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PubMed1988

A mechanism for the spontaneous activation of the first component of complement, C1, and its regulation by C1-inhibitor.

We have developed a method to initiate spontaneous activation of the first component of complement in serum, by the removal of C1-inhibitor through complexation with added C1s. Preliminary experiments to test this method using C1 reconstituted from its purified subcomponents led to an unexpected result: pre-incubation of the reassembled subcomponents with C1-inhibitor, followed by its removal with C1s, altered the subsequent pattern of spontaneous activation. Thus, pre-incubation with C1-inhibitor at 37 degrees C for 1 h resulted in sigmoidal activation of C1 with a prolonged lag phase. In contrast, pre-incubation with C1-inhibitor on ice for the same time resulted in subsequent rapid, pseudo first order activation of C1 with a half-life of about 5 min. We have examined the activation kinetics under a variety of conditions, and our data are consistent with a model proposed by Lepow and coworkers in 1965, involving both spontaneous activation and C1 catalyzed activation: (1) C1----k1 C1 (2) C1----k2C1 C1 According to this model, the role of C1-inhibitor is to eliminate the second step by rapidly forming a tight complex with C1 which becomes irreversible at 37 degrees C. When C1s was added to normal human serum, activation at 37 degrees C was also sigmoidal, similar to that of reconstituted C1.

Complement Activating Enzymes↗
PubMed1975

[Acquired C1-esterase inhibitor deficiencies during lymphoid syndromes].

Very marked abnormalities of the complement system were discovered in two patients suffering from a lymphoid syndrome and an IgM 7S dysglobulinaemia. The abnormalities in the complement system were related to a deficiency in C1-estérase (C1 INH). Several findings suggest that such a deficiency is acquired, in particular the absence of any family history of angio-neurotic oedema and, above all, the detection of a marked fall in levels of the C1 fraction which does not exist in the congenital form of deficiency of the inhibitor. The IgM 7S immunoglobulins found in the serum of both patients are probably responsible for the abnormalities in the complement system observed. Such acquired deficiencies in C1 INH are extremely rare since only a few cases have been reported in the literaute, in particular two cases in patients with lymphosarcoma with a serum IgM 7S.

Aged↗
PubMed1993

Cleavage and inactivation of human C1 inhibitor by the human leukocyte proteinase, proteinase 3.

Incubation of highly purified human C1 inhibitor with equally pure human leukocyte proteinase 3, resulted in a dose- and time-dependent inactivation of C1 inhibitor hemolytic activity. Furthermore, this inactivation was accompanied by proteinase 3-dependent cleavage of the C1 inhibitor into an 83,000 molecular weight fragment. The formation of the 83,000 molecular weight fragment followed a time course which was similar to that observed for the inactivation of hemolytic activity. Within 120 minutes more than 90% of the hemolytic activity was lost. This inactivation of C1 inhibitor appeared to be selective as purified human C1q was not degraded in a similar time period. Moreover, when 100 micrograms IgG, isolated from each of 21 Wegener's granulomatosis patients with cytoplasmic anti-nuclear antibodies immunofluorescent titers to proteinase 3 greater then 1:64, was incubated with 3 milliunits of proteinase 3, little to no cleavage of C1 inhibitor was observed. In contrast, 100 micrograms of IgG isolated from 14 normal donors was ineffective in affording protection to C1 inhibitor upon incubation with proteinase 3. Our results suggest that neutrophil infiltration and activation could lead to local complement consumption at the tissue sites.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1985

Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins.

The syndrome of acquired angioedema and C1-inhibitor deficiency is associated with B-cell lymphoproliferative disease. It is characterized by accelerated consumption of C1q and C1 inhibitor in vivo and by low levels of serum C2 and C4. Four patients with B-cell malignant diseases (IgA myeloma, macroglobulinemia, chronic lymphocytic leukemia, and B-cell lymphoma, respectively) and acquired C1-inhibitor deficiency were found to have circulating antiidiotypic antibodies to the monoclonal immunoglobulin expressed on the surface of their B cells (three patients) or in the cytoplasm of their bone-marrow cells (one patient). Two of the four patients had circulating M components, and their antiidiotypic antibodies reacted with the M components. In three patients studied the percentage of B cells bearing C1q was 18, 24, and 35 per cent, as compared with 2.3 +/- 1.7 per cent (mean +/- S.D.) in six normal controls. These results suggest that an interaction between the idiotype of monoclonal immunoglobulins and antiidiotypic antibodies causes increased consumption of C1q and C1 inhibitor in patients with acquired angioedema and C1-inhibitor deficiency. We propose that the subsequent activation of the early components of complement leads to increased vascular permeability and to angioedema and that these patients have a disease caused by antiidiotypic antibodies.

