system which have increased sensitivity and specificity. We utilize double-antibody ELISA assays for quantitation of complexes of activated Hageman factor-C1 inhibitor, kallikrein-C1 inhibitor, and kallikrein-alpha 2-macroglobulin which reflect activation of each enzyme. The fraction of cleaved high-molecular-weight kininogen is determined by immunoblotting using a monoclonal antibody to the light chain, and bradykinin is determined by radioimmunoassay. Activation of the Hageman factor-dependent pathway of kinin formation can occur when plasma is in contact with initiating surfaces or when C1 inhibitor function is diminished. The latter mechanism can occur in hereditary angioedema, in which the protein is absent or dysfunctional, or when plasma is diluted so that the effect of inhibitors is diminished and Hageman factor autoactivation is facilitated. Thus apparent "spontaneous" generation of bradykinin is seen upon incubation of plasma of hereditary angioedema patients under conditions in which normal plasma is unaffected. Studies of late-phase reactions have used a cutaneous model in which induced blisters are unroofed and challenged with antigen or buffer control using chambers which can be changed hourly. A time course of mediator release is obtained by assay of the blister fluids. Whereas most histamine is released during the first half hour, significantly elevated levels of activated Hageman factor and kallikrein complexes with C1 inactivator are seen in antigen-challenged sites between 4 and 6 hr. The presence of such complexes correlated with the presence of late-phase reactions rather than the histamine values or the magnitude of the immediate reaction. Although late-phase reactions are characterized by cellular infiltration, release of a variety of inflammatory low-molecular-weight mediators, and deposition of fibrin, activation of the Hageman factor-dependent pathway of kinin formation is also likely to be contributory.

Angioedema↗

PubMed1996

Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema.

A complete mutational scan of the gene coding for the serpin C1 inhibitor, comprising all eight exons and adjacent intron sequences and 550 bp preceding the transcription start site, was rapidly accomplished in 36 unrelated angioedema patients by using fluorescence-assisted mismatch analysis (FAMA). Mutations accounting for C1 inhibitor deficiency were identified in every one of 34 patients, with two failures turning out to be spurious cases. Two new substitution dimorphisms were also detected in introns. Changes affecting the C1 inhibitor protein, distributed throughout the seven coding exons, provide new insights into the molecular pathology of serpins. Six different splice-site and two promoter mutations were also found. Among the latter, a C-->T transition within one of two putative CAAT boxes of this TATA-less promoter, the sole idiomorphic nucleotide change in this kindred, was found homozygous in the proband, at variance with the dominant mode of transmission observed for structural mutations. FAMA, in the chemical probes configuration used in this study, is a rapid and robust mutation-scanning procedure, applicable to large DNA segments or transcripts and proved capable of 100% detection. Moreover, it provides accurate positional information--and hence recognition of multiple substitutions, precise relationship with those already known, and often immediate identification of the nucleotide change.

Angioedema↗