Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients.

Zuraw, Bruce L.; Curd, John G.

doi:10.1172/jci112610

Cited by 75 publications

(34 citation statements)

References 58 publications

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“…This hypothesis is based on several observations. First, substantial amounts ofiCl-Inh are present in plasma from patients with angioedema due to Cl-Inh deficiency (53); in these patients activation of the contact system has been shown to occur (54,55). Second, about one-third of native Cl-Inh in plasma is cleaved in vitro to iCl-Inh upon activation of the contact system by kaolin (53) and DXS (45).…”

Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

“…First, substantial amounts ofiCl-Inh are present in plasma from patients with angioedema due to Cl-Inh deficiency (53); in these patients activation of the contact system has been shown to occur (54,55). Second, about one-third of native Cl-Inh in plasma is cleaved in vitro to iCl-Inh upon activation of the contact system by kaolin (53) and DXS (45). Third, analytic gel (SDS-PAGE) studies concerning the interaction of Cl-Inh with either kallikrein, Factor XIa, or plasmin have demonstrated the formation of stable high-molecular weight complexes and the appearance of iCl-Inh species (22,(27)(28)(29)56).…”

Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

“…Conflicting analytic gel studies have been published concerning the interaction of purified Cl-Inh and Cis. Some studies do show evidence of proteolytic degradation of the inhibitor concomitant to the formation of stable complexes on SDS-PAGE (24,55,57), whereas others do not (23,25,26,53). Moreover, studies that have demonstrated proteolysis of Cl-Inh by Cis disagree whether cleavage is enhanced (24) in the presence of heparin or not (57).…”

Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

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Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Nuijens¹,

Eerenberg-Belmer²,

Huijbregts³

et al. 1989

J. Clin. Invest.

138

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Activation of both the complement system and the contact system of intrinsic coagulation is implicated in the pathophysiology of sepsis. Because C1 inhibitor (Cl-Inh) (M, 110,000). Elevated iCl-Inh levels (_ 0.13 ,uM) were found in 81% of all patients, sometimes up to 1.6 MM. Levels of iCl-Inh on admission appeared to be of prognostic value: iCl-Inh was higher in 27 patients who died than in 21 patients who survived (P = 0.003). The mortality in 15 patients with iCl-Inh levels up to 0.2,uM was 27%, but in 12 patients with plasma iCl-Inh exceeding 0.44 gM, the mortality was 83%. The overall mortality in the patients with sepsis was 56%. We propose that the cleavage of Ci-Inh in patients with sepsis reflects processes that play a major role in the development of fatal complications during sepsis.

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Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

See 1 more Smart Citation

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Nuijens¹,

Eerenberg-Belmer²,

Huijbregts³

et al. 1989

J. Clin. Invest.

138

View full text Add to dashboard Cite

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“…31,32 Furthermore, the contact system is activated in vivo during attacks of angioedema in HAE patients, [33][34][35] and increased levels of bradykinin have been measured in plasma during attacks of angioedema. 36 Contact system activation was also shown to cleave C1 inhibitor into a nonfunctional form, 11 and the plasma level of cleaved nonfunctional C1 inhibitor is increased during attacks of angioedema in HAE patients. 37 Importantly, the activity to enhance vascular permeability that is generated by ex vivo incubation of C1 inhibitor-deficient plasma was shown to be independent of C2 but completely dependent on high-molecular-weight kininogen (the substrate for bradykinin).…”