Aged↗
PubMed1997

Beneficial effects of C1 esterase inhibitor in murine traumatic shock.

Activation of the complement system is an integral part of the initiation and maintenance of the inflammatory process such as that occurring in traumatic shock, and is considered responsible for much of the trauma-induced microvascular injury. We investigated the effects of early complement blockade induced by a C1 esterase inhibitor (C1 INH) in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension and a 83.3% mortality rate with a mean survival time of 157.5 +/- 26 min. Accompanying these effects were significant endothelial dysfunction and elevated intestinal myeloperoxidase activity. Treatment with C1 INH 15 mg/kg administered intravenously 10 min post-trauma, increases survival rate to 66.7% (p < .05), and prolonged survival time to 248 +/- 27 min (p < .05). C1 INH significantly preserved the endothelium-dependent relaxation to acetylcholine and attenuated the increase in myeloperoxidase activity in C1 INH-treated rats compared with untreated trauma rats (p < .05). Our results suggest that complement activation plays an important role in tissue injury associated with trauma, and that its inhibition at an early step in the complement cascade through a C1 esterase inhibitor is beneficial in rats experiencing traumatic shock. The mechanisms of the protective effect of C1 INH involves preservation of vascular endothelial function and diminished neutrophil accumulation leading to reduced neutrophil-mediated tissue injury.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

C1 inhibitor deficiency: management.

This is the second of two articles on C1 inhibitor deficiency based on a recent UK consensus document covering its diagnosis and management in adults and children. This summary focuses on the management of the disorder including prophylaxis, emergency treatment and special situations such as pregnancy and dental care.

Adult↗
PubMed1975

[Study of a large family with hereditary angioneurotic edema].

A large kindred (156 members) with hereditary angioneurotic edema is reported. 44 members of the family exhibit typical symptoms of the disease: recurring edemas of the skin and episodes of abdominal pain accompanied by vomiting due to mucosal edema in the stomach and intestine. In 32 patients complement studies were performed which in 28 cases revealed decreased levels of C1-inhibitor and almost normal values for C3 concentration. Among 21 members of the family who had never had symptoms of the disease, 7 also had low levels of C1-inhibitor. In 6 of 16 women, attacks often occur in conjunction with menstruation. In 9 of 10 women the symptoms of the disease had worsened during their first pregnancy. 8 patients have been successfully treated with tranexamic acid for 7-20 months.

Adolescent↗
PubMed1998

[Components of complement in patients with immediate hypersensitivity].

BACKGROUND: This prospective study was undertaken to assess the differences between the levels of the main plasma components of complement in allergic subjects and in those with pseudoallergic clinical manifestations. METHODS: Plasma C3 and C4 were evaluated in a total of 256 subjects examined consecutively at the allergology outpatients clinic of the Internal Medicine Division B, University of Turin. Total IgE and C1-inhibitor levels were also determined in 128 and 44 subjects respectively. RESULTS: C3 and C4 levels were not significantly different (p = 0.398 and p = 0.497) in 123 subjects with a positive and 133 with a negative prick test, nor in allergic subjects with respiratory as opposed to skin symptoms (p = 0.293 and p = 0.462), whereas the C-1 inhibitor was significantly lower (p = 0.046) in the respiratory subgroup. Total IgE was positively correlated with the C3 level (p = 0.036) in 75 allergic subjects. CONCLUSIONS: These findings suggest that plasma C3 and C4 values are not sufficient to discriminate IgE inflammation (positive prick test) and pseudoallergy (negative prick test) in the assessment of subjects with clinically suspected allergy. The positive correlation between IgE synthesis and C3 also points to an interaction between IgE synthesis and C3 regulation proteins in patients with IgE mediated diseases. Further investigation of other acute phase proteins (C reactive protein, fibrinogen) and the cytokines regulating their synthesis (IL-6) in such patients will help to clarify this correlation.

