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PubMed2000

Detection of C1 inhibitor mutations in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) results from a deficiency in the functional level of C1 inhibitor caused by mutations in the C1 inhibitor gene. The mutations responsible for HAE have been shown to be heterogeneous. OBJECTIVE: Because the identification of C1 inhibitor mutations may depend, in part, on the technique used to screen for mutations, we screened the entire C1 inhibitor coding region to identify mutations in a cohort of patients with HAE. METHODS: By using single-stranded conformational polymorphism analysis, 24 subjects with HAE from 16 different kindreds were screened for C1 inhibitor polymorphisms. C1 inhibitor mutations were identified by sequencing the exons containing identified polymorphisms. RESULTS: All 24 subjects with HAE had identifiable polymorphisms, involving exons 2, 3, 4, 5, or 8. Fourteen different C1 inhibitor mutations were identified: 8 missense, 1 nonsense, 4 frameshift, and 1 small deletion mutations. No large deletions or duplications were found. Nine of the 14 mutations represent newly recognized C1 inhibitor mutations, 6 of which involve exon 4. CONCLUSIONS: Single-stranded conformational polymorphism is an effective approach for identifying new mutations in HAE. Elucidation of the range of C1 inhibitor mutations causing HAE is important for both defining which residues are required for C1 inhibitor secretion or function and providing the basis for future studies to define the relationship between the C1 inhibitor genotype and disease severity.

Angioedema↗
PubMed2005

Hereditary angioedema.

PURPOSE OF REVIEW: Hereditary angioedema is an autosomal-dominant deficiency of C1 inhibitor--a serpin inhibitor of kallikrein, C1r, C1s, factor XII, and plasmin. Quantitative or qualitative deficiency of C1 inhibitor leads to the generation of vasoactive mediators, most likely bradykinin. The clinical syndrome is repeated bouts of nonpruritic, nonpitting edema of the face, larynx, extermities, and intestinal viscera. Recently, investigators, physicians, and industry have demonstrated a renewed interest in the biology and treatment of hereditary angioedema. RECENT FINDINGS: Investigators have generated a C1INH-/- mouse model that has demonstrated the importance of the contact activation system for hereditary angioedema-related vascular permeability. An interactive database of mutations is available electronically. Investigators have continued exploration into mRNA/protein levels. The proceedings of a recent workshop have been impressive in the scope and depth. Clinicians have produced consensus documents and expert reviews. The pharmaceutical industry has initiated clinical trails with novel agents. SUMMARY: Hereditary angioedema is often misdiagnosed and poorly treated. Diagnosis requires careful medical and family history and the measurement of functional C1 inhibitor and C4 levels. Attenuated androgens, anti-fibrinolytics, and C1 inhibitor concentrates are used for long-term and preprocedure prophylaxis, but have significant drawbacks. C1 inhibitor concentrates and fresh frozen plasma are available for acute intervention. The mainstays of supportive care are airway monitoring, pain relief, hydration, and control of nausea. New agents such as recombinant C1 inhibitor, kallikrein inhibitors, and bradykinin inhibitors may offer safer and more tolerable treatments.

Angioedema↗
PubMed1976

[Abdominal manifestations of hereditary angioneurotic edema. Importance of the exploration of the complement system (apropos of 29 families)].

Abdominal manifestations are almost constantly present (85% of cases) in the current form of hereditary Quincke's disease. In some cases, these abdominal manifestations occur even when cutaneomucosal edema is not present which leads to unwarranted often repeated and sometimes dangerous surgery. Apart from a story of heredity diagnosis of such troubles is possible, provided the total complement has been assayed to note its sharp fall. It can be subsequently explained by a functional defect of the C1 esterase inhibitor or alpha2-neuraminoglycoprotein.

Adolescent↗
PubMed1995

Complement components C1q, C1r/C1s, and C1INH in rheumatoid arthritis. Correlation of in situ hybridization and northern blot results with function and protein concentration in synovium and primary cell cultures.