Section: What Is the Primary Mediator Of Swelling In Hae?mentioning

confidence: 99%

The Pathophysiology of Hereditary Angioedema

Zuraw

2010

World Allergy Organization Journal

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Abstract:Hereditary angioedema (HAE) causes recurrent episodes of angioedema that may be very severe and are frequently associated with significant morbidity and even mortality. Understanding the pathophysiology of this disease is crucial for proper diagnosis and management of these patients. HAE is caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1 inhibitor. A large number of different mutations have been described that result in HAE. About 15% of patients have a mutation at or near the active site of the reactive mobile loop, resulting in a protein that lacks functional activity (type II HAE). Type I HAE is caused by a diverse range of mutations, some of which cause the nascent protein to misfold and thus to be unable to enter the secretory pathway. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system. Bradykinin induces increased vascular permeability by activating the bradykinin B2 receptor, which results in phosphorylation of vascular endothelial cadherin. The regulation of both the bradykinin B2 receptor and peptidases that degrade bradykinin may influence HAE disease severity. HAE results from mutations in the SERPING1 gene that lead to a loss of functional C1 inhibitor. Attacks of angioedema result from generation of bradykinin, which acts on bradykinin B2 receptors to enhance vascular permeability.Key Words: HAE, C1 inhibitor, contact system, bradykinin, plasma kallikrein, Hageman factor (WAO Journal 2010; 3:S25-S28) I n 1888, William Osler described a familial form of angioedema associated with significant morbidity and mortality. 1 He called this disease hereditary angio-neurotic edema (HANE), a name that has subsequently been shortened to hereditary angioedema (HAE). The prevalence of HAE is not known for certain, but has been estimated to range from 1:30,000 to 1:80,000 in the general population without any known sex, ethnic, or racial differences. 2 HAE is clinically characterized by recurrent episodes of angioedema that typically involve the extremities, gastrointestinal tract, face, oropharynx, larynx, or external genitalia. Patients with HAE experience discrete episodes of nonpruritic nonpitting angioedema at these sites. 2,3 HAE attacks are classically distinguished from allergic or idiopathic angioedema by their longer duration (typically 72-96 hours), absence of accompanying urticaria and failure to respond to antihistamines or corticosteroid therapy.Most often, patients with HAE become symptomatic during childhood. Fifty percent of HAE patients first experience a swelling episode before age 10, with some patients manifesting angioedema as early as 1 year of age. 4,5 Most patients then experience a worsening of symptoms around puberty. 3 Occasionally, patients with HAE do not begin to show evidence of angioedema until their late teens or early adulthood. Rare patients with HAE have been reported who never experience angioedema, but are identified through screening family members of a symptomatic patient. 5...

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“…This discrepancy is due to the presence of cleaved C1-INH in serum. Although this inactive product of C1-INH had been detected in the serum of AAE patients, before any mention of autoantibodymediated C1-INH deficiency [19], it has been used as a characteristic feature of this form. Whether C1-INH is cleaved because the autoantibody has destabilized the complex formed with C1 or because it facilitates cleavage by several proteases, remains controversial [13,[20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Relevance of lymphoproliferative disorders and of anti-C1 inhibitor autoantibodies in acquired angio-oedema

Cicardi

Beretta

Colombo

et al. 1996

Clinical and Experimental Immunology

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SUMMARYWe looked for autoantibodies to C1 inhibitor (C1-INH) and evaluated the relationship of their presence to the associated lymphoproliferative diseases and to the cleaved form of C1-INH in 13 patients with acquired C1-INH deficiency (acquired angio-oedema (AAE)). At the time of manifestation of angiooedema symptoms or within a few years the following diseases were diagnosed: liver angioma (n = 1), M-components (n = 7, one of whom also had echinococcal liver cysts), breast cancer (n = 1), chronic lymphocytic leukaemia (CLL; n = 1); three patients had no associated disease. Anti-C1-INH autoantibodies, measured both as immunoglobulin binding to C1-INH immobilized onto microtitre plates (ELISA) and as plasma inhibitory activity of C1-INH function, were found in 12 patients. Binding of C1-INH to paraproteins, transferred to Immobilon after agarose gel electrophoresis, was detectable in five of seven M-components associated with AAE. Immunoblotting analysis of SDS-PAGE-separated plasma demonstrated that C1-INH circulated in the cleaved 96-kD form in the 12 patients with autoantibodies, but not in the one without. In conclusion, the large majority of our patients have autoantibodies to C1-INH. Circulating autoantibodies are necessary for the generation of cleaved C1-INH. The paraproteins associated with AAE are frequently autoantibodies to C1-INH and thus account for its consumption.

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Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients.

Cited by 75 publications

References 58 publications

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

The Pathophysiology of Hereditary Angioedema

Relevance of lymphoproliferative disorders and of anti-C1 inhibitor autoantibodies in acquired angio-oedema

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