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PubMed2003

Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency.

BACKGROUND: Hereditary angioedema due to C1 esterase inhibitor deficiency is clinically characterized by recurrent and self-limiting skin, intestinal, and laryngeal edema. Asphyxiation by laryngeal edema is the main cause of death among patients who die of hereditary angioedema. This study describes the age at which laryngeal edema first occurs, the time between onset and full development, and the effectiveness of therapy and prophylaxis. METHODS: Information on 123 patients with hereditary angioedema was obtained from medical histories and reports by the general practitioners, emergency physicians, and hospitals involved. RESULTS: Sixty-one patients (49.6%) experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between the ages of 11 and 45 years. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 342 laryngeal edemas cleared spontaneously without treatment, and 208 laryngeal edemas were successfully treated with C1 esterase inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. CONCLUSIONS: Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. To prevent a fatal outcome, it is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.

Adolescent↗
PubMed1997

The presence of a C1-inhibitor-like molecule (C1-INH-L) on human sperm: its involvement in sperm motility.

PROBLEM: An 88-92-kDa C1-inhibitor-like molecule (C1-INH-L) was previously identified to elicit cytotoxic sperm antibody response in infertile men and women. Here, we document that it is present on the human sperm surface and could be detected by an enzyme-labeled immunoglobulin G (IgG) fraction of anti-human C1-INH antibody. METHOD OF STUDY: Western blot analysis, enzyme-lined immunoadsorbent assay (ELISA) and computerized sperm motion analysis. RESULTS: The existence of C1-INH-L on the sperm surface is calcium independent. Phosphatidylinositol-specific phospholipase C (PIPLC), EDTA, and acid (pH 3.0) could not remove the C1-INH-L from sperm, but trypsin did. Activated C1s was able to bind to the sperm surface. Immunofluorescence studies localized the protein to the head and midpiece of the sperm membrane. The C1-INH-L exists on both uncapacitated and capacitated sperm surfaces, which suggests that this protein is a sperm-surface protein. The heat-treated (56 degrees C, 30 min) IgG fraction of anti-C1-INH greatly reduced the percentage of motile spermatozoa and the progressive and path velocities in the absence of complement. CONCLUSION: Our data suggest that C1-INH is a sperm membrane-anchored protein that may have complement and sperm motility regulatory function.

Complement C1 Inactivator Proteins↗
PubMed1978

Management of a patient with hereditary angioneurotic edema.

Patients with a history of hereditary angioneurotic edema can adequate and safely have nonelective surgical procedures performed with proper preoperative and postoperative management. Deficient amounts of C1 esterase inhibitor can be replaced with fresh frozen plasma; capillary permeability and spreading edema can be prevented with antifibrinolytic agents such as Amicar. Once edema has occurred peripherally and no laryngeal symptoms are present, conservative treatment is advisable. When epiglottic and laryngeal edema occurs, intubation or tracheostomy is preferred for maintenance of airway until the edema subsides. During oral surgical procedures, minimal surgical trauma must be achieved. Edema that involves the airway presents the greatest danger to patients. These attacks are usually associated with dental or some sort of oral or pharyngeal manipulation.

Angioedema↗
PubMed1993

Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock.

A postulated role of the contact system in anaphylactic reactions to insect stings was investigated. During prospective, in-hospital sting challenge, we collected serial blood samples from five normal volunteers and 16 patients with a history of insect-sting anaphylaxis. Activation of the contact system was assessed by measuring plasma levels of factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes as well as those of cleaved high molecular weight kininogen (HK). In addition, antigenic levels of (pre)kallikrein, factor XII, and HK were measured. No significant changes in contact system parameters were observed in any of the five volunteers or the four patients who did not develop an anaphylactic reaction after sting challenge. In contrast, significant changes in contact system parameters occurred in 7 of the 12 patients with anaphylactic symptoms after challenge. Peak levels of either C1-inhibitor complex were found 5 minutes after the onset of anaphylactic symptoms. The increase in C1-inhibitor was most pronounced in the 4 patients with angioedema, 2 of which also developed shock. However, activation of HK was observed in all four patients with angioedema, the two patients with shock but no angioedema, as well as in 1 of the remaining 6 patients with anaphylactic symptoms other than angioedema or shock. Thus, activation products of the contact system may be involved in the pathogenesis of angioedema and shock in insect-sting anaphylaxis.

Adult↗
PubMed1998

The therapeutic effect of C1-inhibitor on gut-derived bacterial translocation after thermal injury.

