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PubMed2004

The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q.

C1-inhibitor (C1-INH) is a major regulator of the complement classical pathway. Besides this action, it may also inhibit other related inflammatory systems. We have studied the effect of C1-INH in C57BL/6 mice with focal transient brain ischemia induced by 30 minutes of occlusion of the middle cerebral artery. C1-INH induced a dose-dependent reduction of ischemic volume that, with the dose of 15 U/mouse, reached 10.8% of the volume of saline-treated mice. Four days after ischemia the treated mice had significantly lower general and focal neurological deficit scores. Fluoro-Jade staining, a marker for neuronal degeneration, showed that C1-INH-treated mice had a lower number of degenerating cells. Leukocyte infiltration, as assessed by CD45 immunostaining, was also markedly decreased. We then investigated the response to ischemia in C1q(-/-) mice. There was a slight, nonsignificant decrease in infarct volume in C1q(-/-) mice (reduction to 72.3%) compared to wild types. Administration of C1-INH to these mice was still able to reduce the ischemic volume to 31.4%. The study shows that C1-INH has a strong neuroprotective effect on brain ischemia/reperfusion injury and that its action is independent from C1q-mediated activation of classical pathway.

Animals↗
PubMed1996

Antibody to C1-inhibitor in a patient receiving C1-inhibitor infusions for treatment of hereditary angioneurotic edema with systemic lupus erythematosus reacts with a normal allotype of residue 458 of C1-inhibitor.

Patients with hereditary C4 deficiency are likely to have severe lupus erythematosus. A patient with hereditary angioneurotic edema (HANE) and systemic lupus erythematosus (SLE) had a chronic deficiency in C4 because the hereditary deficiency in C1-inhibitor allowed the C1 in her serum to become activated and then inactivate C4. An attempt was made to repair the C4 deficiency as well as the deficiency in C1-inhibitor by giving infusions of human C1-inhibitor in the hope of inducing remissions of both HANE and SLE. During treatment, antibody to C1-inhibitor developed in the patient; this cleared when the infusions were stopped. During subsequent treatment with danazol alone, measurable C1-inhibitor developed in the patient's serum, but levels of C4 were never significantly increased. Antibody to normal C1-inhibitor was not expected to develop in the patient because she is heterozygous for this autosomal dominant trait. A normal allotype (VAL or MET 458), which would have been in the preparation used but which the patient does not synthesize because she can produce only one allotype (MET 458), appears to have been immunogenic. The antibody isolated from the patient's serum reacted with C1-inhibitor from a normal individual known to be homozygous for 458-VAL but not with one from a homozygote for MET-458.

Adult↗
PubMed1985

Atypical hypocomplementemic vasculitis syndrome in a child.

We report a patient who developed recurrent urticaria and angioedema at age 2 years, severe hypocomplementemic glomerulonephritis at 11 years, and end-stage renal disease at 14 years. His disease resembled the hypocomplementemic vasculitis syndrome but was atypical in its early age of presentation, severe hypocomplementemia, and progression to end-stage renal disease. Serum C1q levels were extremely low, and C4, C2, C3, and C5 levels were significantly reduced. Serum C1 inhibitor (C1INH) levels were slightly low, presumably from consumption. Circulating C1INH-C1r-C1s complexes were evidenced by reduced ratios of functional to antigenic C1INH and antigenic C1r to C1s. Family members had normal functional and antigenic levels of all complement components studied. The patient's serum, erythrocytes, platelets, and mononuclear cells did not activate complement when mixed with normal target serum. Absence of a circulating complement activator and the low serum C3 and C5 levels suggested the presence of a solid-phase complement activator, possibly related to renal or systemic vascular endothelium. As in patients with homozygous deficiencies of classical pathway components, a severe, prolonged, acquired C1q deficiency may have predisposed this patient to the development of glomerulonephritis.

Angioedema↗
PubMed2003

Human C1 esterase inhibitor attenuates murine mesenteric ischemia/reperfusion induced local organ injury.

BACKGROUND: Complement activation contributes to ischemia and reperfusion (IR)-initiated organ injury. C1 inhibitor (C1 Inh) inhibits the earliest steps of the classical and the mannose binding lectin pathways. MATERIALS AND METHODS: To determine whether C1 Inh prevented tissue injury, we performed intestinal IR experiments in BALB/c and C57BL/6 mice. RESULTS: We found that C1 Inh limits mucosal injury in the two strains in a dose dependent manner. Tissue damage was associated with the accumulation of functional polymorphonuclear cells, which was reduced following C1 Inh treatment. Constitutive nitric oxide synthase activity correlated with the development of injury in the C57BL/6 but not in the BALB/c mouse. CONCLUSIONS: These findings emphasize the importance of complement activation in ischemia/reperfusion and highlight the potential therapeutic use of C1 Inh in limiting or preventing damage caused by IR.

