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PubMedDate not supplied

[Biochemical data on C1 intrinsic activation (author's transl)].

C1 activation can be triggered by immune complexes and various effectors such as extrinsic proteases, bacterial or viral membranes, polyanions and polysaccharides. The basic mechanism of activation involves a limited proteolytic cleavage of C1r, with the generation of a proteolytic activity. Highly purified proenzymic C1r was obtained in high yield from human plasma by an indirect affinity chromatography step. Activation of isolated C1r in a fluid phase proceeded according to two distinct coexisting mechanisms: 1) an autocatalytic intradimer activation mediated by the pro-site of non-activated C1r; 2) an autocatalytic interdimer proteolysis triggered by nascent activated C1r formed in the course of the first reaction. DFP and C1-inhibitor did not have any effect on the first mechanism but were able to block the second mechanism. C1 activation is discussed in the light of recent results obtained by others from electron microscopy, and a tentative model is proposed.

Antigen-Antibody Complex↗
PubMed1999

Coincidence of hereditary angioedema (HAE) with Crohn's disease.

A patient with two diseases, based presumably on different immunopathological mechanisms, hereditary angioedema (HAE) and Crohn's disease, was followed for 8 years. For more than three years of this observation period, detailed laboratory data were also available and could be analyzed. Both diseases had severe courses requiring chronic treatment with danazol and sulfasalazine, respectively. During exacerbation of Crohn's disease, the levels of C4 was found to be significantly lower than during the periods free of symptoms of both diseases. This drop was probably due to an impaired C1-inhibitor activity. HAE attacks and acute exacerbation of Crohn's disease never occurred simultaneously. This finding may be a mere chance but may also indicate that the different immunopathological processes underlying HAE and Crohn's disease influence each other.

Adult↗
PubMed2006

[Episodes of angioedema in children with C1 esterase inhibitor deficiency].

A 6-year-old boy and a 3.5-year-old girl presented with unexplained episodes of angioedema without urticaria. Low serum C1 esterase inhibitor activity was found in both children. Family history revealed autosomal dominant inheritance in the girl. The boy had a negative family history for angioedema. C1 esterase inhibitor deficiency is a rare but serious condition that may cause oedema of the upper respiratory tract and death by asphyxiation. Episodes of angioedema occur spontaneously, usually subsiding within 48-72 h. Between episodes, the patients are symptom free. Treatment consists of substitution of synthetic C1 esterase inhibitor during episodes of edema carrying a risk of upper airway obstruction. In patients who have more than one episode of severe angioedema per month, daily treatment with tranexamic acid should be considered. Both of these patients were not receiving daily treatment.

Airway Obstruction↗
PubMed1997

Activation of the coagulation cascade in C1-inhibitor deficiencies.

Activation of the contact and complement systems in C1-inhibitor deficiencies is thought to contribute to the pathogenesis of angioedema attacks by releasing kinins. Trigger stimuli of attacks may also activate coagulation. This is particularly important because experimental data suggest that thrombin, the main enzyme of the coagulation cascade, increases vascular permeability and can thus influence edema formation. We have studied 19 patients with hereditary angioedema (HAE) during remission, 5 HAE patients during acute attacks, and 6 patients with acquired angioedema (AAE) during remission and during seven attacks. Thirty normal subjects, matched for sex and age, served as controls. Generation of thrombin was measured by enzyme-linked immunosorbent assay (ELISA) as plasma levels of the prothrombin fragment 1 + 2 (F1 + 2); the initiators of the tissue factor and contact coagulation pathways were investigated by measuring plasma levels of activated factor VII (FVIIa) coagulometrically and activated factor XII (FXIIa) by ELISA. Cleavage of high molecular weight kininogen (HK) was evaluated by immunoblotting analysis. F1 + 2 was slightly increased during remission and further significantly increased during attacks in both HAE (P = .0115) and AAE. FVIIa and FXIIa, normal during remission, increased strikingly during attacks in both HAE (P = .0022 and P = .0044) and AAE. During remission, cleaved HK was normal in HAE and high in AAE; during attacks it increased in HAE (P = .0008) and remained elevated in AAE. Our data indicate that in C1-inhibitor deficient patients there is increased generation of thrombin during attacks, with signs of activation of both the contact and tissue factor coagulation pathways. In conclusion, C1-inhibitor deficiency, whether hereditary or acquired, has demonstrable activation of the coagulation and kinin-forming cascades during attacks and that thrombin should be considered a possible contributing factor in the pathogenesis of edema in HAE and AAE.