To test the effects of C1-esterase inhibitor in scald burns on bacterial translocation and intestinal damage, standardized deep partial-thickness burns were inflicted on domestic pigs, scalding 30% of the skin surface for 25 s with 75 degrees C hot water. The animals (n = 17; weight 25-35 kg) were divided into three groups: I) the control group (n = 5) without scald burn; II) the group (n = 6) with scald burn; and III) the group with C1-inhibitor (n = 6): scald burn and treatment with C1-inhibitor (C1-INH; BERINERT, Behring, Marburg, Germany). Parameters measured and compared in this model were activity of complement system, hemodynamics, body weight, pathological organ alterations including intestinal lesions, bacterial translocation, and skin damage. C1-INH administration significantly decreased the plasma levels of the specific soluble membrane attack complex (SC5b-9), bacterial translocation, and the degree of intestinal ischemia in the postburn period compared with untreated animals. Moreover, animals treated with C1-INH exhibited a minor degree of organ alterations including damage of the skin and development of edema. The favorable effects of C1-INH may be explained by the protection of the intestinal and dermal microcirculation in the acute phase of thermal injury.

Animals↗
PubMed1996

Inhibition of classical complement activation by sera from HIV-1-positive patients.

It was shown that gp120/160-coupled CD4+ T cells could be lysed by complement activation, but the target cell lysis was strongly inhibited by the majority of HIV-1-positive sera. Significantly more sera from HIV-1-infected patients with CD4+ T cell count higher than 500 microl (N = 38) as well as from patients with 200-500/microl (N = 32) showed strong inhibition of complement activation as compared to sera from those with less than 200 CD4+ T cells/microl (N = 28) (P = 0.0064 and 0.0012, respectively). Consequently, highly significant correlation between CDL inhibitory activity and CD4+ T cell count in HIV-1-infected patients was found by Spearman's rank order analysis (R = 0.399, P < 0.001). CH50 titer and functional C1-inhibitor level were significantly lower in inhibitory as compared to the noninhibitory sera (P < 0.001) and to controls (P < 0.001). The C3 activation products-C3-circulating immune complexes were not increased in inhibitory sera (P = 0.014) suggesting that inhibition of complement activation occurred at or before C3 activation level. C4d fragments and antigenic C1-INH concentration were significantly increased in both categories of HIV-1-positive sera, P < 0.001. These findings indicate that persistent and massive stimulation of complement system with HIV-1 envelope glycoproteins during all stages of the disease induced impairment of classical pathway activation by an inhibitory factor in a majority of patients, which might contribute to the onset of opportunistic infections and AIDS.

Complement Activation↗
PubMed1977

[Anticomplementary activity of a polyanion: pentosan-poly-sulfoester, II.--Mode of action and "in vitro " inhibition of human complement hemolytic activity (author's transl)].

The drug, pentosan-poly-sulfoester (PPS), is a potent in vitro inhibitor of the human complement hemolytic activity. This CH 50 inhibition represents a real anticomplementary activity (ACA), because this drug has no effect on sensitized sheep red blood cells (EA). The inhibition curve of human serum CH 50, by PPS is sigmoidal. The 50% inhibition is obtained for a 1: 650 dilution of PPS, which corresponds to a concentration of 0.08 mg/ml in normal human serum. Hemolytic titrations of C1, C4, C2, C3, and C5 showed a complete inhibition of C4, C2 and C3, and a partial inhibition of C1 (C1q, C1r, C1s, Ca++) and C5, by this drug. The mechanism of such functional inactivation of the different complement components is not yet elucidated.

Complement C2↗
PubMed1998

A newly discovered function for C1 inhibitor, removal of the entire C1qr2s2 complex from immobilized human IgG subclasses.

A new function for C1 inhibitor (C1 INH) is reported. C1 inhibitor dislodged the entire activated C1 complex (C1qr2s2) from immobilized human IgG. C1 binding to doses of immobilized human IgG3, IgG1, or IgG2 was quantified as a function of time. When human serum, as a source of C1qr2s2, was added to relatively low doses of immobilized IgG, C1q binding peaked at 1.0 min then gradually decreased. However when purified C1q was applied to immobilized IgG, C1q binding did not diminish with time. The removal of C1q was duplicated by adding purified C1 INH to C1qr2s2 which had been bound to immobilized IgG. The dislodgement of C1q from immobilized IgG required the presence of intact C1qr2s2 and of C1 INH. This removal of C1q by purified C1 INH was prevented when activated C1s was used to neutralize C1 INH function or when relatively high levels of IgG were immobilized.

