Abstract
BackgroundHereditary angioedema (HAE) is a rare autosomal dominant disease; the most well understood forms concern the haplodeficiency of C1 esterase inhibitor (C1INH) and a gain of function mutation of factor XII (FXII). The acute forms of these conditions are mediated by an excessive bradykinin (BK) formation by plasma kallikrein.MethodsA validated LC-MS/MS platform of picomolar sensitivity developed for the analysis of eleven bradykinin-related peptides was applied to the plasma of HAE-C1INH and HAE-FXII sampled during remission.ResultsIn HAE-C1INH plasma, the concentrations of the relatively stable BK1−5 fragment (mean ± S.E.M.: 12.0 ± 4.2 pmol/L), of BK2−9 (0.7 ± 0.2 pmol/L) and of the sums of BK and its tested fragments (18.0 ± 6.4 pmol/L) are significantly greater than those recorded in the plasma of healthy volunteers (1.9 ± 0.6, 0.03 ± 0.03 and 4.3 ± 0.8 pmol/L, respectively), consistent with the previous evidence of permanent plasma kallikrein activity in this disease. Kinin levels in the plasma of HAE-FXII patients did not differ from controls, suggesting that triggering factors for contact system activation are not active during remission.ConclusionBK1−5, BK2−9 and the sum of BK and its fragments determined by the sensitive LC-MS/MS technique are proposed as potential biomarkers of HAE-C1INH in remission while this was not applicable to HAE-FXII patients.
Highlights
Hereditary angioedema (HAE) is an autosomal dominant group of disorders that are determined by several gene variants proven or postulated to be permissive for bradykinin (BK) production, and possibly repressive for its degradation, with ensuing action on the endothelial BK B2 receptors and localized edema of subcutaneous and submucosal tissues [1, 2]
A rarer form of HAE with normal C1-INH levels is caused by mutation of genes encoding coagulation factor XII (FXII, F12 gene) [3]; further, several other causal gene variants have been identified, some plausibly associated with the kallikrein-kinin system [1]
Using a validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) platform of picomolar sensitivity developed for the analysis of eleven bradykininrelated peptides [12,13,14,15,16], we addressed the presence of BK-related peptides in the plasma of patients with HAE-C1 esterase inhibitor (C1INH) and HAEFXII during remission
Summary
Hereditary angioedema (HAE) is an autosomal dominant group of disorders that are determined by several gene variants proven or postulated to be permissive for bradykinin (BK) production, and possibly repressive for its degradation, with ensuing action on the endothelial BK B2 receptors and localized edema of subcutaneous and submucosal tissues [1, 2]. Many variants of the SERPING1 gene encoding C1 esterase inhibitor (C1INH) with impaired expression or function cause the most common form of HAE (types 1 and 2, respectively). A rarer form of HAE with normal C1-INH levels is caused by mutation of genes encoding coagulation factor XII (FXII, F12 gene) [3]; further, several other causal gene variants have been identified, some plausibly associated with the kallikrein-kinin system (plasminogen PLG and kininogen KNG1) [1]. Hereditary angioedema (HAE) is a rare autosomal dominant disease; the most well understood forms concern the haplodeficiency of C1 esterase inhibitor (C1INH) and a gain of function mutation of factor XII (FXII). The acute forms of these conditions are mediated by an excessive bradykinin (BK) formation by plasma kallikrein
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