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PubMed1999

[C1-inhibitor].

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Complement C1 Inactivator Proteins↗
PubMed1987

In vitro effects of organic solvents on immunity indicators in serum.

Serum treatment in vitro with organic solvents (chloroform, ether, toluene) failed to produce an effect on immunoglobulin levels and activity. After chloroform and ether treatment, no complement activity could be determined, with chloroform-treated serum beginning to express anticomplement activity against autologous, allogenic and xenogenic sera. The classical pathway of complement activation (C1, C4, C2, C3) was primarily inhibited, whereas the alternative pathway remained unaffected. Chloroform-treated sera exhibited significantly declined levels of C1-INH, C3 and C4 as well as of circulating immune complexes. Toluene did not influence any of the parameters tested, while ether blocked complement activity without affecting either the concentration or activity of the other components under investigation. The obtained findings are discussed from the aspect of organic solvent applications in preparing immune products and determining immunity indicators in the serum or other biological fluids.

Antibodies↗
PubMed1979

[Essential cryoglobulinemia with accompanying angioneurotic edema].

A case report of a patient with essential cryoglobulinemia and episodes of angioedema caused by an acquired C1 inhibitor deficiency is presented. The patient had high levels of circulating immune complexes. In the course of complement activation C1 inhibitor may be consumed and the resulting C1 inhibitor deficiency led to the occurrence of angioedema.

Adult↗
PubMed2004

C1 inhibitor gene expression in patients with hereditary angioedema: quantitative evaluation by means of real-time RT-PCR.

BACKGROUND: Hereditary angioedema (HAE) is caused by heterozygous defects in the C1 inhibitor (C1-INH) gene (SERPING1/C1NH). In patients' plasma C1-INH levels range between 5% and 30% of normal levels (ie, far from the 50% expected for an autosomal dominant defect). Most patients have antigenic and functional deficiency (type I HAE), and 15% have reduced C1-INH function but normal to increased antigen because of the presence of a dysfunctional protein (type II HAE). OBJECTIVE: We sought to contribute to the understanding of the pattern of C1-INH gene expression in patients with HAE. METHODS: We used real-time quantitative RT-PCR to measure C1-INH mRNA levels in PBMCs of 57 patients with HAE typed for mutations in the SERPING1/C1NH gene. RESULTS: Thirty-six different mutations were identified in genomic DNA. Compared with healthy control subjects, C1-INH mRNA was significantly and similarly reduced in patients with type I and type II HAE (40% and 47%, respectively; P <.0001). By means of direct sequencing of cDNAs, we found that 74% of patients with type I HAE carrying small mutations presented significant amounts of mutated transcripts at the mRNA level, suggesting that both allelic mRNA products were reduced to approximately 50%. In 4 patients carrying large deletions expected to fully inactivate expression from the mutant allele, C1-INH mRNA was 23% on average compared with that seen in control subjects, confirming that normal mRNA was strongly underexpressed. CONCLUSIONS: These new findings, combined with previous evidence of increased C1-INH consumption, might explain the plasma levels of normal C1-INH that are markedly less than the expected 50%.

Angioedema↗
PubMed2007

Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes.