Binding, Competitive↗
PubMed2003

[Identification of a novel mutation of C1 inhibitor gene in a Chinese family with hereditary angioedema].

OBJECTIVE: To identify the mutation of C1 inhibitor (C1 INH) gene in a Chinese family with hereditary angioedema (HAE). METHODS: Polymerase chain reaction and direct sequencing were used to identify the mutation type. The sequencing results were compared with the normal sequences in GenBank to find the mutation. In order to exclude the polymorphism, 30 normal volunteers were analyzed. RESULTS: One novel mutation (17839 del C) was detected in 5 patients with HAE. The mutation was not found in controls. CONCLUSION: The mutation of C1 INH gene (17839 del C) is identified in the family. Molecular diagnosis can be made by detecting the mutation.

Angioedema↗
PubMed1996

Acquired C1-esterase inhibitor deficiency: three case reports and commentary on the syndrome.

Acquired C1-esterase inhibitor deficiency is a rare syndrome which usually presents with episodes of angioedema. Most patients have an underlying lymphoproliferative disorder. It is important to gastroenterologists, haematologists, immunologists and dermatologists, as these are the more likely specialties to which the patient will present. Recognition of the syndrome is important not only for diagnostic purposes but for investigating and treating any associated underlying lymphoproliferative disorders. In some instances the angioedema may precede the lymphoma by many years. Optimal patient management requires that both angioedema and the underlying lymphoma be recognized and treated.

Aged↗
PubMed2003

Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity.

Activation of complement by beta-amyloid (A beta) contributes to the pathology of Alzheimer's disease (AD). Here, we show that C1-Inhibitor (C1-Inh) protects cultured rat hippocampal cells against beta-amyloid induced complement lysis indicating a classical pathway-mediated activation mechanism. We report on screening of compound libraries to identify compounds that inhibit C1q binding to beta-amyloid. Characterization of these compounds revealed that C1q possessed distinct binding sites for beta-amyloid and antibodies. One selected compound protected cultured hippocampal cells against complement-dependent beta-amyloid toxicity. These results provide evidence that complement has the potential to damage hippocampal cells, and C1q is a relevant target to suspend this deleterious mechanism in Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed2003

[Acquired angioneurotic edema induced by hormonal contraception].

OBJECTIVE: Although frequently pointed out in the aetiology of chronic angioedema or chronic abdominal pain, food allergy is frequently a diagnosis for lack of anything better, as exemplified by disappointing results of eviction regimens. This has resulted in the search for other aetiologies, such as an iatrogenic effect of oral contraceptives. METHODS: Detailed medical history was obtained on 38 young women, aged a mean of 26 years, experiencing chronic angioedema initially ascribed to food hypersensitivity, but in whom a deficit in C1 inhibitor was demonstrated. We investigated the effects of oral contraception on their level of C1-INH, functional C1-INH assay and their clinical symptoms. RESULTS: An interruption of oral contraception induced an increase of the C1-INH level from 0.201 to 0.224 g/L (p < 0.002) and of the C1-INH functional assay fom 0.396 to 0.702 U (p < 0.0001), associated with a recovery or a marked improvement of the clinical symptoms formerly ascribed to food allergy. The replacement of the initial contraception containing ethinyloestradiol by a progestogen maintained or even improved their clinical and biological state. CONCLUSION: Exogenous estrogen such as those contained in most oral contraceptive may play an iatrogenic role in the aetiology of chronic angioedema.

Adolescent↗
PubMed1980

Laboratory findings in patients with psoriasis, with special reference to immunological parameters, associations with arthropathy and sacro-iliitis.

Twenty-five male and 25 female consecutive patients hospitalized because of psoriasis were examined. The clinical and radiographical findings are presented in detail elsewhere. Increased serum IgA, C3, C4, and C3PA concentrations were found in patients both with and without arthropathy and/or sacro-iliitis. Increased IgG concentrations were found in patients without arthropathy, and of C1 inhibitor concentrations in patients with arthropathy and/or sacro-iliitis. IgG and IgA concentrations were lower in patients with arthropathy than in those without, the difference being most significant in patients with arthropathy of large joints. An association was found between increased C4 concentration and sacro-iliitis, increased CRP concentration and sacro-iliitis and increased C3 concentration and phalangeal joint arthropathy. C4 and CRP concentrations were not associated. A close association between CRP and SAA was observed. Our results indicate that psoriatic arthropathy is not a single uniform joint disease, but represents different forms of arthropathy.

Adolescent↗
PubMed1989

Glomerulonephritis and hereditary angioedema: report of 2 cases.