Adolescent↗
PubMed1995

[Life threatening angioedema caused by acquired C1 inhibitor deficiency associated with paraproteinemia and livedo racemosa].

A 61-year-old patient with life-threatening angioneurotic oedema was found to have an acquired C1-inhibitor (C1-INH) deficiency. In addition to lowered serum levels of C1-INH (both protein concentration and enzymatic activity), C2, C4 and CH50, which are characteristic for the hereditary form of angioneurotic oedema, markedly lowered C1q was found, which is typical for the acquired form. There were no antibodies against C1-INH. Repeated thorough examination disclosed no neoplasm, though the presence of neoplasm has often been reported to be associated with the acquired C1-INH deficiency. However, the patient showed persistent paraproteinaemia and paraproteinuria and developed livedo reticularis. Treatment with danazol resulted in a rise of the complement fraction levels and cessation of angioneurotic oedema. Paraproteinaemia and livedo reticularis persisted unchanged.

Angioedema↗
PubMed1986

Surface-bound capsular polysaccharide of type Ia group B Streptococcus mediates C1 binding and activation of the classic complement pathway.

The role of surface-bound type Ia group B Streptococcus (GBS) capsular polysaccharide in antibody-independent binding of C1 and activation of the classic complement pathway was investigated. In a radiolabeled bacterial-polymorphonuclear leukocyte (PMN) association assay, a measure of bacterial opsonization, preincubation of 3H-type Ia GBS with purified F(ab')2 to the organism blocked the association of the bacteria with PMN', and the inhibitory effect was dose dependent. The specificity of F(ab')2 blocking was shown after adsorption of F(ab')2 with type Ia polysaccharide-sensitized erythrocytes. Polysaccharide-adsorbed F(ab')2 had a 70% decrease in ability to block the association of bacteria with PMN. Evidence for the requirement of the capsular polysaccharide in classic complement pathway activation came from a C1 transfer assay with the use of neuraminidase-digested type Ia GBS. Neuraminidase digestion removed 80% of the terminal sialic acid residues from the native polysaccharide. These neuraminidase-digested organisms had a 72% decrease in binding and transfer of purified C1 compared with non-enzyme-treated organisms. Type Ia capsular polysaccharide bound to sheep erythrocytes promoted classic complement pathway-mediated hemolysis of the cells. The role of C1 inhibitor (INH) in modulation of C1 activation by the organisms was investigated. The possibility existed that the C1 INH could be bound by the bacteria, allowing C1 activation to occur in the fluid phase. The inhibitor was purified from human serum, and its activity was measured before and after incubation with type Ia GBS. The organisms had no effect on C1 INH activity. Thus surface-bound capsular polysaccharide of type Ia GBS mediates C1 binding and classic pathway activation, and this does not involve the C1 INH.

Adsorption↗
PubMed1986

Effects of protease inhibitor pretreatment on hemodynamic performances and survival rate in experimental, acute pancreatitis.

Acute pancreatitis was induced in pigs by manual retrograde injection of Na-Taurocholate into the pancreatic duct. Using chromogenic peptide substrate assays, increased plasma kallikrein activity (KK), paralleled by a reduction in functional plasma kallikrein inhibition values (KKI) were found in the peritoneal exudate in untreated animals. Several of the untreated animals experienced an increased trypsin activity (TRY) in the same exudate. Five out of eight animals died during a 6 hour observation period. Pretreatment with either Cl-INH or aprotinin given intravenously, resulted in a significantly increase in KKI capacity paralleled by unchanged KK and TRY activities in the peritoneal exudate. Furthermore, inhibitor pretreatment significantly improved hemodynamic performances (AP and CO) and the survival rate. The study underlines the pathophysiological importance of trypsin and the plasma kallikrein-kinin system during acute, severe pancreatitis.

Acute Disease↗
PubMed1987

Identical complement concentrations in blood obtained from central venous catheters, arterial lines, and antecubital phlebotomy.