OBJECTIVE: To analyze the synovial site and the cell types expressing C1q, C1r/C1s, and C1-esterase inhibitor (C1INH) and to characterize newly synthesized C1q in patients with rheumatoid arthritis (RA). METHODS: Tissue and primary cell cultures of synovium from RA patients were analyzed for C1q, C1r/C1s, and C1INH by Northern blotting, in situ hybridization, and pulse-chase experiments for C1q. RESULTS: The de novo synthesis of C1q, C1r/C1s, and C1INH in synovium and primary cell cultures was proven by Northern blot and by antigenic and functional analysis. In in situ hybridization experiments, the synovial lining cell layer was identified as the site of C1q, C1r, and C1INH expression. In contrast, immunohistologic analysis showed that C1q, C1s, and C1INH proteins were present in a thin film covering the synovial lining cells. In situ hybridization performed on primary cell cultures provided evidence that only macrophages were able to express C1q, whereas fibroblasts and stellate cells synthesized C1r. CONCLUSION: The synovium is important for the synthesis and secretion of C1q and C1r/C1s, as well as the control protein C1INH, which supports the idea of a locally occurring inflammatory process in RA patients.

Arthritis, Rheumatoid↗
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↗
PubMed1991

Substrate properties of C1 inhibitor Ma (alanine 434----glutamic acid). Genetic and structural evidence suggesting that the P12-region contains critical determinants of serine protease inhibitor/substrate status.

The serine protease inhibitor (serpin) C1 inhibitor inactivates enzymes involved in the regulation of vascular permeability. A patient from the Ma family with the genetic disorder hereditary angioedema inherited a dysfunctional C1 inhibitor allele. Relative to normal plasma, the patients's plasma contained an additional C1 inhibitor immunoreactive band, which comigrated with normal C1 inhibitor cleaved by plasma kallikrein, C1s, or factor XIIa. C1 inhibitor Ma did not react with a monoclonal antibody to a neoepitope that is present in complexed and cleaved normal C1 inhibitor, suggesting conformational differences between cleaved normal C1- inhibitor and cleaved C1 inhibitor Ma. Molecular cloning and sequencing of exon 8 of the C1 inhibitor Ma allele revealed a single C to A mutation, changing alanine 434 to glutamic acid. Ala 434 of C1 inhibitor aligns with the P12 residue of the prototypical serpin alpha 1-antitrypsin. The P12 amino acid of all inhibitory serpins is alanine, and it is present in a highly conserved region on the amino-terminal side of the serpin-reactive center loop. Whereas normal C1 inhibitor expressed by transfected COS-1 cells formed complexes with and was cleaved by kallikrein, fXIIa, and C1s, COS-1-expressed Ala434---Glu C1 inhibitor was cleaved by these enzymes but did not form complexes with them. These results, together with evidence from other studies, suggest that serpin protease inhibitor activity is the result of protein conformational change that occurs when the P12 region of a serpin moves from a surface location, on the reactive site loop of the native molecule, to an internal location within sheet A of the complexed inhibitor.

Amino Acid Sequence↗
PubMed2000

Expression of a complete and functional complement system by human neuronal cells in vitro.

We demonstrate in vitro expression of complement components, i.e. C3, factor H (FH), factor B (FB), C4, C1-inhibitor (C1-inh), C1q, C5, C6, C7 and C9, by four human neuroblastoma cell lines IMR32, SKNSH, SH-SY5Y and KELLY. Activating proteins C4, C9 and C1q, and regulatory proteins FH and C1-inh were produced constitutively by the four cell lines. C3, C6 and FB were mainly produced by SKNSH and SH-SY5Y. Western blot experiments showed that secreted proteins were structurally similar to their serum counterparts. An additional polypeptide of 43 kDa with FH immunoreactivity was detected, which could correspond to the N-terminal truncated form found in plasma. Regulation of complement expression by inflammatory cytokines, lipopolysaccharide and dexamethasone was tested in vitro. These factors had no significant effects on activating synthesis of components C3, FB and C4, but expression of regulating components C1-inh and FH was strongly increased particularly by IFN-gamma and tumor necrosis factor-alpha. The rate of synthesis of complement components was dependent on the differentiation of neuroblastoma cells. This effect of differentiation was also observed on normal rat neurons. Rat cerebellar granule cells constitutively expressed mRNA for C4 and C1q, but expression of C3 mRNA was induced by differentiation. This study shows that neurons could be another local source of complement in the brain, besides astrocytes and microglia. Human neuroblastoma cell lines can constitute an interesting model to analyze complement biosynthesis by human neurons. Local complement expression by neurons in vivo may be implicated in some physio-pathological processes.

Animals↗
PubMed1990

Hormonal regulation of complement biosynthesis in human cell lines--II. Upregulation of the biosynthesis of complement components C3, factor B and C1 inhibitor by interleukin-6 and interleukin-1 in human hepatoma cell line.

