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Results for “Complement C1 Inhibitor Protein”

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PubMed1987

Altered C1 inhibitor genes in type I hereditary angioedema.

Hereditary angioedema is an inherited disease transmitted as an autosomal dominant trait and characterized by deficient activity of C1 inhibitor, a glycoprotein that limits intravascular activation of complement. The unavailability of markers for the C1 inhibitor locus has so far precluded access to the genetic bases of the disorder. Using a recombinant-DNA probe for the C1 inhibitor gene, we identified a cluster of four distinctive DNA restriction sites in a multigeneration family. The strict cosegregation of these markers with a low C1 inhibitor level supports the conclusion that a defective structural gene is responsible for the disease. The occurrence of distinct DNA markers in patients from unrelated kinships indicates that, like forms of the condition displaying dysfunctional C1 inhibitor variants, those characterized by protein deficiency are also genetically heterogeneous. Although multiple restriction-site changes in the C1 inhibitor gene are carried by certain patients, DNA markers for this locus are strikingly infrequent among normal persons. These findings indicate that the gene alterations responsible for hereditary angioedema arise more often from DNA rearrangements than from nucleotide substitutions. Such variations in the structure of the C1 inhibitor gene may provide the basis for early and direct identification of persons at risk.

Angioedema↗
PubMed1998

Complement and contact activation during cardiovascular operations in infants.

BACKGROUND: By comparing the results of cardiac operations with or without cardiopulmonary bypass (CPB) in infants in a prospective study, we sought to determine which part of the postoperative systemic inflammatory response was caused by CPB. METHODS: Thirty-five patients were divided into two groups: 11 infants operated on without CPB and 24 infants operated on with CPB. Blood samples were drawn before, during, and after the operation. We assessed complement function and the concentrations or activities of C1q, C3, C4, C1 inhibitor, factor B, the activated split product C3a, and prekallikrein and factor XIIa of the contact system. RESULTS: All of the patients exhibited a decrease of complement proteins. This was greater in infants who underwent CPB. A increase in C3a and factor XIIa and changes in prekallikrein activity occurred only in infants during CPB. CONCLUSIONS: Complement activation occurs in all infants, but is significantly higher in the group with CPB. Contact activation only occurs in patients who undergo CPB. Thus, the inflammatory response is caused by the use of a CPB circuit and to a lesser degree by surgical procedures and anesthesia.

Cardiac Surgical Procedures↗
PubMed1998

Complement activation in relation to capillary leakage in children with septic shock and purpura.

To assess the relationship between capillary leakage and inflammatory mediators during sepsis, blood samples were taken on hospital admission, as well as 24 and 72 h later, from 52 children (median age, 3.3 years) with severe meningococcal sepsis, of whom 38 survived and 14 died. Parameters related to cytokines (interleukin 6 [IL-6] IL-8, plasma phospholipase A2, and C-reactive protein [CRP]), to neutrophil degranulation (elastase and lactoferrin), to complement activation (C3a, C3b/c, C4b/c, and C3- and C4-CRP complexes), and to complement regulation (functional and inactivated C1 inhibitor and C4BP) were determined. The degree of capillary leakage was derived from the amount of plasma infused and the severity of disease by assessing the pediatric risk of mortality (PRISM) score. Levels of IL-6, IL-8, C3b/c, C3-CRP complexes, and C4BP on admission, adjusted for the duration of skin lesions, were significantly different in survivors and nonsurvivors (C3b/c levels were on average 2.2 times higher in nonsurvivors, and C3-CRP levels were 1.9 times higher in survivors). Mortality was independently related to the levels of C3b/c and C3-CRP complexes. In agreement with this, levels of complement activation products correlated well with the PRISM score or capillary leakage. Thus, these data show that complement activation in patients with severe meningococcal sepsis is associated with a poor outcome and a more severe disease course. Further studies should reveal whether complement activation may be a target for therapeutical intervention in this disease.

Adolescent↗
PubMed1987

Restriction fragment length polymorphism of the C1 inhibitor gene in hereditary angioneurotic edema.