Adult↗
PubMed1996

Hereditary angioedema caused by a point mutation of exon 7 in the C1 inhibitor gene.

Hereditary angioedema (HAE) is a genetic disease which may be detected serologically. We present a patient with HAE, in whom we examined the gene defect using the polymerase chain reaction. The patient presented with recurrent episodes of abdominal pain, or non-itchy swellings of the hands, feet, and penis. The serum levels of C1 inhibitor (C1-INH) and C4 were below normal. We determined that a single base change (C-->T) at nucleotide 1482 in the seventh exon was present in the C1-INH gene. This mutation converted the codon for the Gln-339 to a premature translation termination codon TAG. A point mutation in the C1-INH gene can cause type I HAE.

Adult↗
PubMed1994

[Necrobiotic xanthogranuloma in IgG kappa plasmacytoma and Quincke edema].

Necrobiotic xanthogranuloma is a non-X histiocytosis with unknown pathogenesis. It is associated with paraproteinaemia, and in rare cases with multiple myeloma. A decreased level of C1 inhibitor has been found in several cases without clinical manifestations of Quincke oedema. We report on a patient with necrobiotic xanthogranuloma and myeloma, in whom we found a decreased level of C1 inhibitor and recurrent episodes of manifest Quincke oedema. The indirect detection of auto-antibodies against the paraprotein with development of immune complexes is regarded as an explanation for the consumption of the C1 inactivator and the manifestation of Quincke oedema. The possibility of a causal relationship between paraproteinaemia and necrotic xanthogranuloma is discussed.

Adult↗
PubMed1976

Serum complement levels in recurrent aphthous ulceration. An intraindividual pilot study of sequential C3, C4 & C1 esterase inhibitor estimations.

No alterations on different occasions in serum complement levels could be detected in patients suffering from recurrent aphthous stomatitis. General laboratory tests were also normal and these findings are further evaluated in the discussion. It was also found that it is possible to store serum at very low temperature for months and still carry out rather sofisticated laboratory analysis.

Complement C1↗
PubMed2003

Clionasterol: a potent inhibitor of complement component C1.

Clionasterol (1a), clionasterol monoacetate (1b) and 5alpha,8alpha-epidioxy-24alpha-ethylcholest-6-en-3-ol (2), isolated from the marine sponge Xestospongia exigua, and beta-sitosterol (3) were tested for their influence on the classical (CP) and alternative (AP) pathways of activation of the human complement system in vitro. All the sterols inhibited the CP in a dose-dependent manner but no detectable effect was observed in the AP even at concentrations of 400 microM. Clionasterol was found to be a potent inhibitor of CP (IC50 = 4.1 microM) being ten-fold more active than beta-sitosterol. The presence of the epidioxy group on C-5 and C-8 of compound 2 caused a pronounced decrease of the inhibitory effect. Mechanistic studies on the anticomplementary effect of clionasterol revealed that it interferes with the complement component C1.

Animals↗
PubMed2002

[Recurrent attacks of angioedema ascribed to the use of estrogen preparations and a pregnancy (hereditary angioedema type 3)].