The effect of interleukin (IL)-6 and IL-1 on the biosynthesis of complement components C3, factor B, C2, C4 and C1 inhibitor (C1 inh), as well as that of albumin, was studied in vitro in human hepatoma-derived cell line, HepG2. Measuring the amounts of secreted complement proteins we detected a significant upregulation of C3 by both hormones. The enhancement of the factor B and especially that of C1 inh production was predominant by IL-6. In our experimental system neither IL-1 nor IL-6 affected the biosynthesis of C2 and C4. Albumin secretion was significantly decreased only in the simultaneous presence of IL-1 and IL-6. Detection of the changes in the amounts of C3- and factor B-specific mRNA of HepG2 cells suggests a pretranslational regulation by these cytokines. The secretion of C3 and factor B was markedly potentiated when IL-1 and IL-6 were added together. However only the gene expression of factor B, but not of C3, was found to reveal synergism. IL-6 enhanced the in vitro production of C3 in mouse hepatocytes as well. This effect was greatly potentiated in the presence of histamine.

Carcinoma, Hepatocellular↗
PubMed1986

Necrobiotic xanthogranuloma with paraproteinemia. A review of 22 cases.

Cutaneous biopsy specimens from 22 patients showed the distinctive histopathologic pattern of necrobiotic xanthogranuloma within the dermis or subcutaneous tissue (or both). Twenty of the 22 patients had 1 or more serum protein abnormalities, consisting of an IgG monoclonal protein in 16, multiple myeloma in 3, cryoglobulinemia in 3, and an abnormal serum protein electrophoresis in 1. Cutaneous lesions were seen as discrete, slowly developing red nodules and plaques with a xanthomatized hue and a predilection for the face (periorbital region in particular), trunk, and extremities. Ulceration was a notable finding in 10 patients. Histologically, the dermis and lobules of subcutaneous tissue were involved with a granulomatous infiltrate containing bands of hyaline necrobiosis and bizarre foreign body, as well as Touton giant cells. Cholesterol clefts, lymphoid nodules with or without germinal centers, and foci of plasma cells were variable but significant features. Leukocyte monoclonal antibody studies in 6 patients demonstrated helper T cells within the granulomas. Electron microscopy in 3 cases showed lipid vacuoles in macrophages in the dermis and dendritic cells in the epidermis, and study confirmed this entity as a non-X histiocytosis. Pertinent laboratory findings, in addition to the serum protein abnormalities, included elevation of the erythrocyte sedimentation rate, leukopenia with absolute neutropenia, and decreased serum complement levels, as well as decreased levels of C1-esterase inhibitor in some patients. Thirteen of the 22 patients have survived, the mean duration being 9.5 years after the onset of cutaneous disease. While given to only a few patients in the current series, low-dose chemotherapy seems to induce a favorable response in both the cutaneous and the hematologic disease.

Adult↗
PubMed1992

C1-inhibitor prevents PEG fractionation-induced, EDTA-resistant activation of mouse complement.

Fractionation of mouse serum by precipitation with a critical amount of polyethylene glycol 6000 (PEG; 11% w/v) results in a classical and alternative pathway-independent activation of the terminal complement route. The activation can take place after the separation of an activating principle together with the terminal route components from a natural regulator. The isolation and identification of the regulatory component preventing this activation in serum, is subject of this paper. The regulator was purified by fractionated PEG-precipitation (15-25%), followed by heparin-Sepharose affinity, Mono Q anion-exchange, and Superose 12 gel filtration chromatography. The regulator appeared to be a single-chain protein with a Mr of 96 k. A protein with similar activity purified from human serum had a Mr of 104 k and was functionally and antigenically indistinguishable from C1-INH. The mouse 96 k protein inhibited C1-esterase activity indicating that this protein is indeed C1-INH. Mouse C1-INH regulates the PEG fractionation-induced bypass activation of complement, but does not interfere with the assembly or the lytic activity of membrane attack complexes. alpha 2-Macroglobulin appeared also to be capable of inhibiting the PEG-precipitation-induced activation process, but with lower efficiency.

Animals↗
PubMed1992

Manufacture and in vitro characterization of a solvent/detergent-treated human plasma.

