| Towards a specific marker for acute bradykinin-mediated angioedema attacks: a literature review. | Eur J Dermatol | Bradykinin-mediated angioedema (AE) is a rare disease characterised by recurrent angioedema linked to acquired (e.g. angiotensin converting enzyme inhibitor induced AE) or hereditary disorders (e.g. AE type I or II). As the clinical picture can be misleading, diagnosis of this disease is sometimes difficult. A bradykinin-mediated AE attack may be a therapeutic emergency which requires access to effective, but expensive, treatments. Their prescription must therefore be justified. No specific marker of acute bradykinin-mediated AE attacks has yet been identified to facilitate the therapeutic decision but it has been sought in many studies.This article reviews the literature on this type of biomarker, comparing candidate bradykinin-mediated AE markers to candidate markers of mast cell activation.The most interesting biomarkers are those linked to endothelial stress (VE cadherin, E-selectin, endothelin-1, von Willebrand factor and its activity) which is significantly increased during an AE attack. All these markers must now be validated by prospective studies to determine their specificity and utility in diagnosis. |
| 2014 | Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. | J Allergy Clin Immunol | Hereditary angioedema (HAE) caused by C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a potentially life-threatening rare disease caused by the decreased activity of C1-INH. Lack of C1-INH leads to overproduction of bradykinin, a potent vasoactive peptide. Although angioedema is induced by bradykinin, the function and activation of endothelial cells (ECs), the targets of bradykinin, have not yet been studied during HAE attacks.We studied whether EC function is altered during HAE attacks in comparison with attack-free intervals.Forty-six consecutive samples obtained during attacks from 18 patients with HAE-C1-INH were compared with inter-attack samples of the same patients. The patients' sera were tested for von Willebrand factor (VWF) antigen, VWF collagen-binding activity, soluble E-selectin, and endothelin-1 levels by using ELISA and BRAHMS Kryptor technologies.Levels of all 4 EC markers (VWF antigen, VWF collagen-binding activity, soluble E-selectin, and endothelin-1) were significantly increased during HAE attacks. Their increases were even more obvious in the subgroup of patients without any pre-existing risk factors for endothelial dysfunction.In this study we demonstrated that ECs are activated during HAE attacks. Our results might suggest the need for revising the knowledge on the pathogenesis of HAE-C1-INH and for reconsidering the role of ECs as a possible novel therapeutic target in patients with this disease. |
| 2012 | Endothelial cell function in patients with hereditary angioedema: elevated soluble E-selectin level during inter-attack periods. | J Clin Immunol | The bradykinin pathway in the pathomechanism of hereditary angioedema due to C1-inhibitor deficiency (henceforward "hereditary angioedema") has been thoroughly studied; however, much less is known about endothelial cell function. Enhanced endothelial cell permeability is obvious during edematous attacks, but not during inter-attack periods. Our knowledge about other endothelial characteristics is even more incomplete.Therefore the aim of this study was to characterize endothelial cell function in hereditary angioedema patients during symptom-free, inter-attack periods.We measured the serum levels of soluble E-selectin, endothelin-1, and von Willebrand factor along with collagen-binding activity in 49 hereditary angioedema patients and in 50 healthy controls.Endothelin-1 and von Willebrand factor level, as well as its collagen-binding activity, were similar in hereditary angioedema patients and in controls; however, we found elevated soluble E-selectin levels in the patients. Interestingly, soluble E-selectin concentration did not correlate with any of the inflammatory markers or smoking, and it is not the consequence of the known E-selectin/C1-inhibitor interaction (an analytical phenomenon). In a multiple logistic regression model, the difference in soluble E-selectin between hereditary angioedema patients and controls remained highly significant when adjusted for age, gender, smoking, C-reactive protein, and AB0 blood groups.These results demonstrate that in hereditary angioedema, the majority of endothelial functions are normal during inter-attack periods; however, soluble E-selectin levels are elevated. The higher soluble E-selectin plasma concentration is unlikely to result from inflammation; rather, it reflects enhanced shedding mechanisms. |
| 2005 | C1 inhibitor: molecular and clinical aspects. | Springer Semin Immunopathol | C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia-reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent. |
| 1994 | Recurrent cutaneous necrotizing eosinophilic vasculitis. A novel eosinophil-mediated syndrome. | Arch Dermatol | Review of skin biopsy specimens showing necrotizing vasculitis revealed three patients with small dermal vessel eosinophilic vasculitis and common clinical features characterized by glucocorticoid responsive pruritic erythematous, purpuric papules and angioedema associated with peripheral blood eosinophilia. Indirect immunofluorescent localization of eosinophil granule proteins, neutrophil granule proteins, and mast cell tryptase, electron-microscopic evaluation and immunoperoxidase staining for vascular cell adhesion molecule type 1, intercellular adhesion molecule type I, endothelial-leukocyte adhesion molecule type 1, and very-late activation antigen type 4 were performed. Eosinophil-active cytokines in serum were evaluated by an eosinophil survival assay.Eight skin biopsy specimens from the three patients all showed small-vessel necrotizing vasculitis with exclusive eosinophil infiltration. Ultrastructural study demonstrated degenerating eosinophils and eosinophil granules in proximity to damaged endothelium. The affected small vessels showed marked deposition of the toxic eosinophil granule major basic protein in the vessel walls and expression of vascular cell adhesion molecule type 1 and intercellular adhesion molecule type 1 on the endothelium with adherence of very-late activation antigen type 4-positive eosinophils; E-selectin staining was negative. The presence of interleukin 5 in serum available from one patient was detected by an eosinophil survival assay.We studied three patients whose cutaneous lesions showed small-vessel eosinophilic vasculitis and who presented with recurrent glucocorticoid-responsive pruritic purpuric papules and angioedema. The presence of eosinophil-active cytokines in serum and the expression of vascular cell adhesion molecule type 1 on the endothelium of affected vessels may contribute to the selective adherence and localization of activate eosinophils. Subsequent release of cytotoxic proteins such as major basic protein may result in destruction of the endothelium in this unique syndrome. |