A woman experienced recurrent attacks of angioedema from the age of 17 to 21 years and these appeared to be associated with the use of oestrogens. After stopping the medication her complaints disappeared, but they returned during her first pregnancy. Angioedema is a serious condition, which can lead to acute abdominal symptoms, oedema of the upper respiratory tract and death by asphyxiation. The most well-known cause is hereditary angioedema, an autosomal dominant disorder that is characterized by deficiency of C1 esterase inhibitor (C1-INH). Recently, a new type of hereditary angioedema (type 3) has been reported that occurs exclusively in women and is characterised by oestrogen dependency (both endogenous and exogenous), normal C1-INH concentrations and severe attacks of angioedema, which are clinically indistinguishable from the classic form.

Abdominal Pain↗
PubMed2002

Autoimmune acquired form of angioedema that responded to danazol therapy.

A 51-year-old man with recurrent episodes of angioedema was diagnosed as having autoimmune acquired angioedema, based on adult onset, lack of apparent family history, decreased activity of C1 esterase inhibitor (C1 INH) and CH50, decreased levels of serum C4 and Clq and the presence of autoantibodies to C1 INH. The danazol treatment relieved the symptoms of angioedema and increased the C1 INH activity and concentration with the normalization of CH50, C1q and C4 levels. To our knowledge, this is the first case of autoimmune acquired angioedema in Japan.

Angioedema↗
PubMed1996

Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses.

OBJECTIVES: To study clinical and laboratory manifestations of hereditary angio-oedema (HAE). SUBJECTS: Thirty-three affected members of a kindred of 63. RESULTS: Oedematous attacks in the skin, mucous membranes and gastrointestinal tract with fluid displacement were elicited by mental and physical stress, minor traumas, dental and surgical procedures, eruption of teeth, tonsillitis, pregnancies, and use of oestrogen-containing pills including menopausal substitution. Every adult woman with symptomatic HAE (n = 11) showed symptoms of urinary tract infections in conjunction with the attacks (P = 0.010), and also experienced more spontaneous abortions or premature labours (P = 0.037) than healthy relatives. Patients with HAE of both sexes more frequently reported heartburn or peptic ulcers (P = 0.002). Rheumatic complaints were reported by 53% of HAE patients and 12% of their unaffected relatives (P = 0.013), but biochemical screening for 18 autoantibodies and quantitation of immunoglobulins did not reveal statistically significant differences between the two groups. C3, prekallikrein, total kininogen, high molecular weight kininogen (HK), alpha-2-macroglobulin and factor XII were not significantly different in HAE patients. In contrast, levels of C1-INH and C4 were depressed and cleaved HK increased in patients compared to unaffected relatives. CONCLUSIONS: HAE manifests in a variety of ways, and may influence risk of spontaneous abortions and premature labour.

Adolescent↗
PubMed2005

Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor.

The complement system presents a powerful defense against infection and is tightly regulated to prevent damage to self by functionally equivalent soluble and membrane regulators. We describe complement C2 receptor inhibitor trispanning (CRIT), a novel human complement regulatory receptor, expressed on hemopoietic cells and a wide range of tissues throughout the body. CRIT is present in human parasites through horizontal transmission. Serum complement component C2 binds to the N-terminal extracellular domain 1 of CRIT, which, in peptide form, blocks C3 convertase formation and complement-mediated inflammation. Unlike C1 inhibitor, which inhibits the cleavage of C4 and C2, CRIT only blocks C2 cleavage but, in so doing, shares with C1 inhibitor the same functional effect, of preventing classical pathway C3 convertase formation. Ab blockage of cellular CRIT reduces inhibition of cytolysis, indicating that CRIT is a novel complement regulator protecting autologous cells.

Amino Acid Sequence↗
PubMed1989

Complement biosynthesis in human synovial tissue.