Animals↗
PubMed1976

C1 inactivator.

Explore the source record for details and available documents.

Amino Acids↗
PubMed1982

Exacerbation of a lupus-erythematosus-like syndrome during treatment of non-C1-esterase-inhibitor-dependent angioedema with danazol.

A 70-yr-old man presented with symptoms of angioedema and a lupus erythematosus-like syndrome. Because initial studies showed a functional deficiency of C1 esterase inhibitor and low C4 levels, he was treated with danazol, an attenuated androgen that has proven to be effective in the treatment of angioedema associated with C1 esterase inhibitor deficiency. After treatment, the patient's C4 levels returned to normal and his angioedema resolved, but concurrently he experienced clinical and laboratory exacerbations of his lupuslike illness. Specifically, on two occasions after danazol treatment he developed arthralgias, myalgias, hematuria, and pleuritic chest pain, accompanied by increased titers of antinuclear antibodies and circulating immune complexes. Serum testosterone levels were decreased during these episodes. Because treatment with danazol was temporally associated with recurrent exacerbations of a lupuslike illness and low serum testosterone levels, we believe that this case is an example of sex hormonal modulation of a lupuslike disease in man.

Aged↗
PubMed1987

Hereditary angioedema: a decade of management with stanozolol.

Thirty-seven patients with hereditary angioedema, who, without therapy, had attacks of cutaneous angioedema, gastrointestinal colic, and/or upper respiratory symptoms at a frequency and severity sufficient to prompt treatment with an attenuated androgen, have been evaluated for the incidence of side effects and biochemical toxicity during various schedules leading to the minimal effective dose. Stanozolol was administered in a 2 mg daily dose, initially, and after the symptoms and signs were adequately controlled for 2 months at this dose or at 1 mg per day, the drug was administered every other day at 4 mg. Patients who responded adequately to this schedule were administered 2 or 1 mg every other day, and then the interval between doses was gradually increased to 1 week, after which the agent was stopped. Eighteen patients experienced adverse reactions to stanozolol while the minimal effective dose was attained. In each instance the side effect subsided with a reduction in dosage. The most common adverse reactions were biochemical evidence of hepatic dysfunction and, to a lesser extent, hirsutism and menstrual irregularities. Although 21 of 27 patients in an initial study of the minimal effective dose were maintained with daily therapy in 1980, by 1986 this group and 10 additional patients were distributed so that three patients were receiving daily maintenance, 18 were receiving alternate-day maintenance, and 16 patients were receiving no maintenance therapy [corrected]. Thus, stanozolol appears to be a safe and effective agent for management of hereditary angioedema when patients are continually monitored to define the minimal effective dose or the feasibility of stopping the drug.

Adolescent↗
PubMed1995

Acquired deficiency in C1-inhibitor associated with signet ring cell gastric adenocarcinoma: a probable connection of antitumor-associated antibodies, hemolytic anemia, and complement turnover.

BACKGROUND: Acquired deficiency in C1-inhibitor (C1-INH) associated with malignancy is often asymptomatic because clinical manifestations are not dependent on a critical complement threshold (in contrast to hereditary C1-INH deficiency). Increased complement consumption involving different kinds of antibodies is the postulated mechanism for this disease, but other factors must play an important role. CASE REPORT: A 76-year-old woman with unremarkable medical history experienced three episodes of angioedema over 6 months. Investigations revealed a complement profile characteristic of acquired deficiency in C1-INH, a hemolytic anemia, and a signet ring cell adenocarcinoma (linitis plastica). A gastrectomy and a splenectomy were performed. The postoperative course was characterized by a complete disappearance of the symptoms of angioedema and hemolytic anemia. A local recurrence of the tumor 5 months later could not be resected. The patient died 17 months after the initial surgery was performed. RESULTS: Quantitative and functional analyses of the complement factors showed persistent excessive complement consumption. Markers of hemolytic anemia disappeared after tumor removal but recurred in the second part of the disease evolution. Immunohistochemical findings in tumor tissue showed loss of normal blood group antigens but expression of Lea antigen, as well as C1q deposition. CONCLUSION: To explain the whole clinical and laboratory picture, we hypothesize a connection between tumor immunohistochemical profile, complement consumption, and hemolytic anemia. Tumor cell surface antigens might lead to a permanent but asymptomatic complement consumption that is worsened and becomes clinically manifest by superimposed hemolytic anemia caused by cross-reactive antibodies to newly expressed blood group antigens on tumor cells. This hypothesis should be confirmed by other observations.

Aged↗
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↗