BACKGROUND: Hyperacute rejection (HAR) and early graft failure (EGF) have been described in a minority of pig-to-baboon heart transplants using organs transgenic for human complement regulatory proteins (hCRP). Here we investigate the role of coagulation cascade activation in the pathogenesis of HAR and EGF in a consecutive series where a high incidence of these outcomes was observed. METHODS: Twenty-eight naïve wild-caught Papio anubis baboons received heterotopic heart transplants from pigs transgenic for hDAF (n = 23) or hMCP (n = 5). Immunosuppression consisted of cyclosporine A, cyclophosphamide and MMF (n = 18) or anti-CD154 mAb (IDEC-131) and ATG (n = 10). Eleven received anti-Gal carbohydrates (GAS914, n = 8, or NEX1285, n = 3), of which four also underwent extracorporeal immunoadsorption (EIA), and 12 also received pharmacologic complement inhibitors (C1 INH, n = 9, or APT070, n = 3). RESULTS: Excluding one technical failure, 14 of 27 transplants (11 hDAF, 3 hMCP) exhibited either HAR (n = 10) or EGF (n = 4). Surprisingly, neither complement inhibition (with C1 INH or APT070) nor anti-Gal antibody depletion with GAS914, NEX1285, or additional EIA consistently prevented HAR or EGF despite low or undetectable complement deposition. Strikingly, most grafts with HAR/EGF exhibited prominent fibrinogen and platelet deposition associated with systemic coagulation cascade activation, consistent with non-physiologic intravascular coagulation, in many instances despite little evidence for antibody-mediated complement activation. CONCLUSION: We conclude that dysregulated coagulation correlates closely with and probably causes primary failure of pig hearts transgenic for hCRP. These data support efforts to define effective strategies to prevent dysregulated coagulation in pig organ xenografts.

Acute Disease↗
PubMedDate not supplied

[Hereditary angioedema. A report of a case and literature review].

Hereditary angioedema is a congenital disorder with recurrent attacks of localized swelling of submucosal and subcutaneous tissue, or both caused by a deficiency of the plasma protein C1 inhibitor. It is caused by heterozygous defects in the C1 inhibitor gene located on chromosome 11q, and it has an autosomal dominant inheritance pattern. This disease afflicts 1 in 10,000 to 1 in 150,000 persons. Hereditary angioedema has been reported in all races, and no sex predominance has been found. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems, and it can affect the upper airways resulting in severe life-threatening symptoms, including the risk of asphyxiation. There are three types of hereditary angioedema, which difference lies in the inheritance pattern and in the C1 esterase inhibitor and C4 concentrations. The treatment is complicated and it should be treated with intravenous purified C1 inhibitor concentrate; corticosteroids, antihistamines and epinephrine can be useful adjuncts but they are not effective. We report a patient with hereditary angioedema type 1 and make a review of the medical literature.

Adult↗
PubMed1999

A 'de novo' arisen case of angioedema C1-inhibitor deficiency dependent: possible mutagenic effect of azathioprine?

It is reported that a C1-inhibitor (CI-INH) deficiency dependent angiodema case arose 'de novo' in a child without a family history of this disease. His mother was undergoing immunosuppressive therapy (50 mg of azathioprine plus 8 mg of methyl-prednisolone daily) during pregnancy, uninterrupted for seven years because of a kidney transplant. All the other known causes of acquired C1-INH deficiency were excluded. An involvement of an azathioprine-induced C1-INH gene mutation is hypothised.

Angioedema↗
PubMed2003

Recombinant human C1-inhibitor produced in Pichia pastoris has the same inhibitory capacity as plasma C1-inhibitor.

Therapeutic application of the serpin C1-inhibitor (C1-Inh) in inflammatory diseases like sepsis, acute myocardial infarction and vascular leakage syndrome seems promising, but large doses may be required. Therefore, a high-yield recombinant expression system for C1-Inh is very interesting. Earlier attempts to produce high levels of C1-Inh resulted in predominantly inactive C1-Inh. We describe the high yield expression of rhC1-Inh in Pichia pastoris, with 180 mg/l active C1-Inh at maximum. On average, 30 mg/l of 80-100% active C1-Inh was obtained. Progress curves were used to study the interaction with C1s, kallikrein, coagulation factor XIIa and XIa, and demonstrated that rhC1-Inh had the same inhibitory capacity as plasma C1-Inh. Structural integrity, as monitored via heat stability, was comparable despite differences in extent and nature of glycosylation. We conclude that the P. pastoris system is capable of high-level production of functionally and structurally intact human C1 inhibitor.