Hereditary angioneurotic edema (HANE) results from the deficiency of the inhibitor of the first component of human complement (C1-INH). It is inherited as an autosomal dominant trait. Heterogeneity of this defect has been shown at the protein and mRNA level. Southern blot analysis of genomic DNA was performed after digestion with six different restriction endonucleases in 24 families affected with type 1 HANE (low antigenic and functional C1-INH levels) and five with type 2 (low functional C1-INH levels and normal or elevated levels of dysmorphic C1-INH). Blots were hybridized with a C1-INH cDNA probe of 1,227 bp. With one enzyme (Pst I), two different patterns of restriction fragment length polymorphism (RFLP) were detected. One was present in one kindred with type 1 HANE and the other appeared the same in one type 1 and in one type 2 family, thus indicating that each RFLP resulted from a different mutation. Analysis of a total of 34 members of these three families suggested that the polymorphisms are tightly linked to the mutation responsible for the disease. Using a 170-bp probe we showed that the three different mutations leading to these polymorphisms are located in the same region of the C1-INH gene. These data suggest that different mutations in the same region of the C1-INH gene are responsible for C1-INH deficiency in these families. Most of these mutations are probably point mutations or other "minor" defects and do not appear to be due to major deletions or rearrangements.

Angioedema↗
PubMed1991

Inactivation of human plasma C1-inhibitor by human PMN leucocyte matrix metalloproteinases.

Highly purified human polymorphonuclear (PMN) leucocyte matrix metalloproteinases, collagenase and gelatinase, cleaved human plasma C1-inhibitor at the carboxyl site of Ala439 (P6). This led to a concomitant loss of C1-inhibitor activity. An additional cleavage site, at the carboxyl site of Ser441 (P4), was observed during PMN leucocyte gelatinase-induced inactivation, and a minor fragment of the plasma C1-inhibitor was generated.

Amino Acid Sequence↗
PubMed1979

Complement and contrast material reactors.

Patients showing systemic reactions to intravascular contrast media and patients receiving contrast media without reaction have significantly different mean values (p is less than 0.05) for functionally determined serum C1-esterase inhibitor (C1 INH) and total hemolytic complement (CH50). The lower concentration of these components in reactors appears in baseline serum samples (as well as after injection), and suggests that many anaphylactoid reactions to contrast media are conditioned by earlier complement consumption, and result directly from contrast-induced activation of complement, and other activation system components in the presence of inhibitor depression.

Complement C1 Inactivator Proteins↗
PubMed1991

[Hereditary angioedema, a rare cause of recurrent abdominal pains. A report of 2 clinical cases and comments of a general nature].

Two clinical cases of recurrent abdominal pain are reported. These led to the unusual diagnosis of hereditary angioedema due to deficiency of C1 esterase inhibitor (C1-INH). The difficulties of identifying this genetic disease were caused by the variability of its clinical expression: the alteration of an autosomal dominant gene triggers angioedema attacks that may strike the cutaneous, gastroenteric and respiratory apparatus with differing intensity. Various subjects suffering from hereditary angioedema were found in the genealogical trees of the two patients, but all had extraintestinal symptoms of very variable intensity. Measurement of C4 and C1-INH made it is possible to identify in the first family a functional defect of C1 esterase inhibitor and in the second a quantitative defect in the same inhibitor.

Abdominal Pain↗
PubMed1984

Inhibition of the human tissue plasminogen activator in plasma from different species.

The rate and extent of complex formation between protease inhibitors present in plasma from different species and a human plasminogen activator purified to homogeneity from the supernatant of a human melanoma cell line was studied in vitro. The fibrinolytic activity of the one-chain plasminogen activator disappeared form human, cat and rabbit plasma with a half-life of 100 minutes. By means of antibodies directed against purified protease inhibitors the main inhibitor in human, cat, dog and rabbit plasma was identified as alpha 2-antiplasmin. Alpha 2-macroglobulin and C1-esterase-inhibitor functioned as inhibitors to a lesser extent. The main inhibitor in rat plasma was alpha 2-macroglobulin. The plasma half-life was 3 (rabbit and human) to 10 (dog and rat) times shorter for the two-chain form than for the one-chain form of the plasminogen activator molecule. It is also concluded that, with respect to plasma elimination of the fibrinolytic activity, among the common laboratory animals, the rabbit is the most suitable animal available for the study of fibrinolysis.

Animals↗
PubMed1990

A simple index for assessment of disease activity in patients with ulcerative colitis.

Based upon data from a prospective series of 61 patients with ulcerative colitis, most of them with the mild or quiescent form, a simple index for assessment of the disease's activity was devised. The activity index was the sum of three different scores evaluating history, macroscopic findings at endoscopy and microscopic findings in biopsy specimens, respectively. The index was consistent in itself and it may be of value in assessing spontaneous or drug-dependent variations in ulcerative colitis. The serum protein C1 inhibitor, belonging to the acute phase reactants, could not be shown to correlate significantly with the activity index or any of its components.

Adult↗
PubMed1997

Inhibiting the formation of classical C3-convertase on the Alzheimer's beta-amyloid peptide.

