COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy.
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Weckmann Markus, Bahmer Thomas, Sand Jannie Marie, Rank Rønnow Sarah, Pech Martin, Vermeulen Cornelis, Faiz Alen, Leeming Diana Julie, Karsdal Morten Asser, Lunding Lars, Oliver Brian George G, Wegmann Michael, Ulrich-Merzenich Gudrun, Juergens Uwe R, Duhn Jannis, Laumonnier Yves, Danov Olga, Sewald Katherina, Zissler Ulrich, Jonker Marnix, König Inke, Hansen Gesine, von Mutius Erika, Fuchs Oliver, Dittrich Anna-Maria, Schaub Bianca, Happle Christine, Rabe Klaus F, van de Berge Maarten, Burgess Janette Kay, Kopp Matthias Volkmar, ALLIANCE Study Group as part of the German Centre for Lung Research (DZL)
Аннотация
OBJECTIVE: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.
METHODS: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test.
RESULTS: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5).
CONCLUSION: C4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.