We have developed a modified solvent/detergent (S/D) treatment to inactivate viruses in human plasma using 1% w/w final concentration of tri(n-butyl) phosphate (TNBP) and Triton X-100 and an incubation period of 4 h at 30 degrees C. The procedure inactivates > or = 10(6) chimpanzee-infectious doses (CID50) of HBV, > or = 10(5) CID50 of HCV, and > or = 10(6.2) tissue culture infectious doses (TCID50) of HIV. After virus inactivation, eleven plasma batches were lyophilized and 12 batches were deep-frozen until further use. The batches were characterized by extensive laboratory tests including measurement of clotting factors I-XIII, von Willebrand factor, plasminogen, inhibitors of blood coagulation and fibrinolysis, and other clinically important plasma proteins. All parameters were determined before and after S/D treatment. Twelve conventional single donor plasma units served as control. There were no marked losses of activities of clotting factors, antithrombin III, protein C, plasminogen, and C1-esterase inhibitor due to treatment. After the S/D step, the levels of these parameters were within the normal range in all batches. The same holds true for total protein, immunoglobulins, albumin, complement factors C3 and C4, haptoglobin, hemopexin, caeruloplasmin, alpha 1-antitrypsin, and pH. Protein S and alpha 2-antiplasmin activities decreased by about 50% and were frequently found to be slightly below the lower limit of the respective normal range after treatment. The interindividual variations of all proteins analysed were significantly lower than in the single donor plasma units. The S/D procedure did not lead to increases of markers indicating activation of hemostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed1986

The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency.

The correct diagnosis and characterization of C1-inhibitor deficiency depends on both clinical observations and laboratory evaluation of complement in plasma. Rocket immunoelectrophoresis for C4d is a sensitive assay for C4 activation in plasma. We have evaluated the value of this assay in identifying patients with C1-inhibitor deficiency. C4 activation was assessed in the plasmas of 15 patients with hereditary angioedema, five patients with variant form of hereditary angioedema, and four patients with acquired C1-inhibitor deficiency. Control groups consisted of 27 patients with chronic idiopathic urticaria and/or angioedema and seven normal volunteers. C4 activation was detected in all 52 plasma samples collected from the 24 patients with C1-inhibitor deficiency. The degree of C4 activation increased during attacks of angioedema and decreased (but remained elevated) during treatment with attenuated androgens. The concentrations of C4, C2, and C1 inhibitor were also measured; however, none of these measurements identified all of the patients with C1-inhibitor deficiency. Thus, we conclude that the measurement of C4 activation is one of the best tests available to evaluate a patient for C1-inhibitor deficiency, and a normal result will exclude the diagnosis of C1-inhibitor deficiency.

Androgens↗
PubMed1985

[Current diagnostic possibilities in hereditary angioedema and acquired angioedema].

Amidolytic assays for the determination of C1 esterase inhibitor have been proposed some years ago; however, the substrates employed lacked sensitivity. The recent development of a C1 esterase-sensitive substrate (N-alpha-methoxycarbonyl-l-lysyl(epsilon-CBO)-glycyl-arginyl-4-nit roanilide) provides a method that can be routinely used. Any interferences with other plasma proteases could not be observed. Normal range was ascertained to be 1.48 +/- 0.23 kU/l; within-run precision revealed C.V.'s of 1.74% (for the normal range) and 7.3% (for the pathological range). This method can be considered most suitable for functional determination of C1 esterase inhibitor and is superior to the determination of antikallikrein activity. To point out to the diagnostic relevance of a functional C1 esterase inhibitor assay some examples are illustrated.

Angioedema↗
PubMed1980

Inhibition of the hypotensive effect of plasma protein solutions by C1 esterase inhibitor.

The hypotensive effect of stable plasma protein solution (SPPS) is a well-known phenomenon, causing serious problems in surgical patients and patients supported by cardiopulmonary bypass. Kinins are believed to be responsible. A study was made to prevent this hypotension by adding C1 esterase inhibitor to the SPPS and comparing this with 5% human albumin. The results shows a significant difference between the effects of SPPS and SPPS plus C1 esterase inhibitor infusion on bypass. Five percent human albumin did not cause hypotension. Possible sequelae are discussed.

Blood Pressure↗
PubMedDate not supplied

Activities of the MBL-associated serine proteases (MASPs) and their regulation by natural inhibitors.

There has been rapid progress in determining the mechanism by which complement is activated by the complex formed between Mannose-Binding Lectin and its associated proteases (MASPs). MBL and the MASPs are of low abundance, but are similar to the more abundant C1q-C1r2s2 complex (C1), which has been extensively investigated. In this review we summarise recent findings on MBL-MASPs' structure. enzymic activity and regulation, and compare MBL-MASPs with C1.

Animals↗