Cloning, Molecular↗
PubMed1991

Modulation of complement gene expression by glucocorticoids.

The addition of dexamethasone, prednisolone or cortisol (in order of efficacy) to human monocytes in culture produced dose-related increases in the synthesis rates of the complement components C1 inhibitor (C1-inh), factor B (B) and C2. In contrast, concentrations of C3 and lysozyme in the culture supernatants were decreased. Indomethacin stimulated synthesis of C1-inh, C2 and B, but had little effect on synthesis of C3 or lysozyme. The simultaneous addition of cycloheximide (2.5 micrograms/ml) abrogated the effects of dexamethasone on synthesis of C2, B and C1-inh, but the effect of indomethacin on the synthesis of these components was unchanged. These data suggest that protein synthesis is required for the effects of glucocorticoids on the synthesis of C2, B and C1-inh to occur. Dexamethasone and indomethacin increased the abundances of C1-inh mRNA, B mRNA and C2 mRNA in parallel with changes in the synthesis rates of these proteins. The changes in mRNA abundance were not transcriptional, but were shown to be due to increased mRNA stability. In contrast, dexamethasone decreased the expression of C3 and lysozyme by decreasing the rate of transcription of these genes. Indomethacin had no effect on transcription of the C3 and lysozyme genes. The half-lives of C3 mRNA, lysozyme mRNA and actin mRNA were not altered by dexamethasone or indomethacin. It is concluded that the effects of glucocorticoids on monocyte synthesis of C2, B and C1-inh are due to increased mRNA stability and may be related to inhibition of prostaglandin synthesis, as these effects are similar to those produced by indomethacin. The effects of dexamethasone on the synthesis of C3 and lysozyme differ from those on C2, B and C1-inh as they depend upon a decrease in gene transcription, which is not affected by indomethacin.

Cells, Cultured↗
PubMedDate not supplied

[Immunologic parameters in chronic urticaria].

Urticaria and angioedema are common disorders that affect approximately 1/5 of the population at some stage in their lives. Although the clinical diagnosis of this disorder is made without difficulty, its etiology and pathogenesis remain obscure. Extensive clinical studies and the application of different laboratory techniques seldom manage to detect the etiology of chronic urticaria or determine its supposed pathogenic mechanism. Thus, a large number of causal agents have been held responsible for the symptoms of chronic urticaria and/or chronic urticaria and angioedema and for the variety of immunologic and nonimmunologic factors involved in its pathogenesis. The controversial laboratory findings in this type of patients prompted us to undertake this study on 48 subjects with chronic urticaria and/or angioedema. We studied the levels of serum immunoglobulins (IgG, IgA, IgM and IgE), the haemolytic activity of the complement (CH50), the levels of the complement components (C1 inhibitor, C3 and C4), the possible presence of circulating immune complexes and the percentages of the T lymphoid subpopulations (using OKT3, OKT4 and OKT8 markers) and the B population. The results obtained showed an alteration of the complement (CH50) and of some of its components (C3 and C4) as well as of the cytotoxic/suppressor lymphocyte subpopulation (OKT8).

Adult↗
PubMed1981

Inhibition of C1-mediated immune hemolysis by monomeric and dimeric peptides from the second constant domain of human immunoglobulin G.