Hereditary deficiency of C1 esterase inhibitor (C1 INH) responsible for hereditary angioedema (HAE) is the most common hereditary complement deficiency. HAE has occasionally been reported in association with lupus erythematosus and with glomerulonephritis (GN). We report 2 cases of GN-associated C1 INH deficiency. Renal manifestations have been discovered respectively 6 to 17 years before onset of attacks. Kidney biopsy of the 1st patient showed diffuse proliferative GN with a rare and scattered wire loop pattern whereas the 2nd patient displayed a type I membranoproliferative GN. Chronic renal failure appeared in both cases and the 2nd patient recently received a kidney transplant. The onset of GN in patients with HAE outline the relationship between a genetic deficiency of complement components, the susceptibility to immune complex (IC) disease and the role of complement and its receptors in the elimination of IC.

Adolescent↗
PubMed1989

The acquired C1-INH deficiencies with autoantibodies (AAE type II).

A new type of acquired C1-inhibitor (C1-INH) deficiency has been recognized (AAE type II) which is characterized by the presence of autoantibodies to C1-INH and by a circulating 96 KD C1-INH molecule. The clinical manifestations and biochemical abnormalities of this novel autoimmune disease resemble those found in the other forms of acquired C1-INH deficiency (AAE type I), including recurrent angioedema and low serum levels of C2, C4, C1, C1q and C1-INH activity. However, in contrast to AAE type I, AAE type II is not associated to other diseases. Evidence has been provided that the anti-C1-INH antibodies play a major role in the development and maintenance of AAE type II. These autoantibodies seem to impede C1-INH activity, thus allowing unopposed activation of the complement and/or contact system and to induce the generation of the 96 KD C1-INH species in the patients' plasma.

Angioedema↗
PubMed1982

New and rapid functional assay for C1 inhibitor in human plasma.

C1 inhibitor (C1-INH) and alpha 2-macroglobulin (alpha 2M) account for over 90% of the inactivation of purified plasma kallikrein by normal human plasma. The rate of kallikrein inactivation is also dependent on the presence of high molecular weight kininogen (HMWK), which forms a reversible complex with kallikrein protecting the active site of the enzyme against inhibitors. By selectively inactivating alpha 2M with methylamine, and eliminating the protective effect of HMWK by dilution, the inactivation of kallikrein by plasma became almost exclusively dependent on C1-INH. Functional C1 inhibitor was assessed by measuring the pseudo-first-order rate constant for the inactivation of kallikrein by diluted methylamine-treated plasma in 29 individuals, including 11 controls, 11 oral contraceptive users, 5 patients with classical hereditary angioedema (HAE), and 2 patients with variant HAE. Over a wide range of concentrations, an excellent correlation (r = 0.90) was observed between functional and antigenic C1-INH among controls, oral contraceptive users, and patients with classical HAE. This new functional assay for C1-INH can be performed in less than 3 hr with commercially available reagents. Therefore, this assay will be helpful for the diagnosis and management of conditions associated with the deficiency of C1-INH, such as HAE.

Angioedema↗
PubMed1999

Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease.

In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individuals. In HD striatum, neurons, myelin and astrocytes were strongly stained with antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contrast, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and the internal capsule samples but not in normal brain. RT-PCR analysis and in-situ hybridisation were carried out to determine whether complement was synthesised locally by activated glial cells. By RT-PCR, we found that complement activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compared to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor and C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confirmed that C3 mRNA and C9 mRNA were expressed by reactive microglia in HD internal capsule. We propose that complement produced locally by reactive microglia is activated on the membranes of neurons, contributing to neuronal necrosis but also to proinflammatory activities. Complement opsonins (iC3b) and anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimulation of glial cells and phagocytes bearing specific complement receptors.

Adult↗
PubMed1992

Identification of hydrophobic fragments of alpha 1-antitrypsin and C1 protease inhibitor in human bile, plasma and spleen.

Hydrophobic peptides were isolated from the phospholipid fraction of human bile, plasma and spleen by exclusion chromatography in organic solvents. From plasma, the activation peptide of C1 protease inhibitor was recovered, from spleen the activation peptide of alpha 1-antitrypsin, and from bile, both these peptides, as well as a fragment generated by proteolytic cleavage of alpha 1-antitrypsin six residues N-terminal of the P1-P1' peptide bond. Cleavages in this region inactivate antiproteases but have previously not been reported to occur in vivo. These peptides in human bile may reflect physiological actions in regulation of antiproteolytic activity or bile secretion processes, and/or be of importance for the physicochemical state of cholesterol, phospholipids and bile acids in bile.

Bile↗