In vitro complement activation has been detected during passage of blood through tubing used in hemodialysis and cardiopulmonary bypass surgery, in addition to tubing being investigated for vascular grafts. Because tubing from arterial lines and central venous catheters are composed of similar materials and are used when blood is withdrawn from patients for complement assays, a study was undertaken to assess the degree of complement activation in blood obtained from these sites. Complement activation was determined by a terminal complement complex enzyme-linked immunosorbent assay (ELISA), C1rC1s-C1 inhibitor complex ELISA, and 50% complement hemolytic activity (CH50) assay. Blood simultaneously obtained from the arterial lines and central venous catheters had identical terminal complement complex, C1rC1s-C1 inhibitor complex, and CH50 levels when compared with blood withdrawn by antecubital phlebotomy. Because blood may be obtained from the arterial lines and central venous catheters for complement assays, the pain and possible bruising from antecubital phlebotomy could be eliminated. Furthermore, blood may now be withdrawn from indwelling catheters without fear of in vitro complement activation causing a misinterpretation of results.

Arteries↗
PubMed1993

Acquired C1 inhibitor deficiency with lymphoma causing recurrent angioedema.

A 52 year old man who developed recurrent, massive and generalized angioedema for the first time during adult life was found to have an acquired deficiency of C1q esterase inhibitor (C1 INH) in association with a B cell lymphoma producing a paraprotein. He had low levels of C4 and C1 INH during the attacks which returned to normal after the successful treatment of lymphoma. An underlying lymphoproliferative disease should always be considered in adult patients with this immunological profile, recurrent angioedema and a negative family history.

Angioedema↗
PubMed1981

Circulating immune complexes, complement factors C3, C4, C1-inhibitor, alpha-1-antitrypsin and immunoglobulins in asthmatic patients.

Sera from 159 adult asthmatic outpatients (extrinsic, n = 82, intrinsic, n = 65 and acetylosalicylic acid (ASA)-sensitive, n = 12) and from 100 controls were tested for total levels of IgG, IgM, IgA, IgE, complement factors C3, C4, C1-inhibitor, alpha 1-antitrypsin and circulating immune complexes. The following results were observed: (1) a marked increase of IgE in extrinsic asthma; (2) a slight increase of IgM, and (3) an equal increase of complement C4 levels in all three asthma groups; (4) normal mean values of C3 levels with a significantly larger standard deviation of the mean in all three asthma groups; (5) an equally slight decrease of protease inhibitors, such as C1-inhibitor and alpha 1-antitrypsin, and (6) the presence of circulating immune complexes in 22% of extrinsic, in 8% of intrinsic and 13% of ASA-sensitive asthmatics. Circulating immune complexes can be found in all three asthma groups and may correlate with complement deviation.

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↗
PubMed1982

An association between C1 esterase inhibitor deficiency and lupus erythematosus: report of two cases and review of the literature.

Two patients who had lupus erythematosus and C1 esterase inhibitor deficiency are described. The data on eleven previously reported cases are reviewed and summarized with those from our own cases. Early complement component depletion secondary to C1 esterase inhibitor deficiency may predispose to the development of lupuslike syndromes by impairing the ability of the organism to handle foreign antigen. Further study of this unique group of patients may provide insight into the pathogenesis of immune complex disease.

Adolescent↗
PubMed1991

Human recombinant macrophage colony-stimulating factor (M-CSF) increases Cl-esterase inhibitor (Cl-INH) synthesis by human monocytes.

The ability of macrophage colony-stimulating factor (M-CSF) to influence production of complement proteins by cultured human monocytes was studied. Three-day-old cultures of human monocytes were treated with 250-1000 U/ml recombinant human M-CSF (Cetus Corporation, Emeryville, CA). After 3 days the M-CSF containing medium was replaced by the same medium without M-CSF, and the cells were cultured for 3 more days. Samples taken at the removal of M-CSF and 3 days later were tested for the concentration of factor B and Cl-esterase inhibitor (Cl-INH) using ELISA methods, and C2 by using an immunohaemolytic assay. M-CSF induced a marked dose-dependent increase in the synthesis of Cl-INH, but did not significantly change Bf and C2 production. The findings suggest that M-CSF is able to influence selectively the complement protein-producing ability of cultured human monocytes.

Cells, Cultured↗