Activation of the classical complement cascade by immunoglobulin G involves binding of the first complement component (C1) to a multivalent antigen-IgG complex. Binding occurs by interaction of a site on the surface of the C gamma 2 domain of IgG with a globular head of the C1q subcomponent of C1. Previously we found that the synthetic decapeptide consisting of residues 281-290 from the second constant domain of the gamma-chain of the human IgG1 protein Eu inhibited the binding of human C1 to sensitized erythrocytes. The present study describes inhibition of monomeric and dimeric peptides containing residues 289-292 or 282-292: (formula: see text). On a molar basis, monomeric peptide 282-292 is just as active an inhibitor of C1 binding as peptide 281-290, whereas monomeric peptide 289-292 (tuftsin) is 4 times less active. Peptides 282-292 and 289-292 were each cross-linked at the amino terminus through terephthaloyl-bis(iminodiacetic acid) (Tid). Each dimeric peptide is twice as active on a molar basis as the corresponding monomeric peptide. Dimeric peptide Tid(282-292)2 is just as active on a molar basis as the monomeric 7S form of human IgG1 and 60% as active as the Fc fragment of IgG in inhibiting the binding of human C1 to sensitized erythrocytes. These results suggest that the positively charged residues His-285, Lys-288, Lys-290, and Arg-292, which are located on the outer surface of the C gamma 2 domain, may be involved in the C1q-binding site of human IgG.

Animals↗
PubMed2006

Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury.

Complement activation augments myocardial cell injury and apoptosis during ischemia/reperfusion (I/R), whereas complement system inhibition with C1 inhibitor (C1INH), a serine protease inhibitor, exerts markedly cardioprotective effects. Our recent data demonstrate that C1INH prevents vascular endothelial cell apoptosis and a "modified" form of the reactive center loop-cleaved, inactive C1INH (iC1INH) plays an anti-inflammatory role in endotoxin shock. The aim of this study was to determine whether C1INH protects against myocardial cell injury via an anti-apoptotic activity or anti-inflammatory effect. In a rat model of acute myocardial infarction (AMI) induced by I/R, administration of C1INH protected against cardiomyocytic apoptosis via normalization of ratio of the Bcl-2/Bax expression in the myocardial infarct area. C1INH improved parameters of cardiac function and hemodynamics and reduced myocardial infarct size (MIS). In addition, myocardial and blood myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, was decreased by treatment of C1INH. In cultured H9c2 rat cardiomyocytic cells, C1INH blocked hypoxia/reoxygenation-induced apoptosis in the absence of sera associated with inhibition of cytochrome c translocation and suppression of caspase-3 activation. The proportion of Bcl-2/Bax expression induced by hypoxia/reoxygenation was reversed by C1INH. Importantly, iC1INH also revealed these similar effects, indicating that C1INH has a direct anti-apoptotic activity. Therefore, these studies support the hypothesis that C1INH, in addition to inhibition of activation of the complement and contact systems, improves outcome in I/R-mediated myocardial cell injury via an anti-apoptotic activity independent of serine protease inhibitory activity.

Animals↗
PubMed2002

In vivo biosynthesis of endogenous and of human C1 inhibitor in transgenic mice: tissue distribution and colocalization of their expression.

We have produced transgenic mice expressing human C1 inhibitor mRNA and protein under the control of the human promoter and regulatory elements. The transgene was generated using a minigene construct in which most of the human C1 inhibitor gene (C1NH) was replaced by C1 inhibitor cDNA. The construct retained the promoter region extending 1.18 kb upstream of the transcription start site, introns 1 and 2 as well as a stretch of 2.5 kb downstream of the polyadenylation site, and therefore carried all known elements involved in transcriptional regulation of the C1NH gene. Mice with high serum levels of human C1 inhibitor, resulting from multiple tandem integrations of the C1 inhibitor transgene, were selected. Immunohistochemistry in combination with in situ hybridization was applied to localize the sites of C1 inhibitor biosynthesis and to demonstrate its local production in brain, spleen, liver, heart, kidney, and lung. The distribution of human C1 inhibitor-expressing cells was qualitatively indistinguishable from that of its mouse counterpart, but expression levels of the transgene were significantly higher. In the spleen, production of C1 inhibitor was colocalized with that of a specific marker for white pulp follicular dendritic cells. This study demonstrates a stringently regulated expression of both the endogenous and the transgenic human C1 inhibitor gene and reveals local biosynthesis of C1 inhibitor at multiple sites in which the components of the macromolecular C1 complex are also produced.

Animals↗