Amyloid plaques are the pathological hallmark of Alzheimer Disease (AD) brains, being found primarily in the hippocampus and neocortex, where AD pathology is most evident. Complement activation is associated with amyloid plaques which are made from fibrils of aggregated amyloid peptides, 39-42 amino acids long. In vitro studies show that aggregated amyloid peptides activate complement via the classical pathway, implying that amyloid plaques themselves cause complement activation in AD brains. In order to test this hypothesis, we sought to determine if a major peptide component of amyloid plaques, A beta 1-42, supports the formation of the classical pathway C3 convertase. Using normal human serum depleted of C3, we are able to detect C3 convertase activity on aggregated A beta 1-42 in vitro. The convertase activity is associated with the binding of C1q and activation of C4 on the aggregated peptide. Inhibitors of C1 esterase and the cation chelator EGTA both block the formation of the convertase activity. Congo red, a histochemical stain for amyloid deposits and an inhibitor of amyloid aggregation, reduces C3 convertase activity on aggregated A beta 1-42, indicated by decreased C3a production. Our results provide further evidence that aggregated A beta 1-42 alone is sufficient to serve as a nidus for complement activation, and thus may be involved directly in initiating the inflammation seen in AD brains.

Alzheimer Disease↗
PubMed1988

Synovial fibroblast-like cells synthesize seven proteins of the complement system.

Fibroblast-like cells from synovial tissue obtained during arthroscopy in 4 young adults with recent knee trauma were biosynthetically labeled with 35S-methionine, and protein production was quantitated by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Synovial fibroblast-like cells synthesized C1r, C1s, C1 inhibitor, C2, C3, factor B, and factor H, all with the same sizes and subunit structures as the proteins synthesized in skin fibroblasts. The capacity to synthesize these proteins was not lost with passages or freeze-thawing. Gamma-interferon stimulation increased synthesis of all 7 proteins. Lipopolysaccharide increased synthesis of only C3 and factor B. Unlike in whole rheumatoid tissue, C4 and C5 were not detected. Synovial lining cells may be an important source of local complement for participation in local defense or development of pathologic states.

Cell Adhesion↗
PubMed1984

The catabolism of C1(-)-inhibitor and the pathogenesis of hereditary angio-edema.

A sufficient explanation for the observations that HAE is a dominantly transmitted disease and that the hemizygotes have levels of the normal protein of only in the region of 15%-20% of normal can be given by proposing that a substantial proportion of the catabolism of C1(-)-esterase inhibitor involves the prior formation of a complex with one of the enzymes with which the inhibitor reacts. This part of the catabolism will be largely independent of inhibitor concentration, i.e. of zero order, and for this reason occurs similarly in normals and in hemizygotes. Estimates of the extent of this zero order metabolism can be obtained from turnover data with normal and dysfunctional C1(-)-inhibitor and the results are consistent with the observed levels. In the form of the disease associated with the dysfunction protein the dysfunctional protein makes up more than 85% of the total protein found for the same reason. The extent of the enzyme inhibitor complex dependent catabolism (RO) can be determined in vivo by simultaneous turnovers of dysfunctional and normal inhibitor and gives a measure of the extent of activation of this group of enzymes. The value of this technique in clinical practice is described elsewhere.

Angioedema↗
PubMed1995

Effects of C1-esterase inhibitor in three models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of C1-esterase inhibitor in three different models of acute pancreatitis: (1) Edematous pancreatitis with acinar cell necrosis was induced by 7-h ip injections of 50 micrograms/kg cerulein in mice; (2) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice; and (3) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 mL 5% sodium-taurocholate into the pancreatic duct in rats. C1-esterase inhibitor was given at 100 mg/kg iv before the onset of pancreatitis and at certain intervals thereafter. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase, by grading of histological alterations, and by determination of survival (survival determined only in models of hemorrhagic pancreatitis). In some of the models, C1-esterase inhibitor slightly ameliorated the degree of histological alterations; the increase in serum amylase was reduced by C1-esterase inhibitor only in CDE diet-induced pancreatitis. In all three models, C1-esterase inhibitor, however, failed to cause major beneficial effects and also failed to improve survival in taurocholate- and diet-induced pancreatitis. Additional studies in 12 patients with acute pancreatitis showed that C1-esterase inhibitor activity was markedly increased in serum of all patients during the first 9 d of the disease, suggesting that C1-esterase inhibitor behaves like an acute phase protein. Taken together the results from the animal and the human studies, C1-esterase inhibitor appears to only have a limited potential for treatment of acute pancreatitis.

Acute Disease↗