Researchers from the University of Cincinnati College of Medicine uncovered a novel molecular mechanism associated with the progression of the endothelial kinin‐bradykinin‐forming cascade in hereditary angioedema (HAE) attacks.

“Genomic analysis of skin biopsies from HAE‐type‐1 versus control/HAEnCI [HAE with normal C1 inhibitor] suggest novel mechanistic pathways in HAE attacks, including angiopoietin‐activated β1‐integrin signaling leading to endothelial destabilization, and avid binding of F12 [factor XII] to u‐PAR [urokinase plasminogen activator surface receptor] supporting a model for progression of the kinin‐forming cascade on endothelial cells,” the researchers wrote in Clinical Translational Allergy.

They found that PLAUR, the gene encoding the urokinase plasminogen activator surface receptor, was overexpressed compared with HAE with normal C1 inhibitor and non-HAE controls and that its expression further increased during flares. Moreover, increased baseline PLAUR expression was associated with severe acute angioedema attacks in type 1 HAE.

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In addition, the researchers identified 18 differentially expressed genes between baseline and acute angioedema attacks in type 1 HAE that were enriched in β1/β3‐integrin cell surface interactions and interleukin (IL)‐6‐mediated signaling processes.

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Canonical pathway analysis suggested that IL-17 and IL-8 signaling, neuroinflammation signaling, triggering receptor expressed on myeloid cells‐1 signaling, leukocyte extravasation signaling, and the regulation of epithelial mesenchymal transition by growth factors pathway were the most relevant pathways for the pathogenesis of type 1 HAE flares.

Furthermore, natural killer cell signaling, integrin linked kinase signaling, the nuclear factor erythroid 2-related factor 2‐mediated oxidative stress response, the T helper 17 activation pathway, IL-15 production, and the coronavirus pathogenesis pathway were upregulated in type 1 HAE flares compared with controls, whereas the inhibition of matrix metalloproteinase, phosphatase, and tensin homolog signaling and erythropoietin signaling pathways were downregulated.

Regulator effects analysis identified a potential role for IL-1β and acute phase response, interleukin signaling in HAE flares.

These observations were drawn from the analysis of skin biopsies from lesional and nonlesional skin collected during and between attacks in 11 patients with type 1 HAE. Skin biopsies from HAE with normal C1 inhibitor (n=5) and non‐HAE (n=7) subjects were used as controls.


Singh U, Bernstein JA. Determining biomarkers for evaluation and diagnosis of hereditary angioedema. Clin Transl Allergy. 2022;12(10):e12202. doi: