A transcriptomic study of Hereditary Angioedema attacks

Publication date: Available online 4 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Giuseppe Castellano, Chiara Divella, Fabio Sallustio, Vincenzo Montinaro, Claudia Curci, Andrea Zanichelli, Erika Bonanni, Chiara Suffritti, Sonia Caccia, Fleur Bossi, Anna Gallone, Francesco Paolo Schena, Loreto Gesualdo, Marco Cicardi
BackgroundHereditary Angioedema (HAE) due to C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. An activation of the kallikrein/bradykinin pathway at endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved, given the variable clinical expression of the disease in different patients.ObjectiveTo explore the involvement of other putative genes in the edema formation.MethodsWe performed a Peripheral Blood Mononuclear Cells microarray gene expression analysis on RNA isolated from HAE patients during acute attack and compared them with the transcriptome profile of the same patients in the remission phase.ResultsGene expression analysis identified 23 genes significantly modulated during the acute attacks that are primarily involved in "natural killer cells signaling" and "leukocyte extravasation signaling" pathways. GSEA showed a significant activation of relevant biological processes such as the "response to external stimulus" and "protein processing" (q<0.05) suggesting the involvement of PBMCs during HAE acute attacks. Up-regulation of two genes, Adrenomedullin (ADM) and Cellular Receptor for Urokinase Plasminogen Activator (uPAR) that occurs during the acute attack, was confirmed in PBMCs of 20 additional HAE patients by real-time PCR; finally, in vitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage.ConclusionsOur study demonstrates the increase of ADM and uPAR in PBMC during the acute attack of HAE. Activation of these genes usually involved in the regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE.

Teaser

During an acute attack of HAE the up-regulation of two genes, ADM and uPAR, occurs and the products of these genes might be involved in bradykinin formation and edema amplification.


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