Molecular biological and immunochemical techniques have been used to study the synthesis of complement components by synovial tissue from patients with rheumatoid arthritis or osteoarthritis and by normal synovial tissue from a patient undergoing patellectomy. Using Northern and dot-blot analyses, mRNAs coding for C1-inhibitor, C2, C3, C4 and factor B have been detected, but not for C5. Quantitative analyses of the data have not shown any significant differences in the steady state levels of any of the mRNAs in synovium from rheumatoid arthritis and osteoarthritis patients. When synovial membrane fragments from rheumatoid arthritis, osteoarthritis patients or normal synovium were cultured in vitro, synthesis of C1-inhibitor, C2, C3, C4 and factor B detected by ELISA and C2, C3 and factor B were shown to be functionally active. This study thus provides conclusive evidence that synthesis of complement components occurs locally within normal and inflamed synovial tissue. The local synthesis of complement within normal synovial joints may be of importance in their defence against infection, whereas in inflamed joints it may contribute to the inflammatory response.

Arthritis, Rheumatoid↗
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↗
PubMed1989

Studies on the dose dependence of endotoxin-induced in vitro activation of the complement system.

The dose and time dependence of in vitro endotoxin-induced activation of complement was studied in citrated pool plasma at 37 degrees C. C3 activation fragments (C3act) and the fluid-phase terminal complement complex (TCC) were used as indicators of initial and terminal activation, respectively. At 1 h marked elevation of C3act and TCC were found in plasma tested with the highest doses of endotoxin (2.10(9) and 2.10(8) ng/l). In test plasmas with 2.10(7) and 2.10(6) ng/l of endotoxin, no sign of activation was seen during the first 4 h, whereas both C3act and TCC values were increased at 12 h. In thest plasma with 2.10(5) ng/l of endotoxin and in control plasma no elevation of TCC values were seen during the observation period (24 h), whereas C3act values increased slightly and to the same extent in both at 24 h. Parallel to the increases in C3act and TCC concentrations, the functional C1 inhibitor (C1INH) values decreased. Changes in C1INH values, however, occurred with a time lag of approximately 6 h compared to the increases in C3act and TCC. Our in vitro study showed a dose-dependent endotoxin-induced activation of both the initial and the terminal part of the complement cascade evaluated by C3act and TCC.

Complement Activation↗
PubMed1980

Inhibition of immune complex-mediated activation of complement. Effects of agents modulating activation of, and the activated C1 complex.

Several known chemical compounds were shown to selectively inhibit the interaction between immune aggregates and C1q, the activation of C1r-C1s complex by immune aggregate-bound C1q, and the esterolytic activity of the activated C1s, C1s. These reactions are relevant to the functions of the first complement component, C1, and its activation induced by immune complexes. The effects of these inhibitors on tissue injury mediated by immune complex-induced complement activation, such as immune hemolysis, passive cutaneous anaphylaxis, and experimental glomerulonephritis were examined. The results suggest an approximate correlation between the activity shown on the molecular level and that obtained in vivo. One such compound, suramin, was shown to be an effective inhibitor of PCA and the proteinuria manifestation of EGN while not affecting antibody fixation to tissue or histamine-mediated skin reaction. These results suggest that effective suppression of the initial steps of complement activation may be of value of controlling immune complex-mediated tissue injuries in disease.

Animals↗
PubMedDate not supplied

Local and remote ischemia-reperfusion injury is mitigated in mice overexpressing human C1 inhibitor.

Activation of the classical complement pathway is crucially involved in complement-mediated endothelial cell damage in ischemia-reperfusion injury. C1 inhibitor is the only known physiological inhibitor of classical complement pathway activation. Transgenic mice overexpressing human C1 inhibitor were used in a surgical lower torso and a liver ischemia-reperfusion model. Organ-specific endothelial disruption was determined by 125I-tagged albumin extravasation. In the lower torso ischemia-reperfusion model, transgenic mice overexpressing the C1 inhibitor were protected in the muscle and the lungs from endothelial cell damage. In the liver ischemia-reperfusion model, endothelial cell integrity was preserved in transgenic animals in the liver, the gut and the lungs. Our data indicate that inhibiting complement activation by a transgenic approach is effective in protection against ischemia-reperfusion injury.

Albumins↗