Activation of the Complement/Lectin Pathway, Angiopoietin/Tie-2/VEGF-System, Cytokines and Chemokines in Different Angioedema Subtypes

Abstract

The precise molecular mechanisms underlying angioedema attacks in cases of C1-inhibitor-deficient hereditary angioedema (C1-INH-HAE), angiotensin-converting enzyme inhibitor-induced angioedema (ACEi-AE), and mast cell-/histamine-mediated angioedema (Hist-AE) are not well understood. These attacks may involve immune and inflammatory mechanisms. We compared serum biomarkers indicating vascular integrity, leakage, angiogenesis, coagulation, and inflammation. During an attack-free period, we assessed 34 markers simultaneously using multi- and/or singleplex ELISA in 25 patients with C1-INH-HAE, 17 with ACEi-AE, 25 with Hist-AE, and 23 healthy controls. Differential blood counts, C1-INH-HAE-specific laboratory parameters, and recently developed assays addressing early complement and lectin pathways were included. The results revealed significant differences, as well as some similarities. Tie-2, VEGFs, C1s/C1INHc appear to play a role in all AE types regardless of whether they are bradykinin- or histamine-mediated. Furthermore, evidence was found for a role of IL-17, eosinophil, and neutrophil chemotactic factors, and the activation of these granulocytes was found. MASP-1/C1-INHc indicated early activation of the lectin pathway in ACEi-AE and HistAE, but not in C1-INH-HAE. C1s/C1-INHc and MASP-1/C1INHc ratio was able to discriminate C1-INH-HAE from controls and the other AE types. Future investigations in C1-INH-HAE, ACEi-AE, and Hist-AE should not only focus on complement activation but also the interaction with granulocytes.